A38 Cancer Genetics/Clinical Genetics (0141) 1.78

Extra Y chromosome in chronic B-cell lymphoproliferative disorders. H. Xiao, J. Romano. B. Dadey, K. Carr. T. Han. A. W. Block and A. A. Sandber . Roswell Park Memorial Institute, Buffalo, New York and The Cancer Center, Scottsdale, Arizona. All varieties of leukemia occur more often in men than women. The sex disparity is greatest in hairy cell leukemia (HCL) and chronic lymphocytic leukemia (CLL) with 4:1 and 2:1 overall male/female ratios, respectively. This may lead to the assumption that the Y chromosome may play a certain role in the development of malignancy. We have established 142 Epstein-Barr virus (EBV) transformed lymphoblastoid cell lines from 95 patients with B-cell lymphoproliferative disorders. Cytogenetic studies of these cell lines revealed an extra Y chromosome in 5 out of 71 male cell lines. In 3 HCL patients the extra Y chromosome appeared to be the sole karyotypic changes (47,XY,+Y). In patient 4 (CLL) and patient 5 (HCL), the extra Y chromosome was accompanied by extra copies of chromosomes 21 and 12, (48,XY,+Y,+21 and 48,XY,+Y,+12) respectively. PHA-stimulated peripheral blood cultures of all patients revealed a normal 46,XY male constitutional karyotype. An extra Y chromosome as the sole anomaly has not been seen in other conditions, though as an additional change it has been observed in a variety of leukemias including acute non- lymphocytic leukemia (M1,M2,M5,M6), CML, polycythemia vera, follicular lymphoma and carcinoma. Thus, the patients studied by us may constitute a unique group among the lymphoprolifera- tive disorders. Supported by NIH CA-42683.

Clinical Genetics

(0142) 1.79 (0143) 13.7

The natural history of lens dislocation in children with Molecular linkage analysis of Watson syndrome. J.E. the Marf an syndrome. D. M. Alcorn and I. H. Maumenee. Allanonl M.L yy2, G.H. Watson3, M. BPrtiDton4, Johns Hopkins University, Baltimore. P. M 2, and S. HuBD5. lihildren's Hospital of Eastern Since 1982, we prospectively studied 62 children with Ontario, Ottawa, Canada. 2lrstitute of Medical Genetics, definitive Marfan syndrome, diagnosed prior to the age of University Hospital of Wales, Cardiff, UK. 3Royal Manchester 5 years. 52% of the patients had dislocated lenses on initial Children's Hospital, Manchester, UK. 4Western Suburb examination. By 1989, 68% had lens dislocation with a mean Hospital, Newastle, New South Wales, Australia. 5Kennedy- age of diagnosis of lens dislocation at 2.7 years, ranging Galton Centre, Harrow, UK. from 2 months to 6 years. None of 8 patients seen prior Over twenty years ago, Watson (Arch. Dis. Child., 42:302- to 2 months of age had any lens dislocation; 5 subsequently 307, 1967) described three families with a condition developed lens dislocation. Significant progressive lens characterised by puluonary valvular stenosis, cafe au lait dislocation was noted clinically and by retinoscopy between patches, and dull intelligence. Although it was not obvious the ages of 2 and 4 years. All children were placed in the frm the original MOgraph, short stature was also a full cycloplegic refraction and a great majority (92%) obtained universal feature of this syndrome. One other family with excellent visual results (greater than or equal to 20/40.) this condition has since been reported in Canada. Patients with spherophakia had the most pronounced refractive We have had the opportunity to review the two largest errors, with very high astigmatism. families, including extended family members who had not The absence of significant irreversible amblyopia in previously been examined. The clinical phenotype has been these patients may be accounted for by the early detection expanded to include relative macrocephaly and Lisch nodules of the dislocated lenses and appropriate refraction. In in the majority of affected individuals, and neurofibromata addition, symmetry of refractive error and partial accom- in at least four family menters. modative reserve allow reversal of the apparent visual loss Because the additional clinical findings enhance the even after delay of adequate correction. similarity between Watson Syndrcme and neurofibromatosis, molecular linkage studies have been performed using probes flankirn the NF1 gene on dcroscm 17. Probe HHH2O2 dk srmtrames the tightest linkage to Watson Syndrome with 0' = .0, Z = 3.29 (95% confidence limits of AI = .0 - .17). This suggests either that Watson Syndrome and neurofibromatosis are allelic, or that the two genes for these conditions are tightly linked. Clinical Genetics A39

(0144) (0145) 4.7 DiSygotic twins concordant for truncus arteriosus. Autosomal dominant polycystic kidney disease: Ma Aughton. Ka Lang. TW Riags. M Milad. and L ultrasonographic detection and prognosis of PKD1 and PKD2 Bieseck. William Beaumont Hospital, Royal Oak, forms. JJ.C. Bear. P.S. Parfrev. J. Morgan. B.C. Cramer, P.J. MI; Univ. of Michigan, Ann Arbor. McManamon. M.H. Gault. D.N. Churchill. M. Singh. R. Hewitt. Truncus arteriosus (TA) comprises only about 1% S. S. Reeders. Faculty of Medicine, Memorial Univ. of of all congenital heart defects (CHD), and Somlo. occurrence of TA in siblings has been reported Newfoundland, St John's, Canada; and Yale Univ. School of infrequently (Goodyear, 1961; Brunson et al., 1978; Medicine, New Haven CT. Miller and Smith, 1979; Shapiro et al., 1981). We restudied 17 families with autosomal dominant Twins concordant for TA have been reported but polycystic kidney disease (ADPKD) to: a) assess the utility twice previously (Giustra and Tosti, 1939; Raghavan of renal ultrasound for presymptomatically identifying at al., 1983); in these cases, TA was associated persons with a mutation for this condition, where it co- with more complex cardiac defects or with multiple segregates with chromosome 16 markers flanking the PKD1 locus congenital anomalies. Here we describe dizygotic (PKD1 form), and b) compare the prognosis for the PKD1 form twin females who were concordant for isolated TA. with that for ADPKD which does not co-segregate with The probands were born to a 41 y/o G2P1 woman. chromosome 16 markers (PKD2 form). In 10 families, ADPKD Amniocentesis at 15 weeks showed a 46,XX karytotype (i.e. at least 2 cysts in one kidney and one cyst in the in each twin. At 31 weeks, ultrasonography revealed hydrops in both twins. Immunologic and other kidney, by ultrasound, or end-stage renal disease) co- infectious evaluations were negative; routine segregated with chromosome 16 markers, in 2 families it did 4-chamber ultrasonographic views of the fetal not, and in 5 families this distinction could not be made. In hearts showed no defects. The twins were born at the PKD1 families, among asymptomatic persons inheriting an 33 weeks of gestation; each was nondysmorphic but ADPKD mutation, 2/6 aged 0-10 yr had no cysts on ultrasound had marked hydrops and a holosystolic murmur. examination, as did 2/17 aged 11-19 yr and 3/21 aged 20-29 Echocardiography showed type I TA in each twin; DNA yr. All of the 25 persons aged >30 yr with an ADPKD mutation analysis [Lifecodes, Valhalla, NY] indicated that had either cysts or clinical disease, suggesting (P<0.05) the twins were not monozygotic. Twin B died at 2 that the rate of false negative diagnosis by ultrasound does days of age; twin A is alive at 4 months of age. not exceed 0.11. No ultrasound positive diagnosis was The probands' mother was found to have cervical contradicted by a linkage result. In the PKD2 families, squamous cell carcinoma 7 weeks after delivery. We believe this to be the first report of twins proportions of persons at 50% risk of ADPKD with kidney cysts concordant for isolated TA. Both multifactorial were lower at every age than in PKD1 families, e.g. 4/15 vs. and autosomal recessive inheritance have been 17/30 persons examined in the 30-39 yr age interval. Mean age proposed for TA, and occurrence of TA in these of survival to end stage renal disease or death was twins is compatible with either. Although the significantly higher in PKD2 than in PKD1 families, 68.8 vs. occurrence of cervical carcinoma in the mother may 55.7 yr (P<0.005). These findings suggest that persons at 50% simply be an unfortunate coincidence, the risk of ADPKD, aged > 30 yr and not exhibiting kidney cysts possibility of a single cause for the twins' CHD on ultrasonographic examination, are unlikely to have and the mother's cancer cannot be immediately inherited a mutation at PKD1, if, as is likely, this is the dismissed. This case underscores the need to cause of ADPKD in their family. The probability that include fetal echocardiography in the evaluation of ultrasonographic examination will fail to diagnose PKD2 is non-immune hydrops fetalis, even when the screening greater but, in this less common form of ADPKD, the onset of ultrasound evaluation is normal. renal failure is significantly later than in the PKD1 form.

(0146) (0147) 4.3

Hereditary orotic aciduria; an association with an 11:22 X-linked adrenoleukodystrophy in a 362 member kindred. balanced translocation and familial inversion of chromosome KA Berg', TH Beaty', MB Raven2, AB Moser2, HW Moser2. 4. J.T. Bensen, M.J. Pettenati, L.H. Nelson, S.W. Brusilow, Johns Hopkins University Department of Epidemiology', and B.K. Burton. Bowman Gray School of Medicine and Wake The Kennedy Institute2, Baltimore, Md. Forest University, Winston-Salem, North Carolina and Johns Although the underlying defect in all forms of X- Hopkins University School of Medicine, Baltimore, Maryland. linked adrenoleukodystrophy is impaired degradation of Hereditary orotic aciduria Type I (OA Type I) is a rare very long chain fatty acids, the associated clinical disorder involving a defect of two enzymes essential to phenotypes are varied even within the same kindred. The pyrimidine synthesis, orotidylic pyrophosphorylase and most common clinical phenotype is the rapidly orotidylic decarboxylase. We describe the management and progressive childhood form (CALD), while alternate outcome of the first reported pregnancy in a woman with OA forms include the adult onset adrenomyeloneuropathy Type I, treated with oral uridine, which resulted in the (AMN) involving a slowly progressive paraparesis, and delivery of a child with multiple congenital anomalies. Addison's disease alone. Some individuals in cross- Further investigation of this child revealed a 47,XX,inv sectional studies are found to carry the mutant allele (4)(pl2q25)+der(22)t(11;22)(q23;q22) karyotype. The child's and yet be asymptomatic. To investigate the extent and phenotypic findings were compatible with previously reported distribution of phenotypic variation in hemizygotes, we cases of combined partial trisomy 22 and 1lq. The infant's analyzed data from a 362 member kindred spanning 6 mother's karyotype revealed her to be a combination of a generations. This kindred included 25 hemizygotes, 125 balanced 11;22 translocation as well as the pericentrically normal males, 33 heterozygotes, Ill normal females and inverted chromosome 4. In addition, karyotyping performed 68 individuals of unknown genotype. All forms of this on the infant's maternal grandmother and great-grandfather, genetic disorder were represented in the kindred, but both determined enzymatically to carry the OA Type I gene, within individual sibships clustering of phenotype was revealed the pericentric inversion of chromosome 4. We observed. Among 9 sibships in which more than one male propose a theory linking the OA Type I gene to chromosome 4 carried the mutant allele, brothers in 7 sibships were which contradicts previous Chinese hamster-human phenotypically concordant for either AMN, CALD or hybridization studies linking this gene to chromosome 3. Addison's Disease. In one sibship, 2 of 3 brothers were Although the phenotypic findings in the infant described concordant for AMN, but the third was an asymptomatic may all be explained by the unbalanced chromosomal carrier. In only one sibship were the brothers clearly abnormality, an additional teratogenic effect of uridine discordant, with one brother having AMN, and the other administration and/or maternal orotic aciduria cannot be CALD. Since all affected individuals in this kindred ruled out. presumably carried the same mutation, this variation in clinical phenotype may be due to the presence of one or more modifying genes, to as yet undetermined environmental factors, or to chance alone. Study of the causes of this variable expression should be undertaken since identification of modifying factors may improve treatment of affected males or prevent expression of the disease in those who are asymptomatic. A40 Clinical Genetics (0148) (0149) PFEIFFER SYNDROME. David Bixler and Raj-Rajendra A. Patel, Untreated PKU presenting as autism in a 6 year old: dietary Department of Oral Facial Genetics, I.U. School of Dentistry, treatment results in clinical Indianapolis, significant improvement. Indiana. R.D. Blackston, M.C. Naglak, L.J. Elsas, P.M. Fernhoff, Div. A 35 week female Caucasian infant was delivered by C-section Medical Genetics, Dept. Ped. Emory University, Atlanta, GA. with severe craniofacial malformations including a cloverleaf The association between Fragile X Syndrome and autism is skull (Kleeblattschadel) deformity, proptotic eyes, and fixa- well documented. However only a few reports exist of children tion of both arms at the elbow (radio-humeral synostosis) with untreated PKU who present with autism and no reports docu- long tapering fingers with short, broad, medially deviated ment an improvement in these late treated cases. We will show thumbs, broad halluces with 2,3,4 syndactyly of the left video documentation of significant clinical improvement after foot and 2,3 syndactyly of the right; and bilateral calcaneal phenylalanine (phe) restriction in a 6 year old male who pre- vagal deformity of feet. Head CT scan showed mild ventriculo- sented for an evaluation of autism. megaly, calvarial deformity, mild prominence of sulci and A filter paper phe obtained at 2 days of age was recorded as ventricles, hemispheric symmetry and hypertelorism. This normal. His early developmental milestones were normal, and at patient had a number of features of the Antley-Bixler syndrome. 15 months he had a vocabulary of 10-12 words. Thereafter he be- Mild limitation of movement in the fingers was also present came nonverbal, hyperreflexic and hypotonic. His head circum- although was this not classified as camptodactyly. Cloverleaf ference (HC) declined from the 50th to the 2nd percentile. At skull deformity has not been reported to occur in the Antley- age 3 years, he was "untestable" by usual psychometrics. At 6 Bixler syndrome and also because of the syndactylies the 1/2 years he was severely delayed, nonverbal, noninteractive diagnosis of Pfeiffer syndrome was made. However, it is with a short attention span, and constantly flapped his hands. remarkable the number of overlapping features that are present His height and weight were at the 50th percentile, but his HC in these two syndromes featuring multiple bony synostoses. was at the 2nd percentile. His hair was fair, and he emitted a They are not allelic disorders, though, since Pfeiffer is characteristic "wet fur" odor. A diaper ferric chloride a dominant trait while Antley-Bixler is recessive. reaction was dark green and his initial plasma phe was 1362 uM (22.5 mg/dl). After 6 months of dietary restriction of phe to 20 mg/kg/ day, plasma phe declined to 366 uM (6 mgl/dl) and improvement in his behavior was noted. After 12 months of therapy, his hair darkened and his HC had again progressed from the 2nd to the 50th percentile. His temperament, attention span and receptive skills were significantly improved. Although still nonverbal, he had begun learning sign language and using computer communi- cations. The results of his psychometric tests will be discuss- ed. We conclude that in addition to testing for Fragile X, all children with autistic features should have a metabolic evalua- tion. These studies are consistent with our previous observa- tions and indicate that phenylalanine in high concentrations affects cognitive brain function.

(0150) (01 51) Menstrual-Coital rhythms, oocyte organization, prenatal care ATYPICAL ALOBAR HOLOPROSENCEPHALY. E_ Bonioli. and rates of twinning, chromosome anomalies, malformations, A- .a-- nwAStaf~noi A Costas C BeUini. IUGR and infant mortality. Pediatric Clinic. of Ch~,-1es R' And F. University Genova. Radiologic RnirleZe Charles Kirby Department. Gaslini Institute, Genova, Italy. East Carolina Univ Sch of ied Greenville, NC 27858 USA Holoprosencephaly (HPE) is failure of deve- In 500,000 birth records with dates for onset of last normal lopment of the entire prosencephalon. The factors menses (LMP), Monday is the most common LMP onset for cycles causing the abnormalities of HPE to occur in the ending in birth - may represent it the coincidence of average embryo appear to be both environmental and heredi- most fertile cycle day (13th) with average most likely tary; HPE been found in a weekday for coitus (Sunday). Saturday and Sunday ham almo number of I1P onsets which have many extracranial abnormali- are significantly infrequent. myndromes Friday also shows significant ties. HPE was initially graded. according to the excess frequency. Friday/Monday ratio rises with mother's degree of severity, as alobar. semilobar or lobar; age; Friday is most frequent LMP onset for mothers over 30. and the subsequent introduction of CT scan has not Parity k3 shows a Friday excess, with no clear trend over substantially modified this classification. In parities 0-2. all three types the prosencephalon fails to cleave Twins, babies with chromosome anomalies or malformations, 1) sagittaly into cerebral hemispheres. 2) ho- and babies t2 s.d. below mean weight for gestational age show into and no such rhythm when counted directly. rizontally olfactory optic bulbs. and 3) This implies involvement transversally into telencephalon (cerebral hemi- of irregular cycles and poor fertilization timing relative to spheres) and into oocyte development in the causes of these anomalies. diencephalon (thalamus and hypo- Rates of thalamus). Consequently. together with the well these events show significant but abnormal rhythms. White and known black mothers differ in particulars, but rates of telencephalic malformations. the diencepha- twinning, lon is not separated into right and left halves chromosome anomalies, malformations and IUGR are all elevated and remains fused. with Saturday or Sunday LMP dates, and thus associated with Case both the mother's-age shift and with fertilization timing report: A-L.. first child of unrelated pa- rents. was shifted relative to normal single conceptions. born at 41 weeks gestation. after a normal pregnancy: 3.45 Pregnancies with these problems contribute substantially to weight kg: head circum- ference 31.5 cm: normal faces: infant mortality, often attributed to poor prenatal care. general hypertonia: All CT scan: of these groups of problem pregnancies show both elevated single ventricular cavity. communicating with a dorsal sac (tentorial no infant mortality and delayed prenatal care. We will not be dysplasia): hemi- easily spheric scissure: presence of two well separated convinced that late onset of prenatal care can cause thalami. twinning, trisomy, or malformation, and submit instead that causal suppositions must be reversed. Delayed The present case of alobar HPE. with the peculiar prenatal care feature of divided is not a cause, but rather an effect, of many problem paired, thalami. emphasizes that present knowledge of brain pregnancies. Their beginnings are uncertain in both senses of diverticulation the phrase because of irregularities in the relationship process is at least incomplete; moreover it between interacting rhythms suggests that it is possible to hypothesize that of cycle fertility, intercourse, the and development of oocyte organization. development of the two parts of prosencephalon (i-e. telencephalon and diencephalon) may occur in different times and/or under different control. Clinical Genetics A41

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Parent and physician attitutes towards newborn screening Dominant Inheritance of the Langer-Giedion Syndrome. for G6PD deficiency. K. Bournikos, A.E. Lin, E.W. Naylor, P. Brenholz, L. Swayne, S. Twersky, B. Arbeitel, and N. Singer. K. Sasser, B. Mitchell, K.L. Garver. West Penn Hospital, Morristown Memorial Hospital, Morristown, New Jersey. Pittsburgh, PA. The Langer-Giedion Syndrome (LGS), also known as Glucose-6-Phosphate Dehydrogenase Deficiency (G6PDD) Tricho-Rhino-Phalangeal Syndrome Type II, presents with mental can be detected by newborn screening (NBS) utilizing retardation, short stature, peculiar facies, bulbous nose Beutler's (Blood, 1968) fluorescent enzyme assay of a and multiple exostoses. Most cases are sporadic with a filter paper blood spot. Theoretical benefits of NBS for preponderance of males. Some of the propositi exhibit a G6PDD include early identification of affected children, deletion of part of the long arm of chromosome #8. parental and physician education, genetic counseling and Genetic evaluation of two mentally retarded brothers (C.B. avoidance of blood bank donorship. age 31 and V.B. age 27) at Hunterdon Developmental Center From 6/1/86 to 5/31/89, we screened 28,838 newborns in New Jersey revealed features of LGS: short stature (47" (all races) for G6PDD as part of our Supplemental NBS and 4'3h"), hypertelorism, downslanting palpebral fissures, program. West Penn Hospital is the only center in the large nose with a bulbous tip, large and somewhat protruding USA routinely screening all newborns for G6PDD. 220 (1%) ears, brachydactyly and multiple exostoses. Their mother, had a positive newborn screen. Follow-up was sought on A.B. (46"), died at age 58 of complications of Diabetes 69 patients born between 6/1/86 and 4/26/88 allowing a Mellitus. She was said to be "slow" with syndactyly between minimum of 9 months follow-up. Nine families were lost the 3rd and 4th fingers. Photographs revealed a peculiar to follow-up. Of 60 (27%) families contacted (2 survey facies with a bulbous nose and x-rays documented multiple mailings, 1 telephone call), 25 (42%) replied, 34 (57%) exostoses. A.B.'s maternal grandmother (about 4'11") and did not respond, 1 (2%) refused. Of 33 physicians maternal 1st cousin (4'6" with mental retardation) perhaps contacted, 20 (61%) replied. also had the LGS, but x-rays were not available for definitive Demographic data for the responding parents included: diagnosis. The rest of a large kindred was of normal height 62% <30 years, 42% completed 12th grade, 96% black. and intelligence. Using a graded response format, 100% of the parents There are few reported cases of familial LGS. Murachi favored NBS in general, 92% favored NBS for G6PDD. 68% (1981) reported a mildly retarded father and a severely agreed that identifying the child as having G6PDD enabled retarded daughter, Langer(1984) reviewed the literature and them to care for the child better. found a set of MZ twins and Shabtai (1985) described a mother 70% of the physicians favored NBS for G6PDD, 80% and two sons with features of LGS and a pericentric inversion acknowledged its importance even in the absence of of chromosome #8. treatment. Follow-up about clinical course was obtained Our family demonstrates another example of dominant on 33 patients: neonatal jaundice due to congenital inheritance of the LGS with documented transmission from nonspherocytic hemolytic anemia in 3 (9%), asymptomatic mother to sons, and with possible variable expression in in 30 (91%). other family members. Although the feasibility and cost effectiveness of G6PDD NBS in the USA has not yet been established, these favorable parental and physician attitudes may play a role in deciding whether such screening should be performed on a broader scope.

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Autosomal Dominant Dystonia in a Large North American Family: Predictive testing for Huntington's disease: achievements Clinical Features. MF Brin. CB Moskowitz. SB Bressman. RE and problems. Burke. D de Leon. N Risch*. S Fahn. Dystonia Clinical D.J.H. Brock, M. Mennie, A. Curtis, F. Millan, L. Barron, Research Center, Columbia University, New York, NY; *Yale TA. Raeburn, D. Dinwoodie, S. Holloway, A. Crosbie? University, New Haven, CT. A. Wright, I. Pullen. Human Genetics Unit, University of Torsion dystonia is a neurological syndrome dominated by Edinburgh, Scotland. sustained muscle contractions frequently causing twisting and Through a molecular genetics consortium serving the repetitive movements, or abnormal postures. 2/3 of all cases four medical genetics centres in Scotland, the Human are idiopathic; the remainder are secondary to other nervous Genetics Unit in Edinburgh provides predictive testing system disorders. In childhood and adolescent onset cases, for Huntington's disease (HD) to a population of 5 autosomal dominant transmission has been found. Disease million. 180 adults with 25% or greater risk of frequency, estimated at 1/160,000 in the general population, inheriting the HD gene have entered the presymptcmatic is higher in Ashkenazi Jews (1/23,000). Variable expression testing progranme and are at various stages of a lengthy of clinical features previously suggested genetic subtypes series of genetic and psychiatric counselling sessions between Jews and non-Jews; this is now disputed. provided by local centres. Predictive testing has been We have conducted an extensive evaluation of the largest completed on 34 consultands, 14 of whom had a substantially available non-Jewish family with idiopathic torsion dystonia increased risk of carrying the HD gene and 20 a sub- exhibiting autosomal dominant transmission and 3 generations stantially reduced risk. Another 7 couples where a affected (Family R), and have reported tight linkage with the pregnancy was in progress entered the Prenatal exclusion gene encoding the actin binding protein, gelsolin, on 9q32- programme; in two cases the HD gene was excluded while q34 (Ozelius, 1989). We now now detail the clinical in 5 the residual risk remained at 50%. characteristics. Where only M4S10 markers were informative and where The 165 members are of French, English and American phase information had to be acquired from affected Indian descent; 74 were examined for linkage. Rigorous individuals in the same generation, final risk pre- criteria were used to classify exam status; 14 had definite dictions were often less than satisfactory. This dystonia, 3 were probable. The apparent penetrance was 75%. necessitated a change in the testing protocol, whereby Age at onset range from 4-43 yrs, mean 14.4+3.1, median 10.0. consultands would be advised in advance of all the risks 11 had childhood-onset, 3 had adult-onset; generalization associated with their possible genotypes and allowed to occurred within a median time of 3.0+2.2 years; onset in the decide whether to proceed. Surprisingly, no consultand leg predicted earlier generalization median (2.0+0.7 years). has yet elected not to proceed even when a final risk One 6.5 yo was unable to walk within 3 months of onset. might be in the 20/80% range. We conclude that con- The clinical features of this family were compared to sultands regard any change from 50/50 status as a major those in other non-Jewish and Jewish families with dominant step forward in resolving the dilemna of uncertainty. inheritance. Age at onset, region of presentation, and time to generalization were not significantly different; however, penetrance was higher in Family R. Our studies thus far fail to confirm significant differences in the phenotype of the Jewish and non-Jewish dystonias. The phenotypic expression in Family R is representative of autosomal dominant dystonia. A42 Clinical Genetics (0156) (0157) 1.83

Parental consanguinity and incidence: the use of Dahlberg's Anthropometric analysis of mentally retarded males with and formula to disprove autosomal recessive inheritance in without the fragile X syndrome. ataxia telangiectasia (AT). M. G. Bubtler. J. L. Haynes1. G. A. Allen2. and D. S. Bundey, C. G. Woods. Department of Clinical Genetics, Singh Vanderbilt Univ. School of Medicine, and Meharry University of Birmingham, Birmingham, UK. Medical College, Nashville, Tennessee. Dahlberg described the robust relationship which exists An anthropometric survey with multivariate discriminant between the birth frequency of an autosomal recessive analysis of 31 anthropometric measurements (weight, height, disease and the proportion of parents of patients who 8 linear, 4 breadth, 14 craniofacial, 2 skinfold and are first cousins. In order to apply Dahlberg's formula testicular volume) was undertaken on 66 mentally retarded we need to know the birth frequency of the disease, and males (16 with and 50 without the fra (X) syndrome). The the parental consanguinity rate both among parents of mean Z scores for the fra (X) syndrome males were between patients and in the general population. We have performed -1.87 and 11.08 for outer canthal distance and testicular a prevalence study of ataxia telangiectasia in the West volume, respectively, while the range for the mean Z scores Midlands and have observed a prevalence for all ages of for the non fra (X) males was from -2.91 to 2.29 for foot 1 in 700,000, a prevalence for ages below 50 years of breadth and testicular volume, respectively. There was a 1 in 500,000, and, by including the numbers of patients who statistically significant difference (p<.05) between fra (X) have recently died, a birth frequency of 1 in 300,000. and non fra (X) males for 16 measurements (weight, height, 6 The population data for parental consanguinity comes from linear, 3 breadth, 4 craniofacial, and testicular volume) a study of the parents of babies born in Birmingham in 1986. with the greater measurements found in fra (X) males. Five of 2432 European couples were first cousins or more Sitting height, middle finger length, hand length, knee- closely related, and the corresponding figures for other buttock length, and foot breadth were negatively correlated couples were 1 out of 509 Afro-Caribbeans, 1 out of 553 (p<.05) with age while bizygomatic diameter and ear length Indian Sikhs and Hindus and 553 of 1284 Muslims (mainly were positively correlated with age and head circumference Pakistanis). Applying these figures to Dahlberg's formula, and head length were positively correlated with fra CX) we would expect 10% of parents of AT patients to be first chromosome expression in the fra (X) males. Outer canthal cousins; and we would expect a greater percentage if AT distance and subscapular skinfold were negatively correlated really consisted of several distinct recessive entities, as with age while ear length was positively correlated in the has been proposed from complementation studies. In a UK non fra (X) males. Discriminant analysis of the fra (X) and based genetic study we observed no first cousin parents out non fra (X) males resulted in a discriminant function based of 47 couples, and the overall figure from the literature on 5 of the 31 anthropometric variables and age. In the is 5 out of 384. This level of parental consanguinity is discriminant analysis, patients with the fra (X) syndrome higher than that in the general population but much lower were distinguished from mentally retarded males without the than that expected on Dahlberg's formula and is inconsistent fra (X) syndrome at an overall correct classification rate with the supposition that ataxia telangiectasia is always an of 95 percent for our sample. The 5 anthropometric autosomal recessive condition. We therefore believe variables in the discriminant function were the Z scores that there must be other causes for the familiarity of AT. representing testicular volume, ear width, foot breadth, head breadth, and bizygomatic diameter. Additional research is needed to test the usefulness of these variables in screening mentally retarded males for the fra (X) syndrome.

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Dermatoglyphic asymmetry in an Hispanic cleft lip Sleep Disorders in Prader-Willi Syndrome. S.B.Cassidy, and palate population: R.M. Cantor. M.A. Spence. J.A.McKillop, and W.J.Morgan. Univ. of Arizona, Tucson and V.K. Cortessis. K.A. Svitil. S. Korula. and L.F. Univ. of Connecticut, Farmington. Wilson. Univ. of Ca., Los Angeles and Rancho Los Many of the characteristic features of Prader-Willi Amigos Hospital, Ca. syndrome (PWS) are attributable to hypothalamic dysfunction. The formation of dermal ridges and the closing of Since the sleep-wake cycle is also controlled by the hypo- the palatal shelves occur during the same period of thalamus, a survey of symptoms of sleep disturbance was con- embryonic development. Analyses have suggested that ducted during a 4-day PWS clinic. a disruption at this stage may be expressed in the The 25 completed questionnaires included 12 males and 13 failure of the palate to close and in dermal females, with ages ranging from 20 months to 42 years. asymmetry. From our registry of 1657 cases of cleft Daytime xomnolence was seen in 52%, and regular daytime naps lip and palate among Hispanic individuals living in in 89% over 5 years. Snoring occurred in 44%, and restless the Los Angeles area we have thus far collected movements in 44%. Cataplexy (hypotonia with emotion) was dermatoglyphic data on 68 probands and 149 of their reported in 16%. Nocturia was in 83% and enuresis in 26% over first degree relatives (controls). 2 years. There was no relationship between the number or A higher correlation between left and right hand severity of sleep disorder symptoms and the degree of obesity. atd angles is observed for controls (;7*=61, n=80), Three of the patients had had formal sleep studies. These compared with probands (:=56, n=43). (* = Kendall showed sleep onset REM (SOREM) or short REM latency, symptoms Tau Statistic) Selection for a right-sided or of obstrutive sleep apnea, excessive sleepiness (abnormal bilateral cleft of the palate in the proband (the multiple sleep latency test) and decreased 0 saturation to rarer forms) shows little difference between the 40% in one. Literature review reveals one study of 9 adults correlations CJ=67, n=50), (:X=65, n=26), while with PWS. Eight had excessive daytime sleepiness, 5 had selection for a positive family history of clefting SOREM, and one had desaturation to 40%. results in an increased difference between the Anterior hypothalamic lesions in animals abolish the correlations (;=71, n=25), (1=61, n=14). In sleep-wake cycle, produce dissociated periods of REM sleep, probandstests for fingerprint pattern asymmetry and cause emotional disturbances and abnormal regulation of reveal a marked increase in the number of whorls on feeding. All of these findings are present in patients with the left middle digit as compared to the number of PWS. These are features of narcolepsy and obstructive apnea. whorls on the right middle digit. This is not We conclude that it is likely that the sleep disturbances observed in controls. Patterns on the other digits in PWS are hypothalamic in origin, as are other features such show no significant asymmetry. as hypogonadism, temperature instability, neurosecretory Continued data collection will sufficiently growth hormone deficiency, hyperphagia, and possibly the high increase the sample size to permit further pain threshold. No structural hypothalamic lesion has yet stratification on variables such as family history been found. We hypothesize that there is a gene involved in and type of cleft. metabolism or neurotransmission within the hypothalamus in the region of chromosome 15q that is deleted in the majority of patients with PWS. If narcolepsy and/or sleep apnea are confirmed in PWS through sleep laboratory studies, it is possible that some of the characteristics of PWS can be improved through treatment of these abnormalities. Clinical Genetics A43

(0160) 1.85 (0161) 1.86 Crouzon Syndroas: Exidence of incomplete penetrance. L. Noonan syndrome and neurofibromatosis type 1 segregating independently in a family. Charnas , K.J. I1ofman . K.N. Ros 1HGB, NICHD, NIH, Bethe~da, Md., ZJohn Hopkins Univ. Sch. of Med. Baltimore, A. Colley, J. Clayton-Smith and D. Donnai. St Mary's MD., Children's Hospital Natl. Med. Ctr., Washington, D.C. Hospital, Manchester, United Kingdom. The Crouzon syndrome is an autosomal dominant condition A family is presented demonstrating independent characterized by craniosynostosis, midface hypoplasia, segregation of Noonan syndrome and neurofibromatosis type 1 shallow orbits with resulting ocular proptosis, and the (NF1). The mother has both Noonan syndrome and NF1, she absence of digital anomalies. Cases of incomplete penetrance has 4 children from her first marriage; one child also has have not been previously recognized in the Crouzon syndrome, both conditions, 1 child has only Noonan syndrome and 2 although variable expressivity is well documented. This is children have neither condition. From her second marriage the first description of incomplete penetrance in the Crouzon she has 3 children; 1 child with only NF1, 1 child with only syndrome. Noonan syndrome and 1 child with both conditions. We describe a male and a female who are second cousins Chromosome analyses on family members did not show any through nonconsanguineous matings both of whom show severe abnormality. A molecular study is in progress. A number midface hypoplasia, choanal atresia, ocular proptosis, of people have been reported with both Noonan syndrome and congenital craniosynostosis and hydrocephalus requiring NF1 and it has been suggested that this may represent a neurosurgical intervention. The male was born to a 32 year discrete genetic entity. Our family suggests that this is old G2P1 mother and a 35 year old father. The female was not so, as Noonan syndrome and NF1 have segregated born to a G7P7 34 year old female and a 36 year old father. independently in some of the children. Another suggestion Siblings, parents, and grandparents have no clinical or is that the Noonan syndrome phenotype is a manifestation radiographic features of the Crouzon syndrome. At ages 4 and of NF1 but in our family a child with NF1 has no features 7, both patients have normal intellect. Routine banding of of Noonan syndrome, thus lending no support for this. It karyotypes shows 46XY and 46XX, respectively. Incomplete is possible that these conditions could be present penetrance in autosomal dominant conditions is widely coincidentally in an individual and segregate independently recognized, but the mechanisms underlying reduced penetrance in offspring. Our family supports this, as the mother with are poorly understood. The likelihood of these two cases both conditions has 1 child with only NF1, 2 children with arising as sponta eous new mutations within this pedigree is Noonan syndrome only and 2 children with both Noonan syndrome and NF1. approximately 10- . This pedigree cannot be explained by gonadal mosaicism, somatic mutation, or recessive inheritance. An alternative hypothesis, previously invoked for incomplete penetrance in other autosomal dominant disorders, suggests the inheritance of a molecular predisposition. A second mutational event would be required in order to produce the clinical phenotype.

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Familial amyloidotic polyneuropathy and Machado-Joseph disease: Possible common pathogenetic mechanisms for the Poland two rare autosomal dominant neurologic diseases in the same anomalad and Adams-Oliver syndrome. V.M. Der Kaloustian, E. family - The "Iiyama type" of FAP? P Coutinho and J Sequeiros. Hoyme, H. Hogg, M. Entin and A. Guttmacher. McGill University Hosp. Geral de Santo Ant6nio; Centro de Estudos da Paramiloido- - Montreal Children's Hospital Research Institute, Montreal, se; Inst. Cienc. Biomed. Abel Salazar, Univ. Porto, Portugal. Quebec; Health Sciences Center, University of Arizona, Tucson, Familial amyloidotic polyneuropathy (FAP) - type I (Portu- Arizona; Shriners' Hospital, Montreal, Quebec; University of guese, Andrade) is more prevalent in the north littoral of Por- Vermont, Burl i ngton, Vermont. tugal (most of the 505 Portuguese kindreds). Machado-Joseph Poland anomalad consists of unilateral symbrachydactyly and disease (MJD) is a rarer disorder (about 150 kindreds world- ipsilateral aplasia of the sternal head of the pectoralis wide); it is a rather pleomorphic disease, due to multi-system major muscle. Most of the patients reported with this anoma- degeneration, mainly characterized by a cerebellar ataxia, py- lad have been sporadic. ramidal, extra-pyramidal and peripheral signs, and progressive external ophthalmoplegia; it is also inherited as an autosomal Adams-Oliver syndrome consists of central skull and scalp de- dominant, but affects primarily the residents of Sao Miguel and fects and transverse defects of the limbs. It is considered Flores (Portuguese islands of Azores) and their descendants. to be due to a single gene with autosomal dominant pattern of Present epidemiological data suggest that both mutations may i nheri tance. have occurred in mainland Portugal, more than four to five cen- We report here two families having members affected with the turies ago, spreading to many other countries following the sea and the Adams-Oliver enterprises of the 1500s and later emigration routes. With the Poland anomalad syndrome. exception of the US (where MJD is far more prevalent, due to S.R.-L. a 5 month old boy, presented with scalp defects and Azorean immigration), the world dissemination of both mutants short, stubby and partially syndactylous toes bilaterally. A has been strikingly similar. In Portugal (as in Japan), both diagnosis of Adams-Oliver syndrome was made. The mother is diseases share a secondary focus in the central mountains, affected with the Poland anomalad with hypoplasia of the where we have been following, for the last ten years, a single pectoralis muscle on the left side of the chest and a combi- family (unreported so far) where FAP and MJD coexist. nation of syndactyly and ectrodactyly of the left hand. A woman, who died from FAP at age 60, married a man affected M.M., a 12 year old boy, has scarring over a large area of the with MJD. Among their four children, two daughters and one son posterior part of his scalp (status post-aplasia cutis congen- died with MJD (at ages 51, 40 and 36); each had one child with af- ita) absent right nipple and a rudimentary left nipple; short the same disease: one of them is our MJD proband, who is mild of the fingers; and son of the fifth metacarpals; 3,4 syndactyly fected with MJD (type 1) since age 32. The youngest mild 2,3 syndactyly of the toes. The diagnosis of the Adams- couple was affected with FAP since age 36, and died at age 47; Oliver syndrome was made. His mother has similar findings he was the FAP proband. Presumably just by chance, none of the and, in addition, she has no breasts bilaterally and has hypo- children (or grand-children) of that couple had both diseases. plasia of the pectoralis muscle. We believe that the "Iiyama (Japan) type" of FAP (a periph- eral amyloid neuropathy associated with cerebellar and pyrami- We hypothesize that the Poland anomalad and the Adams-Oliver dal signs, related to TTRMet3O like the Portuguese and the syndrome are the result of the interruption of the early emb- other Japanese cases), may be just the simultaneous occurrence ryonic blood supply in the subclavian arteries and that the of FAP type I and MJD in the same family. Both diseases are gene predisposing to this interruption follows the autosomal present in the same region. Unlike ours, however, some Iiyama dominant pattern of inheritance. patients seem to have received and expressed both mutant genes. A44 Clinical Genetics

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Do chrarnsanally normal heterozygotes for Fragile X have short term memry Clinical manifestations and causal heterogeneity in isolated and visuospatial defects? R. de von Flindt, A.E. Chudley, and B. Bybel. lissencephaly sequence. W.B. Dobyns and D.H. Ledbetter. Univ. of Manitoba and Children's Hospital, Winnipeg, Manitoba, Canada. Indiana Univ. School of Medicine, Indianapolis, and Baylor Thirteen fenale adult Fra X carriers (2 of whom are Fra X positive) and College of Medicine, Houston, TX. age and sex matched controls were tested with Wechsler Adult Intelligence Isolated lissencephaly sequence (ILS) consists of type I Scales-Revised (WAIS-R) and the Revised Visual Retention Test (RVRT). Tw lissencephaly and sequela but no other consistent abnormal- equivalent fonrs of RVRT were administered: AdTinistration A - 10 second ities. We review the clinical manifestations and possible exposure of each design; Aduinistration D - additional 15 second delay after causes in 20 patients with ILS. removal of the design before design reproduction. Subject mean scores were Significant historical data included parental consanguin- significantly lower (p<.05) on Verbal IQ (90.33 vs. 111.38), Performance IQ ity or affected sibs (2/20), and maternal bleeding (3/20) (101.46 vs. 119.46), and Full Scale IQ (94.08 vs. 116.23), hwaever, subject or severe viral illness (1/20) at 3-4 months gestation. CT scores ware not significantly different from the standardized nortm for the or MRI scans showed either widespread agyria (8/20) or mixed WMIS-R as were control scores, which suggests sawe ascertairment bias in the agyria/pachygyria (12/20), intracerebral calcifications control group. A specific pattern of cognitive performance on the WAIS-R was (3/20), and porencephaly (1/20). Consistent craniofacial not identified. The subject group performed most poorly on the Digit Span abnormalities included microcephaly (15/19), bitemporal and Information subtests, and best on Block Design and Object Assembly hollowing (17/18) and small jaw (11/20). Several patients subtests. Subjects performed significantly lae- on number correct on both had other non-specific facial changes. Chromosome analysis Administration A on the RVRT (p = .0158) and total nurber of errors was normal in all patients, and molecular analysis of the (p = .0068), and Adninistration D (p = .0005 and p = .0016). As intellectual 17p13 region failed to detect a deletion in 8 patients. ability may contribute to RVRT performance, comparisons were also done on Based on this data, causal heterogeneity is apparent. normative "expected' scores based on intellectual functioning. Subject Autosomal recessive inheritance in some families is proven by performnce was again significantly lowar, i.e.: nunber correct on parental consanguinity and affected sibs. Arterial insuffic- Administration A of the RVRT (p = .0114) and total nurber of errors iency during early pregnancy is supported by prolonged vaginal (p = .0025) (normative data for expected score was not available for bleeding in 2 pregnancies, and intracerebral calcifications Administration D). Comparisons were also done without the tw Fra X positive in 3 patients, one of whom also had porencephaly. Viral carriers with similar findings, lcrer on ntrber correct on both teratogenesis is suggested by a history of severe viral ill- Administration A of the RVRT (p = .0601) and total nunber of errors ness in one pregnancy, with the child having bilateral (p = .0104), and Adninistration D (p = .0021 and p = .0081). Comparisons calcifications of the basal ganglia. While unproven at this based on "expected" scores were also consistent with p = .0115 on number time, submicroscopic deletion within chromosome band 17p13 correct and p = .0036 on total nudter of errors. Perfonrance on may be another cause. Manifestations most useful in differ- Administration D was also similar with p = .0021 on number correct and entiating ILS from Miller-Dieker syndrome include less severe p = .0081 on total number of errors. As RVRT performance is a function of lissencephaly, atypical calcifications, intact corpus both memory and visuo-spatial ability, it is difficult to isolate which callosum, relatively normal facial appearance, and better factor may be more contributory to the deficits displayed by the Fra X development. carriers. With general lowar functioning on mnmry related tasks on the WAIS-R and general higher functioning on visuo-spatial related tasks, mary functioning may be a mere significant factor.

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Apparent C (Trigonocephaly) Syndrome Without Severe Early diagnosis of hermaphroditism in a Mixed Arab population Developmental Delay. A.C. Dowman and J. Bodurtha, Medical College of Virginia, Richmond. M.Y.El-Khalifa, T.I.Faraq, K.K.Naguib, A.S.Teebi, M.J. C (Trigonocephaly) or Opitz syndrome is an autosomal Marafie, L..Bastaki, S.A.Al-Awadi, and M.H.El-Badramany(*) recessive condition characterized by trigonocephaly, distinctive oral and facial features and abnormalities of Kuwait Medical Genetics Centre, (KMGC) and Psychological : limbs and skeleton. Previous reports of children with C Medicine Hospitai(C), P.O.Box 4080, Safat 13041 Kuwait. syndrome have emphasized high infant mortality and Forty nine patients with heterogeneous deviant sex differen- moderate to profound retardation. We report the case of tiation problems were detected during their infancy and a 29-month-old female with many characteristics of C childhood among the 69 ascertained hermaphrodite cases (71%). syndrome but without severe developmental delay. The 49 patients referred to the KMGC during a period from The patient was the term product of an uncomplicated Jan 1979 to Jan 1988 showed either (1) ambiguity of the pregnancy, via spontaneous vaginal delivery, to a 23-year- external genitalia (40 cases) or (2) inguinal hernia + mass old G II SAB I Caucasian. Birth weight: 3005 gr (>25%). in females (4 cases) or (3) cryptorchidism and inguinal OFC: 32 cm (10%). Apgars were 8 and 9 at 1 and 5 minutes, hernia in males (5 cases). respectively. Neonatal evaluation revealed many features consistent with C syndrome, including trigonocephaly, In general, the 69 ascertained hermaphrodite cases were cleft of the secondary palate, constricted maxillary arch, categorized into 3 main groups including (1) 5 true herma- broadened alveolar ridges, upslanted palpebral fissures, phrodite and mixed gonadal dysgenesis patients (2) 19 female epicanthic folds, small, low set, overfolded helixes, pseudohermaphrodites (FPH). All of them had congenital small nose with broad root, long philtrum, retrognathia, adrenal hyperplasia (CAH) and (3) 45 male pseudoherrnaphro- webbed neck, and wide spaced nipples. There were single dites (MPH): 7 patients with persistent mullerian duct syn- palmar creases bilaterally, hyperflexible thumbs, drome, 19 XY females and 19.patients with Reifenstein or cutaneous 2-3 syndactyly of the feet, and hypoplastic 5Ohypertension + salt loosing in most FPH of age. She initally required nasogastric tube feedings with CAH challenged the pediatricians for critical aseessment due to poor suck, however, was able to mouth feed after and management. This supports the views discussing the fitting with a removable appliance. She is otherwise in importance of early detection of similar cases. Certainly, good health. this will be also helpful in the appropriate psychological Developmentally, at 20 months, she was age appropriate upbringing of hermaphrodite cases. in social and self-help skills, cruising, and able to stand without support for several seconds. Receptive and expressive language skills were at 16-month levels. Visual motor abilities tested at a 16-month level. Clinical Genetics A45

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Osteopathia striata with cranial sclerosis: variable Terminal transverse defects are associated with familial caver- expression within a family including bilateral absence of nous angiomatosis Michele R. Filling-Katz, Depts. of Neurology the fibulas. G. L. Feldman. M. L. Wagner and J. W. and Ophthalmology university of Louisville, Louisville KY, Belmont. Institute for Molecular Genetics, Howard Hughes Sondra W. Levin Dept of Pediatrics Walter Reed Army Medical Medical Institute and Departments of Pediatrics and Center Wash. DC and Uniformed Serv. Univ. Health Sci. Bethesda Radiology, Baylor College of Medicine, Houston, Texas. MD, Nicholas J. Patronas Clinical Center National Insitutes of Osteopathia striata is a rare bone dysplasia which may Health Bethesda MD and Norman N. K. Katz Dept of Ophthalmology occur as an isolated radiographic finding or in association University of Louisville, Louisville KY with cranial sclerosis. An autosomal dominant syndrome has Terminal transverse limb defects are usually sporadic and been established including associations with other only rarely reported as familial. Multiple pathogenic mechan- malformations. We have investigated a family with three isms, including vascular disruption, have been proposed to ac- affected members in two generations, including a previously count for these defects. We report a family followed over the unreported feature in the proband, bilateral absence of last four years known to have familial cavernous angiomatosis fibulas. The infant was born at 32 weeks gestation; (McKusick Catalogue No. 11686) in which two members have simi- physical features included macrocephaly, ocular lar terminal transverse defects at the mid-forearm. Multiple hypertelorism, low set ears, a cleft of the hard and soft family members have had episodic bleeding from cavernous angi- palate, and bilateral club feet. A karyotype revealed a omas of the central nervous system, a distinctive feature of 46XY pattern and a skeletal survey revealed absence of both this dominant disorder. Other features of this family include fibulas. The long bones were noted to be dense but retinal cavernous angiomas (two patients), a high incidence of osteopathia striata was not present. The mother, B.C., and skin angiomas, hepatic angioma (one patient) and cavernous a sibling of the patient, L.C., were noted to have similar angiomas of the soft tissue (two patients). One of the two facial features as the proband, including macrocephaly, individuals with the limb defect has been extensively evaluated hypertelorism and high arched palate with speech by us. Magnetic resonance imaging of the forearm with the ter- difficulties. Radiologic evaluation revealed changes of minal transverse defect using gadolinium DTPA enhancement mild to moderate osteopathia striata in the sibling with showed abrupt termination distal to the normal radius and ulnar prominence of the skull and dense bone structure, and heads as well as apparently normal blood vessels. The absence moderately advanced changes of osteopathia striata with of visible vascular malformation lends support to the hypo- thickened, dense bones of the skull in the mother. thesis of acute vascular disruption as the causative mechanism Our proband has had a very complicated neonatal course, for the limb defect. We propose that familial cavernous ang- some of which may be attributable to his prematurity. iomatosis may be a new cause of vascular disruption resulting However, the absence of the fibulas, not previously in transverse terminal limb defects. described in association with this syndrome, and other clinical features are much more severe in this individual, emphasizing the variable expressivity of this syndrome. In addition, the lack of radiologic changes of osteopathia striata in the newborn period of this infant emphasize the necessity of long term follow-up of patients with macrocephaly and other features consistent with this syndrome.

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Idiopathic torsion dystonia: a genetic study of 107 index Sensorineural hearing loss, enamel hypoplasia cases in the UK. N.A. Fletcher, A.E. Harding and and nail defects. A new syndrome? J. E. Fox, C.D. Marsden. Institute of Neurology, London, UK. A. Heimler. J.E. Hershey and P. Crespi. The genetics of idiopathic torsion dystonia (ITD) are Schneider Children's Hospital of Long Island controversial. Autosomal dominant, autosomal recessive, and Jewish Medical Center, New Hyde Park, NY. X-linked types have been proposed, and it has been suggested We report a brother and sister, 11 and 9 that there is a high incidence of a severe autosomal years of age respectively, with profound recessive form amongst Ashkenazi Jews. The relative sensorineural hearing loss, enamel hypoplasia proportions of these disorders are unclear, and many inconsistent with amelogenesis imperfecta patients do not have affected relatives, creating diffi- because of the occurrence of the enamel defect culties in genetic counseling. Most recent genetic studies in the permanent dentition only and nail defects of ITD have concentrated on predominantly Jewish populations involving leukonychia of some fingernails and in Israel and the USA. Beau's lines on all toenails. Serum calcium, Family studies were undertaken on 107 index cases, of phosphorus, creatinine and urine analysis were which 11 were Jewish, with generalized or segmental ITD from within normal limits for both children. The 100 British kindreds. About half of the families contained parents are unaffected and nonconsanguineous. affected members in more than one generation. Segregation An environmental insult is an unlikely analysis of single generation cases did not support autosomal explanation for the Qbserved abnormalities recessive inheritance, and the parental consanguinity rate because any significant time related insult was not increased. These patients did not differ clinically would have had an impact on primary and from multigeneration cases, and there were no detectable permanent dentitions. The association of clinical or genetic differences between Jewish and non- hearing loss, enamel defect and nail defects has Jewish patients. In singleton cases, mean paternal age was not been previously reported as an ectodermal significantly increased. We conclude that ITD is caused by dysplasia. We believe that the findings in an autosomal dominant gene with 40% penetrance and variable these patients most likely represent the in 80-90% of cases. The remainder be non- pleiotropic effects of a single gene with expression may on the of autosomal recessive genetic phenocopies. There was no evidence for the transmission basis in this inheritance. Additional case reports are needed existence of an autosomal recessive form of ITD study. to confirm that the associated defects in these children represent a new syndrome. A46 Clinical Genetics (0172) (0173) 13.4 Dominant localized pruritus. K. Fried and Clinical heterogeneity in a family with spcndyloepiphysial I. Gold. Departments of Genetics and dysplasiI congenita1(SEDC). R.B. Goldberg, R.W. Marion, H. Dermatology, Assaf Harofeh Medical Center, Pritzker, F.M. Wang, I. Andersonzand P. Tsipouras. Center Tel Aviv Univ. Medical School, Zerifin, for Congenital Disorders, Montefiore Medical Center/ Albert Israel. Einstein Col of Med, Bronx, New Yorkland Department of Pruritus, hereditary localized McKusick Pediatrics, U Conn Health Science Center, Farmington, Connec- 17710 was previously reported in the area ticut.2 overlying the lower end of the scapula. We SEDC is a clinically heterogeneous disorder that affects report a Moslem Arab family in which the the vertebrae and the epiphyses of the appendicular skeleton. pruritus was located in the palms of the Common features of SEDC include short stature, myopia with hands and the soles of the feet. The progressive vitreo-retinal degeneration and retinal detach- propositus born in 1965 started to feel ment, and cleft palate. Although most cases are sporadic, itching at the age of 18 years. He was the autosomal dominant inheritance has been reported. We have sixth child of unrelated parents. His mother studied a four generation family in which SEDC occurs as an had similar pruritus. The sibship of the autosomal dominant trait, and have demonstrated genetic proband: 1) F Pruritus (oldest sister), 2) M linkage to the COL2A1 locus on chromosome 12, thus confirming Hemophilia A, 3) M Normal, 4) F Normal, 5) F that this disorder is caused by a defect in type II collagen. Normal, 6) M (Proband) Pruritus, 7) F Eleven affected members of this family have been evaluated. Pruritus, 8) M Normal, 9) M Hemophilia. The Adult height ranged from 43 to 50.3 inches, with an average mother has 7 sibs 1) F Normal, 2) M of 45.8 inches, and upper to lower segment ratio ranged from Hemophilia, 3) F Normal, 4) M Pruritus, 5) F 0.87 to 0.95. One patient has had repair of a cleft of the Normal, 6) M Pruritus, 7) F Normal. The palate; no other individuals had evidence of palatal clefts. maternal grandfather died when he was over All adult patients had scoliosis, but the degree ranged from sixty years old and the maternal grandmother mild to severe; additionally, lordosis and kyphosis were is alive at the age of about 80, and neither present in variable degrees in eight patients. Radiographs of them having had pruritus. Incomplete were available in 5 patients. Findings included flattening of penetrance in one of the grandparents is the acetabular roofs (5/5), degeneration of the hips (2/5), likely. There were 3M:3F with pruritus so delayed ossification of the symphysis pubis (1/5), femoral that autosomal dominant inheritance is likely heads (3/5), and knees (1/5), ovoid shaped vertebral bodies although X-linked dominant inheritance cannot with decreased interpediculate distance (2/5), and hypoplasia yet be ruled out. Because of the adult age of the dens of the axis (1/5). Complete ophthalmologic exam of onset, children are not informative. The was performed in 2 individuals. No abnormalities were chance finding of Hemophilia in the family present. This family, the largest reported in which SEDC may be useful in ruling out X-linkage of the occurs, confirms the marked variability of phenotypic pruritus in this kindred in future studies. expression in this rare disorder.

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Gestational Age Evaluation in the Dysmorphic Neonate: Errors Hypomelanosis of Ito. R. Greene, R. Maclean, C. Salinas* in the Dubowitz Assessment. C. L. Greene. University of and C. B. Lozzio. Univ. of Tennessee Medical Center, Colorado Health Science Center, Denver, Colorado. Developmental and Genetic Center, Knoxville, TN and *Medical Gestational age assessment is an important tool in the Univ. of South Carolina Div. of Craniofacial Genetics, evaluation and management of neonates. Determination of Charleston, S.C. gestational age by examination of the newborn depends upon This disorder is characterized by macular hypopigmented standard scales developed in populations of apparently normal whirls, streaks, and patches associated with multiple neonates. Birth defects, dysmorphic features and genetic congenital anomalies. Abnormalities of the eyes, teeth, disease have specific and predictable effects on most of the musculoskeletal and central nervous systems, cleft palate, items used in a variety of scales used for gestational age mental retardation and seizures have been described in assessment. Every item used in the Dubowitz scale can be some of these cases. Various chromosomal abnormalities altered by genetic disorders. For each item the physical have been reported. finding(s) which alter the score are described, examples of We report here six unrelated cases of Hypomelanosis diseases which include that finding are given, and the of Ito. Chromosome studies have been performed in four direction of the resulting error in estimation of gestational of them and two showed different chromosome abnormalities: age is shown. As an example, a typical term Down syndrome one had mosaicism for trisomy 14 and the other had a "de baby is scored on the Dubowitz scale. This exercise is novo" unbalanced chromosome rearrangement of one X suggested as a useful teaching tool, since a 40 week chromosome. The five females and one male of this report, gestation neonate with Down syndrome is most likely to score all demonstrate the characteristic hypomelanosis. The 36 weeks on the Dubowitz scale. five females are developmentally delayed or mentally retarded The consequences of error in assignment of gestational age with short stature. The male has short stature and normal are considered; with examples given including failure to mental development. Two of the six cases have a cleft identify microcephaly and intrauterine growth retardation palate. One has a congenital heart defect (ASD) surgically because of a falsely low estimate of gestational age. repaired. The case with mosaicism for trisomy 14 is a Finally, the Dubowitz scale itself is shown to be a useful 6 year old girl with mild mental retardation, short stature tool for identifying dysmorphic or genetically abnormal (-3 SD) mild asymmetry of face, leg asymmetry in size and neonates. In the normal neonate, scores on each individual length. Only 10% of the cells in peripheral blood are item of the scale are usually similar. If a neonate has trisomic. The other case with a chromosomal abnormality abnormal findings which affect some of the items on the is a year old girl with developmental delay, small stature Dubowitz scale, individual scores show increased scatter. (-4SD) with dysmorphic features: frontal bossing, epicanthal This should be considered a clue to the presence of folds, coloboma of iris, nystagmus and retrognathia. She dysworphic features or genetic disease. has a "de novo" rearrangement involving the long arm of It is suggested that while the Dubowitz and other scales one X chromosome and partial trisomy for a region of an are useful in the management of the newborn, use of such unknown chromosome. scales should be ccxbined with a clinical understanding of Chromosomal abnormalities reported by others include the origin of each scale and it's potential errors. two X autosome translocations and a mosaic for microdeletion l5q. The variety of chromosomal abnormalities found suggests that this is not a specific deletion or duplication syndrome and appears to support the hypothesis that the disorder is a nonspecific marker for mosaicism. Clinical Genetics A47

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Xeroderma pigmentosa with severe neurological involvement Autistic behaviors in Ruvalcaba-Myhre-Smith Syndrome: a possible association. M.A. Greenstein and S.S. Budden. without significant DNA repair defect. GA Greenhaw. JT St. Francis Hospital and Medical Center, Hartford, CT and Hecht, AA Hebert, IJ Butler. JE Cleaver. WA Horton. Univ of Emanuel Hospital, Portland, OR. Texas Med School, Houston, Univ of Calif, San Francisco. Ruvalcaba-Myhre-Smith syndrome (RMS) is a hamartomatous We evaluated 3 sibs (8y male, 7y female and a female who condition of unknown incidence and probable autosomal dominant died at 10y) in a consanguineous hispanic family who had inheritance. Recent investigations have expanded the clinical photosensitivity, facial freckling, microcephaly, developmental spectrum, which now includes macrocephaly, pigmented macules delay, growth retardation, ataxia and seizures. The male also of the glans penis in males, intestinal polyposis and other had bilateral cryptorchidism. Clinically, the presentation was hamartomas, as well as several ocular findings and hypotonia, consistent with the DeSanctis-Cacchione syndrome (DCS), a at least in childhood. This latter has been correlated with a subgroup within xeroderma pigmentosum. This diagnosis lipid storage myopathy demonstrated on muscle biopsy. was also supported by skin biopsy results and MRI brain Associated intelligence ranges from significant mental scans, the latter showing extensive leukodystrophy with retardation to normal. We report 4 boys with RMS, one of whom diffuse cerebral, cerebellar and brainstem hypotrophy/atrophy. fulfills diagnostic criteria for autism; the other three have behaviors generally associated with autism and often referred Skin fibroblasts from the 2 living sibs were abnormally to as "atypical". UV exposure as sensitive to UV-light with post cell survival On evaluation for educational problems, a 5 year old with measured by uptake of [3H] hypoxanthine 1/2 that of control known macrocephaly, motor weaknesses and a negative fragile X fibroblasts. However, post UV exposure DNA repair rate as study was found to have RMS on clinical grounds. His mother, measured by % unscheduled DNA synthesis (UDS) was 70% of of normal intelligence, is suspected of being affected as well. normal control, demonstrating that the cells have no During the evaluation he displayed hyperlexia, decoding college significant DNA repair defect. This is distinctly unusual for level reading materials with comprenhension only in the low- patients with DCS whose %UDS is usually < 10%. The XP average range for his age. The evaluation also revealed variant group has high rates of %UDS but do not have perseverative behaviors, poor social contact skills and other neurologic complications. findings consistent with a diagnosis of autism and corroborated It has been assumed that the neurologic involvement seen by positive diagnostic scores. Subsequently, 3 boys have been found (ages 5, 8 and 10 in DCS was secondary to inability to repair DNA, causing cell years) who have RMS based on clinical and muscle biopsy death and either CNS atrophy or arrested development. Our 2 findings, and who have atypical development with features of living patients had only moderate skin involvement without autism, including perseverative behaviors and disordered signs of cutaneous malignancy but severe neurologic compli- communication not representative of their cognitive levels. cations. This may indicate that factors influencing DNA While they are not classically autistic, their behaviors do injury, DNA repair or post repair DNA utilization differ place them within the associated category of "atypical" or between fibroblasts and neurons in these patients and from "not otherwise specified" pervasive developmental disorders. photosensitivity disorders already known. These are the only These findings suggest that there may be an association hispanic patients with DCS of which we are aware and may, between RMS and autistic-like behaviors. Since many autistic therefore, represent a genetically unique subgroup of XP. males with macrocephaly will be evaluated for the fragile X syndrome, we suggest that such children also be evaluated for RMS as well. Additionally, individuals with RMS should be assessed for evidence of behavioral/communicative disorders.

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Complicated Hereditary Spastic Paraparesis with Cerebral White Hydrocephalus and VATER Association. Is the Matter Lesions: Lack of Linkage to Xq28. David H. Gutmann. relationship real and what does it mean? B. D John Kamholz. and Kenneth H. Flschbeck. Hospital of The Univ. Hall1. University of Kentucky, Lexington, of Pennsylvania, Philadelphia, Pennsylvania. Kentucky, USA. We extend our characterization of a nonconsangulnous family Briard et al. (Ann Genet 27:220, 84) and Evans with five males In a single generation affected with hereditary et al. (Proc Greenwood Genet Ctr 7:212, 88) have spastic paraparesis (HSP). The disease Is characterized by raised the possibility that the VATER Association speech difficulties, lower extremity spasticity and hyper-reflexia, can have hydrocephalus. If this is true, the and learning disabilities with cerebellar ataxia and tremor. Its usually good neurological prognosis may be poor. onset Is In the first decade of life and progresses for three to six years before stabilizing. Magnetic resonance Imaging of the I reviewed 63 records at University Hospital brain demonstrated bilateral periventricular white matter lesions (1962-1989) under lCD 750.3 congenital tracheo- that fall to enhance with Gadolinium. NMR-spectroscopy of the esophageal fistula/esophageal atresia. Eleven brain revealed patterns consistent with demyellnating disorders. (17.4%) had hydrocephalus, 6 (9.5%) had the VATER Plasma very long chain fatty acids, aryl A-sulfatase, ceramide Association, 4 (6.35%) had Trisomy 18, and 1 beta-galactosidase and urinary N-aspartic glutamate were normal. (1.6%) had the CHARGE Association. The remaining Visual evoked responses were markedly prolonged but nerve 41 (65%) had only T-E fistula/esophageal atresia conduction velocity studies were normal. Three of the four with or without heart or other singular defects affected males demonstrated acquired red-green not associated with the above entities. dyschromatopla secondary to profound visual pathway white matter destruction. Restriction fragment length polymorphism All 11 patients with hydrocephalus had analysis failed to demonstrate linkage to St14, as reported by additional abnormalities seen in the VATER KenwrIck. et al. In a pedigree with complicated X-linked HSP Association. They included radial/thumb defects (Human Genetics 7.: 264-266, 1986). The lack of linkage to (6/11, 54.5%), vertebral anomalies (5/11, 45.4%), St14 suggests that the disease gene In this complicated HSP imperforate anus (4/11, 36.4%), renal defects syndrome Is not closely linked to Xq28 and may represent a (3/11, 27%) and heart defects (2/11, 18.2%). In unique neurogenetic disorder. 9 patients, where a judgement could be made, all were mentally retarded. Also of interest was that 5 of 11 (45.4%) had ear anomalies and 3 of 11 (27%) had eye anomalies. ren of 11 (9o%) were females and all patients were born after 1980 despite the study period being from 1962 to 1989. The VATER Association may have expanded to a point of uselessness if we continue to add new anomalies since it dramatically alters the prognosis. Also, there appears to be a higher frequency of eye and ear anomalies when hydrocephalus is present. Recurrence risk may be higher (Sujansky and Leoanard, Amer J Hum Genet 6:119-A, 83) also. A48 Clinical Genetics (0180) 13.1 (0181) 1.101

Areas of human chromosomes homologous to areas of mouse Perlman syndrome: report of a case and results of imprinting - implications for interpreting pedigrees and molecular studies. examining "at risk" disorders. J.G. Hall and J.H. Edwards. B.C.J. Hamell. M. Mannens2. J.P.M. Bokkerink2. Genetics Laboratory, Department of Biochemistry, Univ. of Institute of Human Genetics1, Institute of Oxford, U.K. and Department of Medical Genetics, Univ. of Pediatrics2, Univ. Hospital Nijmegen; Institute of British Columbia, Vancouver, Canada. Human Genetics3, Univ. of Amsterdam, The Nether- Differential functioning of maternally and paternally lands. inherited genetic information is known as genomic Perlman syndrome is often considered to be a imprinting. Over the last few years compelling evidence has variant of the Beckwith-Wiedemann Syndrome (BWS). accumulated in the mouse that genomic imprinting occurs. Sofar 9 patients from 4 families have been Utilizing the man-mouse homologous map it is possible to described (Greenberg et al, Am J Med Genet 1988; predict "at risk" areas of human chromosomes and suggest 29: 773-776). We have observed a boy, who showed diseases that should be examined for potential imprinting many of the features that alre consistent with the effects. Characteristic pedigrees "skip" generations, have diagnosis of Perlman syndrome: macrosomia, dys- equal sex ratios, and could be interpreted as having a high morphic facial features, severe hypotonia, cryptor- degree of non-penetrance or as "multifactorial" inheritance. chidism, hepatomegaly, nephromegaly and bilateral The application of this concept requires re-examination of Wilms tumor with nodular renal blastomas and renal inheritance patterns for the commoner mendelian diseases. dysplasia at autopsy. Not yet described features Differential expression by parental origin may also explain were volvulus and distal ileal atresia, and some of the phenotypic variation and segregation ratios agenesis of the corpus callosum. observed in chromosomal aberrations. Since BWS and particularly Wilms tumor are frequently characterized by chromosome llp rearrangements, skin fibroblasts and tumortissue were screened for rearrangements involving 5 different gene markers from llp. For FSHB and D11S151 dosimetry revealed the presence of 2 copies of the same allele. For CAT, HRAS1 and INS the presence of 2 different alleles could be demonstrated by RFLP studies. In addition, for none of the markers RB(13ql4), IGLV(22q1.1-11.2), D17S30 (17p), Erb-Abeta (3), D5S6 (5q22-31) loss of heterozygosity was observed. At least in this case no evidence could be obtained for chromosomal rearrangements, involving any of the afore-mentioned loci, suggesting that Perlman syndrome is etiologically unrelated to BWS. However other unrelated patients will have to be studied similarly before this can be concluded with certainty.

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Monocephalus Diprosopus: Analysis of developmental mechanisms Prenatal Onset Edema and the "Noonan Phenotype" in the and report of an unusual case. 0. J. Hood, M. K. Sarman and Klinefelter Syndrome: A Previously Unrecognized Association. H. S. Rosenberg. Univ. of Texas Medical School, Houston, TX. H.E. Hoyme and K.E. Byrne-Essif. Univ. of Arizona, Tucson. Rare congenital defects are instructive in mechanisms of The Klinefelter syndrome represents a widely variable development. Incomplete monozygotic twinning with cranial and pattern of malformation, most commonly associated with a 47, facial duplication occurring within a single head (mono- XXY karyotype'. Features most frequently observed in affected cephalus diprosopus) lies at the borderline of defective males include: learning disability, behavior problems, speech development of midline structures and of twinning. The and language dysfunction, tall stature with decreased upper/ frequently associated anencephaly of previously reported cases lower segment ratio, and hypogenitalism and hypogonadism. has limited their contribution to understanding developmental The diagnosis of Klinefelter syndrome is rarely made in the processes. We report a male infant with monocephalus neonatal period or in infancy. We have recently evaluated diprosopus who had complete duplication of the telencephalon three boys with the Klinefelter syndrome, all of whom presen- and partial duplication of the anterior calvaria, four eyes ted with signs of prenatal onset edema. In these children, with fusion of the medial pair and two noses and maxillae with a diagnosis of the Noonan syndrome was initially entertained. a closely approximated but probably cleft mandible. The Patient #1 was noted to have the following unusual features optic nerves and chiasm and the pituitary were duplicated. at the time of birth: a short neck with excessive folds of Associated midline defects were cleft lips with highly arched loose skin posteriorly, low posterior hair line, low set post- and grooved palates, anterior duplication of the tongue with eriorly rotated pinnae, downslanting palpebral fissures, a a single base and defects in the cervical vertebrae. The only single transverse palmar crease, bilateral cryptorchidism, other defect was a diaphragmatic hernia due to agenesis of a unilateral clubbed foot, and a congenital heart defect. the left hemidiaphragm. Chromosomes were normal. The Karyotype revealed a 47,XXY pattern. placenta, cord and membranes were without defects. While the Patient #2 was found to have generalized edema at the time etiology remains unknown, proposed mechanisms for monocephalus of birth. Physical examination revealed: generalized anasarca, diprosopus based on experimental studies suggest that environ- short webbed neck, low set posteriorly rotated pinnae with mental changes during pregastrulation can produce anterior incomplete infolding, downslanting palpebral fissures, widely duplications, perhaps by focal developmental arrest in spaced nipples and deeply set nails. Karyotype revealed a primary germ layers. Once duplication occurs, the abnormal 47,XXY pattern. side-by-side spatial configuration interferes with normal Patient #3 was found to have multiple anomalies at birth: induction. Aplasia may result at points of divergence to the pulmonic valvular stenosis, short neck with loose skin poste- neoaxes from the archeoasis. The complete anatomical study riorly, low posterior hairline, bilateral cryptorchidism, of both neural and somatic defects in this case illustrates clinodactyly of the 5th fingers and bilateral calcaneovalgus. involvement of derivatives of all three primary germ layers, He was found to have a 46,XY/47,XXY chromosome complement. suggesting pregastrulation timing consistent with focal Data from these patients and one similar case from the developmental arrest. The abnormal side-by-side configura- literature imply that the jugular lymphatic obstruction tion likely contributed to the more cephalad anomalies by sequence (leading to a cystic hygroma or fetal hydrops) may interference with induction, but does not explain the be an occasional manifestation of a 47,XXY chromosome comple- diaphragmatic hernia and absence of somatic midline defects. ment. The findings of fetal or neonatal edema or the Noonan phenotype in a male infant should prompt the clinician to consider the Klinefelter syndrome as a diagnostic possibility. Clinical Genetics A49

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Is human parvovirus B19 teratogenic: follow up on 39 VACTERL with Hydrocephalus Reexamined: Report of Survival infected pregnancies. L. Hudgins, K. Wilson-Miller, D. Quinn, with Good Neurologic Outcome AK Iafolla, A McConkie-Rosell, J. Rodis, M. Cartter, S. Rosengren. Univ. of Connecticut Y.T. Chen Department of Pediatrics Duke University Medical Health Center, Farmington, and Connecticut Dept. of Health, Center Durham, North Carolina 27710 Hartford. VACTERL association with hydrocephalus has been rarely Fifth disease (erythema infectiosum) is a common pediatric reported, and is thought to be an autosomal recessive illness caused by human parvovirus B19 (HpB19) which usually uniformly lethal disorder. We have observed 3 patients in a results in a mild flu-like illness in children. In 1984, it twelve month period with features of the VACTERL association was suggested that HpB19 infection during pregnancy caused in which massive hydrocephalus was noted. Parents were fetal death, following anemia and hydrops. Since then, non-consanguinous and family history was negative. Mothers numerous reports worldwide have confirmed this and, in were primiparous, 32-36 years old. Infants were: several of these, the fetal anemia has been successfully term:premature(2:1), white:black(2:1), male:female(2:1). treated with in utero transfusion. Animal parvoviruses are Features of the VACTERL association included: vertebral teratogenic and at least two reports in the literature suggest anomalies (3/3), anal anomalies (3/3), cardiac anomalies that HpB19 may be teratogenic in humans as well. It is (3/3), tracheoesophageal fistula (1/3), renal anomalies important to demonstrate that HpB19 has no teratogenic effect (3/3), limb anomalies (3/3), single umbilical artery (2/3), outside the hematopoetic system before embarking on such a hypospadias (1/3), and cryptorchidism (1/3). All three had treatment program. massive hydrocephalus with stenosis of the cerebral aqueduct. An outbreak of fifth disease in Connecticut during the Chromosome analysis was normal. Two of three patients (white winter of 1987-88 involved approximately 1000 pregnancies female, 24 mos; black male, 12 mos) have survived with good at risk for HpB19 infection, of which 866 were tested neurological outcome following aggressive early neurosurgical serologically. Four hundred fifty-nine (53%) were found to be intervention. The former, the oldest reported survivor, sits immune, 382 (44%) were non-immune, and 25 (3%) showed without support, feeds herself, drinks from a cup, and evidence of recent infection. Another 14 pregnant women who babbles. The latter sits with support, bears weight on his were infected were referred for evaluation outside of the legs, says "dada", and feeds himself. Although motorically original study. All 39 infected pregnancies were followed to delayed, both are interactive, social and continue to achieve term. Two of the 39 resulted in spontaneous abortion, one of developmental milestones. Neither survivor was diagnosed which did not appear to be related to the HpB19 infection and prior to delivery, both were delivered at term by cesarean the other were erythroblastosis noted on placental pathology section. The infant who died was delivered at 33 weeks was presumed to be a response to fetal anemia. One of the gestation by cesarean section for prenatally diagnosed offspring developed aplastic anemia at 4 mos. of age, however, rapidly progressive hydrocephalus and had severe hyaline HpB19 infection could not be documented in this infant. The membrane disease. Appropriate surgical intervention, offspring of the remaining 36 pregnancies are currently being including early ventriculoperitoneal shunting, allowed for evaluated in a blinded case-control study for major and minor the survival of two patients with an unexpectedly good anomalies, as well as for serologic evidence of infection and outcome. Our experience suggests that the extremely poor anemia. No major anomalies have yet been detected, nor has prognosis previously ascribed is not universal. We caution a pattern of minor anomalies been identified. We conclude against labeling VACTERL with hydrocephalus as a uniformly that HpB19 infection in pregnancy poses a small excess risk lethal, developmentally devastating disorder, and believe for fetal loss but that no reproducible teratogenic effects that caution should be exercised in counseling the parents of outside of the hematopoetic system have been identified. these infants.

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Possible homozygosity for the myotonic dystrophy Germ line mutation in Waardenburg syndrome.S.iapur gene. 1 2 2 and S.Karam.Dept. of Pediatrics and Human Deelop- State East E. J. Ives , H. Harley , P. S. Harper , M. -ment, Michigan University, Lansing, Elleker , W. G. Pearce , M. De Braekeleer1. 48824. Memorial University of Newfoundlasnd, St. John's Phenotypically normal parentswhen having more University of Albe41ta, Edmonton , University du than affected child, is explained on the basis of one of the parents carrying a germ line mutation Quebec a Ct4coutime , Canada, University of Wales, Cardiff, UK . for that condition. This phenomena is reported in Myotonic dystrophy (DM) is widely prevalent in tuberous sclerosisachondroplasia, Apert syndrome, the Saguenay, Quebec from whence several families dominantly inherited ectrodactyly and some other moved to northern Alberta around 1930. Among these conditions. a consanguineous mating is known between two Presented here is a family with three children individuals affected by DM. Their four children, (two males and one female) all with white forelock now aged 25-35 years, all have DM but of markedly marked lateral displacement of inner canthus, different severity. None had the typical congenital heterochromia irides,sensorineural hearing impair- syndrome, but one institutionalized son is -ment and one of the three children with white profoundly mentally and physically handicapped. A streaked eyebrows. Parents of these children, both daughter, at home, is also severely affected but youngshow no features of Waardenburg syndrome. the other son and daughter live independently with extended family history is also negative. borderline low intelligence and mild physical The presentaion in this family supports the disability. Their mother, now aged 58, and her phenomena of germ line mutation in one of the sister are also mildly affected but their father parents of these children with Waardenburg syndrome. died suddenly at 59 after at least ten years of known progressive disease. All eight of his sibs who survived to adult life are similarly affected by DM. It is predicted that one or both of the severely affected offspring are DM homozygotes. However, conclusive testing of this prediction by molecular analysis has proved very difficult due to a combination of the need to reconstruct the deceased father's haplotype, family non compliance, some questionable paternity and an apparent crossover. Currently retesting is underway with newly isolated probes which both flank and are nearer to DM than those previously available. Confirmation of homozygosity would indicate that DM meets the expectation of more severe expression compared to the heterzygote. Homozygote individuals could be valuable for studies of the basic defect. A50 Clinical Genetics (0188) (0189)

The De Barsy Syndrome: Report of a case and detailed Linkage Studies of Polycystic Kidney Disease, Type 2. W.J. microscopic and molecular analysis of the skin. P.S. Karnes, A. Shamban, Rby]. Falk. Childrens Hospital of Los Kimberling. S.A. Pieke. P. Gabow. Boys Town National Research Angeles and Harbor-UCLA Medical Center. Hospital, Omaha, NE. University of Colorado Health Sciences Multiple genetic conditions may lead to a progeroid phenotype. In 1968 De Barsy described a new syndrome Center, Denver, CO. characterized by dwarfism, mental deficiency and an aged A large family of Sicilian descent with Autosomal Dominant appearance associated with 'elastic fiber degeneration' . We report detailed histopathologic, electron microscopic and Polycystic Kidney Disease (ADPKD) has been reported previously elastin gene expression studies on skin from a two not to be linked to 3'HVR on year old girl with the De Barsy syndrome. (D16S85) chromosome 16p C.R. was born at 36 weeks gestation following a pregnancy (Kimberling, et al., New Engl J Med 319:913, 1988). This finding in which IUGR was noted. Unusual physical features were suggested strongly that a second locus for ADPKD exists noted including a small, aged appearing face; thin, wrinkled skin with a prominent venous pattern; sparse hair with elsewhere in the genome. Heterogeneity of ADPKD has bilateral posterior hair whorls; large fontanelles with for widely separated sutures; deep set eyes with alternating important implications presymptomatic testing and genetic esotropia; a narrow, small nose and long, smooth philtrum; counseling. A small family may be difficult to categorize because large superiorly simplified helices with deficient lobules; it presents insufficient information to allow a decision about which a small mandible with midline synostozis; a small umbilical hernia; hypoplastic labia majora; an anteriorly displaced type it is. The prospects for subtyping ADPKD will be improved anus; joint hyperextensibility; dislocated hips; an adducted left thumb; bilateral fifth finger clinodactyly and by finding the location of the gene for ADPKD2. This would hyperconvex fingernails. Development is delayed. also allow presymptomatic diagnosis in families unlinked to Histopathology of her skin revealed a normal epidermis, a very thin dermis with adnexal structures present at the chromosome 16 and help in the ultimate isolation and cloning of dermal-epidermal junction. Special stains demonstrated an the second ADPKD gene. This is a report of a linkage study of apparent decrease in the number of elastic fibers. Electron microscopy showed variability in the size of collagen the large Sicilian family with ADPKD2. There were 77 bundles. Additionally, in elastic fibers there was an informative and at-risk persons in the family. All persons in the increase in the microfibrillar component and a thinning of the amorphous component. Fibroblast cultures were study have had recent ultrasonography. The definition of affected established from the patient and an unrelated age and site was at least one cyst in each kidney and at least two cysts in one matched control. The relative steady state le~els of elastin mRNA in affected fibroblasts were half of unaffected kidney. Pairwise linkage analyses of the families were done with controls while steady state beta-actin mRNA levels were not the program LINKAGE. Thirty five DNA and classical markers significantly different from control. Thus decreased elastin production may account for the observed histologic have been tested on these individuals. Close linkage (less than decrease in elastic fibers and the clinical cutaneous 10% recombination) can be excluded for 25 markers. No laxity. The relationship of the molecular findings to the development of the dysmorphism will be discussed. evidence of linkage with any of the informative markers has thus far been obtained. Approximately 35% of the genome has been thus far excluded. New markers are being typed in the effort to localize the ADPKD2 gene. (Supported by USPHS Grant DK34039)

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Ovarian Tumors in a 10 year-old girl with Hand-Foot-Genital Tourette Syndrome (TS) and Attention Deficit Disorder (ADD) Syndrome. K.A. Klein. J. Piserchio. R. Bump. K Knapp. D. Johnson. in 337 First-degree Relatives of TS Probands. E. Knell and D1 P. Kaplowitz. D. Narla. J. Nogi. J.N. Bodurtha. Medical College of Comings City of Hope National Medical Center, Duarte CA, 91010. Virginia, Richmond. We analyzed self-reported questionnaire responses from 337 first-degree A 10 1/2 year old female with short relatives of 118 male and 23 female TS probands. Of these, 92 male presented stature, leg length probands (78%) and 12 female probands (52%) had ADD. discrepancy, accelerated puberty with menarche and Tanner III To determine if the Ultrasound and association of ADD with TS was due to ascertainment breast and pubic hair development. subsequent bias or was an integral part of the expression of this genetic disorder, we surgery revealed bilateral ovarian tumors, a normal right kidney and examined the frequency of ADD among first-degree relatives of 141 TS pelvic left kidney. Pathologic examination of the excised ovaries probands. Of the 72 relatives with tics, 40.3% had ADD. This is showed a sertoli cell neoplasm of intermediate differentiation on the significantly greater than control frequencies which range from 5 to 10%. Of left and a mixed germ cell sex cord stromal tumor on the right. the 265 relatives without tics, 17.7% had ADD. This is also higher than for These types of neoplasia comprise less than 1% of female tumors controls and suggests some relatives are expressing ADD without tics. under 17 years of age. However, it is significantly lower than for those relatives with tics. These Family history was remarkable for a 4'9" G2P2A1 Armenian data were further analyzed by comparing the frequency of ADD in mother with asymmetric toe size and placement. The father was individuals with TS, chronic motor tics, chronic vocal tics or no tics, compared to the expected based on independent assortment of ADD and tics. unrelated. The patient herself was 145 cm tall and 30 kg in weight These distributions also indicated the ADD segregated with the tics. The Chi with a triangular face. She has somewhat small thumbs and great square was 22.4 with p < 0.0005. toes, short metacarpals, clinodactyly of the fifth fingers and irregular Of the 104 TS probands with ADD, 46.3% of the relatives with tics also toe size and placement. X-rays of the hands revealed carpal bone had ADD. This value was the same whether the proband was male or female. fusion and short 4th and 5th metacarpals. The feet showed short Of the 37 TS probands who did not have ADD, 22.2% of the relatives with phalanges on the right 3rd and left 2nd and 3rd toes, hallux valgus, tics also had ADD. Thus, while both figures are higher than for controls, the short 3rd metatarsal on the right and 2nd and 3rd metatarsals on the frequency of ADD in the first-degree relatives with tics was approximately left. The patient also has a double uterus with a single cervix and doubled when the proband had both TS and ADD. These figures are similar no history of ambiguous genitalia. She is a bright and cooperative to those reported in a previous independent study which showed 37% ADD child with slight loss and no vision There were no in relatives with tics when the proband had TS and ADD versus 21% ADD in hearing problems. relatives with tics when the TS proband did not ADD cardiac abnormalities noted. Karyotypic analysis was normal have (1). 46,XX. These findings indicate that when TS patients are ascertained as being This case exhibits features of a dominantly inherited Hand-Foot- relatives of TS probands, thus avoiding ascertainment bias, ADD is part of Genital Syndrome. The presence of rare germ cell neoplasms, the expression of the Gts gene, and that TS and ADD tend to segregate however, is remarkable and possibly suggests a developmental together. disturbance influencing the symmetry and regulation of growth. (1) Comings, D.E. and Comings, B.G. Amer. J. Hum. Genet. 41:701-741, 1987. Clinical Genetics A51 (0192) 1.109 (0193)

"BILATERAL ULNA HYPOPLASIA AND MENTAL RETARDATION A NEW Segregation of a 1;3 translocation through three generations AUTOSOMAL RECESSIVE SYNDROME" resulting in different recombinant chromosomes in multiple Kohn, G(1), El Shawwa, R.(2), Tepper, R.(3), Scheinfeld, A,(3), family members. C. Kozma, J. Meck, and M. Motz. Georgetown Malinger, M.(1), Ornoy, A.(4), Lachman, R.(5), and Rimoin,D.(6) University Medical Center, Washington, D.C. (l)The Edith Wolfson Medical Center, Holon, Israel, (2)Nassr A three generation family with a subtle chromosome Children's Hospital, Gaza, Israel, (3)Beilinson Medical Center, translocation was identified following the birth of a term Petah Tikva, Israel, (4)Hebrew University School of Medicine, female infant weighing 2440 grams. An amniocentesis performed Jerusalem, Israel, (5)Harbor-UCLA Medical Center, Torrance, at 20 weeks gestation for evaluation of fetal cardiac pathology CA, U.S.A., and (6)Cedar-Sinai Medical Center, Los Angeles, disclosed normal chromosomes. Phenotypic abnormalities at CA, U.S.A. birth revealed wide nasal bridge with a prominent nose, tri- angular facies, smooth philtrum, irregularity of dental arch A 2 2 month old male infant was referred to the Genetics and palate, excess skin on neck, endocardial cushion defect, Clinic at Nassr Children's Hospital because of unusual ap- ambiguous genitalia and minor anomalies of hands and feet. The pearance and severe hypotonia. He was born to healthy, father has a family history of three siblings with congenital consanguineous parents who were first and second cousins. A heart defects, two of whom died in infancy. The third sibling, previous child, which presented with identical clinical find- age 27, is institutionalized for multiple congenital anomalies ings, died at 6 months. and profound mental retardation. A fourth sibling is normal. Physical examination revealed a markedly hypotonic infant Two weeks following the birth of the proband, this normal with severe head lag. He had a round facies with mild sibling had a female infant who was born with multiple congen- maxillary hypoplasia and normal eyes, ears, nose and mouth. ital anomalies including single umbilical artery, tetralogy of The neck was short. Chest, abdomen and genitalia were normal. Fallot, absent corpus callosum, dysmorphic features and growth The most marked anomalies were confined to the extremities retardation. The family history is also positive for two cous- and were bilateral and symmetrical. The upper extremities ins of the father of the proband who died of multiple congen- limitation movement at revealed of the elbows and short fore- ital anomalies in childhood. With the aid of high resolution arms. There was ulnar deviation of both hands, ulnar devia- chromosome techniques, a very small unbalanced translocation tion of fingers III-V and absence of all fingernails. The between the distal portions of the long arm of chromosome I and lower extremities revealed limitation of movement at the knees, the short arm of chromosome 3 resulting in partial trisomy lq/ severe varus deformity and absence of all toenails. partial monosomy 3p was detected in the proband(46,XX,-3,+der patient was last seen at 2 years of age and was The (3)t(1;3)(q43;p25). The cousin and affected uncle had the severely impaired neurologically. Nails were present on toes converse rearrangement consistent with lq-/3p+. The father as III-V. He died at 3 years of age. well as his normal brother, mother and maternal aunt were Prenatal diagnosis was made by ultrasound in a subsequent carriers for a balanced translocation between chromosomes I pregnancy and an affected fetus confirmed. and 3. The proband died at 3 weeks of age of multiple systemic family documents a previously undiagnosed autosomal This involvement. On the basis of the phenotypic and cytogenetic Prenatal diagnosis is feasible. recessive syndrome. findings observed in these three family members and from review of available medical records of other deceased subjects, we conclude that recombinant rearrangement involving the termini of chromosomes 1 and 3 in this family (lq+/3p-, lq-/3p+) are characterized by definable dysmorphic features, congenital heart defects, poor prognosis and high recurrence risk.

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A new skeletal dysplasia resulting in mild short Ectodermal dysplasia with arthrogryposis and cleft lip and stature, delayed epiphyseal ossification, cone- palate: A new combination. R. L. Ladda, P. N. Mowrey, M. shaped epiphyses and mild abnormalities of the J. Mascari and J. C. Ramer. PA State Univ., Col. of Med., hands: a possible autosonal dominant. Hershey. H. Krassikoff1. L.O. Langer, Jr.2. A. Gledionm and A newborn presented with distal contractures of the hands Wf H Finiulx. University of Alabama at Birmingham5, and feet with decreased muscle mass and subcutaneous tissue. Minneapolis, Minnisota2 and Children's Hospital, Other features included unilateral cleft lip and palate, Zurich*' brachycephaly, dry scaly scalp with fine brittle hair with little pigmentation, few eyelashes and no eyebrows. Eyes An 8 year-old male was referred for evaluation were deeply set with narrow palpebral fissures (blepharo- after post-traumatic wrist X-rays detected no phemosis) and bilateral ptosis; fundal exams were normal. carpal bone ossification. On physical Mandible, zygomatic and maxillary bones were hypoplastic. examination, he was 116.9 cms. tall which was less Nails appeared normal. Over the course of the first year than 55. percentile for age and the average height of life, significant psychomotor and growth delay became of a 6 year-old. He had fifth digit clinodactyly, apparent. At age 24 months, the child functioned at the distal phalangeal tapering and a "swan neck" 3-4 month normal level. The child fed poorly and was position abnormality on the extension of his recognized to have severe gastroesophageal reflux requiring fingers. Total hand size was 10*l to 25"* Nissan fundoplication. Pneumogram documented obstructive percentile for chronological age with a and central apnea. Suck was poor and nasogastric feedings proportionate middle finger length. His father was were required. Bilateral hip dislocation required mechanical 5'11l, his mother was 5'2* and two half siblings bracing. Brain scan was normal. Sweating was decreased were reportedly not short. Although there was a particularly on the head. Chromosomal analysis at the 500 family history of relatively short stature, there band level was normal. was no known history of similar radiographic This combination of ectodermal abnormalities and arthro- findings, hand appearance or arthritis. The gryposis appears to be a rare association. Four cases with radiographic findings included a delayed epiphyseal related ectodermal abnormalities, two with bilateral cleft and carpal bone ossification resulting in a delayed palate and two others with arthrogryposis have been bone age, marked shortening of the first referred to in the text by Newton Freire-Maia and Marta metacarpals, bilateral fifth digit clinodactyly, Pinheiro. Psychomotor and growth development were normal abnormally short and broad middle phalanges and in all four cases in contrast to our case. This patient cone-shaped epiphyses. A similarly affected mother may represent a distinct syndrome or may provide an and two daughters from an Swiss family had indication of the extreme expression of a rare form of previously been evaluated by one of the authors ectodermal dysplasia with arthrogryposis, facial clefts (A.G.). Because of the familial occurrence, it is and other anomalies. Parents in all cases have been normal likely that this previously undescribed bone suggesting an autosomal recessive trait. dysplasia Is inherited as a dominant, perhaps autosomal, disorder. A52 Clinical Genetics (0196) (0197) 1.111 Placental pathology: a clue to the pathogenesis of amyoplasia Alzheimer Disease and Down Syndrome Lymphoblasts Show associated with intestinal atresia. S. Langlois, R.D. Wilson, Slower Microtubule Repolymerization Rates After Colcemid and V.J. Baldwin. Univ. of British Columbia, B.C., Canada. Exposure K.P. Lele, M.S. Krawczun, E.C. Jenkins. H.M. Wlsnlewsk. Institute for Basic Research, NYS OMRDD, Staten Island. Amyoplasia is a common form of congenital contractures Numerous intraneuronal neurofibrillary tangles and senile associated with an increased frequency of bowel atresia, (Neuritic) plaques are the two chartacteristic lesions In both Alzheimer gastroschisis, defects of the musculature of the trunk wall disease (AD) and adult Down Syndrome (DS). Evidence indicates that and discordantly affected monozygotic twins. Two hypotheses microtubule associated proteins (Tau) are involved in the formation of have been raised in the literature regarding the excess of tangles. Further evidence shows microtubule assembly is also monozygotic twins amongst amyoplasia patients: 1) that the impaired in AD. We are Investigating whether abnormalities seen In twinning process predisposes to amyoplasia; 2) that the normal microtubules of neuronal cells from AD and DS can also be seen in discordant twin maintains the pregnancy of an amyoplasia non-neuronal cells from these patients. We studied microtubule patient . repolymerization rates after colcemid exposure in EBV-transformed We report a case of a female infant with amyoplasia and AD and DS lymphoblasts and controls. Studies show most of the intestinal atresia. She presented at birth with a high nasal tubulin components of cytoplasmic microtubules are reutilized in bridge, narrow high arched palate and anomalies of her upper assembly of mitotic spindle at mitosis. The distinctive arrangement of limbs. These included decreased muscle mass, dimples over her microtubules and size of this structure make spindle an obvious choice round and sloping shoulders, elbows held in extension, hands for microtubule study. Two responses were tested: sensitivity to flexed with thumbs held against the radii and camptodactyly colcemid concentration, and microtubule repolymerization rate in cells of her second and fifth fingers. A few hours after birth she after colcemid-induced mitotic block. When blocked cells were allowed developed abdominal distention and at laparatomy was found to to recover, microtubule repolymerization in cells from the three cell have complete intestinal atresia from the mid jejunum to the types were not identical. Analysis of mitotic cells showed earlier transverse colon. Pathological examination of the placenta appearance of intact spindle microtubules, indicating repolyerization revealed a diamniotic, monochorionic placenta with a six weeks of complete microtubules, in controls then in either AD of DS cells. developmental age embryo. Both differed significantly from controls. Log linear analysis showed We postulate that the death of one twin resulted in a each of the samples types had different rates of microtubule vascular disruptive process affecting the other twin due to repolymerization over time (P <.0001). Other researchers found vascular interconnections usually present in monochorionic similar results using AD skin fibroblasts. There was no significant placentas. supports a This vascular etiology in some cases of difference between AD and DS cells. Also, we found no difference in amyoplasia. In addition, the timing of the death of one twin sensitivity to varying colcemid concentrations. It is unclear how corresponds to the time the midgut herniates into the microtubules from AD and DS differ from controls, or whether a umbilical cord, time of possible increased susceptibility to a relationship exists between the altered microtubule repolymerization vascular insult resulting in intestinal atresia. kinetics observed here and the presence of neurofibrillary tangles in The pathological examination of the placenta was an AD and DS patients. At present confirmation of AD is attained only at important clue to understanding the pathogenesis of this autopsy. An early diagnostic test for AD is urgently needed. patient's congenital anomalies and illustrates the importance Investigations are underway to determine if the delay in mitotic spindle of studying the placenta of apparent singleton pregnancies microtubule repolymerization is found in all AD patients, and whether with unexplained birth defects. the rate variation can be observed in persons at risk but not yet expressing the disease. Persons with other related disorders which do not express plaques and tangles must also be investigated.

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DEAFILES: A database system for hereditary deafness families. Optic gliomata in von Recklinghausen neurofibromatosis (NF-1). M. LLempke and P.S. Ing. Boys Town National Research Hospital, Richard Alan Lewis. Sophia M. Chung. and Vincent M. Riccardi. Omaha, Nebraska. Baylor College of Medicine, Houston, Texas. A database system for tracking information about families with Since the initial description of optic nerve tumor with "ele- hereditary deafness has been developed for the National Research phantiasis" in 1873, the association of optic pathway gliomata (OPG) Register for Hereditary Hearing Loss ("Register"). with von Recklinghausen NF-1 has become well established. The incidence of OPG in NF has ranged historically from 0.9% to 20%, The data are managed on an IBM PC-compatible microcomputer varying with the minimal definitional criteria of the disease, the using PARADOX (Borland International/ Ansa Software). Although the nature of the retrospective surveys, the sources of the population software currently runs on a single PC, it is compatible with a multi-user, under study, and the specialty interests of the investigators. PC-based, local area network. In 1981, LewiseLaI. reported an incidence of 15% of OPG in The three major databases are linked by Family number and NF-1, determined by CT scan, in a prospective survey of 217 subjects Individual number: Master Mailing List (MML), FAMILY, and DEAF. in an unbiased (for optic tumors) population in a neurofibromatosis referral center. Only one-third of the detected tumors were clinically Linked tables store data very efficiently since relatively few fields are symptomatic, causing loss of vision, optic atrophy, changes in visual blank and tables without data are not stored. field, or other objective signs. MML contains names and addresses for corresponding to familes and Subjects with NF-1, defined by the criteria of the recent NIH and other individuals of interest to the Register. Consensus Conference, were studied prospectively by the Neurofibro- Family history data are found in FAMILY. This includes total matosis Program at Baylor College of Medicine from March 1978 numbers of deaf and hearing individuals, all possible modes of through December 1989. 817 subjects met the minimal diagnostic inheritance, and numbers of different types of nuclear families. These criteria for NF-1. Of those, 357 completed all portions of the protocol for evaluation including an ophthalmologic examination and are defined by the hearing status of the children of deaf parents or the neuroimaging. 176 subjects (49%) were male; 181 subjects (51%) sex of the deaf children of two hearing parents or one deaf parent. were female. OPG were detected in 55 (15.4%), equally distributed Audiologic and physical findings of each deaf or hearing-impaired in- by gender. In 23 subjects (42%), one or both optic nerves only were dividual in the pedigree are in DEAF. These include names, sex, demo- involved, the left optic nerve more than twice as often as the right. graphic information (DOB, year of death, residence), diagnosis, codes Among the 32 subjects (58%) with chiasmal tumors, there was nearly for physical findings, and codes describing the deafness in terms of age equal distribution of tumors confined to the chiasm, those involving of onset, progression, severity, laterality, audiologic slope, and type. one, or both, optic nerves. Nearly one-half of radiologically detected tumors were asymptomatic With an understanding of the items coded by the Register, research- and clinically unsuspected. The frequencies of OPG, whether chiasmal or non-chaismal, ers in hereditary deafness should be able to better utilize Register data were equal for inherited and isolated NF-1. Among subjects with to find families for their specific research projects. inherited NF-1, the frequency of OPG among affected probands was equal to that among non-proband affecteds. Among hereditary cases, Supported in part by the Deafness Research Foundation, NIH there was no evidence for an influence of parental gender on the NS19624, and Father Flanagan's Boys' Home. occurrence of OPG. Clinical Genetics A53

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Fetal disruptions: Assessment of frequency, heterogeneity and Observations on Familial Hyperlipoproteinemias embryologic mechanisms in a population referred to a (FHLP) in Jahra area. community-based stillbirth assessment program. H.J.Luebke. DA ManandhAr SA Rafes MT Para&. M Palkovic. De- C.A.Reiser. S. Chandra and R.M.Pauli. Univ. of Wisconsin-Madison. partment of Pediatrics, Department of Clinical The Wisconsin Stillbirth Service Project (WiSSP) is a Laboratories, Al Jahra Hospital and Genetic Center. community based program for the investigation of the cause of fetal P.O.Box 40146, Al Jahra, 01752, Al Jahra, Kuwait. death. From its inception in 1983 through July, 1988, 629 referrals were made to WiSSP. All referrals were assessed for the In Jahra area with 500,000 Arab inhabitants, 14 have been presence of disruptional characteristics and 23 were found to have patients with different FHLP detected recently by a multi speciality team in 3 unrelated major or primary disruptive effects. Most of these were either early consanguineous Bedouin families. FHLP type I was amnion disruption/limb body wall disruption (which are treated as a detected in 3 sibs (aged 1,6 and 8 years) with single group since analysis suggests a continuum of clinical recurrent abdominal pain, vomiting and characteri- characteristics) and twin-twin disruptions. Disruptions, therefore, stic lipid profile. All had elevated serum trigly- account for 3.6% of all referrals (including liveborn and cerides with predominantly apo B-48 and reduced miscarriage referrals) to WiSSP. When only stillborns are post heparin lipolytic activity. The parents are considered (n=502), 12, or approximately 2.4%, appear to have carriers with milder elevation of serum trigly- died because of disruptions. This makes disruptions one of the most cerides. FHLP type IIa was detected in 2 families. frequent, identifiable classes of cause of late intrauterine death. We Family A had 4 sibs (3M,1F) with multiple xantho- estimate that 0.6%-1.4% of all stillborns die because of early mas, high total and LDL cholesterol characteristic amnion disruption/limb body wall disruption which, when taken with of familial hypercholesterolemia (FH) homozygotes. previous estimates of the frequency of such problems in early The index patient, 7 years old and a younger miscarriages and liveborns, suggests that these disruptions result in sister had ischaemic heart'disease with ECG changes. a 95% prenatal mortality rate. Both died suddenly. Other 2 sibs are well except are We will present a unified model of likely pathogenetic for xanthomas. Both parents heterozygotes to FH type IIa gene. In family B, both parents mechanisms which may help explain the continuum of multi-system and one child are heterozygotes and one child is involvement seen in those with early amnion disruption/limb body homozygous dominant with classical phenotype and wall disruption. In addition, three patients with atypical disruptions lipid profile. It seems that both neonatal scree- will be presented who exemplify the difficulty and importance of ning and genetic registration may be beneficial differentiating disruptional and malformational processes. in defined populationswith high gene frequency and inbreeding coefficient.

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The GRANDDAD syndrome: A disorder combining growth delay, Genetic Studies ofAutosomal Dominant Progressive Hearing Loss. "aged facies," normal development, and deficiency of M.K McBrown. W.J. Kimberling. and C.M. Asleson. Boys Town subcutaneous fat. R.W. Marion, R.B. Goldberg, R.S. Young, R. Jorgenson, R.J. Shprintzen, and R.J.Shroer. National Research Hospital, Omaha, NE. Montefiore Med Ctr/Albert Einstein Col of Med, Bronx, NY, Progressive hearing loss accounts for approximately 5 percent of Univ of Texas Health Science Ctr, San Antonio, TX, and genetic hearing loss. The onset of hearing loss occurs between the Greenwood Genetic Center, Greenwood, SC. the first and third decades of life. Our laboratory is conducting a A prematurely aged facial appearance is part of a of the which includes the group of disorders including the Cockayne, Progeria, and longitudinal study disorder, mapping Werner syndromes, in which short stature, cataracts, and responsible gene(s) through the use of restriction fragment length loss of subcutaneous fat also occur. We have evaluated polymorphisms (RFLPs) and linkage analysis. Pure tone seven patients who have had many of the above features audiograms and blood samples were obtained from each but who appear to have a distinct syndrome. Five of these individual, and each family had three to four generations available seven were female; ages at initial evaluation ranged from five weeks to 36 years. All had the following for testing. Red blood cells and serum were used for blood findings: intrauterine growth retardation (average birth group typing and classical electrophoretic markers, and weight of 1840g and birth length of 44cm) with postnatal lymphocytes were extracted for transformation and DNA. To growth delay (all below 3rd centile for height and 175 individual DNA have been collected from seven weight); a strikingly similar "aged" facial appearance, date, samples including triangular facies, prominent forehead, thin or families. Preliminary genetic analysis indicates that the hearing abnormal scalp hair, deep set eyes, midfacial hypoplasia, loss follows a dominant pattern of inheritance in these families, prominent nasal septum with hypoplasia of the alae nasae, and that the specific audiologic pattern and rate of loss is prominent ears, and thin lips; normal development; and decreased subcutaneous fat. Additional features included consistent within each family. A set of 11 markers on hypermetropia (in 4/7), congenital heart disease (3/7), chromosome 1 is being tested for linkage with the disorder. strabismus (2/7), microcephaly (2/7), sensorineural These markers are FY, RH, PGM1, pHRnES1.9 (REN), JA110 hearing loss (2/7), syndactyly of toes II and III (2/7). (PND), L1.22 (D1S2), D1S62 (pTH154), D1S65 (pEKH7.4), All patients had normal karyotypes and endocrinologic evaluations. Autosomal dominant inheritance is suggested pAT3c, and FUCA1 (AF3). Pairwise linkage analysis has failed (but not proven) by the fact that three patients come to reveal any linkages with these markers. Other DNA markers from the same family (two daughters and their father). onthis andother chromosomesare inthe process of being typed. This disorder shares some similarities with the (Supported by NSPHS Grant NS19624). Russell-Silver (a diagnosis entertained in every case) and SHORT syndromes. The facial features of our patients, however, appear to be distinctive. We propose the acronym GRANDDAD syndrome (for Growth Retardation, Aged facies, Normal Development, Decreased subcutaneous fat, Autosomal Dominant inheritance) for this disorder. A54 Clinical Genetics

(0204) 4.9 (0205) 1.114

Incidence of Stickler Syndrome Among Isolated Cleft Palate Can heterozygotes for homocystinuria (homocyst(e)inemia), at Patients. D.M. McDonald. E. Cordonick. D. LaRossa. P. Onyx . presumed higher risk for occlusive vascular disease, be G. Ouinn. P. Borns. D.E. Stambolian. S.D. Kronwith. and E.H. anticipated reliably by phenotype? J.J. McGill, G. Mettler, Zackai. Divisions of Human Genetics and Molecular Biology, D.S. Rosenblatt and C.R. Scriver. Divisions of Medical Plastic and Reconstructive Surgery, Ophthalmology, and Genetics, Montreal Children's and Royal Victoria Hospitals, Radiology. The Children' s Hospital of Philadelphia and The Depts. of Medicine and Pediatrics, MRC Genetics Group, and University of Pennsylvania School of Medicine, Philadelphia. Centre for Human Genetics, McGill University. Cleft palate may be seen as an isolated finding or as Excess homocyst(e)ine is implicated in the pathogenesis of part of a multiple anomaly syndrome. Stickler syndrome (SS) occlusive vascular disease. If heterozygotes for inborn is an autosomal dominant disorder first described in 1965 errors of homocysteine metabolism affecting its trans- by Stickler et al. It is characterized by: cleft palate, sulfuration or remethylation are at increased risk of disease, midfacial hypoplasia, micrognathia, myopia, retinal it follows that reliable detection of heterozygotes by a detachment, cataracts, glaucoma, enlarged joints, screening test or otherwise would be important for counselling scoliosis, radiographic abnormalities, hearing loss, and purposes. We used cystathionine B-synthase deficiency as a mitral valve prolapse. It is important to distinguish model to evaluate feasibility of heterozygote detection and patients with isolated clefts from those with SS in order reviewed: i) published blood metabolite values in a) fasted to l)ensure early detection of myopia and monitor for signs subjects and b) after methionine loads, and ii) measures of of retinal detachment and 2)provide definitive recurrence enzyme activity. We used articles (n=31) reporting homozy- counseling for families (50% v. 2.3%). Over a 3 year gotes, obligate heterozygotes and controls together. We period we examined 52 patients with isolated cleft palate found: i) Heterozygotes cuinot be detected unambigously by looking carefully for the abnormalities associated with SS. any single measure. ii) Prevailing evidence for an effect of This included an ophthalmologic exam in all patients and negative allelic complementation on enzyme activity in hetero- radiographs where applicable. Initially, 10 patients zygotes [mean value, 34% (vs 50%) normal] does not assist dis- suspected of having SS by facies and/or family history were crimination. The absence of an unambiguous metabolic pheno- examined and 4 were found to be affected. Based on the type in heterozygotes reflects the low values, on average, of significant visual complications seen in these families the sensitivity coefficients (Kacser and Burns terminology) (retinal detachment and cataracts) we undertook a for catalysts in this particularly complex multicomponent net- prospective study to uncover the hidden cases of SS in the work dedicated to homocyst(e)ine homeostasis. Allelic hetero- cleft clinic. Thirty-eight of 90 patients contacted by geneity is likely to perturb classification further. In phone or mail agreed to participate. Of the 38 examined, 4 summary, no single measure of phenotype can classify the (10.5%) were found to have SS. We subsequently selected 4 heterozygote reliably at present and measures of blood homo- additional patients and found all 4 to be affected. Thus, cyst(e)ine concentration, regardless of sophistication, do not in a blind study 4/38 (10.5%) were affected, whereas in have satisfactory sensitivity for the biological reason given those screened by facial appearance and/or family history here. 8/14 (57%) were affected. Details of the ophthalmologic and radiographic findings will be discussed, as well as our recommendation that all patients with isolated cleft palate undergo ophthalmologic exams in order to provide appropriate clinical care and genetic counseling for SS.

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Anencephalic Infants as Organ Donors: Two Unaddressed Issues. Moyamoya disease: an autosomal recessive condition? W.S. D.N. Medearis, Jr. and L.B. llolmes. Massachusetts General Meschino and H.E. Hughes, North York General Hospital and Hospital and Brigham and Women's Hospital, Boston, MA. Hospital for Sick Children, Toronto, Ontario, Canada and Uni- It has been suggested (Harrison MR: Lancet 2: 1383. 1986) versity Hospital of Wales, Cardiff, Wales. that a newborn with anencephaly is not likely to survive and Moyamoya disease refers to an arterial occlusive phenomenon could be a donor of organs, including heart and kidney, for which affects the distal internal carotid arteries, and which transplantation. We find two important issues are missing usually progresses to involve the anterior and middle cerebral from the reviews of the legal and ethical issues (Pediatrics arteries. The term moyamoya is a Japanese expression for "some- 1988; 82: 257 and Transplant Proc. Suppl.5: 1988). First, the thing hazy like a puff of smoke drifting in the air". It repre- number of liveborn term infants with anencephaly has decreased sents the unusual angiographic pattern of proliferation of ab- dramatically in recent years. Between 1972 and 1988 at normal, net-like, collateral vessels at the base of the brain Brigham and Women's Hospital 112 infants with anencephaly were typically seen in the disease. Affected children usually pre- identified among 87,445 births. The prevalence rate of sent during the first decade with recurrent episodes of cere- anencephaly was 0.5/1,000 among births to women who had bral ischemia manifesting as hemiplegia. Adults more commonly planned to deliver at BWH; in addition, many were tranferred develop intracerebral, intraventricular or subarachnoid after the diagnosis had been established elsewhere. The birth hemorrhage. status of affected infants changed from 47% liveborn (LB). 53% The etiology and pathogenesis of moyamoya disease are unknown. stillborn (SB), 0% therapeutic abortion in 1972-1975 to 3% LB, In most instances, the angiopathic finding of occluded cerebral 7% SB and 90% terapeutic abortion in 1986-1987. This change arteries is isolated and is presumed to be congenital. In other reflects the increase in the prenatal detection, primarily by cases, the association of moyamoya disease with one of many prenatal ultrasonography (U/S). and the decision by almost all conditions, either genetic or acquired, underscores the hetero- parents to terminate the pregnancy before 24 weeks. 9% of the geneous nature of the disorder. pregnancies with affected infants were terminated in the A review of the Japanese literature suggests a familial inci- pre-U/S era and 68% in U/S era. Second, we and others have dence of between 2 and 12%. We describe the occurence of moya- found high frequency of associated major malformations (6/17; moya disease in monozygotic twin boys and in one of their male 35% of LB & SB infants born 1972-1975). often involving heart sibs. The children were born to consanguineous parents from a or kidneys, organs often considered for transplantation. We socially-isolated Mennonite community. This history, together believe the very low rate of occurrence of term liveborn with the absence of any manifestation of the disorder in the infants with anencephaly and the relatively high rate of parents or in any other individual in a large, extended pedi- significant associated malformations should be a more gree, is strongly suggestive of autosomal recessive inheritance significant part of the discussions of transplantation Isolated moyamoya occuring in one of monozygotic twins, there- involving infants with anencephaly. (Supported by New England fore, constitutes a high risk to the other twin and possibly Regional Genetics Group). also to other sibs. Clinical Genetics A55 (0208) 4.8 (0209) 1.116

Frequency of Familial Dilated Cardiomyopathy in an Unselected X-Linked mental retardation - multiple anomaly syndrome Series of Patients With Idiopathic Dilated Cardiomyopathy. localized to Xq21.31. J.H. Miles and N.J. Carpenter.1 V. V. Michels, P. P. Moll*, F. A. Miller, A. J. Tajik, D. J. University of Missouri Health Sciences Center, Columbia and Driscoll, J. S. Chu*, J. C. Burnett, J. H. Chesebro and R. J. H.A. Chapman Research Institute, Children's Medical Center, Rodeheffer. Mayo Clinic, Rochester, MN and *University of Tulsa, Oklahoma.1 Michigan, Ann Arbor, MI. Ten members of a four generation Missouri kindred were Familial dilated cardiomyopathy has been considered to previously reported (AJHG 31:120A, 1979) with a dominant account for only a small proportion of cases of idiopathic mental retardation syndrome with increased severity in males. dilated cardiomypathy (IDC), but the true proportion has not The 21 year old proband presented with severe mental retard- been determined in a prospective series of unselected cases. ation, microcephaly, assymetric facies, exotropia, hypo- Genetic factors that serve as markers for presymptomatic gonadism, joint hypermobility, rocker bottom feet and 10 low family members have not been identified previously. We digital arches. Two brothers and a cousin had similar feat- prospectively studied an unselected series of 49 patients with ures. The mother, sister, neice, maternal aunt, cousin and IDC to estimate the proportion with familial disease. Physical grandmother were examined and each had 10 low digital arches. examinations, electrocardiograms and echocardiograms were Some of the women were slow learners but all functioned in- performed on 237 first-degree relatives. Twelve (24%) index dependently. Four of the women had exotropia and one had patients had familial disease; of these, only 4 had been pes cavus feet. Chromosome analysis for fragile X and met- suspected to have familial disease based on family history abolic screens were normal. alone. In addition, 10 of 78 (13%) healthy relatives of In order to determine the likelihood that this was an familial cases had left ventricular (LV) size above normal, X-linked syndrome rather than autosomal dominant with in- and 14 of 140 (10%) healthy relatives of apparently non- creased male severity, DNA extracted from the blood of 16 familial cases had LV size above normal. [In a separate study family members was hybridized to probes which detect 13 diff- of 112 healthy volunteers, only 2 (1.8%) had LV size above erent loci spanning the length of the X chromosome. There normal.] LV size of relatives without IDC, after correcting was no evidence of linkage between the syndrome locus and for height, weight, age and sex, showed significant familial the xp loci tested. However, a peak lod score of 2.78 at aggregation for both diastolic (p<.Ol) and systolic (p<.05) 9 equal to 0.0 was calculated for the syndrome locus and volumes. In addition, unaffected relatives from families with DXYS1 (pDP34). The more distal Xq loci showed increasing familial IDC had significantly larger mean LV size in systole recombination with the syndrome locus. These results are and diastole than unaffected relatives from families with consistent with location for this syndrome at Xq21.31, the non-familial disease (p<.01). Mean LV function (ejection chromosomal location for DXYS1. It is of considerable in- fraction) was significantly higher for unaffected relatives terest that of the small number of X-linked mental retard- from non-familial vs familial disease families (p<.01). ation syndromes already linked to loci on the X chromosome, Studies are in progress to determine the mode of inheritance each maps at a different locus. for IDC and LV size in these families. In conclusion: 1) familial IDC is more common (24%) than previously recognized and cannot always be ascertained by family history; 2) this is the first evidence that a) left ventricular size shows significant familial aggregation in healthy individuals and b) that left ventricular size in healthy relatives of IDC patients may be a predisposing factor or early sign of IDC.

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Hb H Inclusion Bodies in the Hemoglobin H Diseases. Autosomal Recessive Encephaloclastic Proliferative F. Miyakawa. D.Y. Teshima. and Y.E. Hsia. Depts Vasculopathy (Hydrocephaly/Hydranencephaly). John B. Genetics and Med Technology, Univ. of Hawaii. Moeschler and Miguel Marin-Padilla, Maternal and Child Health, and Triple deletion Hb H disease (--/-a ) and double Dept. of Pathology, Dartmouth-Hitchcock Medical Center, Dartmouth deletion Hb H/Hb Constant Spring [Hb H/CS] disease Medical School, Hanover, NH. ( a) are important hereditary a-thalassemias We report 25 week gestation identical male twins with a rare and [csT42as] in South-east Asia. Supravital staining distinctive proliferative vascular CNS anomaly like that reported by Harper with Brilliant Cresyl Blue precipitates excess fi- and Hockey (1983) in siblings, one with hydranencephaly at birth and the globin as ,84inclusion bodies [Hb H Bodies]. These other with normal ultrasound examination at 22 weeks who later developed bodies are multiple, rounded, speckled, well- hydranencephaly noted on ultrasound at 26 weeks. This disorder causes defined intracellular inclusions, distinct from progressive destruction of the developing CNS resulting in the irregularly filamentous RNA in reticulocytes. hydrocephalus/hydranencephaly as well as in the focal involvement of other neural regions. Our cases were born because of uncontrolled premature Hb H Body percentages were studied in 4 patients with reticulocytosis who had monthly transfusions. labor at 25 weeks gestation after a normal pregnancy. Ultrasound at 16 weeks was for 12 minutes. The single Two Hb patients consistently had Hb H Bodies, gestation normal. They survived H/CS placenta had 2 cavities separated by a diarnniotic membrane. Placental two never had Hb H Bodies Hb E/,Thal patients any. arteriovenous anastomoses between the twins and fetal-fetal transfusion decreased with storage, but 8 out of 9 samples were still positive after 3 days. were recognized. The fetuses were entirely normal aside from the transfusion effects and the CNS proliferative vasculopathy noted only on Fifteen subjects with MCV < 60 fl were tested microscopic examination of the brains. On gross examination, the brains prospectively for Hb H Bodies. One subject who had were normal. On microscopic, the brains had identical anomalies located Hb H on electrophoresis had Hb H Bodies, but the 14 each in the dorso-lateral aspect of the posterior region of the right frontal without Hb H had no Hb H Bodies. lobe. Noted were the distinctive so-called "glomeruloid" lesions The clinical or hematological severity in 15 Hb representing abnormal focal vascularization of the cortical mantle by tufts H Body positive subjects [10 Hb H, 4 Hb H/CS, 1 of blood vessels. These "glomeruloids" were formed by the focal homozygous alThai] were compared with those in 29 proliferation of endothelial cells and represent the most distinctive other subjects [6 normal, 1 iron deficient, 2 pathologic feature of this disorder. This proliferative vasculopathy a Thal, 10 aclThal, 7 pA/pThal, 2 pE/pTh1, 1 PThal/pThaI, damaged the developing CNS in at least 3 different ways: 1) disruption Ht H Bodies increased with degree of anemia. In 3 and disorganization of the developing CNS, 2) rupture of the pial/glial Hb H/CS subjects, the Hb H Body percentage rose surface, 3) hemorrhagic necrosis of developing neurons and glial cells. On with increased Hb H seen on electrophoresis. the basis of these findings, we feel that these twins would have eventually Although it was no more sensitive or accurate developed typical hydranencephaly, but were born prior to the full than Hb electrophoresis for detecting Hb H disease, evolution of this clinical presentation. Autosomal recessive inheritance Hb H Body staining was simple and reliable for has been suggested by the Harper and Hockey report and an earlier report confirming Hb H disease. Reticulocytes did not of Fowler et al (1972) of five affected siblings. interfere or produce false positives, no Hb H patient was missed, even on 3 day old blood, but the test was best done on fresh blood. A56 Clinical Genetics (0212) (0213) 1.118

Triploidy syndrome: A report of a liveborn Bedouin baby Weissenbacher-Zweymuller Syndrome in monozygous twins with with multiple congenital anomalies, ambiguous external neural tube defects and septo-optic dysplasia. S. J. Moore, genitalia and non-mosaic 69,XXY karyotype. R. L. Ladda, P. N. Mowrey, M. J. Mascari and J. C. Ramer. PA State Univ., Col. of Med., Hershey. Fawzia M Mohammed, T. I.Farag.2 S.A.Al-Awadi, S.A.Al-Othman Monozygotic twins were referred for evaluation because of L.A.El-Gervarn. Kuwait Medical Genetics Centre (KMGC), short limbs and unusual craniofacial features. Twin A had a large occipital bulge considered to be a cephalohematoma. Maternity Hospital, P.O.Box : 4080, Safat 13041 - Kuwait. The occiput bulge was a large depressable fluid-filled sac over the occipital-parietal area was a Triploidy is a frequent cause of fetal wastage prior to tht which parietal meningocephalocele. Twin B had a small skull defect at 8th intrauterine weak. About 1% of conceptuses and 20% of a site similar to Twin A; a small meningocele was chromosomally abnormal abortuses are triploid. There have identified. The twins had proximal limb shortening, midfacial been several examples of pure triploidy but in general flattening diploid/triploid mosaicism is occassionally compatible witi with small upturned nose and brachycephaly. Orbital ridges survival. were downturned and anterior fontanelles were 5 x 5 cm. Skeletal survey of the twins showed rhizomelic short limbed dwarfism with bulbous metaphyses. Lumbar vertebrae In Kuwait, the first case of was had triploidy detected among small coronal clefts. On the basis the 1350 patients with and of the skeletal and major numerical structural chro- craniofacial features, the diagnosis of Weissenbacher- mosome abnormalities ascertained in the KMGC during the Zweymuller Syndrome was offered. MRI revealed partial period from Jan 1979 to Jan 1989. The baby was delivered agenesis of the corpus callosum in Twin A. Ophthalmologic spontaneously at 28 weeks gestation to young consanguineou evaluation confirmed optic nerve hypoplasia and bilateral Bedouin parents. They have 3 nonnal children. The mother myopia. Chromosomal studies on the twins revealed normal was exposed to diagnostic X'ray six months before her last male karyotypes. pregnancy. Birth weight was 1170 gm, head circumference w;I: These twins provide evidence of central nervous system 27 cuns, arid was length 37 cms. Apgar scores were 2 & 5 at abnormalities in the Weissenbacher-Zweymuller Syndrome, 1 & 5 minutes The respectively. baby had slanting palpebra features not described previously. Developmental outlook fissures, hypertelorism, peaked nose, poorly developed ear for individuals with this form of dwarfism been pinnae, abnormal chest has shape, abdominal distension with le essentially normal, but in these twins, developmental delay kidney mass and ambiguous external was genitalia. Placenta associated with central apnea has been prominent. Skeletal and a large big cystic swelling was seen in the umbilical features typical of the Weissenbacher-Zweymuller Syndrome cord at 4 cm distance from the fetal attachement. Peripher appear to be dynamic and ultimately evolve into variable blood karyotyping -with trypsin-G-banding showed 69,XXY features of the Stickler Syndrome. karyotype in more than one hundred cells. The baby had a progressive respiratory distress. He died when 18 hours ol Autopsy was not done. Parental karyotyping showed normal chromosome constitution.

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An unusual phenotype of Niemann-Pick disease. M Morris. Recurrence and prenatal diagnosis of lethal Larsen Syndrome. A McBride. MA Harper. OM Gibby. PS Haroer.Institute of D. Mostello, L. Medical Genetics and Dept of Psychiatry, University of Hoechstetter. R. Bendon, T. Siddigi and Wales College of Medicine, Cardiff, Wales and Royal P. Dignan. Univ. of Cincinnati and Children's Hospital Medical Gwent Hospital, Newport, Wales. Center, Cincinnati, Ohio. Typical clinical presentation of Niemann-Pick disease Larsen first a (NPD) consists of central nervous involvement and described syndrome of multiple skeletal ab- enlargement of the viscera. The great majority of cases normalities and characteristic facies in 1950. Diagnostic have an onset in early childhood, usually the first year features include multiple congenital dislocations of the limb of life. Psychiatric presentation, especially with joints, spatulate thumbs, short metacarpals, prominent fore- psychosis, is very rare. We describe two cases, one of whom had a schizophreniform psychosis. head, hypertelorism and depressed nasal bridge. Reports of this disorder have suggested sporadic, autosomal dominant and A 17 year youth, who was previously well had a sudden recessive patterns of inheritance. The variability in both onset of disturbed behaviour and paranoid delusions. He insisted on the door being locked and he hid behind a the clinical manifestations and apparent mode of inheritance chair. On psychiatric assessment, he had bizarre indicates that genetic heterogeneity is likely. A lethal form posturing, catatonia, disjointed speech and was has been described; each of the 3 previously reported lethal disoriented. The after admission he had a mal day grand cases has been an seizure. Initial differential diagnosis included isolated occurrence. We report a unique encephalitis and drug psychosis. He failed to improve family with a recurrence of the lethal form despite prenatal and extensive investigations revealed Niemann-Pick cells diagnosis and perinatal preparation for anticipated complica- (also known as "foam cells"), the hallmark of the tions. disorder. Biochemically, there was accumulation of tissue sphingomyelin. The parents are a healthy, nonconsanguineous couple. Their first child, a term male, was noted to have both facial and The proband's younger brother (aged 16 years) had a long orthopedic features of Larsen Syndrome (LS). He expired at medical history beginning at age 8 years when he was investigated for intermittent episodes of abdominal 24 hrs. of age. He had pulmonary insufficiency; pathologically pain. Splenomegaly was noted at that time.There was a the etiology was complicated by the presence of bronchopneumo- decline in his school performance and he attended nia, sepsis, hypoplastic lungs, cord compression, chest insta- remedial classes. At age 16 he indecently exposed himself and was referred to a child psychiatrist. On bility and collapsible trachea. psychological testing, he was severely educationally The next pregnancy ended in the birth of a healthy daughter. subnormal. After it became clear his brother had NPD The woman was referred for Level II ultrasound (US) at 20 (type C), he was investigated and also diagnosed as weeks having this autosomal recessive disorder. gestation in her third pregnancy. Serial US findings were consistent with a diagnosis of recurrent LS and included: genu recurvatum, clubbed feet and moderate oligohydramnios. Other dislocations were suspected because of the large separa- tion between bones in the joint spaces. Sonographic evidence of these findings will be presented. Delivery occurred at 37 weeks. The male infant presented with the facial and orthopedic features of LS. Death occurred on the 8th day of life from a complicated respiratory distress syndrome. Permission for autopsy was refused. This family provides the first reported prenatal diagnosis of LS as well as the first recurrent lethal case. Clinical Genetics A57

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Au uosanal ninant spirno lar ataxia in Holguin, Autosomal Dominant Granulomatous Arthritis, Uveitis and Rash. Caba. An analysis of 306 affected individuals. G. G. M. Pastores, V. V. Michels, G. B. Stickler, W. P. D. Su Orozoo, A. Nodarse and R. Cordbves. Hospital Proincial and A. M. Nelson. Mayo Clinic, Rochester, Minnesota. Docente V.I. Lenin, Holguin, Cuab (intro, by V.B. In 1985, Blau reported a 4-generation family with 11 Penchaszadsh). members affected by granulomatous arthritis, iritis, A cluster of au nnald siant cerebellar ataxia is granulomatous skin rash and unique subcutaneous cysts being studied in the province of Holguin, Cuba with a overlying the joints. We report a second family with these minimal estimate of aoe thousand affected individuals. abnormalities, thereby confirming Blau syndrome as a unique We report herae the clinical findings of the first 306 familial entity. Affected family members included a mother examined patients fru 70 families. The ccndition is and 2 daughters. Disease onset was 10 months to 8 years of characterized by progressive ataxia of gait, cerebellar age. Each had uveitis and symmetric polyarthritis. Both dysarthria, dyrmetria and adi ckinesis. The initial daughters also had cysts overlying the wrist and ankle joints. synptcm was ataxic gait in 93.8% of the cases, with a In addition, both daughters had intermittent generalized mean age of onset of 32 years and a range between 2 to 66 erythematous papular rash which on histopathologic examination years. Extrapiremidal rigidity was ant observed in any revealed noncaseating granulomatous infiltration. Rheumatoid patient, while c1xeiform svvtants were present in sane factor, ANA and HLA-B27 were negative. Radiographic meners of only cne family. Only aoe patient dsvelcped abnormalities in the mother were minimal despite 22 years of Palenss of the aptic discs were faond in a active disease. emall ruter of cases, but pigmentary retinal This condition differs from a similar disorder of degneration was never present. External granulomatous synovitis and uveitis described by Jabs cathabmhparesis was present in over nae half of the (McK 18658) in which steroid responsive cranial neuropathies affected irniduals. A very peculiar facial expressian occurred and no family members had cysts. Our family differs (tamazemt face") is c r c in patients with from the family described by Rotenstein (McK 10805) in which anderate to disease, probably due to affected members had polyarthritis, iritis and rash plus differential atrophy of facial nuscles. The condition is noncaseating granulomas in vascular and extra-vascular slowly and steadily progressive and most patients become distribution resulting in fever, hypertension, pericardial and ricn-ambulatory 10-15 years after the first symptans. pleural effusions, liver disease and arteritis but without Both sexes are equally affected and there is wide cysts. The disorder in our family also differs from juvenile inlrafamilial variability in c expressi, rheumatoid arthritis with uveitis by the presence of particularly in age of onset and severity of the noncaseating granulomatous skin infiltration and subcutaneous progression. sies in 7 deceased individuals cysts in our family. d--nstrated olivo-ponto-cerebellar atrcphy. Work is in Conclusion: the existence of a second family with progress towards camplete p-hatypic delineation and apparently autosomal dominant granulomatous arthritis, gmealogic analysis to establish relationships between uveitis, rash and unique subcutaneous cysts overlying the families and trace the origin of the mutation. Gene joints confirms this as a distinct entity. Recognition of mapping studies are also in progress. this disorder as distinct from more common forms of juvenile arthritis is important because of apparent autosomal dominant transmission and because of dramatic response to intermittent, low-dose steroid therapy.

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AMNIOTIC BAND SYNDROME WITH ASSOCIATED HOLOPROSENCEPHALY. R.R. Hypomelanosis of Ito in a girl with a de rxwo Patel and D. Bixler. Department of Oral Facial Genetics, translocaticn (X;14)(qll;ql3). V.B. Penchaszadeh, A. I.U. School of Dentistry, Indianapolis, Indiana. Babu, M. Schwartz, K.L. David, S. Popescu and C. Case #1: Ultrasound studies indicated that proband, TJ, Rubenstein. Divisicn of Medical Genetics, Beth Israel had severe hydrocephaly and he was in a breech position. Medical Center, New York, NY. and Division of Genetics, Delivery was by C-section. TJ showed amniotic band syndrome Brooklyn spal, Brooklyn, N.Y. including amputation and fusion of fingers and toes, bilateral Hypanelanosis of Ito (HI) is a rare ccrdition of cleft lip and palate with an oblique cleft extending to the unkn origin characterized by macular hypopigrented right eye. His nose was absent except two nostrils between whirls, streaks and patches in the skin, and variable his eyes which were hyperteloric and had no globes in the akrrrmalities of the eyes, teeth and nuscuoskeletal and sockets. Head circumference was +6 SD. Al. these indicated central nervous systems. It is usually sporadic and a holoprosencephaly sequence. Chromosomes were normal and females oatnumber males by 2:1. A diversity of head CT scan showed little brain material. crase rear ts have been described, usually in Case #2: Ultrasound exam indicated decreased amniotic nosaic form. Irxxntinentia pignenti (IP) is an X-linked fluid. Premature white male was liveborn and survived for doninant discr with ptetypic overlap with HI. Six two days, was estimated to be 35 weeks GA. He had asymmetric cases of IP have been reported with X-autenal cranial cleft involving left upper lip, hard and soft palate, translocations with a breakint at Xpll and cne with a left nares, left frontal area, crosses midline to right parietal ring irnolving the same X regio. However, in situ area with protruding cranial contents and ruptured sac i iizati gsed that in at least ae case the (encephalocele and holoprosencephaly); flattened AP diameter breakpoint was within the cntranere (Crolla et al, Hm. of skull; bilateral anophthalmia; right nostril had fibrous Genet, 1989). Furtherte, DNA linkage studies are strand with skin tag; medial right upper arm has ring constric- conflicting and the IP locus might in fact be at Xql1 tion with attached fibrous strand and skin tag; right hand (Harris et al, Clin. Genet, 1989). The relationship was monodactyly; left foot had distal syndactyly of 3,4,5 between HI and IP is unclear and sane cases of HI may with absent nails; right foot had talipes equinovarus, proximal represent nmsaiciam for an allelic variant of the IP gene syndactyly 4-5, absent #1, distal absent #2 and fibrous strands (Moss and Bum, Clin. Genet, 1988). We reprt a sporadic between 1-2 and 2-3; bilateral cryptorchidism; normal heart case of HI in a 6 month old female with multiple was donated for transplant. Chromosomes and head CT scan hypopigmented whorls and streaks, hypotonia, were not done. develcpnental delay and seizures. C(ramseae analysis Due to early rupture of the amnion, morphogenesis defects showed a de ravo X;14 translocation in all exanined cells occur because of compression of the early embryo. Case #1 fron peripheral lynmpscytes and fibroblasts grown fran and #2 show classic signs of Amniotic Band syndrome; however, pigmented and rxn-pigmented areas of the skin: 46,X, holoprosencephaly and associated problems seem unrelated to t(X;14)(qll;ql3). The rS in Xq is banding. juxtacentraneric, cosistent with similar observations on IP but not previaosly i in HI. This finding LB the hypothesis that same foram of HI may be allelic to IP with a gene locus in the juxtaoentraneric region of the X -cP. More clinical, ntic and molecular studies are needed to resolve issues of clinical and genetic heterogeeity. A58 Clinical Genetics (0220) (0221) 1.122

Rett Syndrome: Degeneration or Developmental Arrest? Genetic Heterogeneity of Polycystic Kidney Disease: An Estimate M. Philippart, H. V. Vinters and A. Scheibel, UCLA, the of Families Los Angeles, California. of Proportion Unlinked to Chromosome 16. ,A. Rett Syndrome (RS) presents as one of the so-called Pieke. W.J. Kimberling. J.B. Kenyon. P. Gabow. Boys Town neurodegenerative disorders. After a period of normal National Research Hospital, Omaha, NE. Univ. of Colorado development lasting months or years, progressive regression Health Sciences Center, Denver, CO. resulting from ongoing damage to the nervous system occurs. The Autosomal Dominant Polycystic Kidney Disease The lysosomal storage disorders such as metachromatic (ADPKD) gene has been localized to the arm leukodystrophy are classic examples of such processes. An short of chromosome 16 accumulation of undegradable metabolites causes dysfunction (Reeders et al., Nature 317:542, 1985). Four families have been and/or cell loss associated with astrocytic gliosis. previously reported which failed to show linkage with markers on Complications such as secondary malnutrition and vitamin chromosome 16p. This unlinked type of ADPKD has been deficiencies may supervene. Intractable epilepsy is a well recognized cause of progressive brain damage. In RS, termed ADPKD2. The present study was undertaken to development appears normal in the initial stages which at determine the proportion of ADPKD2 in a large series of most may include ambulation and limited language facility. unselected ADPKD families. DNA was extracted from 454 An obvious regression then takes place with loss of hand use individuals in 42 ADPKD families and for two DNA during the second year. EEG abnormalities and less typed frequently seizures may be associated with this stage. The markers on chromosome 16: 3'HVR (D16S85) and pEKMDA2.1 seizures are brief with mostly absences, myoclonus and (D16S83). Age dependent penetrances were assumed to be 0.32, automatisms not easily observed or described. Between 2 and 0.72, and 0.90 within three liability classes 15 to 20 years, 21 to 4 years of age, the seizures become generalized, ambulation 30 years, and over 31, respectively. All unaffected individuals may be lost and the child may appear demented. Dystonia develops slowly from the feet upwards. By the mid-teens, the have had a recent ultrasonography and affected individuals had dystonia has usually progressed to the upper trunk and is their diagnosis confirmed by ultrasonography or past medical probably a major factor in the scoliosis. As pointed out by records. Pairwise and multipoint linkage analyses of the families Hagberg et al, little regression takes place later. Except were done with the program LINKAGE. Linkage data were then for a personal case of progressive dystonia occurring during the 4th decade, objective evidence of regression has been analyzed for heterogeneity with the HOMOG computer program. difficult to document. Body weight in 67 patients aged 1 to The analysis showed that the proportion of ADPKD2 was 4% 18 years, plotted as deviance from normal mean against age, (upper 95% confidence limit of 7%) with a recombination of 3% shows- regression which may reflect an additive effect of for linkage of ADPKD1 with 3'HVR. This analysis was chronic malnutrition. Abnormal brain CT scans are more repeated common in older patients but scarce neuropathological data do using an added 27 families from the literature with similar results. not support progressive brain atrophy. Golgi preparations in The likelihood that each family belonged to either Type I or II a 16 year-old patient show immature cortical neuronal was calculated. All except two of 69 families had a posterior dendritic branching and spine formation. A defect in a key likelihood greater than 90% of linkage with 3'HVR and step of brain development may be involved. R-S may be an example of developmental impairment which precludes the final pEKMDA2.1. (SupportedbyUSPHSGrant DK34039) stage of dendrite proliferation and synapse formation.

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Platelet Serotonin, A Possible Marker for Familial Autism. J. A clinical study of hereditary haemorrhagic telangiectasia Piven. G. Tsai. E. Nehme. J. Coyle. G. chase. and S. and preliminary mapping results. M. E. M. Porteous, Folstein. The Jchns Hopldins Uhiv. Schol of Medicine, J. Burn,-S. Proctor. Royal Victoria Infirmary, Newcastle Baltimore, Maryland. upon Tyne, England. Intro by D. F. Roberts. Platelet serotonin (SUT) was measured in 5 autistic Hereditary haemorrhagic telangiectasia is an autosomal subjects (the multiplex groc) who had siblings with either dominant disorder of the vascular wall. We have identi- autism (N4) or Pervasive Developmental Disorder (PMD) (N-1). fied 11 families affected by the disease in a detailed These values were ompared to the 5H levels of 23 autistic population survey of the North-East of England and, to subjects (the sinplec group) who did not have siblings with date, personally examined 33 affected and 17 unaffected either autism or PMD and to the 5lr levels of 10 cntrols. members over the age of 16. The mean (±SD) nifs in the conol group was 97.7 nq/ml Twenty-nine developed symptoms before the age of 18. (±58.1), the simplex group was 237.0 nr/ml (±128.4), and the The presenting feature in 31 was epistaxis and telangiec- multiplex group was 422.6 rn/ml (+183.1). The mean SlI value tasia in 2. Each family exhibited the full spectrum for the multiplex group was significantly greater than that of the disease. Seven individuals had pulmonary arterio- of the simplec group (t- -2.72; df-30; pm.01). The mean 5HT venous fistulae (21%), 2 central nervous system involve- value for the simplex group was significantly greater than ment (6%) and 5 gastro-intestinal bleeds (15%). that for the controls (to -3.27; df-30; p-.003). The results Investigation of the families has uncovered several of a one-way analysis of variance showed a significant linear affected individuals who are not under medical super- trend among the means for the three groups (F ratio-24.6; vision and have low haemoglobins requiring iron supple- df-2,35; p<.0001). Analyses done on log transfon- data to mentation. We have also discovered a 17 year old boy adjust for differences in variance showed significant with severe symptoms due to a pulmonary arterio-venous differences between the means of the multiplex and simplex malformation. groups (tp-4.16; df-30; p<.001) and the means of the simplex Patients with hereditary haemorrhagic telangiectasia and control groups (t- -2.31; df-26; p-.03), and it seldom present to a geneticist, so family follow-up is continued to show a significant linear trend among the means often inadequate. In the North-East Region of England (F ratio-24.6; df-2,35; p<.0001). we have established a register of families at risk. We present preliminary data showing that. 5Hr is A molecular genetic study to localise the gene using significantly higher in autistic irdividuals who have a linkage analysis is in progress, based on 29 families sibling with autism or PDD than in those without a sibling ascertained nationally, preliminary results of which with thes disorders. These findings indicate that 5ST level will be presented. is associated with genetic liability to autism and that elevated 5Sr may be a marker for a subgroup of individuals with a high genetic liability for this disorder. These results suggest that meurent of 5HT may eventually play a role in genetic counseling in autism. Replication of this study in other samples is warranted. Clinical Genetics A59

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THE MEDIAN CLEFT FACE/SKELETAL SYNDROME (FRONTONASAI, Major gene inheritance of extreme obesity. R. DYSPLASIA): A DISTINCT SUBGROUP WITH NASAL AGIENESIS, TIBIAL Arlen Price, Roberta Ness and Peter Laskarzewski. APLASIA, HALLUCAL POLYDACTYLY AND MENTAL RETARDATION. Dept. of Psychiatry, University of Pennsylvania, K.E. Prescott, M. Sheridan-Pereira, D.K. Manchester, B. Ellers, and Philadelphia, PA and University of Cincinnati, B.D. Hall. Division of Genetics and Department of Perinatology, The Cincinnati, OH Childrens Hospital, Denver, CO., *Department of Pediatrics, Extreme obesity in humans is strongly University of Kentucky, Lexington. influenced by genetic factors. We report on a The Median Cleft Face Syndrome (MCF), or Frontonasal Dysplasia, recently completed segregation analysis of 3925 represents a broad spectrum of facial malformations. The main individuals in 961 randomly ascertained families. features include two or more of the following: ocular hypertelorism, The measure of body fat used was the body mass broad nasal root, median facial clefting of the nose, lip or palate, index (BMI, weight in kilograms divided by height widows peak and cranium bifidum occultum. The wide variability squared in meters). Standard statistical encountered in this syndrome renders prognostication and genetic criteria for acceptance of major gene inheritance counseling difficult. A review of the literature reveals a distinct were met: major gene inheritance was supported subgroup of patients whose phenotype, development and prognosis within a mixed model after transformation to are all similar. We present a new MCP subgroup - Median Cleft remove skewness, and transmission probabilities Face/Skeletal syndrome -consisting of 2 new cases and 6 from the were Mendelian. Obesity appears to be influenced literature. by polygenic inheritance (h2=0.23, many genes This distinct subgroup represents the severe end of the MCF with small effects) as well as by major genes spectrum with agenesis of the nasal root, marked separation of slit (q=0.24, a few genes with large effects on the like nares, tibial aplasia, hallucal polydactyly, varus deformity and individuals who possess them). A lower observed severe mental retardation. Other features variably described in the than expected rate of extreme obesity (14% vs. subgroup include interhemispheric lipoma, agencsis of the corpus 36%) among offspring of two obese parents callosum, lipodermoid of Lhe eye, cryptorchidism, penile hypoplasia suggests genetic heterogeneity. Thus, several and anteriorly placed anus. Chromosome analysis was normal on 4 major genes are probably involved. Our results patients studied. Males and females are both equally represented indicate a recessive mode of expression for and similarly affected. Consanguinity has not been ruled out in 3 common obesity predisposing genes. Recessive of the cases - raising the possibility of autosomal recessive gene expression is consistent with that of the inheritance although a sporadic occurrence appears mnost likely. most common obesity syndromes in humans and Mortality in the described cases was due to pneumonia with or obesity mutations in animals. Major gene without aspiration. The oldest of the 2 known survivors is influence is especially likely for obesity that institutionalized at 12 years, with all others having died prior to exceeds a threshold of 40% or more over ideal 3 years. weight (BMI>30). Our findings make it possible This phenotype is clearly unique among patients with MCF and to begin molecular studies aimed at isolating carries a poor survival and cognitive prognosis in all cases genes that influence risk for extreme obesity. described to date. Candidates include genes involved in appetite, satiety, carbohydrate metabolism, lipid metabolism and storage, and endocrine function. (Supported by NIMH Grant MH43409).

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Marshall syndrome: evidence for genetic heterogeneity and phenotypic Natal Teeth in Native Americans. L.R. Ribnik, Phoenix variability. L.J. Raffel. G. A. McDowell and H.M. Saal. University of Indian Medical Center, Phoenix and H.E. Hoyme, Maryland School of Medicine, Baltimore and Children's Hospital National University of Arizona, Tucson. Medical Center, Washington, D.C. Natal teeth are teeth present in the oral cavity at the Marshall syndrome is an autosomal dominant disorder characterized by time of birth. Neonatal teeth erupt within the first 30 days eyes, nasal cataracts and prominent hypoplasia, micrognathia, myopia, of postnatal life. Natal teeth have been a source of fasci- sensorineural loss. More than 20 cases have been but hearing reported nation in folklore, history, and medicine for thousands of controversy exists as to whether this disorder is a separate entity or falls within the phenotypic spectrum of Stickler syndrome. We report seven new years. Although usually an isolated anomaly, natal teeth cases which demonstrate significant phenotypic variability and raise the have been described as one feature of several multiple mal- possibility of genetic heterogeneity. Four of the seven cases represent the formation syndromes (e.g., Hallerman-Streiff, Ellis van- only affected individuals in their families, with phenotypically normal Creveld, and pachyonychia congenita syndromes). The incidence parents. The father of the fifth case has mild nasal hypoplasia and probably of natal teeth in the general population in the United States is affected. The remaining two probands are affected brothers who have and Canada has been described as between 1:3,392 and 1:1,397. phenotypically normal parents. Possible explanations for this observation It has been suggested that there exists an increased incidence include genetic heterogeneity with an autosomal recessive or X-linked form of natal teeth in Native Americans and Alaska Natives. The of Marshall syndrome, or germinal mosaicism. Additional clinical features, purpose of this report is to document the incidence, associ- not previously appreciated as part of the phenotypic spectrum of Marshall ated anomalies, and tribal epidemiology of natal teeth in have been observed in these 7 closure syndrome children, including delayed Southwestern Native American infants. of anterior fontanelle (4/7), megalocornea (4/7), minor ear anomalies (4/7), albinotic fundi (2/7), and congenital heart defects (2/7). Five of the seven Over a period of six months, all newborns delivered at the also had a posterior cleft palate, a higher incidence than previously Phoenix Indian Medical Center were examined for the presence reported. The number of cases ascertained, along with the phenotypic of natal teeth. The tribe of origin of each child and any variability, suggests that this disorder (or group of disorders) is more associated anomalies were also recorded. common than previously thought and, frequently, goes undiagnosed. Of 440 infants, 15 (3.4% or 1:28) had natal teeth. Ninety- five percent (95%) of affected children had mandibular central incisors. Fifty-seven percent (57%) of affected infants had two natal teeth. There was a preponderance of females, with a sex ration of 3:1. Nineteen percent (19%) of the teeth were erupted at the time of delivery. One infant had a unilateral preauricular tag. There were no other associated anomalies. Of note was a higher incidence of natal teeth in tribes of Athabascan origin (i.e., Apache, Navajo, Sioux) than in other tribes (notably the Pima and Tohono O'odham). The results of this study confirm an increased incidence of natal teeth in Native Americans particularly in those of Athabascan origin. In Native American infants, the presence of a natal tooth does not appear to increase the likelihood of associated anomalies. (The opinions herein expressed are those of the authors and do not necessarily reflect those of the Indian Health Service). A60 Clinical Genetics

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Proband Fallacies: Analysis of ascertainment biases Disjoining of height and head circumference in in disease-specific clinics -- NF-1 as an example. patients with NF-1: Implications for CNS pathogen- S.L. Riccardi and V.M. Riccardi. The Neurofibroma- esis. V.M. Riccardi and Veronica F. Haeberlen. NF tosis Institute, Inc., and the NF Program, Baylor Program, Baylor College of Medicine, and the School College of Medicine, Houston, Texas. of Public Health, Univ. of Texas, Houston. For genetic disorders with variable expressivi- The point of this study was to study macrocepha- ty, such as NF-1, there is a reluctance to presume ly with respect to stature in NF-1. (Patients with that index cases accurately portray the overall confounding factors such as optic gliomas and burden of the disorder. This reluctance is commonly scoliosis were excluded.) For 300 NF-1 patients, translated to the extreme position that index cases age- and sex-adjusted head circumference (HC) and do not provide reliable data for genetic counseling height measurements were compared to those from or for understanding the disorder's natural histo- subjects reported for the NHANES II and Fels Longi- ry. We suggest that this extreme view is unwar- tudinal studies, establishing differences for NF-1. ranted and that it is based on two fallacies. Proportions of NF-1 males and females above the 1) The presumption that all index cases are the 95th centile for HC were 26% and 13%, respectively. same: Part of the fallacy is a matter of defini- The proportions of NF-1 males and females below the tions, e.g., considering unaffected index cases as 5th centile for height were 34% and 34%, respec- "consultands," and displacing atypical cases to tively. Each HC and height measurement was con- alternative nosologic categories. In the course of verted to a standard score (multiples of the stand- evaluating 853 cases of NF-1 over a 12-year period, ard deviations of the comparison population meas- we have characterized index cases in terms of their urements), demonstrating a significant difference basis for participation in the program, whether for HC and height in both sexes (p <0.001). they are the original instance of the disorder in Age-stratified comparisons, using the Kolmorgo- their respective families, their presenting problem rov-Smirnov statistic, determined if measurement (vs. subsequent problems), the full range of prob- differences were present at birth or became appar- lems, and overall severity. The data indicate that ent later. At 4 years, males began to show en- index cases are extremely heterogeneous and that larged HC, with continued statistical significance the among them differences are likely to be more through 18 years; females were different only at 1 important than the index case assignment. year of age. Detectable differences in male and 2) Index cases are not representative: While it female height were scattered throughout the various is arguable whether index cases to an NF Center are age strata, with no discernible pattern or trend. representative of all NF-1 patients, certainly such NF-1 macrocephaly is striking because the same persons are representative of those who utilize the population was also short. The MacNear test, resources of such a Center. In addition, the nature comparing paired HC and height measurements for of the Center has to be respected (e.g., attendance each sex, was very significant (chi-square = 68). at the clinic is not equivalent to being admitted a This NF-1 population demonstrated both short hospital). Moreover, the rigor of consequent evalu- stature and macrocephaly more frequently than the ations is to be considered: many cases with his- comparison groups. The combination of enlarged HC torically "mild" NF-1 have more serious problems if and short stature suggests a disjoining of growth a comprehensive evaluation is performed. processes that determine head size and height.

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Autosomal Dominant Inheritance of Idiopathic Torsion Dystonia Familial Postaxial Polydactyly, Craniofacial Ancmalies and in Ashkenazi Jews. N. Risch. S.B. Bressman. D. deLeon. M.F. Hypopituitarism: Case Report and Prenatal Diagnosis, Brin. R.E. Burke. P.E. Greene. H. Shale. E.B. Claus. L.A. L.P. Robinson, C. Lieber, LY Shih, R. Rappaport, J. Rakow, Cupples. S. Fahn. Yale Univ. School of Medicine, New Haven, S. Peters, F. Desposito. Hackensack Med. Ctr, Hackensack, NJ. CT and Dystonia Clinical Research Center, Neurological Inst., Postaxial polydactyly and endocrine abnormalities have Columbia Univ., New York, NY. been described in several conditions, including Pallister-Hall Syndrame (PHS) and the Acrooollosal Syndrame (ACS). We Idiopathic (primary) torsion dystonia (ITD) is a describe a one-year old male born to a 27-year G2 P1001 neurological disorder characterized by involuntary twisting Colcabian female and non-consanguinous, 28-year old movements and postures. Several epidemiologic studies have Colanbian male who presented in the newborn period with demonstrated a higher incidence (1/15,000) among Ashkenazi postaxial polydactyly, microphthalmia, high arched palate, Jews (AJ), compared to either non-Ashkenazi Jews or non Jews short upper lip, small nose with anteverted nares, (about 1/100,000 for each). While many studies have described praninent forehead and panhypopituitarism. Now one year of familial clusters in the AJ population, the mode of age, he is severely growth and developmentally delayed. MI inheritance has remained controversial, with arguments for has revealed a CNS tumor manifested by divergent strabismus both recessive and dominant inheritance. and lack of visionand a hypoplastic corpus callosum. The To clarify this issue, we have performed a family study couple's subsequent pregnancy was monitored with serial of early onset AJ ITD patients. Forty-three probands with a ultrasonography which revealed hydrocephalus at fifteen diagnosis of definite ITD with onset prior to age 28 were menstrual weeks. Two subsequent monograms confirmed progress- ascertained independent of family history. All available ive hydrocephalus, and polydactyly was identified. A maternal first (n-149) and second (n-96) degree relatives were examined serum AFP at 16 weeks was .29 MOM. The patient elected to by trained neurologists and videotapes made. Examination terminate the pregnancy at 18 weeks gestation. Autopsy notes and blinded videotape review were used to classify confirmed the sonographic findings in the female fetus who relatives as having definite, probable, possible or no ITD. had postaxial polydactyly on all extremities, micropthalmia, Age-adjusted lifetime risks (LTR) were obtained for each a cleft palate, abnormal upper lip and an absent pituitary type of relative. The LTR for parents (n-62) was 11.4%, for gland. Tissue culture revealed a normal 45, XX female. siblings (n-63) 17.2%, and for offspring (n-24) 26.0%. These Although a non-specific finding, low MSAFP may signify either rates are not significantly different from one another, and a liver, placental, or growth abnormality. Familial occurrence combined rate for all first-degree relatives is 15.5%. For may indicate an autosomal recessive pattern of inheritance. second-degree relatives combined the LTR was 7.7%. These Findings in both Pallister-Hall Syndrome and Acrocallosal results are consistent with autosomal dominant inheritance Syndrcme enccspass a spectrum of CNS anomalies, hypopituitar- with about 30% penetrance, but inconsistent with recessive ism, polysyndactyly and craniofacial dysmorphism. Hamarto- inheritance. This conclusion was confirmed by segregation blastcma is seen in PHS while CNS lesions in ACS are analysis using the computer programs POINTER and MENDEL. The usually structural and not neoplastic. Internal malformations, best fitting model was autosomal dominant with gene frequency imperforate anus and renal ananalies are seen in PHS and .00011 and penetrance 30%; a recessive model was strongly infrequently in ACS. The two conditions are distinguishable rejected. The high incidence and dominant inheritance by different craniofacial and skeletal manifestations. This suggests that ITD may be largely genetically homogeneous in family most likely represents a case of PHS. However, the the AJ population, which may therefore be particularly useful two conditions may represent a continuum of the same disorder. for genetic linkage studies of this disorder. Clinical Genetics A61

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Hereditary persistence of alpha fetoprotein. L. Rose. Non-immune hydrops fetalis in the McKusick-Kaufman Syndrome. F. Greenberg., and Alpert. Institute for Molecular R.S. Rosen and M.E. Bocian. Univ. of California, Irvine. Genetics and Department of Medicine, Baylor College of McKusick-Kaufman Syndrome is a well defined autosomal Medicine, Houston, Texas. recessive syndrome of hydrometrocolpos and polydactyly. Over 60 Alpha fetoprotein (AFP) is a major serum protein seen cases have been reported, with a strong bias toward ascertainment in the fetus where it is produced by the yolk sac and of affected females. Other anomalies including syndactyly, fetal liver. Levels of AFP decline from birth and reach hip dislocation, and abnormalities of the genitourinary low concentrations between 6-8 months of age. Adult congenital serum concentrations of AFP are low except in association tract, gastrointestinal system, heart and eyes have been described with pregnancy or malignancy, primarily hepato-cellular in affected individuals. carcinoma and teratoma. Ataxia telangectasia is also Prenatal diagnosis is uncommon and has depended on the associated with serum AFP elevations. In 1984, Ferguson observation of a large fetal pelvic mass during ultrasound. Lower Smith et al reported a family in Scotland with hereditary extremity edema has been described in a number of cases and has persistence of AFP (HPAFP) as an autosomal dominant been attributed to inferior vena cava compression and lymphatic trait. A second possible family was reported by Staples obstruction by a large pelvic mass. A single fetus with McKusick- in 1986. We report a third family with HPAFP. Kaufman Syndrome and non-immune hydrops has been reported. Persistently elevated alpha fetoprotein levels were This fetus had a large pelvic mass and presumed infenor vena found in a 42 year old male in the absence of any specif- cava compression. However, the additional presence of short ic pathology. Elevated serum alpha-fetoprotein levels limbed dwarfism, pre-axial polydactyly and intrauterine death shed were subsequently found in three first degree relatives, as two siblings and one daughter. This represents heredi- doubt on McKusick-Kaufman Syndrome the actual diagnosis tary persistence of alpha-fetoprotein, and is consistent since these have not been found in any other affected individuals. with autosomal dominant inheritance of this rare but We report a patient with McKusick-Kaufman Syndrome and benign condition. Such elevated alpha-fetoprotein marked fetal hydrops in the absence of a large pelvic mass. Other levels may be difficult to interpret in patients being unusual features of this case were the presence of polyhydramnios screened for malignancy or in pregnant women utilizing in the face of unnary obstruction both distally and at the uretero- maternal serum alpha-fetoprotein screening for neural pelvic junction, and subtle sonographic findings including the tube defects or Down syndrome. persistent visualization of the fetal bladder, which, in retrospect, may have led to prenatal diagnosis of the condition. Our case suggests a different etiology for edema in McKusick-Kaufman patients than the previously proposed mass effect. This appears to be the first reported occurence of non- immune hydrops in a true McKusick-Kaufman Syndrome patient. This case also illustrates clues which can be used for prenatal diagnosis in fetuses at risk.

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Hereditary startle disease: clinical features and response to Ear malformations and hearing loss in the VATER clonazepam in a large pedigree amenable to linkage analysis. association. H.M. Saal. K.N. Rosenbaum. H.J. Stern. S. C. Ryan. D. P. Bick. R. W. Mackey. and S. L. Naylor. and E. Sidransky, Children's National Medical Center University of Texas Health Science Center at San Antonio, San and Nation&l Institutes of Health, Washington, DC and Antonio, Texas. Bethesda, MD. We have identified a five-generation pedigree in which 30 In 1973 Quan and Smith described seven patients of 52 at-risk individuals are affected with startle disease with variable combinations of vertebral defects, anal (hyperekplexia, MIM #14940). The disorder is inherited in an atresia, tracheoesophageal fistulae, renal anomalies, autosomal dominant fashion with complete penetrance and and radial limb defects and suggested the acronym variable expressivity. As in hereditary stiff-man syndrome VATER association. Of the seven original patients (MIM #18485), continuous and occasionally fatal muscular reported, two were noted to have auricular anomalies. rigidity is present in infancy, and electromyography reveals External ear defects have been described in several continuous motor unit activity. An exaggerated startle additional reports of the VATER association. We have response persists throughout life: sudden, unexpected seen 41 patients with the VATER association of whom acoustic or tactile stimuli may precipitate a brief attack of 10 have been found to have external ear malformations intense rigidity, with subsequent unchecked falling. and/or hearing loss, as determined by brainstem audio Umbilical and inguinal hernias, presumably due to increased evoked responses. All individuals have normal intra-abdominal pressure, are common, as is nocturnal karyotypes, and none has a family history suggestive myoclonus. Intelligence is preserved. Echolalia and forced of a well defined monogenic disorder, such as Townes- obedience, conspicuous in the so-called "jumping Frenchmen of Brocks syndrome. Of these 10 patients, 6 have Maine," (MIM #24410) are absent. Ten adults were treated with external ear malformations with hearing loss, 2 have clonazepam, 0.5 to 1.0 mg two to three times daily, and hearing loss without auricular defects, and 2 have experienced dramatic improvement of symptoms. auricular defects with normal hearing. Four of the Because of its potential dysfunction in acquired stiff-man 10 have vertebral defects, 6 have anorectal syndrome, the candidate gene glutamate decarboxylase (GAD), anomalies, 1 has a tracheoesophageal fistula, 6 have which catalyzes the synthesis of the inhibitory radial anomalies, 8 have renal anomalies, and 6 have neurotransmitter gamma-aminobutyric acid, was examined in this cardiovascular defects. The VATER association pedigree. Restriction fragment analysis using the GAD cDNA clearly encompasses a heterogeneous group of failed to reveal polymorphism with HindIII, MspI, and TaqI. disorders. In the past the significance of ear No deletion, however, was detected. A computer simulation of anomalies has been overlooked. We feel that ear a proposed linkage study (M Boehnke (1986), Am J Hum Genet, anomalies are more frequently seen than has been 39:513-527) yielded a 75.2% probability of obtaining a maximum previously appreciated. All children with VATER lod score of 2.0 or more using a theoretical spanning set of association should have audiometric studies as part probes, each with a PIC of 0. 38, spaced at 20 cM. We have of their initial evaluation. therefore begun a systematic search for linkage. Our observations, and a critical review of reported electromyographic findings in startle disease and hereditary stiff-man syndrome, suggest that the two disorders are iden- tical. Startle disease is markedly sensitive to clonazepam and the disease gene can be localized with linkage analysis. A62 Clinical Genetics (0236) (0237)

ASSOCIATION OF APOLIPOPROTEIN A-IV IN CORONARY ARTERY DISEASE Morphometric Facial Diagnosis in the Clinical Screening of IN SINGAPORE INDIANS Gene Carriers with X-linked Hypohidrotic Ectodermal Dysplasia.

N Sahaa, , J. S Tya. aDepartment of Paediatrics S.S. Saksena and D. Bixler. I.U. Medical Center, Indianapolis, (Division of Genetics), National University of Singapore; Indiana. bDepartment of Cardiothoracic Surgery, Singapore General Patients with X-linked hypohidrotic ectodermal dysplasia Hospital, Singapore. (HED) are characterized by 4 clinical symptoms: (a) hypodontia; (b) hypohidrosis; (c) hypotrichosis; and (d) distinct facial Apoliprotein A-IV polymorphism was studied in 127 healthy physiognomy. Affected males show complete expression of clini- adults and 51 coronary arterery disease (CAD) patients of cal findings whereas affected females representing lyonization Indian origin of comparable age and sex. The patients were effects exhibit a wide spectrum of signs, ranging from very confirmed cases of coronary arterery disease as established subtle to the most severe. The probability of detection of by clinical and biochemical tests as well as a mildly affected female ranges from 42% to 80% of cases (Freire electrocardiogram and angiogram. Fasting samples of blood -Maia and Pinheiro, 1984) The use of currently available clini- were collected in plain vials and sera were separated by cal methods (such as, sweat-pore counts, Blaschko patterns, centrifugation at 3000 r.p.m. at 4'C. Apolipoprotein A-IV missing and/or misshapen teeth, and DNA markers) does not easily types were determined by the immunoblotting technique after allow the routine identification of the gene carriers. isoelectric focusing on thin polyacrylamide gel containing 2% Facial physiognomy of fully affected HED individuals is Ampholine of pH 4.0-6.5 (LKB) and 6M urea. The first highly diagnostic. The present study employed roentgenographic antibody used was anti-human Apo A-IV raised in rabbit measurements and multivariate analysis for the characteriza- (kindly donated by Dr K H Weisgraber) and the second antibody tion, classification, and identification of HED gene carriers. was anti-rabbit peroxidase-conjugated IgG raised in goat In particular it 1) develops discriminant functions that effi- (Calbiochem). Apo A-IV polymorphism was visualised by ciently distinguish affected from normal individuals, and 2) developing the stain with 3,3' diaminobinzidine and hydrogen identifies and describes HED-specific facial anomalies. prioxide. In an analysis of 13 HED families with 16 known-affected, 12 known-gene carriers and 12 normal individuals, we have gener- A significant excess of Apo A-IV2(0.08) was observed in ated two discriminant functions (each based on 3 facial measure- CAD patients compared to that (0.04) in healthy controls ments taken either from the lateral-LA or frontal-PA cephalo- (X2 = 9.40), P 0.005). It appears that individuals with grams). These functions can correctly diagnose 100% of the Apo A-IV2 are more susceptible to develop CAD than Apo A-IV1 affected, gene carriers and normal relatives. The discriminat- individuals. ing ability of these functions were further tested on 4 obligate "gene carriers" and 12 known-affected cases. Only an elementary knowledge of cephalometric radiography is required to make this rapid and reliable morphometric facial diagnosis of the asymptomatic heterozygote females. Facial anomalies characteristic of the gene carriers were: (a) abnormally narrow and short maxillary width and depth dimensions; (b) very small and retrusive malar regions; (c) small head height, prominent forehead and high-set orbits; and (d) a generalized, symmetric reduction of the whole cranio- facial complex.

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Oral Facial Digital Syndrome (Type I) in a Male. DQN. Saer, C. Wilson, Type II collagen abnormalities in a bovine model of C.R. Medani. C.L.M. Keene and L.J. Raffel. University of Maryland achondrogenesis type II (Langer-Saldino). JA Sanford. J School of Medicine, Baltimore. The Oral Facial Digital Syndrome (OFD) is an association of Ellard. WA Horton. Univ of Texas Med. School, Houston. malformations including mild facial and oral findings with asymmetric Previous studies of growth cartilage have established the abnormalities of the digits (brachydactyly and syndactyly). At least four bulldog calf (BC) as a valid model of human achondrogenesis types of OFD exist, but only type I is associated with multicystic or type II. In both, type I collagen replaces type II collagen as the polycystic renal disease. It is thought to be an X-linked dominant trait; predominant collagen in cartilage extracellular matrix (ECM); OFD Type I has never been convincingly described before in a living male, their absence being attributed to prenatal lethality. the cartilage is composed of hypertrophic-like chondrocytes B.T. was the product of a 36-week gestation complicated by the prenatal with sparse ECM and extensive cartilage vascular canals. EM diagnosis of a fetal intra-abdominal cystic mass felt to involve the right shows distention of rough endoplasmic reticulum (RER) and kidney and its collecting system. No other anomalies were noted on abnormal collagen fibrils in the ECM. ultrasound. Amniocentesis demonstrated a 46,XY karyotype. A fetal To further elucidate the pathogenesis of the echocardiogram was normal. As the cystic mass enlarged, concern for achondrogenesis phenotype, we studied chondrocytes from BC pulmonary hypoplasia increased resulting in placement of a urinary diversion stent at 22 weeks. The stent appeared to function with a decrease in vitro. The chondrocytes were first dedifferentiated in in the size of the cystic mass for approximately 4 weeks. At this point the monolayer culture and then cultured separately 'in' and 'on' mass again enlarged but never to a size necessitating stent replacement. agarose gels; both agarose systems promote chondrocyte Amniotic fluid volume remained normal throughout and the patient differentiation similar to that which occurs during normal underwent serial ultrasound examinations. bone formation and growth. After 3 weeks, cell morphology of At delivery, the 2870 gram male demonstrated several malformations suggestive of OFD. The oropharynx exhibited partial clefting of alveolar the in agarose cultures resembled that of intact BC growth ridge with prominent bridging from the alveolar ridge to the buccal mucosa. cartilage: paucity of ECM containing thick irregular collagen The ears were low-set with prominent folding of the antihelix. There was fibrils and RER distention, neither of which was seen in wide spacing between the first and second toes of the right foot with normal calf cultures. Labeled collagen synthesized by cells brachydactyly and hypoplasia of all nails. The left foot was cleft with cultured on agarose showed that the collagen secreted into the absence of the second toe and there was complete syndactyly of the third media was mainly type I collagen while the collagen and fourth toes. There was syndactyly of the third and fourth fingers or the left hand, with absence of the second digit distal to the DIP joint. The right associated with the cells (presumably retained in RER) was hand demonstrated syndactyly of the thumb and forefinger as well as partial type II collagen. Most of the latter had slower electrophoretic syndactyly of the third and fourth digits. There was a contracture of the mobility than normal. Southern and Northern blot analysis PIP joint on the third digit. Bilateral shortening and hypoplasia of all distal done on DNA and RNA from the cultured BC chondrocytes digits and nails were present. Neonatal renal findings included multicystic showed no gross alterations in the size of the COL2A1 gene or dysplastic changes on the right with a right hydroureter. The left side demonstrated good function but with mild reflux. its mRNA transcripts. This appears to be the first case of a liveborn male with OFD type I. These data suggest that the achondrogenesis (type II) Alternatively, this case could represent yet another type of OFD or an phenotype may result from mutations of COL2A1 which entirely new syndrome. It is interesting to speculate if the prenatal interfere with the secretion and extracellular organization of diagnosis of fetal renal disease and subsequent intervention may have type II collagen. In this case, a small deletion/insertion or altered the natural course of this disease. point mutation that disrupts posttranslational processing is suggested so that a larger than normal or overmodified protein accumulates in RER. Clinical Genetics A63

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Campomelic Dysplasia confirmed by growth plate studies. Using Online Mendelian Inheritance in Man (OMIM) as an expert system in Medical A. Schneider and W. Horton. Hahnemann Univ. Hospital, Genetics. Daniel F. Schorderet, Univ. of Washington, Seattle. Philadelphia, PA and The Univ. of Texas Health Science Dr. McKusick's Mendelian Inheritance in Man (The Johns Hopkins University Center, Houston. Press) has been widely used among medical geneticists for many years. Since its Campomelic Dysplasia was diagnosed clinically in a newborn computerization 2 years ago however, OMIM has opened a completely new way of female who presented with cyanosis and apnea. Intubation was reading that book. Besides having continuous up-to-date information, this system required shortly after birth although Apgar scores were 7 and allows for easy and fast access, cross referencing and annotations. 9. X-rays confirmed the clinical examination. The infant I report here an attempt to use OMIM as an expert system in Medical Genetics. In maintained an opisthotonic posturing. Stridor remained a previous study (Am J Med Genet 28:-37,1987), I used the description of 100 audible during ventilation. dysmorphic cases to check the accuracy of SYNDROC a computer program Postmortem histologic and biochemical studies were especially developed for the diagnosis of human malformation patterns. From these performed and interpreted as normal. These findings are 100 cases, 7 dealt with chromosomal aberrations not covered by OMIM and were compatible with the diagnosis of Campomelic Dysplasia. therefore excluded from the present study. The description of the 93 remaining cases Death occurred at 23 days. A literature review and was used for searching OMIM. The mean uumber of signs (+/- 1 standard deviation) communications with several of the authors revealed that describing these cases was 8.1 +/- 4.5 signs. All the signs were typed in OMIM and approximately 10% of these patients survive infancy. Of the transactions recorded on a diskette and subsequently printed. For each search, these survivors, virtually all had continuing difficulties OMIM proposed a mean of 1538.8 +/- 692.2 diagnoses. In OMIM, each diagnosis is with aspiration pneumonia. These recurrent infections were accompanied by a weight from 100 to 1 depending on how well that diagnosis complicated by the development of scoliosis as the children answers the question. In order to deal with a more appropriate number of diagnoses, grew. Aggressive treatment with early tracheostomy has I only considered the diagnoses having a weight of 50 or more. With that restriction, shown an improved prognosis. However, lengthy hospitaliza- OMIM then proposed only 37.0+/- 24.6d agnoses. The overall accuracy was 76 %. tions for multiple orthopedic procedures result in repeated When one considers only the first propostd diagnosis, OMIM was correct 29% of intubations and ongoing problems in managing nutritional the time. This score jumped to almost half (44%) when the first two diagnoses were have considered. Considering the weight instead of the position is less useful; we would requirements. The frequent respiratory complications may have to include all the diagnoses having a weight of 87 or more in an adverse effect on the potential for normal intellect in order to achieve the above mentioned 44% accuracy with a consequently considerable increase in the these children. number of proposed diagnoses. As one c in expect from a bibliographic database, this study shows thatOMIM is less efficient in proposing a correct diagnosis than a true expert system. Two modifications however could dramatically increase OMIM's efficiency as an expert system: 1) inclusion of a clinical description for each entry using a specific and standardized thesaurus (10,000 signs should be enough) and 2) modification of the ponde -dtion system in a way that would take into account the frequency of the diagnoses.

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Magnetic resonance imaging in children with neurofibromatosis. Unbalanced male karyotype involving a translocation between E.K. Schorry and W.S. Ball. Children's Hospital Medical the long arms of chromosomes 18 and 21, consistent with tri- Center, Cincinnati, Ohio. somy 21 and monosomy 18p. N. Scribanu, J. Meck and J. Neurofibromatosis-l(NF-1) is a relatively common genetic Benkendorf. Georgetown Univ. Medical Center. disorder which frequently affects the central nervous system A male infant with both trisomy 21 and 18p monosomy was (CNS). The advent of Magnetic Resonance Imaging (MRI) has born at 30 weeks gestation to a 29 year old G3P2Abl mother, provided a new modality to examine the CNS of patients with whose pregnancy was complicated by polyhydramnios and prema- NF-1. We are presenting our data on MRI in a group of ture labor. Ultrasound studies performed at 25 weeks gesta- patients who were evaluated in a neurofibromatosis clinic. tion revealed findings consistent with duodenal atresia. Am- Forty-five patients with a diagnosis of NF-1 confirmed niocentesis performed subsequently revealed a fetal karyotype using the diagnostic criteria from the NIH Consensus Confer- 46,XY,-18,+der(18)t(18;21)(pll;qll). This karyotype was ence underwent MRI of the brain. MR scans were ordered consistent with trisomy 21 and monosomy for the short arm of routinely on all NF-1 patients at their first clinic visit as chromosome 18, and was later confirmed by blood studies per- part of our screening protocol. Only 7 patients (15%) had formed shorty after birth. The phenotypic features of our completely normal MR scans; 38 patients (84%) had various patient were predominantly those associated with trisomy 21: abnormalities noted. Five patients were found to have optic upslanting of palpebral fissures, flat facial profile, folded nerve gliomas. An additional 5 patients had dural ectasia of helices and posteriorly rotated ears, redundant skin at the the optic nerve. Two patients had astrocytomas, 1 patient nape of the neck, duodenal atresia, and marked hypotonia. had porencephaly, and 1 had a brainstem lesion with mass Peripheral blood chromosome studies performed on both parents effect. revealed that neither carried the translocation in a balanced The most commonly noted abnormalities on MRI were multiple form. The baby expired at 12 days of life due to the congeni- scattered focal areas of increased signal intensity on T2 tal anomalies. Literature search did not reveal any cases weighted images. These areas of increased signal were noted with similar karyotypic findings. Although epistatic behavior in 36 patients (80%). The regions most commonly involved of one chromosomal phenotype over the other has been observed included the basal ganglia, brainstem, and middle cerebellar in other complex chromosomal rearrangements, we speculated peduncles. These lesions typically showed no mass effect, that the potential additive effect of this deletion duplica- were not present on CT scanning, and were clinically asymp- tion complex could have a more deleterious effect on the over- tomatic. Their clinical significance is unknown; they have all development of this patient. been postulated at various times to represent hamartomas, vascular dysplasia, areas of demyelination, or gliosis. We did not find any difference in the age of the patient or the presence of learning disabilities between the group of patients with normal MRIs and those with abnormal MRIs. We did find, however, that of the 5 patients in the study with mental retardation (IQ(70), all of them had these areas of increased signal present on MRI. We feel that a larger study involving psychological testing and MRI is necessary to determine if these findings on MRI have any correlation with intellectual functioning in patients withNF-1. A64 Clinical Genetics (0244) (0245) 2.4

Cerebral venous thrombosis in a patient with Clinical, radiological and biochemical classification of heterozygous Protein C deficiency. S.D Shapiro. chondrodysplasia punctata. L.J. Sheffield, J.L. Halliday, C.W. Kisabeth. and F.W. TecklenburQ. Department D.M. Danks, J.G. Rogers, A. Poulos and N. Morrison. Murdoch of Pediatrics, Medical Univ. of South Carolina, Institute, Melbourne; Adelaide Children's Hospital, Adelaide; Charleston, South Carolina, U.S.A. Garvan Institute, Sydney, Australia. Protein C is a vitamin K-dependent serine 103 cases of chondrodysplasia punctata (CDP) seen in protease which possesses anticoagulating effects Melbourne over a 20 year period have been reviewed and by inhibiting factor V and VIII. Deficiency of classified according to clinical, radiological and biochemical this protein has been reported to be an grounds. 8 cases of rhizomelic CDP were seen and biochemical autosomal dominant trait with variability of abnormalities were found in the two who had tissues available expression. However with dominant inheritance for study. 21 cases of Conradi-Hunermann CDP were seen and there appears to be clinical differences with the difficulty of defining this subcategory will be discussed the homozygote and heterozygote genotypes. The in the light of the knowledge that many of the criteria for homozygous state has been associated with severe diagnosis are actually those of X linked dominant CDP. 2 cases disease in neonates including intracerebral of X linked dominant type are described and no definite X thrombosis and purpura fulminans but the linked recessive types were seen. The most common type was the heterozygous state is generally believed to be Mild type of CDP and cases of Binder Syndrome were categorised associated with only minor thrombotic events in here as well. 57 cases of Mild type were seen including 9 due later life. We would like to report a family in to phenytoin exposure during pregnancy and 3 cases due to which there are two affected heterozygous Warfarin embryopathy. 2 cases were classified as mesomelic, a Protein C deficient individuals. The proband, new subclassification. There were 13 cases not classifiable. an eight week old white female presented with All types were investigated biochemically. Only the multi-focal clonic seizure activity. Evaluation rhizomelic type were found to have abnormalities of perixosomal with head C-T and carotid angiogram showed function. Conradi-Hunermann and some mild types were found to thrombosis of the internal cerebral veins, have abnormalities related to serum osteocalcin levels and the straight sinus, sagittal sinus and the vein of possible metabolic error is discussed. The serum osteocalcin Galen. Further work-up showed normal level may be a way of separating out the two types. coagulation factors but markedly low Protein C in this patient and the proband's mother, who had a deep vein thrombosis associated with one of her previous pregnancies. The proband appears to be the first heterozygote of Protein C deficiency to have deep cerebral vein thrombosis. This case suggests that heterozygotes may be severely affected. Further identifications of heterozygotes may demonstrate variability of expression of this gene not appreciated in the current literature.

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Behavior, cognitive and psychiatric sequelae in tuberous sclerosis.

WITH DRAWN S. L. Smalley, M. Smith, R. F. Asarnow, & M. A. Spence. University of California, Los Angeles and University of California, Irvine.

Tuberous sclerosis is an autosomal dominant disorder with variable expression and genetic heterogeneity. Clinical features include abnormal tissue growth of many organs including brain, skin, nails, eyes, heart, and kidneys. Although seizures and mental retardation are often present in tuberous sclerosis, there is little known about specific cognitive deficits, behavioral problems, or psychiatric sequelae although increased frequencies of autism, hyperactivity, and language deficits have been reported. We examined two distantly related, extended kindreds in which the tuberous sclerosis gene is segregating for the presence of psychiatric disorders as well as cognitive deficits in memory, attention, language, and visuo-spatial ability. We identified several cases of schizotypal Dersonality disorder based on the Millon Inventory (MCMI) as well as one case of probable auitism based on the Autism Behavior Checklist. Results from analyses of clinical and behavioral measures examining the degree of variable expression of the tuberous sclerosis gene in this kindred will be presented. Clinical Genetics A65

(0248) 4.1 (0249) 1.136 Craniofrontonasal dysplasia (CFND): Continuing evidence for Genetic Linkage Analysis of Twenty Families with Specific Johnson's metabolic interference hypothesis for an X-linked Reading Disability. S.D. Smith, W.J. Kimberling. Y.Y. Shugart. locus. A.C.M. Smith, D.K. Manchester, P. McBogg. Children's Hosp.. Denver. P.S.Ing. and B.F. Pennington. Boys Town National Research Rollnick et. al. (AJHG 33:823-826,19811 proposed that W.G. Hospital, Omaha, NE and Univ of Denver, CO. Johnson's hypothesis of metabolic interference [AJHG 32:374- Specific reading disability (SRD) can be inherited as an 386, 19801 could explain the unusual inheritance and phenotypic autosomal dominant. Previous research has suggested some variability of craniofrontonasal dysplasia (CFND). In support of this hypothesis, we describe a new 3 generational family with families with SRD show linkage to the short arm/centromere of CFND. chromosome 15. This study tested DNA polymorphisms on 15, CFND is a distinct syndrome which affects females more plus markers on other chromosomes, to confirm the linkage with severely than males. The phenotype in females includes 15 and to determine if heterogeneity exists. A total of 20 SRD hypertelorism, broad nasal root and/or grooved nasal tip, craniosynostosis (coronal), frontal bossing, syndactyly of fingers families have now been studied. All informative family members and toes and longitudinally grooved nails. Craniosynostosis is have been typed for chromosomal variants and the DNA not seen in affected males, whose milder phenotype includes polymorphisms DiSS1, D15S2, D15S3, and D1524. One family' increased interorbital distance, hypertelorism, broad nasal root, has a LOD score of 3.215 between SRD and 15p broad great toes, and grooved nails. The inheritance of CFND has been unclear. X-linked dominant inheritance has been heteromorphisms. The total LOD score from all families suggested based on published pedigrees which show transmission maximized to 1.742 at a recombination of 30%. The from affected fathers to all of their daughters but to no sons. heterogeneity analysis resulted in a significance level of 0.002. The existence of mildly affected males without craniosynostosis This should be less than 0.001 in order to accept heterogeneity in CFND families argues against classic X-linked dominant inheritance. Furthermore, an altered sex ratio has been observed (Ott, Analysis of Genetic Linkage, 1985). Multipoint analysis of in several families which cannot be explained by simple chromosomal and DNA markers revealed that the DNA markers mendelian genetics. were too distant from the centromere/short arm to be useful in In a new family with CFND, the paternal grandmother and the heterogeneity analysis. Families were also typed and analyzed female proband present with craniosynostosis and features of CFND; the proband's father is normocephalic with ocular for three loci on chromosome 6 : BF, Glyoxylase (GLO), and hypertelorism and slight widows peak. Further, the original D6S8. With multipoint mapping, a maximal LOD score of 1.71 family reported by Slover and Sujansky IBDOAS XV(5B):75-83. was obtained at approximately 10 cM proximal to GLO. children whom we have also 19791 has had 5 additional (G8P8) Hetergeneity analysis was not significant for the chromosome 6 had the opportunity to evaluate. The additional 2 daughters are both affected like their 3 sisters and have had craniectomies; all markers (p = 0.02). Families with positive scores for 3 sons are normal, without evidence of CFND. These 2 families chromosome 15 showed no evidence of linkage with chromsome 6 coupled with previously reported pedigrees of CFND are best and families with positive scores for 6 showed negative or with an X- explained by the metabolic interference hypothesis equivocal scores with 15. Additional DNA markers on linked locus. Families with CFND may provide material with which to test this hypothesis in humans. chromosome 6 are now being typed in order to clarify this possible linkage. (Supported by USPHS grant HD11681).

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A case of gonadal agenesis associated with cardiac and pul- Detection of early signs of vascular disease in monary malformations. C.K. Steigman, A.K. Uri and J.G. Davis heterozygotes for cysthationine f-synthase Children's Hospital of Philadelphia,PA, and The New York Hos- deficiency. pital-Cornell Medical Center, New York,NY. P.StrisciuqliQ', R. Carrozzo, R.- Sartori 'X G- We report an instance of gonadal agenesis in the setting Andria°. P. Rubba-, E.acna .,edUciullo-, of cardiovascular and pulmonary malformations, an association L. Carbone. M 1ancini. not previously described. A 2780g, nondysmorphic phenotypic Depts. of Pediatrics, Universities of 'Naples female was born at term. Pre- and postnatal karyotypes were and *Reggio Calabria, -Institute of Internal 46,XY without mosaicism. Endocrinologic studies did not sup- medicine and Metabolic Disease, University of port the clinical diagnosis of testicular feminization. Naples, Italy. Evaluation for cyanosis at 2 days of age demonstrated mitral Heterozygous status for cysthationine 3- and aortic atresia, consistent with hypoplastic left heart synthase (CBS) deficiency has been reported to syndrome(HLHS). The infant died during palliative surgery be associated to an increased risk for premature at 10 weeks of age. vascular disease. We studied 12 heterozygotes At autopsy, cardiac pathology was typical of HLHS. The (aged from 22 to 67) and 46 age and sex matched right lung was unilobate and hypoplastic (55% of expected healthy controls. A continous wave Doppler was weight). The urinary system, external genitalia, and vag- used for the determination of systolic ankle inal introitus were normal. There was no cervix, but there pressure and for a non-invasive investigation of was a pelvic midline viscus contiguous with the vagina and the deep venous system of the legs. Echo-Doppler entirely lined by squamous epithelium. This structure bi- examination of carotid, iliac and femoral furcated into a small right cornu lined by columnar epithel- arteries was performed by a Duplex scanner (ATL, ium and an atretic left tornu. The cornua tapered into tub- USA). Mean ankle/arm pressure ratio was reduced ular structures histologically resembling vasa deferentia, in heterozygotes as compared to controls (p< terminating over the inferior poles of the kidneys. No 0.05). Echo-Doppler abnormalities of the iliac gonads were seen, although epididymis-like tubules were pres- and carotid arteries (wall irregularities, all ent on the right. not flow reducing) were detected in 6 and 4 Gonadal agenesis is an unusual type of aberrant sexual heterozygotes, respectively. Echo-Doppler development, occasionally associated with minor somatic examination of femoral and popliteal arteries abnormalitites and rarely reported in sibships. This case gave abnormal results in I heterozygote. Deep may represent syndromal gonadal agenesis and warrants consid- venous insufficiency, suggesting previous deep eration of the various teratogenetic processes that could venous thrombosis, was detected in 1 subject. In give rise to this malformation complex. conclusion our results demonstrated vascular abnormalities in 6 out of 12 heterozygotes as compared to 5 out of 46 helthy controls. These data demonstrate vascular abnormalities in a relevant number of heterozygotes for CBS deficiency as compared to healthy controls with the same age and gender distribution (p<0.02). A66 Clinical Genetics (0252) (0253) 1.139

New Monogenic Disorders in a Mixed Arab Population. Clinical problems associated with presymptomatic testing for Huntington's disease. A Tyler. M Morris. LP Lazarou. A.S.TEEBI, T. I.FARAG. AL Meredith. PS Harper. Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UK. Medical Genetics Centre POB 36660 Raas 24757 Kuwait. A series of referrals has been accepted for presymptomatic testing for Huntington's disease (HD) The population of Kuwait (1.7 million) is character- from Wales and the south of England. Entry to the study is conditional on a verifiable family history and a ized by wide ethnic heterogeneity, large sibship potentially informative family structure. Applicants size, high average inbreeding coefficient, existence should be aged over 18 years and be at 50% a priori of genetic isolates and Bedouins, and in general risk. Of 187 referrals, 57 have been excluded for high frequency of autosomal recessive disorders. reasons such as age under 18 years and not at 50% risk. Over the past 7 years several new mendelizing gene As part of the preliminary analysis of this series, we disorders have been delineated here most of which have analysed a wide range of practical problems encountered and these may be classified as those are also autosomal recessive. I-AUTOSOMAL RECESSIVE: occurring before, during and after presymptomatic Limb-pelvis/hypoplasia-aplasia (Al-Awadi), Grebe- testing. Examples of problems occurring before testing like, Kniest-like, Osteoporosis-pseudoglimoa (?vari- are inappropriate referrals, family history not established and counselling of the affected applicant, ant), Acromesomelic-like, pseudodiastrophic-like, the "suspicious" applicant and the applicant who is Rizomelic dwarfism, Weaver-like, Macrosomia-micro- unaware of affected family members necessary for the phthalmia, Craniofacial-hair-finger-caudal, Bedouin test. The main problems occurring during the testing process concern collection of blood samples; they spastic ataxia, Microcephaly (variant), Anencephaly include refusal to donate samples, inadequate labelling, (variant), Hydrocephalus, 2 Hypogonadism syndromes, applicants who use pseudonyms and wastage or degradation MCA/MR syndrome, Faciodigitogenital Mandibuloacral of samples. Other pitfalls are unintentional risk dysplasia (variant), Hypertelorism-hypospadias-poly- alteration and inadvertent disclosure of the diagnosis of HD. Problems after testing are requests from third syndactyly, Hypertelorism-hypospadias-Fallots parties for the result of the test and refusal of tetralogy, and Ehler-Danols (variant). II-AUTOSOMAL follow-up by applicants. Full documentation of this wide DOMINANT: Hypoplastic tibiae-postaxial polysyndacty- range of problems should be of help to other centres ly, Hypertelorism (Teebi type), and Stomach-Sneeze embarking on presymptomatic testing. disorder. III-X-LINKED: Frequent relapser minimal change nephrosis. Although a few appear to be "Private syndromes", they are probably existing more frequently among Arabs (200 million) and other un- studied populations. The apparent increased incidence of new disorders observed here calls for persistent and careful work to help more characterization, estimate the actual frequencies, and plan for pre- vention and treatment.

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5' Insulin gene polymorphism and the genetics of vascular Treatment of chondrodystrophic myotonia (Schwartz- complications in IDDM. C. Vadheim. L.J. Raffel. M-P. Roth. R. Jampel syndrome) with diphenylhydantoin. D. T. Vine Klein. S.E. Moss. J.I. Rotter. Medical Genetics, Cedars-Sinai and A. M. Strongwater. Hospital for Joint Diseases- Medical Center, Los Angeles, CA; University of Maryland Orthopaedic Institute, New York, N.Y. School of Medicine, Baltimore; University of Wisconsin, Chondrodystrophic myotonia or Schwartz-Jampel syn- Madison. drome is characterized by an immobile mask-like face, Recent data suggest genetic contributions to the blepharophimosis, microstomia, widespread limitation microvascular complications of IDDM. Most research has of joint movement, osteochondrodysplasia, and myo- focused on the HLA region, and the potential role of other tonia. Because of the myotonic discharges, treat- genetic loci has not been adequately explored. We examined ment with membrane stabilizing drugs, such as di- the possible relationship between DNA polymorphisms in the phenylhydantoin and procainamide has been attempted region 5' to the insulin gene on chromosome 11 (5' IP) and by several investigators. Mixed results have been diabetic nephropathy and/or proliferative retinopathy. This reported with clinical improvement being noted by was done by comparison of those diabetics homozygous for some, but not by others. No objective parameters to class 1 alleles at the 5' IP locus to 1/3 heterozygotes, in a assess the effect of drug treatment on the patients' well-characterized series of 425 insulin requiring diabetics gait were used. We treated a 5 year-old girl with from the Wisconsin Study of Diabetic Retinopathy (WESDR). Schwartz-Jampel syndrome who had been experiencing Presence or absence of proliferative retinopathy was increasing gait difficulties, with diphenylhydantoin. assessed using a modified Arlie House protocol. Proteinuria, Diphenylhvdantoin was administered at 8.8 mg/kg dai- defined as >30 mg protein/dl, was used as suggestive evidence ly in two divided oral doses, to achieve a serum for diabetic nephropathy. Hypertension, a frequent associated phenytoin level of 10.7 mg/l. Computerized motion finding in diabetic patients with nephropathy, was defined as analysis was performed before and after treatment a history of previous treatment for hypertension. The two was instituted. These studies demonstrated a signi- genotypically defined groups did not differ from each other ficant increase in dynamic range of motion at the in regard to sex ratio, age at diagnosis, age at examination, hips and knees, and an increase of the step length, duration of diabetes, body mass, HbAlC or C-peptide. There and stride length, resulting in a 30% increase in was no difference in frequency of proliferative retinopathy forward velocity, following maintenance of the pa- between the 1/1 and 1/3 5' IP genotypes. In contrast, the tient on the above dose for one month. In addition, 1/1 group had a higher prevalence ofjroteinuria, 24.2% as the ratio of stance to swing time as a percentage of compared to 10.9% in the 1/3 group (X =6.6; p<0.01). the gait cycle decreased from 72%/28% to 64%/36%. Although there was no difference in systolic or diastolic Although the gait parameters remained markedly ab- blood pressure at the time of exam, the prevalence of normal for a child of her age, definite improvement hypertension by history was also greater in the 1/1 group. was present. The patient has now been maintained on These findings suggest that the 5' IP may be associated with diphenylhydantoin for 15 months with continued risk for nephropathy and/or hypertension, but does not appear clinical response and no adverse reactions. These to have an etiologic role in proliferative diabetic studies provide objective evidence for improvement retinopathy. Thus, separate genetic factors may contribute to in mobility in a patient with Schwartz-Jampel syn- different diabetic vascular complications. drome with use of phenytoin. Clinical Genetics A67 (0256) (0257)

Rhizomelic chondrodysplasia punctata and survival beyond one CONGENITAL MUSCULAR DYSTROPHY: WEAT IS THE year: A review of the literature and five case reports. SPECTRUM? A REPORT OF AN ATYPICAL CASE. D.S. T. D. Wardinsky, R. A. Pagon, B. R. Powell, B. McGillvray, M. Wargowski. D. Chitayat. R.W. Tyson, E.W.Y. Ling. Stephan and J. Zonana. Children's Hospital and Medical and M.G. Norman. Univ. of British Columbia. Center and Univ. of Washington School of Medicine, Seattle; Congenital muscular dystrophy (CMD) is often Oregon Health Sciences Univ., Portland; Univ. of British associated with abnormalities of the central Columbia, Vancouver; Madigan Army Medical Center, Tacoma, WA. nervous system and eyes. We report a case of Rhizomelic chondrodysplasia punctata (RCDP) is a lethal lethal CMD with brain and eye abnormalities not autosomal recessive peroxisomal disorder. We report five previously described in this context. patients with RCDP, all of whom had shortening of the The patient was a term AGA male infant who was proximal limbs, punctate stippling of long bone epiphyses and flaccid and had minimal respiratory effort at deficiency of plasmalogen synthesis. Three survived beyond birth. He had multiple contractures, bilateral one year. All five patients had (1) microcephaly with cataracts and dysmorphic facial features. Major growth failure and feeding problems; (2) severe psychomotor CNS lesions, inborn errors of metabolism, intra- retardation with immobility and no communication skills; (3) uterine infection, and associated nephropathy were hypertonicity, spasticity, and large joint contractures. excluded. The chromosome analysis and placental Additional findings were progressive cataracts (3/5); histology were normal. The baby died on the fourth kyphoscoliosis (3/5); recurrent respiratory infection (3/5); day of life of respiratory failure. On autopsy the seizures (3/5); sensorineural deafness (2/5); optic nerve skeletal muscles were noted to be markedly hypotro- hypoplasia (1/4); ichthyosis (1/5). Although the prognosis phic and had a yellow fatty appearance. Histologic for growth and development was poor in all RCDP patients, our examination revealed extensive perimysial and endo- study did not identify phenotypic features that, in and of mysial fibrosis, fatty replacement, naked myofiber themselves, predicted long term survival. nuclei, empty myofibers without macrophage infil- Some of our patients had features atypical for RCDP. tration, and focal regenerative features. Examin- Three had no radiographic evidence of vertebral body clefts, ation of the brain revealed a focal parieto- a finding which has previously been considered invariable in occipital defect of the cortical molecular layer. RCDP. Three had distinctive facies with a bullous nasal tip No pachygyria, agyria, polymicrogyria, heterotopia that differed from the hypoplastic nares seen in Conradi- or ventricular abnormalities were seen. The eyes Hunermann syndrome, which is a distinct chondrodysplasia showed posterior lens calcifications with retention punctata. of the lens fiber nuclei and signs of mild chronic inflammation of the iris. This patient's muscle histopathology is typi- cal of CMD, but his eye and brain findings have not been previously described in association with lethal CMD. The different CMD syndromes may represent variable expression of the same genetic abnormality. However, the severity of the myopa- thy and the unique eye and brain changes in this case raise the possibility that this is a new syndrome with a different genetic basis.

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THE STORM SYNDROME: A NEW, PLEIOTROPIC, AUTOSOMAL Molecular basis of clinical heterogeneity in nonlethal DOMINANT DISORDER AFFECTING CONNECTIVE TISSUE. variants of osteogenesis imperfecta (OI): distinct HF Weisman, NS Gaither. J Moore. KM Rgan, DB Hellmann, biochemical phenotypes predict clinical outcome. R.J. VA McKusick & RE Pyeritz. Johns Hopkins Univ School of Medicine, Wenstrup. M.C. Willing. B.J. Starman. and P.H. Byers Duke Baltimore, MD, & Walter Reed Army Medical Center, Washington, DC. University, Durham, NC and Univ. of Washington, Seattle. To determine the diagnostic effectiveness of Five generations of a family of German ethnicity show a consistent and biochemical analysis of type I collagen in nonlethal OI pleiotropic phenotype. The most striking and clinically important and to determine whether correlations between biochemical manifestation is early, progressive, calcific cardiac valvular degener- findings and clinical severity could be made, we reviewed ation: 4 relatives have died by age 40 y of this problem, and 2 have clinical and biochemical findings from 132 nonlethal OI required mitral valve surgery by age 30 y. Some adults develop atrial probands whose fibroblasts were sent to the University of and ventricular dysrhythmia. Two children show atrioventricular valve Washington in the years 1981-1987. In cells from 87% of thickening, annular calcification and mild mitral regurgitation. Loss probands with nonlethal OI we identified alterations in of eyebrows and eyelashes and thinning of scalp hair begins in adoles- the amount or structure of type I procollagen molecules cence. Skin over the hands and face becomes taut, palmar skin becomes due to dominant mutations in the genes that encode one of excessively wrinkled and dermatofibromas develop on the limbs. Several the chains of type I collagen. Two major biochemical young adults show a polyarticular arthropathy and intestinal fat malab- phenotypes were identified by SDS-polyacrylamide gel sorption. Normal studies thus far include all tests of coagulation and electrophoresis of 3(H)proline-labeled proa and a chains. rheumatologic and immunologic function. Biochemical and ultrastructural Group A: cells from forty probands synthesized studies of the extracellular matrix are in progress, and it remains approximately half the normal amount of type I unclear whether this condition is a primary or a secondary disorder of procollagen with no identifiable abnormal molecules. connective tissue. Transmission of this phenotype is most consistent These patients had OI type I: only 13% had short with autosomal dominant inheritance. We propose the eponymous stature, 8% had long bone deformity and 9% had designation 'Storm syndrome" after the patriarch. dentinogenesis imperfecta. Group B: cells from sixty- nine probands produced and secreted both normal and abnormal populations of type I procollagen molecules. These patients had OI type III or type IV: 91% had short stature, 84% had long bone deformity, and 77% had dentinogenesis imperfecta. In addition, cells from 5 patients with variable phenotypes synthesized a population of type I procollagen molecules with atypical abnormalities. We were unable to identify altered type I procollagen synthesis or structure in cells from 18 probands, all with moderate to severely deforming OI phenotypes. Biochemical testing has value in the diagnosis of nonlethal OI and can, by distinguishing between mutations affecting quantity or structure of type I collagen, aid in prediction of clinical outcome and in determination of mode of inheritance. A68 Clinical Genetics

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Treatment of tienkes disease with cupric chloride Linkage Analysis of Usher Syndrome with markers on L-histidine. J.A. Westman and G. Morrow. Children's Chromosome 1. M.D. Weston, WJ. Kimberling. and M. Temp. Hospital and The Ohio State Univ., Columbus. Cupric chloride L-histidine (CCLH) was used to treat 10 Boys Town National Research Hospital, Omaha, NE. children with Menkes disease. Menkes disease is an Usher Syndrome is an autosomal recessive disease characterized X-linked recessive disorder with growth retardation, by congenital hearing loss, progressive retinitis pigmentosa and peculiar hair, focal cerebral and cerebellar degeneration, involvement of the vestibular system. Genetic heterogeneity may irnitability, bladder diverticulae, and death usually the clinical variation observed with this disorder. The two within the first few years of life. A defect in copper explain metabolism is presumed to be the basis for the disease. most common subtypes of Usher Syndrome are Types I and II. Eight children were enrolled in a prospective study to Together they comprise approximately 90% of all Usher Syndrome evaluate the effect of CCLH on temperament. Two children patients. To test the genetic heterogeneity hypothesis, our group withdrew from the study prior to re-evaluation at 6 months. a term gene Three individuals died (mean age 18.3 months, range 16-22 has started long study of this disease which includes months) pricr to re-evaluation; two from urinary tract mapping through the use of RFLPs and linkage analysis. disorders and one from post-operative complications. One Extensive clinical studies have been done on 59 families 2 of life and child has been treated with CCLH since day cooperating in this longitudinal study. To date, DNA samples on has demonstrated excellent psychomotor development with were independent sitting, hands crossing the midline, and a 30 families have been collected. Four families excluded 2-word vocabulary by 8 months of age. Normal serum copper from the linkage study because a clear subtype diagnosis could and ceruloplasmin levels were present after I month of not be made. Of the others, 20 were diagnosed as Type I and 7 therapy in all patients. No serious adverse reactions were as Type II. A preliminary set of 7 genetic markers on noted. The Carey Infant Temperament Scale was completed by were a parent every 3 months. The mean change for the study chromosome 1 tested for linkage with the disease. The population was -1.41 + 4.30 standard deviations indicating markers are FY, RH, PGM1, PGD, NGFB (pN8C6), PND a trend towards an "easier" personality. The 2 patients (pJA110) and DIS4 (pDR78). The results of pairwise linkage who withdrew from the study were the only 2 whc indicated analysis using MLINK excluded both subtypes of Usher Syndrome progression towards a more 'difficult" personality. There is no evidence from this study that treatment with CCLH from close proximity around those markers. More DNA markers reverses existing damage in the central nervous system or included on a recently published multi-point map of chromosome in the bladder. It seems likely that copper therapy has 1 are currently being typed. (Supported in part by USPHS grant little major effect on a patient past a certain age NS19624 and by a grant from the Retinitis Pigmentosa and threshold. This study is the first to document a possible improvement in temperament with CCL.H therapy and may George Gund Foundations.) suggest the use of CCLH as an adjunct to facilitate management of the patient by the caretaker.

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Nephrocalcinosis in a Young Child with Williams Syndrome: Hypotrichosis with spondyloepimetaphyseal dysplasia in three Diagnosis and Management. D.A.H. Whiteman, R.A. D'Arcangelo, generations: a new autosomal dominant syndrome. Michael P. N.D. Adams & D.W. Rowe. University of Connecticut Health Whyte, Deborah J. Petersen and William H. McAlister. Center, Farmington. Metabolic Research Unit, Shriners Hospital, and Departments of Nephrocalcinosis (NC) has been reported from Britain in the Medicine, Pediatrics, and Radiology, Washington University past in children with the Williams/Infantile Hypercalcemia School of Medicine; St. Louis, Missouri. Syndrome (WS), but has rarely been reported in children with Hypotrichosis occurs with skeletal dysplasia in several WS in North America. We have studied a boy in whom renal conditions; e.g., cartilage-hair hypoplasia, chondrodysplasia failure (BUN 43 mg/dl;serum creatinine 1.4 mg/dl) with dense punctata, and trichorhinophalangeal syndrome. We describe a NC on ultrasound was present when diagnosed at 14 mo. with WS. new entity of hypotrichosis with spondyloepimetaphyseal Family, maternal health, maternal dietary, pregnancy and dysplasia that is transmitted as an autosomal dominant trait. neonatal history were unremarkable. At 2 weeks a cardiac Four affected individuals in 3 generations, wherein male- murmur was heard, but repeated echocardiograms have been to-male transmission was documented, are affected by reported as showing no significant cardiac abnormality. At 14 rhizomelic short stature and marked lifelong hypotrichosis mo., WS was diagnosed based upon characteristic facies and without other ectodermal abnormalities. In these subjects, growth and behavioral delays. Careful review of feeding skeletal manifestations become clinically apparent during history was unremarkable. Serum calcium, phosphorus, alkaline early childhood and involve predominantly limited abduction of phosphatase, N-terminal parathyroid hormone, calcitonin and the hips. Rhizomelia affects the upper extremities more 25-OH-Vitamin D levels were normal. 1,25-(OH)2-Vitamin D was severely than the lower extremities. Mild genu varum low (5 pg/ml). Radiographs showed no alteration of pattern of deformity is also commonly present. Arthralgias appear to mineralization, or ectopic calcification. High resolution complicate the skeletal disease during late adult life. cytogenetic analysis was normal. Radiographic studies show rhizomelic shortening of long Baseline urinary calcium excretion was elevated (2 mg/kg/d) bones with metaphyseal flaring and irregularity and epiphyseal with an elevated calcium/creatinine ratio (0.25). Tubular ossification delay and irregularity. The changes in the long phosphate reabsorption was low (0.77). Urinary citrate and bones are greatest in the proximal limbs and most marked in oxalate were normal. Following an oral calcium load (16.5mg/kg the proximal femora. The metaphyses become more irregular single dose, as whole milk), serum values were unchanged, but with age and develop defined lytic areas. The mineral content urinary calcium excretion increased to 71 mg/kg/d, with a of the skeleton elsewhere is normal. Pear-shaped vertebral calcium/creatinine ratio of 2.46. After 5 months on a calcium bodies with increased vertical heights anteriorly are apparent restricted diet, NC was unchanged ultrasonographically, but in the thoracolumbar spine. Accordingly, this is a form of BUN and serum creatinine had normalised, and age-normal linear spondyloepimetaphyseal dysplasia wherein the vertebral changes and weight growth velocity had resumed. Serum calcium had are more subtle than are the abnormalities in the long bones. fallen from 10.6 mg/dl at diagnosis to 9.7 mg/dl. Urinary Routine serum biochemistries are normal. Conventional calcium excretion remained at his baseline level. Giemsa banding chromosonal studies are unremarkable. These observations suggest that NC in this child with WS might be due to a primary defect in calcium absorption and excretion, not mediated by any classical calcium endocrine disorder. Clinical Genetics A69 (0264) 4.6 (0265) 1.145 A genetic study of classical ataxia telangiectasia. A third black family with possible Joseph-Machado disease C. G. Woods, S. Bundey, A. M. R. Taylor. Departments of of non-Portuguese origin. L.G. Wrabetz*, J. Kamholz*, D.M. Clinical Genetics and Cancer Studies, University of Mcdonald', C.D. Andersonl1, D. Romanoff§, and E.H. Zachai'. Birmingham, Birmingham, UK. Department of Neurology*, Hospital of the University of We studied 45 families from throughout the UK in whom Pennsylvania; Division of Human Genetics and Molecular there was at least one living member with ataxia Biology", Children's Hospital of Philadelphia; Department telangiectasia (AT). These families contained 47 index of Medical Genetics11, Thomas Jefferson University Hospital; cases (26 males and 21 females); 11 out of 77 sibs also had Department of Medicine§, Inglis House; Philadelphia. AT; no other relative was affected; no patient had a child; Joseph-Machado disease is an autosomal dominant hereditary one set of parents was half-first-cousins. There was ataxia reported in Portuguese families or descendents of no clinical evidence for heterogeneity among the index Portuguese families from the Azore Islands. Two previously and secondary cases. All but six of the healthy sibs were reported black families and three Japanese families with clinically examined and had radiation studies performed on a similar clinical syndrome have no known Portuguese ancestry. lymphocytic chromosomes. There was no suggestion of We report a black family with onset in the late second or increased fetal loss, nor of unexplained childhood deaths, early third decade of progressive generalized dystonia, spasticity, to suggest that further sibs had been affected, nor was supranuclear loss of vertical gaze, and proptosis. The affected there any family limitation after the birth of the index family members have normal intelligence and no evidence case. The incidence of affected sibs is significantly less of cerebellar ataxia. Brainstem and cerebellar atrophy are than the 25% expected if all patients had an autosomal demonstrated on CT and MRI scan. Pedigree analysis suggests recessive condition, and we suggest that earlier studies that the disease segregates with an autosomal dominant pattern which found a high incidence in sibs did so because they of inheritance. Two generations of this family are affected were based on literature reports biased towards familial including the mother and six of her eight children. None cases. We suggest that other forms of inheritance account of her nine grandchildren are affected, the oldest now age for some cases of ataxia telangiectasia. 16. Her family originated in Tupelo, MI and is apparently unrelated to the two other previously reported black families with presumed Joseph-Machado disease. HLA haplotype screening of the largest of the three generations did not demonstrate linkage. This family in combination with the other previously reported families with non-Portuguese Joseph-Machado disease may be useful in searching for a marker for this subtype of autosomal dominant hereditary ataxia.

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Facio-auriculo-vertebral Spectrum with the MALIGIANT MELANOMA IN MULTIPLE LENTIGINES Rokitansky Sequence: The Axial Mesodermal (LEOPARD) SYXDROME. S.L. Yong, A.Z. Lozinski, Dysplasia Spectrum? E. A. Wulfsberg and T. M. D.I. McLean, A.J. Worth. Dept. of Medical Grigbsy. National Naval Medical Center, Bethesda, Genetics, Univ. of British Columbia, Div. of Maryland. Dermatology and Pathology, Cancer Control Agency A three year old identical twin girl was born with of British Columbia, Vancouver, B.C. Canada. a hypoplastic left face, hypoplastic left mandible A 26 year old male with Multiple Lentigines and zygoma, left microtia without an external (LEOPARD) Syndrome developed fatal malignant auditory canal, Robin type cleft palate, crossed melanoma. In addition to multiple lentigines he fused right renal ectopia, blind vaginal pouch and had mental retardation, sensorineural deafness, absent uterus. These typical features of the craniofacial dysmorphism and skeletal anomalies. Facio-auriculo-vertebral Spectrum and the Echocardiograms, EKG and chromosome analysis were Rokitansky Sequence have been reported together normal. Family history was non-contributory. twice before. Russell et al. in 1981 in reporting Biopsy of the right clavicular lesion revealed a case of the Goldenhar Syndrome and the Caudal a high grade, mitotically active, predominantly Regression Syndrome used the term Axial Mesodermal epitheloid malignant melanoma with a depth of 4.5 Dysplasia Spectrum to describe patients who have m. He had a wide excision and right radical overlapping features of the Facio-auriculo- neck dissection and one lymph node was positive. vertebral Spectrum, Cardiofacial Syndrome, CNS and chest wall metastases were diagnosed 3 Wildervanck Syndrome, Klippel-Feil Anomaly, MURCS months later. Association, Rokitansky Sequence, VATER Extensive histologic examination of his Association, Potter Complex, Caudal Regression, pigmented lesions revealed a spectrum of findings and Femoral Hypoplasia Unusual Facies Syndrome. ranging from benign lentigines to benign Two of these conditions, the Wildervanck Syndrome junctional intradermal and compound nevi to and the MURCS Association can be described as lesions with melanocytic atypia and architectural overlapping associations of previous conditions in features of dysplastic nevi through to invasic this group. The Wildervanck Syndrome being an malignant melanoma. We submit that contiguous association of Klippel-Feil Anomaly and the benign, atypical, dysplastic and malignant Facio-auriculo-vertebral and the MURCS Spectrum lesions, suggest an evolution from the former to Association being an association of the the and the latter. We recommend monitoring the Klippel-Feil Anomaly Rokitansky Sequence. pigmented lesions of Multiple Lentigines Syndrome The anomalies in all these disorders can be for dysplastic or malignant change. thought of as deriving from defects of fetal mesoderm or its progenitor tissue the primitive streak. The importance of recognizing the Axial Mesodermal Dysplasia Spectrum is to encourage the search for defects of other developmental fields spatially separated from the original defects. We review the Axial Mesodermal Dysplasia Spectrum and discuss how it relates to our patient and other patients with multiple mesodermal malformations. A70 Clinical Genetics/Clinical Cytogenetics (0268) 1.146 Micropenis and Polydactyly Associated with Multiple Sulfatase Deficiency. J. L. Zenger, W. B. Rizzo, and J. N. Bodurtha. Va Commonwealth Univ./Medical College of Virginia, Richmond. We report a white male child with polydactyly, micropenis, and multiple sulfatase deficiency (MSD). The patient was a 3125 gm term product of an uncomplicated pregnancy without known drug or infectious exposure to a 26 yo G1 PO female. Patient presented at birth with micropenis, postaxial polydactyly, syndactyly,, limited supination at elbows, an alveolar frenulum, long eyelashes, and squared ears. Chromosomes were normal 46, XY. A tentative diagnosis of Bardet- Biedl syndrome was made. Family history is positive for delayed puberty in a paternal grandfather and negative for consanguinity. At 5 months the patient developed a severe respiratory syncitial virus infection, and selective IgA and primary gonadotropin deficiencies were found. He was noted to have hepatosplenomegaly, but a normal ophthalmologic exam. Mucopolysaccharide (MPS) screen was positive in one of 3 urine specimens. Questionable seizures occurred at 6 months. Re- evaluation at 17 months revealed recurrent respiratory infections, hypotonia, loss of developmental milestones, hepatosplenomegaly, skeletal abnormalities, and coarse facies. Urine MPS screen was again negative but a diagnosis of MSD was confirmed in cultured fibroblasts. A review of the literature did not reveal any other MSD patients with micropenis and polydactyly. The basic defects in Bardet-Biedl syndrome and MSD are unknown. Both are recessive disorders. While it is possible this patient has two distinct disorders, micropenis and polydactyly may be rare anatomic features of MSD.

Clinical Cytogenetics

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Trisomy llpi5 in a patient lacking Beckwith-Wiedemann Obesity and learning disabilities associated with interstitial Syndrome. I.J. Anderson, B.A. Camillucci, J.A. Delach & deletion of chromosome 15q. M.A. Angulo, M. Castro-Magana, D.A.H. Whiteman. Department of Pediatrics, University of A. Palekar, J.S. Uy, J.A. Canas, J. Dailey. Department of Connecticut Health Center, Farmington. Pediatrics, Nassau County Medical Center, East Meadow, New Duplication of chromosome band lpl5 in patients with York and State University of New York, Health Sciences Center features of Beckwith-Wiedemann Syndrome was first described at Stony Brook, Stony Brook, New York. by Waziri in 1983. Subsequently, genetic linkage of Prader-Willi Syndrome (PWS), associated with learning autosomal dominant Beckwith-Wiedemann Syndrome to llpl5 disabilities, short stature, and hypogonadism, is the most has been established in families without cytogenetically common dysmorphic form of human obesity. Interstitial visible mutation of lip. deletion on the proximal long arm of chromosome 15, del We report a 16 month old boy with a cytogenetically 15q11-13, has been detected in 50% to 70% of patients with demonstrated de novo ilpl5 duplication, presenting with PWS. Patients with Angelman Syndrome (AS), associated with symmetric overgrowth, but lacking other diagnostic microbrachycephaly, protruding tongue, prognathia, severe features of Beckwith-Wiedemann Syndrome such as typical mental retardation, ataxia, jerky movements, and paroxysms facies, macroglossia, omphalocele, hypoglycemia or linear of inappropriate laughter, may also have a similar chromosome ear lobe fissures. He was born at term after a pregnancy 15q12 deletion. complicated by unexplained maternal hypokalemia, discovered 12 patients from our obesity clinic, ages 5 through 17 during the third month and resolving upon delivery. Because years, with voracious appetites and learning disabilities but the genes for Insulin and Insulin-like Growth Factor (IGFII) without dysmorphic features, were evaluated. Body mass index have been mapped to 1lpl5, serum assays were performed. was greater than 30 in all of them. Normal stature and Values of Insulin 12 mIU/ml (7-27) and of IGFII 333 ng/ml growth rate was noticed in all but one who had the clinical (334-642) obtained were within normal limits. and biochemical diagnosis of pseudohypoparathyroidism. High These observations suggest the possible existence of a resolution chromosome analysis (HRCA) revealed a small set of contiguous genes on chromosome lip, mutations in which deletion of chromosome 15q11.2-12 in each of these patients. can cause Beckwith-Wiedemann Syndrome with variable expression These findings suggest that deletion beyond 15q11.2 can be of features dependent upon specific gene duplication or associated with a wide spectrum of clinical pictures and that disruption. Furthermore, in this case it is possible that the patients other than those with PWS and AS may require HRCA, embryopathic effect of overproduction of Insulin or of IGFII especially those with obesity, uncontrollable appetite, and in utero caused both the macrosomia and maternal hypokalemia. learning disorders. These gene products may have been developmentally down- regulated, and thus no longer overexpressed in postnatal life. Further studies are in progress to define the molecular extent of this duplication, and to correlate this with the clinical findings. As some of this patient's features (macrocrania and macrosomia with broad forehead) would not be inconsistent with the condition known as Sotos Syndrome, and Wilms tumor, (mapped to 1lpl3) has been reported in children with Sotos Syndrome, we would suggest that individuals with the Sotos phenotype should in future be examined for abnormalities of llp. Clinical Cytogenetics A71

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Centraceric separation in a low birth weight infant without The natural history of trisomy 18 and trisomy 13. Laz.., features of Roberts-SC phocaelia. K. Anyane-Yeboa, Carey. ann.S1~'1,hnr,~*Univ. of Utah, Salt Lake City. D. Warburton and P. Taterka. Columbia-Univ Babies Hospital, The purpose of this study was to help delineate the natural history of trisomy 18 (tri 18) and New York. trisomy 13 (tri 13). Ques- Premature centraneric separation has been a frequent tionnaires were sent to families nationwide who were registered finding in Roberts-SC phoelia but not in microcephalic with the Support Organization for Trisomy 18/13. Data were an- primordial dwarfism. We have recently detected this cyto- alyzed from 97 individuals with non-mosaic tri 18 and 33 indi- genetic phenon in a severely SGA infant with none of the viduals with non-mosaic tri 13. There are more girls than major clinical features of Roberts-SC phocamelia. The infant boys at all ages for both conditions. The preponderance of weighed 710gm at full term and was severely growth retarded girls increases with longer survival and is more striking for at 8 months. He weighed 3.4kg and measured 58cm, both 6SD tri 18. The mean maternal and paternal ages are higher for below mean for his age. His head circumference of 33an was both conditions, but the difference from population norms is 7SD below mean. Additional clinical features were severe not significant. There is an excess of postmature babies and dolicho-microcephaly with narrowed bifrontal diameter, C-sections for tri 18, and breech deliveries for both condi- narrow facies, thin hair, beaked nose, micrognathia and mild tions. It is of interest that prior to widespread prenatal proptosis. His development was moderately delayed at 8 diagnosis of tri 18, about half of the cases were delivered by months of age. C-section. Forty-five percent of tri 18 and 33% of tri 13 He did not have phoccaelia, cleft lip and cleft palate children survived to 1 year. Because of ascertainment bias, or ocular malformations. CAT Scan showed a microcephalic survival data are weighted toward longer survival than the brain but no exencephaly. Centrameric separation giving a whole population of tri 18 and tri 13 individuals. The oldest rodlike appearance to the chramosames was observed in many tri 18 individual was 22 years (she is now 24 years) and 9 chmrosrses in many lymphocytes. years for tri 13. Sixty-nine percent of tri 18 and 91% of tri This observation is of great importance in the inter- 13 children living at age 6 months had had immunizations. pretation of premature centronseric separation on cytognrctic After 138 immunizations, 2 had serious illnesses, both occur- analysis of amniocytes if the pregnancy is not known to be ring more than a week later. There is no evidence for an in- at risk for Roberts-SC phocamelia. Great caution should be crease in adverse reactions to immunizations, although the exercised because same cases may not represent Roberts-SC numbers are small. Twelve tri 18 and 3 tri 13 children sat phocanelia, thus the natural history may differ. Detailed alone at an average age of 38.5 and 31.0 months respectively. ultrasonographic assessment would be useful prior to genetic No tri 18 child walked alone, but one tri 13 child walked at counseling. the age of 9 years, 4 months. A few children used several con- We hypothesize that this could represent (1)a mild sistent signs or words in a meaningful way. Although it is expression of the Roberts-SC phoccrelia gene(s) (2)a well known that children with tri 18 and tri 13 have severe different mutation at the Roberts-SC phocanelia locus or (3) developmental retardation, surviving children reach some normal expression of a recessive gene nonalellic to Roberts-SC developmental milestones. Additional data will be presented phoccmelia. concerning delivery, newborn intensive care, surgeries and hospitalizations, physical birth defects, disability after hos- pital release, survival by sex, cause of death, developmental skills, and immunizations. Growth curves will be available. These data provide information useful in counseling families of newborns with tri 18 and tri 13.

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CYTOGENETIC STUDY OF SPONTANEOUS ABORTION (SAB) IN PATIENTS Mosaic Duplication 5 q31 qter and Deletion X WITH NON-CYTOGENETIC CAUSES FOR REPRODUCTIVE FAILURE. K.J. p22 -* pter Due to Nondisjunction and Segregation Blakewore, K.S. Reddy, C. M. Tuck-Muller, G. Stetten. The of a Maternal Balanced Translocation Presenting Johns Hopkins Univ. School of Medicine, Baltimore, Maryland. with the Phenotype of Duplication 5q. L.. Cytogenetic analysis on the products of conception (POC) Blakenore. N. Krassikoff, K. Weaver. A. J. Carroll. after SAB in couples with normal blood karyotypes is not HLFinley Univ. of Alabama at Birmingham. widely recommended. If a non-cytogenetic cause of reproductive failure exists, most POC are expected to be This 10 month old patient was referred to the cytogenetically normal. We studied 15 first trimester SABs Genetics clinic after she was determined to have from such couples using chorionic villi. Surprisingly seven 46,XX/ 47,XX, + der(X), t(X;5), (p22;q3l) mat in of the POCs or 47Z had abnormal karyotypes: all non-mosaic mosaicism lymphocytes. A review of previously aneuploidy or triploidy. Twelve couples had habitual abortion reported patients shoved that this patient's (mean 3.4 losses, range 2 to 6). Three couples had primary physical features were most consistent with the infertility with SAB of the first conceived pregnancy: two had phenotype described in patients with duplication 5 artificial insemination by donor resulting in aneuploidy (45,X q31 or 33 -g qter. These features included and 47,XX,+20); the third had a 46,XX SAB after intrauterine microcephaly; a short nose with a broad nasal insemination. Mean maternal age in the 15 women was elevated bridge and bulbous tip; hypertelorism; a long, at 34.5 years, not atypical in this clinical setting, but hypoplastic philtrum; a small, downturned mouth probably contributory to the high yield of cytogenetic with thin vermilion; aicrognathia; dysplastic ears; abnormality. No statistically significant difference existed fifth finger clinodactyly; abnormal muscle tone and between the cytogenetically abnormal and normal groups for dermatoglyphics. She had a short, broad neck with mean maternal age (35.6 versus 33.6 years) or mean gestational a low and upswept posterior hairline, a highly age (10.1 versus 9.3 weeks), nor for number of losses in the arched palate and cubitus valgus which have been 12 habitual aborters (3.0 and 3.7, respectively). Review of described both in patients with a terminal 13 Monograme revealed no discriminating features between the monosomy of Xp and duplication 5q. She also had a two groups. shield shaped chest which has been described in Prior to the advent of a chorionic villus sampling patients with a monosomy of Xp but not with program, POC from 8 similar couples were all 46,XX; only two duplication 5q. She was not short and was not were definitively non-maternal by parental polymorphisms. failing to thrive. Motor development was only With more recent discriminating selection of chorionic villi mildly delayed in spite of obvious cortical atrophy and the use of direct harvests to supplement the long-term, by CT scan and lover extremity hypertonicity. X maternal contamination was eliminated. inactivation studies by Brdu staining showed that In couples with an established non-cytogenetic diagnosis the der(X) chromosome was inactivated except for for reproductive failure, an abnormal cytogenetic finding on the autosomal segment in the majority of the the POC was very helpful in not altering the management or patient's lymphocytes. This was consistent with outlook for subsequent pregnancies. The reverse was also the clinical interpretation of the patient's true; normal POC karyotypes prompted further gynecologic phenotype. Marker studies are underway to workup. We conclude that POC karyotypes are valuable in determine the parental origin of the two normal couples with habitual abortion or infertility even when a appearing Xs. non-cytogenetic etiology has been established. A72 Cliniccal Cytogenetics

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Absence of Dystrophin in a Patient with a Complex Form of Glycerol Kinase Deficiency (GKD). E. Bonilla, S. Blethen, J. Fox, M. Freedman, P. Lipkin, J. Maytal, A. Rcmano, WITHDRAWN A.Shanske, Schneider Children's Hospital, Long Island Jewish Medical Center, New Hyde Park, New York; Dept. of Neurology, Columbia University, New York, N.Y. (E.B.). Dystrophin is the gene product that is affected in Duchenne Muscular Dystrophy (D4D)). The protein is present at the sarcolenna of nonual muscle fibers, but is lacking or markedly reduced in muscle fran patients with DMD. In sane patients, DND may be associated with a visible deletion inmolving other linked markers on Xp2l. We have identified a 15 month old boy with this type of deletion that is afflicted with DM), glycerol kinase deficiency (GKD), mental retardation and adrenal insufficiency (the Duplex form of (GIOD). T.S. was the 7 lb. 6 oz. product of a term, uneventful pregnancy. He is the first-born to unrelated Greek Cypriots. He was admitted at 11.5 months for evaluation of growth and developmental retardation and was noted to be unstigmatized and markedly hypotonic. Admission electrolytes revealed a sodium of 114 req/L and a potassium of 5.5 neq/L. Sub- sequent laboratory studies showed a CPK of 8260 (NL 0-225 U/L), cortisol of 11.5 microgram/dl, aldosterone less than 1.0 ng/dl, and glyceroluria. A CAT scan showed cortical atrophy and microcephaly. He has an abnormal male karyotype containing an interstitial deletion of the X chromnsame (46,Y,del(X) (pll.4p22.1) inherited fran his mother. A muscle biopsy showed a myopathic pattern and using i unohistochemical techniques dystrophin was undetectable in frozen sections of the muscle sample. We have demonstrated the absence of dystrophin in a patient with GKD syndrome. Studies are in progress to define the precise extent of the deletion using probes spanning the Xp2l region.

(0277) (0278) 1.152

Isodicentric chromosome 18 in a dysmorphic male neonate Different recombinant chromosomes in two brothers with a mosaic karyotype [46,XY/46,XY,-18,+idic(18)(pl2.2)]. with Vater syndrome traced to a pericentric inversion C. Brykel'2. V. Lindgren1. J. Fryburg and T.L. Yang-Feng of chromosome 7 inherited from the maternal grand- 'Yale University, New Haven, CT; SUNY HSC, Syracuse, NY. father. J.P.Burns, D.Starkman, -. Jackson, L.Piotrow- ski, C.Walsh. Danbury Hospital, Danbury, Connecticut Although isochromosomes involving chromosome 18 are Cord blood from a newborn infant with multiple rare constitutional cytogenetic aberrations, isochromosomes congenital anomalies revealed a karyotype of 46,XY, of both the long arm [i(18q) or dic(18)(pll.1)] and the rec(7),dup p,inv(7)(p21.2q35)mat. This karyotype was short arm [i(18p)] have been described. Patients with finally determined after parental cytogenetic studies i(l8q) have a phenotype resembling trisomy 18 syndrome, revealed that his mother had a pericentric inversion while patients with i(18p) have a distinctly different of chromosome 7. It appeared that the recombinant phenotype characterized by psychomotor retardation, chromosome had a duplication of 7p21.lepter and a de- hypertonicity, an asthenic body habitus, delicate facies, letion of 7q35+qter. However, because bands 7p21.1 renal malformations, scoliosis, and immunologic defects. and 7q35 are similar in size and difficult to distin- We report here the features of a dysmorphic male infant quish, the duplication might also be 7p21.2+pter and with a previously undescribed isochromosome 18 present in a the deletion 7q36+qter. The proband died from res- proportion (35%) of his lymphocytes [46,XY/ piratory distress 19 hours after birth. Clinical 46,XY,-18,+dic(18)(q12.2)]. findings included hypoplastic lungs, bilateral hydro- This isodicentric chromosome was composed of a nephrosis, absence of sacrum, club feet, hypospadias duplication of the entire short arm and the proximal long with chordee, cryptorchidism, corneal opacification, arm of chromosome 18 (pter-ql2.2) and was deficient for the 13 ribs, and atropic thymus. It is of interest to distal long arm of chromosome 18 (qI2.2-qter). Only one note that the gene for the beta subunit of the T-cell centromere was apparent on the G-banded isochromosome 18. receptor has been localized to 7q35. A family his- However, C-banding indicated the presence of two tory revealed the presence of a three year old sib centromeres, one strongly stained. The one without the with similar but less life-threatening anomalies in- usual centromeric constriction was faintly stained and cluding sacral agenesis. Shortly after his birth probably inactive. The infant's abnormalities correspond cytogenetic studies were done in another state and well with those seen in patients with the 18q- syndrome had been characterized as normal. He was diagnosed rather than the phenotype associated with either i(l8q) or as having Vater syndrome. Chromosome studies by our i(18p). His congenital anomalies included brachycephaly, lab revealed a subtle recombinant 7 chromosome which markedly redundant skin, hypoplastic widely spaced nipples, was different from his brother's. It had a duplica- a small penis, long tapering tightly flexed fingers, feet tion of 7p21.3+pter and a deletion of 7q35+qter. with varus deformity, and severe hypotonia. His facies Both recombinants resulted from unequal crossing-over were significant for a large glabellar hemangioma, in the pachytene loop which was formed by the normal hypertelorism, horizontal palpebral fissures, a depressed and inverted #7 chromosomes during maternal meiosis. nasal bridge, nostrils that slanted upward and outward, a This stage of oogenesis took place while the mother flat poorly defined philtrum, a carp shaped mouth, herself was a fetus. Cytogenetic studies have found malformed ears, and a cleft palate. the pericentric inversion in one of the mother's sisters as well as in their father. Chromosome studies of other family members are pending. Clinical Cytogenetics A73

(0279) 1.153 (0280)

Rett syndrome seen in association with a complex Head circumference and psychomotor development of chromosomal translocation. M. E. Carlin. J.F. P. Arena and P. S. Ing. Down syndrome infants. R. Carmi. M. Admati. L. Division of Genetics, Department of Pediatrics, U. of Miami/Mailman Noiman. D. Abeliovich. Soroka University Hospital, Center for Child Development, Miami, FL and Cytogenetics Laboratory, Faculty of Health Sciences, Ben-Gurion University Boys Town National Institute, Omaha, NE. of the Negev, Beer-Sheva, Israel. Reft syndrome (RS) is a progressive, neuro-degenerative disorder that Head circumference (HC) is invariably related to presents a recognizable phenotype somewhat similar to autism, but is the intracranial volume and thus reflects the also characterized by decelerating head growth, developmental growth of the brain. HC of Down syndrome (DS) regression, ataxia and characteristic, stereotypic hand movements. All newborns is 3-4 cm. lower than that of normal cases thus far have been female and the vast majority are sporadic. newborns and its growth is slower and almost Monozygotic twin pairs have been concordant; dyzygotic, discordant. RS negligible beyond the age of 21/3-3 years. The aim has been postulated to be inherited as an X-linked dominant trait that is of this study was to evaluate a possible relation- lethal In males with the handful of familial recurrences being attributed ship between Hc and its growth rate during the to germ line mosaicism. To date, no autosomal abnormalities, X first year of life and the development quotient chromosome rearrangements or deletions have been detected. Some (DQ) at around one year of age, in DS infants. preliminary evidence suggests that affected girls may have an unusual First year physical growth parameters of 16 DS pattern of X chromosome inactivation. We present the first known case and 30 normal infants were recorded. DQ was with a documented chromosomal abnormality. determined at 1 year of age by the Denver The proband, now 16, presented at age 9 yrs. In a wheel chair with development test. While the growth curves of the autistic-like behaviors and repetitive hand movements; she had never normal infants followed approximately the 50th developed purposeful movements or speech. She was not dysmorphic, but centile, those of DS followed the 10th centile for demonstrated hyperventilation, seizures, hyperreflexia, ataxia and weight and length. Their HC curves tended to leave scoliosis. High resolution banding has confirmed a complex the 3rd centile around the age of 6-7 months. No rearrangement Involving chromosomes 13, 15 and 18; breakpoints are at correlation was found between DQ and either weight 13q32, 15q13 and 18q21 with distal 15q attached to 13q. distal 18q on lenth or the growth rate of HC in the first 6 15q and 13q on 18q. No deletion Is detectable by curent cytogenetic months of life. However, some correlation was found techniques. Mother's karyotype is normal; the father has been between DQ and HC at 6 months and at the age of the unavailable, but a previous unbanded study appears normal. development assessment (correlation coefficients We are now using the available molecular techniques to study the 3 of 0.483 and 0.556 respectively, meaning that 23% specific areas of the genome suggested by this unique patient, searching and 31% of the DQ variance is explained by HC). for any deletions or perturbations in the DNA that might be involved Although the significance of the relationship either directly or indirectly in the pathogenesis and/or inheritance of RS. between HC and the long term development of DS Since these sites are autosomal, one must assume some sex-influenced children remain to be shown, HC might prove to have modification. a predictive value for future cognitive capacity.

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Abnormal heterochromatin condensation in a Chromosojue 10 short arm interstitial deletion child with a chromosome instability/immuno- J.Chemke- and M.Vekemans-. deficiency syndrome. N.J. Carpenter. Children's Department of Pediatrics, Division of Medical Medical Center, Tulsa, OK. Genetics1 and Department of Pathology, Division of A female infant with low levels of IgG and Cytogenetics2 The Montreal Children's Hospital, IgM, undetectable levels of IgA and IgE, mild McGill University, Montreal, Canada. facial dysmorphology and developmental delay We report a de novo deletion of the short arm of was found to have multiple aberrations of chromosome 10, in a 5 years old dysmorphic and chromosomes 1, 9 and 16. These were observed severely retarded female. The patient was born in cells in peripheral lymphocytes (82-94%) and after 39 weeks gestation to healthy and cell line as well as in from a lymphoblastoid nonconsanguineous parents (maternal and paternal Skin fibroblasts were bone marrow (<10%). ages 34 and 40 years, respectively). Birth weight normal. GTG and CBG revealed that banding was 2.1 There was ultrasonographic evidence of was undercondensation and of the Kg. there breakage of heterochromatin resulting in somatic pairing polyhydramnios during the third trimester and interchanges between homologous and pregnancy. At birth, a large PDA and multiple non-homologous chromosomes. Isochromosomes, small VSD's were detected. She had several attacks deleted chromosomes, triradials, and of generalized seizures during the first day of "multibranched" chromosomes specifically life and was given phenobarbital. A congenital involved chromosomes 1, 9 and 16. The communicating hydrocephalus with large ventricles aberrations were also seen in the parents in and a hypoplastic cerebellum were found. At 5 low frequency (2-5%). Sister chromatid years of age, the patient is microcephalic (HC 45.5 exchanges (SCEs) in the infant were normal. cm) and severely retarded. She has no speech. She Exposure of her lymphocytes to di oxybutane is hypertonic and jittery. She has a flat occiput, (0.1 ug/ml), 5-azacytidine (5xl , low frontal and posterior hairline, and two fluorodeoxyuridine (10- M), thymidine (300 occipital hair whorls. The palate is high and ug/ml) and folate-deficient medium did not narrow with an unusually shaped hard palate. alter the frequency or type of aberrations. External genitalia are normal female but the Treatment with mitomycin C (30-70 ng/ml) perineum is very short and there is anterior decreased the proportion of abnormal metaphases placement of the anal orifice. Dermatoglyphics are but resulted in a normal increase in SCE abnormal: bilateral hypothenar patterns with a The formation of the multibranched frequency. markedly distal palmar axial triradius. The first chromosomes chromatid by homologous toes are and wide with a space between the their large translocation is supported by SCE There is of the and the confluence of the hetero- first and second toes. incurving patterns by Chromosome of the chromosome abnormalities 4th toe underneath the 3rd. analysis chromatin. Thus, chromosomes revealed a observed are distinct from those of other high-resolution karyotype chromosome breakage syndromes. It is speculated 46,XX del(10)(p12.2p13). To our knowledge, this of interstitial deletion of chromosome 10p has that repetitive DNA sequences or a protein type involved in the tertiary structure of hetero- not been previously reported. chromatin may be defective in this disorder. A74 Clinical Cytogenetics

(0283) 1.155 (0284)

Cytogenetic and molecular characterization of marker A dicentric (Y; 5) chramosaie in a boy with developrental de- chromosomes in patients with ty~ical and atypical Turner lay and attention deficit disorder with hyperactivity. syndrome. C. P. Chen1'2. C. Bryke . S. Katz . V. Lindgren1. J.E. Chernos, D.R. McLeod, and D.M. Cox. Division of Medical and T.L. Yang-Feng . 'Yale University, New Haven, CT; Genetics, Alberta Children's Hospital, Calgary, Alberta, Can. MacKay Memorial Hospital, Taipei, Taiwan; 3SUNY HSC, Reported cases of Y-autosane translocations have been of Syracuse, NY two general types, 1) involving the attachment of extra heterochrowatin derived fran the Y-chrcmoscxe to the short About half of the patients with Turner syndrome have a arS of an aCrcentric chrcsosce, and 2) truly reciprocal mosaic 45,X karyotype, where the second cell line may Y-autosame translocations. The former produces no pheno- contain a structurally abnormal sex chromosome. We have typic effect in both male and female carriers while the identified four female patients who had a 45,X clone latter usually results in male sterility. Only one case of accompanied by a cell line containing a small ring or a dicentric dcrcmscme involving a Y-hrmmscme and an auto- marker chromosome (G-group size) whose origin could not be same has previously been reported (Vignetti, et al, 1977, determined by G-, Q-, C- or NOR- staining methods. We have Clin. Genet. 12,: 319-322). This irxividual was a mosaic, characterized these rings and markers using cloned X- and 45,X,del (5) (pl4)/45,X,t(Y;5) (qll;pl4), and displayed clin- Y- centromere-specific probes. ical features of Cri du chat syndrae. By Southern analysis and in situ hybridization, the The present case is a 7j year old boy, referred because of ring chromosomes in three patients were determined to be developmental delay and minor dysemrphic features. His derived from the X chromosome. An isodicentric marker present height and weight are at the 75th percentile. The chromosome in one patient was found to be composed of the only health problem was alternating extropia due to abnorm- short arm and proximal long arm of the Y chromosome, since ally anteriorly inserted interior oblique muscles which were it was positive for the sequences on Y centromere as well surgically corrected. Biochemical investigations ware all as the putative testis-determining factor gene on Yp(ZFY). rnaral. Chrannsame investigations on peripheral blood These findings certainly facilitate the management of these showed a karyotype of 45,X,-5,+dic(Y;5) (pll.3;pl5.3) with no patients with respect to their risks of gonadoblastoma. obvious loss of chramosame material and apparent inactivation Three of these four patients have features typical of of the Y centramere in all cells. Turner syndrome. One patient was studied in the newborn In a subsequent pregnancy the mother had amniocentesis for period because of her striking dysmorphic features. In late maternal age. Coincidentally this shlwed trisary 20 addition to some Turner stigmata, her facies were mosaicism although peripheral blood karyotyping showed only a significant for marked hypertelorism, frontal bossing, a 46,XY cell line. Development of this child is normal. large crimson glabellar hemangioma, a broad flat nasal bridge, and a long philtrum. She is also significantly delayed in growth and development. Such unusual clinical findings in a patient with a karyotype compatible with Turner syndrome could be explained if the ring X chromosome r(X) does not retain the inactivation center and remains active. In that case, there would be no dosage compensation of the genes on the r(X). Examination of the replication pattern of the r(X) is in progress.

(0285) 1.156 (0286) 1.157

Mosaic Down Syndrome with Three Cell Lines. M.A. Linear growth in trisomy 18 fetuses. Donlan, C.R. Dolan, H.C. Thuline, C. Bradley, D. S. Droste. J. FitzSimmnons. T.H. Shepard Salk. Inland Empire Genetics Counseling Service, Department of Oh-Gyn and Central Laboratory for Human Spokane, WA (MAD, CRD), Genetics Program, State of Embryology, Uiniv. of Washington, Seattle. Washington, Seattle, (HCT), Cytogenetics Laboratory Children's Orthopedic Hospital & Medical Center, Intrauterine growth retardation is thought to be a common component Seattle, WA, (CB, DS). of the 18 We studied the between fetal Mosaic Down Syndrome with two separate cell trisomy syndrome. relationship long bone, crown rump and foot length and gestational age in 17 post-mortem fetal lines has been frequently reported. We wish to with 18. The records of the Central for Human report a case of mosaic Down Syndrome with three specimen trisomy Laboratory Embryology were reviewed and 17 fetal specimens with the trisomy 18 separate cell lines. This patient was noted at the from 18 to 38 weeks' were time of birth to have the stigmata of Down Syndrome karyotype ranging gestation identified. Crown rump and foot lengths were measured. Long bone lengths of both the upper including flat facies, prominent tongue, mild up- and lower extremities were obtained from X-rays of the fetal specimens. slant of the palpebral fissures and a chromosome Bone were to lines for that bone obtained from test was performed. Karyotype from the peripheral lengths compared regression 174 normal fetuses. The crown was to our leukocytes revealed 45, XX, t(13;21)/47, XXX, del rump length compared normal line for and foot was to (21)(pll)/47, XXX, -21, +i2lq to be present in 31%, regression gestational age, length compared based on menstrual dates. The and 5% of the gestational age data were analyzed with the 64%, cells respectively. Fibroblast test for and the t-test for karyotype showed only 47, XXX, del(21)(pll). The sign nonparametric 2-tailed paired parametric data. Correlation between foot and menstrual dates was parents have normal chromosomes. A proposed length much weaker for trisomy 18 fetuses (R=0.63) than we have previously noted for normal mechanism for the origin of these cell lines (other and 15own fetuses. The than bad luck) will be offered. (R=0.94) syndrome (R=0.90) gestational age predicted by crown rump length was significantly lower than gestational age based on menstrual dates (p<<0.01, paired t-test). All long bone lengths fell below normal regression lines for gestational age (sign test; p<0.001 for lower extremity long bones; p<<0.01 for upper extremity long bones). Compared to expected bone length for gestational age calculated from the normal regression equations, upper and lower extremity bone lengths were significantly shorter (p<0.005; paired t-test). Linear growth in fetuses with trisomy 18 was found to be significantly retarded. The observed growth retardation is symmetrical and involves the fetal foot, which is thought to be an excellent measure of gestational age in normal and Down syndrome fetuses. No endogenous measure of gestational age appears to exist in trisomy 18, forcing reliance on menstrual dates. This combination of growth alterations would appear to make the sonographic diagnosis of intrauterine growth retardation in trisomy 18 difficult and likely precludes the development of effective biometric screens for the prenatal detection of this syndrome. Clinical Cytogenetics A75

(0287) 1.158 (0288) 1.159

DiGeorge sequence in an infant with deletion of chromosome 22 Beckwith-Wiedemann Syndrome in twins with a and trisomy 9p secondary to adjacent type II nondisjunction. duplication of chromosome 15(ql1.2-q1)mat. L.L. M.H. El-Fouly, J.V. Higgins, S. Kapur and D. Matisoff. Estabrooks , A.N. Lamb , H.N. Kirkman , §. Boyer2, Department of Pediatrics/Human Development, College of Human I.E. Wiley ,N.P. Callanan and K.W. Rao . Medicine, Michigan State Univ., E. Lansing, MI 48824. University of North Carolina at Chapel Hill, 6East Carolina University, Greenville, North Carolina. A term newborn caucasian female presented with low birth- Presumably identical twins were born to an weight, dysmorphic features and congenital heart defects. The apparently normal 24 year old GlP2 white female. The pregnancy was remarkable for polyhydramnios. The abnormal pregnancy was complicated by polyhydramnios and features included low-set ears, upslanting palpebral fissures preterm labor(31 weeks). As a result of a breech and a prominent nasal bridge. The hands showed proximal place- presentation of twin B, both twins were delivered by ment of the thumbs, clinodactyly of the index fingers and C-section. A diagnosis of Beckwith-Wiedemann bilateral simian crease. The feet were remarkable for talipus Syndrome (BWS) in both twins was indicated by their valgus and bilateral dorsiflexion of the metatarsophalangeal macroglossia with occlusion of the airways, joints. All nails were hypoplastic. The patient's karyotype hepatomegaly, splenomegaly, weight in the 90th showed a 46,XX,-22,+der(22)t(9;22) (ql3;ql2)mat. The mother has percentile, and hypoglycemia. They also had a a balanced translocation 46,XX,t(9;22) (ql3;ql2). slightly prominent occiput, flattened nasal bridge, The patient expired at ten days of age and autopsy was prominent eyes, relative microcephaly, diastasis performed and revealed absent thymus and absent isthmus of the recti, severe apnea and polycythemia. Twin A had an thyroid gland. The lungs showed hypoplastic changes and ab- umbilical hernia and twin B had capillary flame normal lobulation. The cardiac anomalies included a truncus nevus, and skin which cracked and bled. Twin A, Twin arteriosus, truncal valve stenosis, single carotid trunk, B, and the mother had an apparent duplication of subclavian arteries arising from distal part of aortic arch, chromosome 15(qll.2-q13). The father's karyotype was atrial and ventricular septal defects, right ventricular normal. At the twins' delivery the mother was noted hypertrophy and a hypoplastic left pulmonary artery. Also, to have large ovaries (an occasional finding in multiple small accessory spleens were present in addition to a BWS). Although the mother lacks many of the features normal size spleen. of BWS, a pending examination for microstigmata may This case combines features associated with both DiGeorge uncover additional characteristics. Duplication of sequence and trisomy 9p. The origin of the karyotypic abnorma- 15qll.2-ql3 has been associated with Prader-Willi lity in this patient appears to have arisen in the maternal Syndrome; while BWS has been associated with a germ cell secondary to an adjacent II non-dysjunction event. duplication of 11p15. The karyotypes of this family show no evidence of an abnormality in llp, although we cannot rule out the possibility that the extra material in 15q originated from chromosome 11. However, reported cases of duplication llp are usually associated with mental retardation. Although a definitive answer will have to await molecular characterization, this family probably represents the first observation of the BWS phenotype in patients with a 15q11.2-13 duplication.

(0289) (0290) 9.9

Intrachrcxmsanal insertion of chranosame 7. S.A. Farrell Diagnosis of Angelman (happy puppet) syndrome in infants. and G. Chow. The Credit Valley Hospital, Mississauga, Ontario, YES. Fryburg, V. Lindgren, W.R. Breg, and T.L. Yang-Feng. Canada. Yale University, New Haven, CT. An intrachrcvosanal insertion is an uncannon chrcnoscrre Although patients with Angelman syndrome (AS) have rearrangement. We describe a new case of a familial direct characteristic features beginning at about two years of age, intrachrcmscmnal insertion of chranosme 7 and review previous diagnosis is difficult in younger children. We have recently reports. This is the first case presenting with multiple identified three AS patients who were less than two years old pregnancy losses. All others were ascertained by a pheno- and one patient, now 7j, who was an infant when first typically abnormal proband. Since the risk of chramosanally evaluated. Three of the four were diagnosed when they were abnormal liveborns is appreciable, prenatal diagnosis should found to have deletions of the region qll.2-q13 of chromosome be made available to families carrying intrachrcomsanal 15 but did not have the features of Prader-Willi syndrome insertions. (PWS). One of the four, who has the same deletion, was initially diagnosed because of the features she shares with one of the others. In three of the cases the deleted chromosome 15 was maternally derived, as determined by cytological markers; the fourth child's parents are not available for study. This finding is consistent with the observation [Knoll et al., Amer. J. Med. Genet. 32;285 (1989)] that the deletions in AS are of the maternal chromosome 15 while the deletions in PWS are of the paternal chromosome. Some features of AS were evident in these patients. All presented with severe developmental delay and postnatal onset microcephaly. Three suffered seizures. All were fair skinned, blond, and blue eyed. However, these findings were not particularly suggestive of AS. Only one of the four thrust her tongue, and two moved in a hyperkinetic fashion. None was described as dysmorphic. Features of our patients which have not been previously emphasized in AS are nystagmus and hypopigmentation. Three of these patients have nystagmus. Interestingly, albinism was considered in two of the cases, and the child now 71 was thought to have oculocutaneous albinism. Hypopigmeritation and oculocutaneous "albinoidism" are recognized manifestations of PWS with chromosome deletions and on the basis of our cases may well be associated with AS deletions. Our experience combined with that of others suggests that AS may be relatively common and should be included in the differential for young children who are microcephalic and developmentally delayed for unexplained reasons. A76 Clinical Cytogenetics

(0291) (0292) 1.94

An unusual tissue specific normal/recombinant 11 chromosomal New syndrome of type A2 brachydactyly, microcephaly, and mosaicism in a male infant. A. Garnica. R.S. Muneer, D. Hopcus. H. diabetes in siblings born to consanguineous parents. J.M. Ruth K. McCampbell and J. Lynch. Division of C togenetics, Graham. Jr. Ahmanson Pediatric Center, Medical Genetics Oklahioma University Health Sciences Center an Children's and Birth Defects Center, Cedars-Sinai Medical Center, UCLA Hospital of Oklahoma, Oklahoma City, Oklahoma. School of Medicine, 444 South San Vicente Blvd., Los A 32-week premature infant was found to have an unusual Angeles, CA. We report a unique pattern of altered morphogenesis in blood/skin karyotype mosaicism involving an unbalanced male and female siblings born to unaffected second cousin recombinant chromosome 11. His blood karyotype was: 46, XY, rec parents with no other known affected family members and (11) dup p, inv(pl 1.2q25); and his skin karyotype was mosaic: 46, normal gestational histories. An older sister of the XY/46,XY,rec(l 1), dup p(pl 1.2q25) with 8:92 ratio. Family studies affected siblings was normal. Skin fibroblast and leukocyte demonstrated a percentric inversion of the entire long arm of karyotypes on the affected 16-year-old boy were normal, as chromosome 11 in the father and his father's twin brother [46, XY, was a serum amino acid screen. Amniocyte karyotype on his inv(11)(p11.2q25)J. There was also an occurrence of multiple 1-year-old affected sister, was also normal. Both affected miscarriages. Studies on the paternal grandparents, a severely siblings were normal sized at birth, but had relatively retarded aunt and a normal sibling are underway. small head circumferences. The boy presented at 11 yrs. of The child died at 2 days of age. The clinical and autopsy findings age with hypoplastic thumbs and halluces with bulbous tips, were: Diffuse cutaneous and viceral petechial rash, multiple short index fingers with absent middle phalanges, and congenital malformations comprised of microthalmia, cleft left lip, clinodactyly of the second toes (type A2 brachydactyly). Adult height for the older affected sibling was at the 75th high arched palate, low-set ears, short thick neck, simian crease in centile, with weight at the 95th centile, and head right palm, micropenis, malrotation of large intestine, involution of circumference at the 10th centile. During childhood, he had thymus, congested lungs compatible with pulmonary hyaline mild hypotonia and weakness, with learning disabilities, membrane disease and umbilical arterial catheter. primary encopresis, occasional daytime enuresis, and small Further chromosomal, histologic, and biochemical studies with external genitalia with bilateral gynecomastia. Endocrine regard to LDH and catalase are in progress. work-up demonstrated delayed puberty, with fasting hyperglycemia and glucosuria that was subsequently controlled by diet. Insulin and cortisol levels were normal, as were an EKG and renal ultrasound. At 13 years of age he manifested a seizure disorder with generalized spike-wave discharges by EEG. His younger sister was born with similar morphologic abnormalities of her 1st and 2nd digits, normal length and weight, and head circumference at the 2nd centile. This appears to be a new syndrome, with recurrence in siblings born to consanguineous unaffected parents suggesting autosomal recessive inheritance; the possibility of germinal mosaicism cannot be ruled out.

(0293) 1.160 (0294) 1.161

Molecular confirmation of Wolf-Hirschhorn syndrome with The fragile X checklist. R. J. Hagerman. K. Amiri and A. Cronister. Child apparently normal chromosomes. F. Greenberg. F.F.B. Development Unit Children's Hospital, Department of Pediatrics, Univ. of Colorado Elder. D.H. Ledbetter. M. Altherr. J.J. Wasmuth. Insti- Health Sciences Center and Sewall Rehabilitation Center, Denver, Colorado. tute for Molecular Genetics, Baylor College of Medicine, A 13-item checklist has been used prospectively in screening 116 retarded and Houston, Texas, and Department of Biological Chemistry, learning disabled males for fragile X syndrome prior to cytogenetic testing. Twenty- University of California at Irvine. five individuals were cytogenetically positive for the fragile X chromosome with a Wolf-Hirschhorn syndrome consists of prenatal growth mean age of 20 years (range 5 to 56 years) and 91 were negative with a mean age retardation, microcephaly, ocular hypertelorism with a of 18.5 years. prominent glabella, cleft lip and/or cleft palate, mi- The 13 items evaluated on this checklist are mental retardation, hyperactivity, crognathia, cardiac defects and mental retardation. A short attention span, tactile defensiveness, hand-flapping, hand-biting, poor eye terminal deletion of 4p is usually seen in association contact, perseverative speech, hyperextensible metacarpal phalangeal joints, large with this phenotype and is used to confirm the diagnosis. or prominent ears, macroorchidism, simian crease or sidney line and family history We report a child with clinical findings of Wolf-Hirsch- of mental retardation. A score of 0 to 2 points is possible for each feature horn syndrome including growth delay, microcephaly, cleft corresponding to 0 points if the feature is not present, 1 point if the feature was palate, sloping forehead, flat glabella, telecanthus, and present in the past or present to a borderline degree at the present time and 2 a secundum type atrial septal defect. Multiple chromo- points if the feature is definitely present at the present time. In those individuals some analyses done on the child and on both parents did with a total score of 6 to 10 points, only 3% who were screened were fragile X not reveal any detectable abnormalities of chromosome 4. positive cytogenetically. In those individuals with a total score of 11 to 15 points, Molecular studies showed the child to be hemizygous for 11% were fragile X positive; in those with a total score of 16 to 20, 50% were two probes from distal 4p, 674E-D (D4S95) with an AccI fragile X positive and in those with a score of 21 to 25 points, 86% were fragile digest and 252-3 (D4S115) with an MboI digest. For both X positive. The total scores of fragile X positive and negative patients demonstrate markers no maternal allele was present in the child. 2 differentiable populations (t-test p<.0001). Chi square analysis was used to These findings are thus consistent with a molecular identify which features had a significant difference in prevalence between those deletion of 4p confirming the diagnosis of Wolf-Hirsch- who were fragile X positive and those who were fragile X negative. These features horn syndrome. Because of a question of a submicroscopic included hand-biting, hand-flapping, perseverative speech, tactile defensiveness, translocation in the mother, chorionic villus sampling hyperextensible finger joints, large or prominent ears, macroorchidism and a family for prenatal diagnosis in a subsequent pregnancy, showed history of mental retardation. Step-wise logistic regression analysis was used to the fetus to be heterozygous for both the AccI and the answer the question of which combination of features was most useful in predicting MboI polymorphisms indicating that the fetus is unaffect- membership in the fragile X positive group. This demonstrated that ed. Chromosome analysis of 40 cells from chorionic villi macroorchidism, long ears and tactile defensiveness were the best independent showed a 46,XY chromosome pattern with no obvious abnor- predictors and the additive effects of perseverative speech, hand-flapping and a mality of chromosome 4. This provides the first evidence family history of mental retardation were not significant after the first three features were identified. of a submicroscopic molecular deletion of chromosome 4p leading to the Wolf-Hirschhorn phenotype. Evaluation of This checklist is a useful tool to increase the clinician's awareness of features associated with X and are at other cases of Wolf-Hirschhorn with fragile to better identify patients who high risk for syndrome apparently the X normal chromosomes may provide better localization of the having fragile syndrome. phenotype on 4p and may lead to better mapping of this region. Clinical Cytogenetics A77 (0295) (0296) 1.162

Mosaicism involving the X chromosome in a mother Clinical. cytogenetic, and molecular findings in a patient and son. J.K. Hartsfield. Jr.. P.R. Papenhausen and effectively tetrasomic for the euchromatic region of the Y T.A. Tedesco. Univ. of South Florida, Tampa. chromosome. R. Hassan, B.F. Crandall, P.Yen, T. Mohandas, Mosaicism has generally been thought to be a and L.J. Shapiro. UCLA School of Medicine, Los Angeles. CA; random post-zygotic event with the chromosomal Harbor-UCLA Medical Center. Torrance, CA; and Martin Luther analysis of the parents not performed. There have King-Charles Drew Medical Center. Los Angeles, CA. been, however, reports of more than one individual Tetrasomy for the human Y chromosome is rarely observed. in a family with mosaicism. This is a report of an Here we report a male infant who is effectively tetrasomic as 18 year old white male who was referred to rule out a result of the presence of two copies of a Y-derived marker Marfan syndrome. Relatively small testes, the lack chromosome. Physical examination of patient at one and five of arachnodactyly and the presence of mild mental months of age revealed dolichocephaly, flat facies with retardation lead to a karyotype which showed hypoplastic supraorbital ridges, upslanting palpebral mosaicism for Klinefelter syndrome. Subsequent fissures, hypertelorism, depressed nasal bridge, long philtrum chromosomal analyses of the family were as follows: with a thin vermilion border, low set ears with over folded Chromosome Number helices, micrognathia, short neck, brachydactyly, and TISSUE 45 46 47 bilateral clinodactyly of the fifth fingers. The infant was cell # (%) cell # (%) cell # (%) also hypotonic and developmentally delayed. Cytogenetic PROBAND blood - 5 (14) 32 (86) analysis of peripheral lymphocytes revealed 47 chromosomes in (XY/XXY) blood - 11 (22) 39 (78) each of 100 cells analysed. There was a single X chromosome skin - - 50* (96) and two marker chromosomes that appeared to be isodicentric chromosomes consisting of the short arm and euchromatic region MOTHER blood 5 (7) 70 (92) 1 (1) of the long arm of the Y chromosome. The karyotype of the (X/XX/XXX) blood 3 (6) 47 (94) patient, therefore is 47,X.+2 idic(Y) (pter-qll.23::qll.234 skin _ 30 (100) pter). There was no fluorescent heterochromatin and C-banding showed two blocks of heterochromatin on the marker FATHER blood _ 30 (100) chromosomes. The mother's chromosomes were normal and father (XY) was not available for study. In order to verify the cytogenetic findings, dosage blots were done on genomic DNA of SISTER blood - 52 (100) - the patient using five different probes (hYfin, pDP132, STS-X, (XX) STS-Y1, and STS-Y2) derived from the X and Y chromosomes. The * Random loss of different chromosomes in two cells probes detect sequences located in interval 1 (distal short were not included. arm) and interval 6 (distal euchromatic region of the long The consistent findings observed in the blood arm) of the Y chromosome in addition to sequences on the X karyotypes in the proband and his mother indicate chromosome. The intensity of the Y specific bands relative to a familial tendency for mosaicism involving the X the X specific bands was consistent with the patient having 4 chromosome. The 46,XX skin karyotype of the mother copies of the Y sequences compared to male controls. Clinical and the 47,XXY skin karyotype of the proband findings in this patient and two previously reported cases suggests that these were the zygotic chromosomal with 4 Y chromosomes indicate that increasing numbers of Y constitutions. The meiotic non-disjunction may be chromosomes affect the phenotype more severely. associated with this familial predisposition.

(0297) 1.163 (0298) 1.102

Paternal age and trisomy among spontaneous abortions. M. Hatch,.J. THE MICROCEPHALY LYMPHEDEMA PHENOTYPE: A POSSIBLE Kline. B. Levin and D. Warburton. Columbia University and N.Y. State HETEROGENEOUS GROUP OF DISORDERS WITH INTELLECTUAL VARIABILITY Psychiatric Institute. J. H. HERSH, J. W. HOLMES, University of Louisville, KY The relationship of paternal age to specific types of trisomy was Louisville, Microcephaly is etiologically heterogeneous and frequently investigated in a series of karyotyped spontaneous abortions that associated with mental retardation. An autosomal dominant included 461 trisomies. Because of the strong association between (AD) form of prenatal microcephaly with congenital lymphedema trisomy and maternal age, paternal age effects were also specifically and normal intelligence has been reported by Leung and by searched for in younger women with trisomies. Two analytical Crowe and Dickerman. We describe two cases of microcephaly approaches were taken, a standard least squares regression analysis and lymphedema with psychomotor delays to emphasize that and a more robust analysis of residuals. For both analyses we lymphedema can be a nonspecific finding in an infant with adjusted for the effects of design and demographic variables microcephaly, and not necessarily associated with a favorable including maternal age. outcome cognitively. Among the 14 trisomy categories examined four (7,9,18,21) An unrelated male and female presented with lymphedema and showed increased paternal age (>1 year above expectation), three microcephaly. In the male, there was prenatal microcephaly (13,20,22) showed decreased paternal age and the rest, including and excessive scalp rugae, and in the female, microcephaly was the most common, trisomy 16, showed negligible differences. Only present at 4 months; she also had scoliosis. Neither had sibs; and the parents had normal head sizes and no the trisomy 22 association was statistically significant at the nominal lymphedema. Pregnancies and deliveries were uneventful. TORCH titers, 5% level. Among women under 30, although numbers are few for viral studies and karyotypes were normal. The male had a individual trisomies, 6 showed increased paternal age normal CT head scan and the female had decreased cerebral and (8,9,14,15,18,21), 3 showed decreased paternal age (13,20,22) and cerebellar sizes on MRI head scan. He had chorioretinal the rest showed negligible differences. Only the increase for trisomy scarring and her eyes were normal. Mental age in him at 6 8/12 21 was statistically significant. The decrease for trisomy 22 was not years was 3 6/12 years and in her at 19 months was 7 months. stronger in younger mothers, as might be expected if it were a real Lymphedema is a feature of a number of syndromes. Although effect. associated with microcephaly in our cases, clinical differ- Both in the total data and in younger women the direction of effect ences were apparent in contrast to families with AD micro- was not consistent for chromosomes grouped according to cephaly and lymphedema. These included mental retardation in characteristics which might relate to the probability of both, eye changes and scalp rugae in the male, and postnatal microcephaly with scoliosis in the female. nondisjunction, such as size, arm ratio, or NOR content , or to the Although findings in these patients may be the result of potential viability of the trisomy. Thus the data provide no variable expressivity of the same disorder, the greater like- evidence of a effect on trisomies found compelling paternal age lihood is that they represent separate entities. Caution among spontaneous abortions. should be used when prognosticating in an infant with lymph- edema and microcephaly, and particularly when it occurs sporadically and is associated with other manifestations. Lymphedema may be a nonspecific feature associated with a certain phenotype which is causally heterogeneous, or simply an incidental finding in an infant with microcephaly. If present, intellectual outcome may vary greatly. A78 Clinical Cytogenetics (0299) 14.4 (0300) 1.164

Possible location of a recessive testis forming gene on 9p24. Trisay 8 in a male/female dhiera. P.N. Howard-Peebles. J.J. Hoo, I.S. Salafsky, C.C. Lin and L. Pinsky. University S.H. Black, M. Bustillo. A. Maddalena. E.A. Steane & B. of Illinois at Chicago, Children's Memorial Hospital at Litj1rbemr. Genetics & IVF Institute, Fairfax, VA; Chicago, University of Alberta at Edmonton and McGill Univer- Medical College of Virginia, Ricdmord; & U IX Southwestern sity at Montreal. Medical Center at Dallas. Chromosome study on a female infant with multiple congenital A 13 year old female was referred for further genetic anomalies revealed a karyotype of 46,XY,9p+. G-, C- and Q- workup because of dysmxrphic features associated with bandings of the Y-chromosome were entirely unconspicuous and learning and behavioral priblems. Due to the learning were identical with that of the father. Both parents' karyo- problems & suggestion of a connective tissue disorder, types were normal. High resolution study revealed that the fragile X screenirg was initiated. (Previous dchrca-ce extra chromosome segment was most likely originated from 2p. analyses at 2 different institutions at birth & 5 years were The karyotype is therefore 46,XY,-9,+der(9)(2pter-,.2p21::9p24 reported as 46,XX.) Fragile X scorirn (on GIT-banded cells) b.i9qter). Southern blotting using 1) a genomic 1.3 kb HindIII revealed the presence of both male and female cells with all fragment (pDP1007), 2) a 4.3 kb DNA fragment (Y-156) and 3) a male cells havirg an extra #8 cirse; all cells were 3.4 kb probe (pY3.4), showed a result compatible with that of fragile X negative. The frequency of the 47,XY,+8 line was the normal Y-chromosome of a normal 46,XY male and thus further about 26% in the lynphocyte preparation. verified the intactness of the Y-chromosome. Further studies were initiated cn the patient and her Review of literature revealed three other similar cases of parents. Physical exam was cocpatible with the mosaic total sex reversal in association with a de-novo translocation triscmy 8 syndrcze. Pelvic ultrasound revealed a small involving 9p. All four cases showed female external genitalia prepubertal uterus; serum gcnadotrcpins and sex steroids were with the presence of uterus. Histological studies of the in the normal prepubertal range. Pubertal develcplat will gonads in two cases revealed immature testicular tissue con- be followed prcspectively. he male line was present in taining Sertoli cells but no germinal cells. The gonads ap- approximately 30% of the cells grown frym a skin biopsy (frcm peared to produce sufficient androgens and responded to HCG underside of forearm). In continued culture, the male line stimulation. became predominant indicating selection for an abnormal cell All four cases showed deletion of 9p with concurrent dupli- line. Blood group studies (Dallas) revealed confirmation of cation of different chromosome segments, 2p,3p, 7q and 13q chimerism in the MNSs and Rh systems; a quantitation study by respectively. The shortest region of overlap regarding the de- flaw cytcmetry (using an S tag) was 25.5% positive. Studies letion was 9p24. Since the majority of 9p deletion cases do are cotinuing on the Rh system. To address the embryonic not show sex reversal, we postulate that there might be a re- origin of the cell lines, polymorphisms were studied to cessive gene on the 9p24, which is important in the early de- determine parental contributions. Based on blood groups and velopment of testis. The lack of this gene product, likely an the DXS52 RFLP, the father cArtributed 2 gametes. Blood enzyme, causes a delayed and incomplete testicular formation graups and special stains were inconclusive in the mother. resulting in the absence of influence of testosterone and [CA analysis is in progress to determine if there is evidence Millerian inhibiting factor in the crucial period of sexual for 2 independ maternal gametes and the origin of the differentiation. All four cases might carry a defective gene extra (hrtyxse 8. on their normal chromosome 9 and concurrent deletion of the This interesting patient illustrates the importance of healthy allele on the other 9p had apparently caused the sex repeat cytogenetic analysis when the pienotype is highly reversal. suggestive of a chrceoscrl syndrze.

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A multi-center dNOR variant study: Standardization Rare euchrouatic 16p+ variant chromosome: First and incidence in trisomy 21 families. C.Jackson-Cook. report in North America. S.N. Jalal (1), N.R. J. Melnyk, C. Moore, G. Persinger. M.C. Phelan. The Schneider (2), M.K. Kukolich (1), G.N. Wilson (2). Medical College of Virginia, Richmond; Medical (1) Univ. of Texas Southwestern Medical Center at Genetics, Fountain Valley, CA; The Univ. of Texas Dallas (2) Genetics Screening and Counseling Health Science Center, San Antonio; Greenwood Genetics Services, Denton, TX. Center, Greenwood, SC. A 16p+ variant chromosome was discovered in two One explanation for inconsistencies in reported dNOR infants with dysmorphic features from two unrelated variant frequencies in control and trisomy 21 families families. At the 400-550 band stage, a light and a is methodology, including differences in 1) silver medium-dark G-band just distal to the centromere staining; and 2) microscopic evaluation. We initiated were observed proximal to a complete 16p arm. The our study by having investigators from 4 different extra segment is C-band negative and was examined centers blindly stain and analyze slides from the same also by RF-banding. The resulting increase in 8 selected individuals, a total of 80 acrocentric length of about 1/3 of the p arm is of undetermined chromosomes, using 2 different standardized silver origin. In one case the 16p+ was also present in staining protocols. To test for consistency in dNOR the phenotypically normal father who is a college variant assignment of the same chromosome in relatives graduate. In the second case it was present in the 3/8 cases were a mother, father, and child (family R). mother who is mildly dysmorphic and of borderline Family R was selected because a very large single NOR intelligence. The dysmorphisms of the two infants chromosome 13 was noted in each of the parents and the are not similar and are probably unrelated to the child. Agreement in dNOR status was noted for 76/80 16p+ chromosome. (95%) chromosomes. Three of the 4 discrepancies This same variant 16p+ has been ascertained involved the chromosome 13 noted in family R. Regard- recently in 6 unrelated European cases, only one of less of the protocol used, over staining was noted as whom had an abnormal phenotype (Thompson & Roberts a factor in false (+) and (-) dNOR assignment. To 1987, Hum Genet 76:100-100; Clark et al. 1988, Clin standardize, chromosomes should be counterstained for Genet 33:418-423; Pinel et al. 1988, Hum Genet banding (-550 band length). Also, chromosomes may be 80:194). The 16p+ was carried by normal healthy inaccurately scored for dNOR status when involved in relative(s) of 3 of these cases, including 8 normal satellite association. Criteria for dNOR identifica- relatives in 3 generations of the one abnormal tion include 1) elongated stalks; 2) 2 distinct proband's kindred. Parents of the other 3 cases vertical areas of stain (confluent or separate); 3) were not studied. Though polymorphisms of expression of 2 stained areas in > 20% spreads. To constitutive heterochromatin pervade human date, we have studied 70 newly ascertained couples populations, C-band-negative variants without having children with trisomy 21 and noted 19/70 (27%) detectable pathogenic features have been documented to be dNOR(+). In contrast, dNORs were noted in 12/183 very rarely. A possibly similar rare variant is a (7%) control subjects. Our further studies, including 9p+ chromosome studied most recently by Webb et al. parental origin determinations, should help resolve 1989, Hum Genet 82:59-62; however, unlike the 9p+, the controversy of the role of dNOR variants in the 16p+ does not appear to be a homogeneously nondisjunction and could allow more accurate staining region. The significance of such rare counseling of families having a child with trisomy 21. variant chromosomes remains to be elucidated. Clinical Cytogenetics A79

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Deletion 14(q24.3q32.1): evidence for a Exceptions to the Xq critical region hypothesis distinctive clinical phenotype. S. Karnitis. K. are only relative. T.E. Kelly. University of Burns. K.W. Sudduth. and W.G. Wilson. Univ. of Virginia, Charlottesville, Virginia. Virginia Health Sciences Center, Charlottesville. The critical region hypothesis holds that We report on a 42 month-old Caucasian girl with balanced X/autosomal translocations (X/At) with moderate developmental delay and distinctive an Xq breakpoint between Xql3-26 result in primary facies who has a de novo interstitial deletion of gonadal dysgenesis. Exceptions to this hypothesis 14q, or 46,XX,del(14)(pter-4q24.3::q32.1-*qter). have included some, but not all, X/At with an Xq Her physical findings are strikingly similar to breakpoint at q22. A 30 year old woman underwent those of two other reported patients, both amniocentesis because of an elevated MSAFP. The fe- Japanese infants, who have similar deletions (J tal karyotype revealed an unbalanced X/9 transloca- Pediatr Pract (Jon) 48:32-34, 1985; Hum Genet tion rendering the fetus trisomic for distal 9q and 74:190-192, 1986]. Common features seen in these monosomic for distal Xq. At termination the fetus three children include a round face, bushy demonstrated the distal 9q phenotype. The Xq eyebrows with synophrys, upper lid ptosis and breakpoint was at q22 and the mother proved to be epicanthal folds, a short, upturned nose with flat a balanced translocation carrier. Her 2 year old nasal bridge, a "carp mouth" appearance, fleshy daughter was 46,XX and her parents', siblings' and ears, redundant skin, particularly over the cheeks husband's karyotypes were normal. and extremities, complete palmar creases, and Among 15 reported cases of X/At with an Xq22 mental retardation of variable degree. An breakpoint, seven were ascertained clinically be- additional finding in our patient is the presence cause of primary amenorrhea; two presented with of only three maxillary and three mandibular infertility and secondary amenorrhea. The excep- incisors. tions to the hypothesis include six fertile females The findings in these three children confirm ascertained by an offspring with an unbalanced the suggestion of Yamamoto et al. [Hum Genet karyotype. Of these, 5 have experienced premature 74:190-192, 1986] that there is a specific menopause (ages 30 to 37 years). Individuals with clinical phenotype associated with this deletion. an X/At and an Xq22 breakpoint are much like The finding of a normal level of alpha 1- patients with 45,X/46,XX mosaicism in that the antitrypsin in our patient, in contrast to the phenotype spans primary gonadal dysgenesis to fer- reduced level in the patient of Yamamoto et al., tility with premature menopause. No patients with suggests that our patient has a breakpoint more an X/At and a breakpoint adjacent to the Xq22 band proximally located in band 14q32.1, and that the have reproduced. Molecular studies are necessary alpha 1-antitrypsin locus is in the midportion of to determine whether breakpoints at discrete loca- this band. tions within the Xq22 band are associated with specific phenotypic consequences.

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Del(15)(qllql3) with a non-Prader-Willi syndrome/ Down Syndrome and band 21q22.2: Molecular definition of the non-Angelman syndrome phenotype. L. Kirson. K. phenotype. J.R. Korenbere. T.L. Koiis. C. Bradley. C. Disteche. Sudduth. J. Wyatt. and T.E. Kelly. Univ. of Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, CA; Virginia Health Sciences Center, Charlottesville. Children's Orthopedic Hospital, Seattle, WA. The major phenotypic features of Down Syndrome can be caused by High resolution cytogenetic techniques have partial trisomy 21. Molecular definition of this region has revealed that a similar cytogenetic abnormality, excluded all known DNAfragments in band 21q22.1, but the more 15qllql3 deletion, can have a broad range of distal region is undefined. We now present a detailed molecular clinical presentations. While many cases of and cytogenetic analysis of DNA from a patient with the facies, Prader-Willi syndrome (PWS) and Angelman syndrome hands and mental retardation of Down Syndrome that defines this (AS) are associated with a 15qllql3 deletion, region. High resolution cytogenetic evaluation revealed a there are reports of patients with 15qllql3 duplication, 46,XY,dir dup(2lXq2l.l-->q22.1 or q22.2). For the deletions who cannot be classified as PWS or AS. molecular analysis, we have constructed a molecular map of These include individuals with only a few features chromosome 21 that divides the chromosome into 23 regions. To of PWS ("partial PWS") and individuals with define the complexity of the chromosomal rearrangement and the molecular breakpoints, we determined the copy number of 11 DNA developmental delay and dysmorphic features not fragments using quantitative Southern blot analysis. Two to 5 DNA consistent with a recognized syndrome. We report fragments unique to chromosome 21 and one unique to chromosome 17 on a 27 year old man found to have a 46,XY del(15) (the reference probe) were hybridized simultaneously to Southern (qllql3) karyotype with some clinical features blots containing 6 lanes of Eco RI digested DNA from the patient observed in patients with PWS and AS, but without and 6 from a diploid control. The resulting bands were analyzed on a phenotype that would allow diagnosis of either the autoradiographs by quantitative densitometry. We used DNA syndrome. He has moderate mental retardation with fragments from the following regions: 21q21.l (D21S16); 21q 21.105 significant behavior problems, lack of speech, - 21.05 (D21S46 and FB68L, a cDNA probe for the amyloid precursor profound bilateral neurosensory hearing loss, and protein, APP); 21q 22.1 (D21S47, SF57, and a cDNA probe for superoxide dismutase 1, SODI); 21q 22.2 - 22.3 (D21S17); and a history of childhood seizures. He presented 21q 22.3 (D21S55, D21S3, D21S44, and D21S39). We found 3 copies of with short stature, hypogonadism, absence of the DNA sequences detected by probes for APP, SODI, SF57, D21S47, secondary sexual hair, mild scoliosis, and right D21S17 and D21S55 and 2 copies of all others. These results place microphthalmia. He had normal cerebellar testing the proximal border of the duplicated region in mid band q21 and normal deep tendon reflexes with no evidence between APP and D21S46 and the distal border between D21S55/D21S17 of hypotonia. Endocrine evaluation revealed low and D21S3 in band 21q 22.2 or very proximal 22.3 at a distance serum FSH (6.7 mIU/ml) and LH (<2.5 mIU/ml). below the limit of cytogenetic detection. In addition, we can Further analysis at the molecular level is assign probes D21S55 and D21S17 to the G band 22.2 and can exclude necessary to determine if the diversity of most, if not all, of band 21q 22.3 from the region generating the phenotypes associated with 15qllql3 deletions Down Syndrome facies. Cytogenetically, the data narrows the Down Syndrome region to include only band 21q 22.2. Molecularly, the involve the same DNA segments. Such studies will region is defined by probes D21S55 and D21S17. This surprising also help determine the role of genomic imprinting result suggests that only I or a few genes may be involved in on phenotypic expression of mutations within the generating the classical facies, hands and some of the mental proximal 15q region. retardation seen in Down Syndrome. A80 Clinical Cytogenetics (0307) 9.8 (0308)

Parental origin of the supernumerary chromosome 18 in High Dose Pyridoxine Treatment of Maternal Homocystinuria Edwards' syndrome. K.G. Kuke. U. Miller. Division of and Follow-up Amino Acid Studies of the Mother and Infant. Genetics, The Children's Hospital, Boston; Department of T.W. Kurczynski, R.R. Lenke, D. Mohammadione and J.D. Kramer. Pediatrics, Harvard Medical School. Medical College of Ohio, Toledo, Ohio. A 27 year old lady with homocystinuria due to Twenty-three patients with Edwards' syndrome were cystathionine synthase deficiency unresponsive to treatment studied for parental origin of the supernumerary chromosome with 500-1000 mg. pyridoxine daily was followed during 18 using a chromosome-specific variable number tandem repeat pregnancy. Periodic amino acid studies of plasma and urine (VNTR) probe, pERT25. Of the 20 informative cases, the showed persistent elevation of methionine and homocystine extra chromosome was of maternal origin in 19 and paternal which gradually improved with increasing the pyridoxine to in one. The distal location of the pERT25 locus 3000 mg. per day and administration of 1 mg. of necessitated a statistical analysis to evaluate the meiotic cyanocobalamin IM 1 month prior to delivery because of a stage of nondisjunction. It was calculated that 70% of the borderline low plasma B12 level. There were no untoward maternal cases were due to meiosis I errors and the side-effects of the treatment. At the time of delivery the remaining cases were due to meiosis II errors or later mothers plasma methionine was normal, 26 umol/l and no plasma events. In one of the three indeterminate cases, an homocystine was detected. The cord blood showed an elevated recombination event took within apparent place the pERT25 methionine of 55 umol/l and no homocystine. The baby's locus. A second indeterminate case was uninformative due to plasma methionine was 40 umol/l with no homocystine. At 2 mosaicism. The overall high degree of informativeness of days of age the plasma methionine decreased to 23 umol/l. pERT25 illustrates the power of VNTR sequences in parental He was a normal male infant with a birth weight of 7 lbs. origin studies of human trisomies. 11 oz. and length 22". These data indicate that apparent nonresponders to usual amounts of pyridoxine may respond to high doses without untoward effects and confirm a maternal-fetal gradient of methionine which rapidly dissipates following birth.

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Embryonic Testicular Regression Syndrome with CHARGE A satellited chromosome 4 in two families. A.N. Association. T Kushnick, JE Wiley, A Ricker, SM Palmer. Lamb L.L. Estabrooks. N.P. Callanan, P. Friedman Department of Pediatrics, East Carolina University School of and K.W. Rao. Departments of Pediatrics and Medicine, Greenville, NC. Pathology, The University of North Carolina at The patient was a 2130 gram 37 week AGA white infant who Chapel Hill. was born to a 21 year old gravida II abortus I woman with An otherwise normal chromosome 4 with history of seizure disorder on Tegretol therapy. The baby had satellites on the short arm (4ps) was identified in CHARGE-association phenotype, occipital encephalocele, anal two apparently unrelated families. In family 1, the atresia, plus normal female external genitalia. No neural proband was a 2 year old female with stigmata of tissue was in the encephalocele at operation. Blood and skin Turner syndrome and borderline to mild mental cytogenetic studies revealed 46,XY, without rearrangements, retardation. Her karyotype was 45,X,4ps. The and parental cytogenetic analyses were normal. The patient proband's father, paternal grandmother, and sister had apparent rectovaginal fistula with the anal atresia. all carry the 4ps chromosome. Although none of However, a separate orifice through which radiopaque material these relatives have physical anomalies, all three was instilled showed an elongated urethra, rudimentary vagina are reported to have learning disabilities. There and uterus with one fallopian tube. No gonads were was no evidence of reciprocal involvement of another demonstrable by various ultrasonographic techniques. chromosome in this family. Family 2 was identified Gonadotrophins at 18 days were markedly elevated and during prenatal diagnosis (performed for elevated compatible with agonadism. DNA probes proved the presence of MSAFP) when a female fetus was found to carry a 4ps a normal Y. She had ongoing failure to thrive with neurologic chromosome. Intrauterine fetal demise was reported abnormality and worsening congenital heart problems which led at 32 weeks gestation. The father and a to surgical intervention. Although misquoted in later phenotypically normal 29 month old half-brother also articles, Sarto and Opitz had described very few malformations carry the 4ps chromosome. With G-banding (850 band in their 1973 review of 8 cases with XY gonadal agenesis level) all of 4p16 appears to be present, with NOR syndrome. External genital anomalies were common but positive stalks and satellites attached to 4p16.3. accompanied in only two patients by turricephaly, and one Since there is no evidence for a reciprocal patient had epicanthus and bilateral ptosis. Normal translocation, 4ps carriers may have a minute intelligence was the rule. A review of 21 patients by deletion of 4p. Wolf-Hirschhorn syndrome can occur Rosenburg (1984) again revealed mainly ambiguous genitalia and with a deletion of 4pl6.3, but no member of either a few male phenotypes. All lacked gonadal tissue but had some family has characteristics of the syndrome. The genital virilization suggesting prior presence of embryonic only phenotype suggestive of a small deletion is the testes with subsequent regression. Our patient had "normal" observation of learning disabilities in three external female genitalia until the radiographic exploration individuals from family 1 who have the 4ps which followed the cytogenetic results. Autosomal recessive chromosome. Molecular characterization of this inheritance of testicular regression syndrome seems most unusual satellited chromosome 4 should clarify the likely. Exploratory surgery for gonadal tissue has not been clinical significance of this chromosome. performed. A 1988 review of CHARGE association noted that all males had evidence of hypogonadism with normal cytogenetic studies. One had a variant pericentric inversion Y chromosome acquired from his father. Clinical Cytogenetics A81

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Transdermal Testosterone Supplementation in Hypogonadal Cytogenetic and molecular characterization of two chromosome Adolescent Males with Sex Chromosome Anomalies. M. G. 5q deletions near the familial adenomatous polyposis gene. Linden, B. G. Bender, and A. Robinson. National Jewish Center V. Lindgren'. C. Bryke'2. T. Ozcelik1'3. T.L.YanP-Feng1. and for Immunology and Respiratory Medicine and Univ. of Colorado U. Francke1l 3 'Yale Univ., New Haven, CT; 3SUNY HSC, Health Sciences Center, Denver. Syracuse, NY; 3Stanford Univ., Stanford, CA. Testosterone supplementation is an accepted method of Interstitial deletions of the long arm of chromosome 5 treatment of hypogonadism in 47,XXY men. Various forms of are relatively rare constitutional abnormalities, and the androgen replacement therapy have been utilized, the most repetitious nature of the banding pattern causes different common being intramuscular injections of long-acting deletions to appear similar at low resolution. Consequently, testosterone esters every two to three weeks. Oral therapy and the phenotypes associated with various deletions are not well testosterone pellet implants have also been available, but none defined, and clinical diagnosis can be difficult. Since a of these methods is entirely satisfactory. A new method gene associated with familial adenomatous polyposis (FAP) is utilizing a transdermal preparation of testosterone has been at 5q21-q22 [Bodmer et al., Nature 32, 614 (1987)], accurate developed which has proven to be an effective treatment for delineation of these deletions is crucial to the identifica- hypogonadism in men. Its application to adolescents has not tion of individuals at risk of colon cancer. been examined. Current literature suggests that 47,XXY males A 13 year old male (S.D.) with minor dysmorphic features can benefit from testosterone therapy as early as age 12 to and mild mental retardation was referred for fragile X test- promote feelings of well-being, increase muscle mass, and ing but was found to have a deletion of 5ql5-q21.3 in subse- prevent osteoporosis. The purpose of this study was to quent high resolution banding analysis. A second boy (C.C.) determine the effectiveness of transdermal testosterone has striking facial dysmorphism, congenital contractures, and systems in this age group. Seven 47,XXY and one 48,XXXY severe delay of growth and development. His somewhat larger males, ages 12-17, participated in an eight-month double blind deletion includes 5q22.3-q31.l as determined by high resolu- crossover study using 20 cm (5 mg testosterone) transdermal tion analysis. Southern blotting and in situ hybridizations patches applied daily to the genital area. The subjects were were performed using 3 probes derived from the region of the evaluated at 0, 2, 4, 6, and 8 months using physical and FAP gene--Cllpll, the most proximal; YN5.48, closest to the psychological measures. Results indicated no significant FAP gene; and MC5.61, the most distal [Nakamura et al., AJHG elevation of testosterone levels or other changes. At the end of 43; 638 (1988)]. The deletion of S.D. includes the sequences the eight months, the subjects all elected to continue the recognized by Cllpll and YN5.48, but these sequences are protocol but switched to patches containing 10 mg present on C.C. 's deleted chromosome 5. In contrast, the testosterone. All subjects are currently using these patches, and sequence detected by MC5.61 is present on S.D. 's deleted testosterone blood levels are now in the normal range. The boys chromosome but not on that of C.C. These data confirm the are generally satisfied with these patches as an alternative to cytogenetic analyses and provide cytological map locations injections, although compliance is a problem. Transdermal for YN5.48 and MC5.61, which previously were positioned only testosterone may offer a safe and effective approach to by linkage. Further, until YN5.48 is mapped either distally androgen substitution therapy in hypogonadal adolescents. or proximally with respect to the FAP locus, both S.D. and C.C. will need to be monitored for polyps and colon cancer. Cell lines established from these individuals may be helpful in identifying the FAP gene. Comparison of these cases with those in the literature clarifies the phenotypes associated with specific deletions.

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The use of stimulated peripheral blood for verifica- Inherited microdeletion syndrome, due to loss of single band tion of the leukemic origin of unusual transloca- 9q31.3: the continuing case for high resolution chromosome tions. Michael J. Macera and Ram S. Verma. Long studies in unexplained mild mental retardation. R.E. Magenis', Island College Hospital, SUNY Health Science Center, M. Lahr2, V.A. Hafits-Borchardt1, H. Lawcel', T. Wilson3. Brooklyn, N.Y. Univ. Hospitals and Clinics1, Oregon Health Sciences Univ., The use of chromosomal analysis is now a reliable Portland; Fairview Training Center2, Salem, Oregon; and Salem diagnostic tool for the identification of various Memorial Hospital3, Salem, Oregon. leukemias. Standard procedure at cytogenetic lab- FG was referred at age 14 mo to the Genetics program OHSU oratories is to culture bone marrow cells for 24hrs for developmental delay, failure to thrive and somewhat allowing one to analyze only leukemic cells. A pat- unusual appearance. His mother is mildly mentally retarded ient with CML was recently referred to our laborato- (IQ 71) and there was a question as to whether the delay ry to confirm an unusual t(5;8)(ql4;p22) transloca- noted in FG was due to psychosocial deprivation or organic tion in addition to the usual t(9;22) found in her factors. marrow cells. The 5q abnormality is indicative of FG was always slow to feed and all growth parameters were refractory anemia and would therefore require a dif- below the 3rd centile. He was hospitalized at age 12 mo for ferent chemotherapy regimen. Our bone marrow anal- chronic failure to gain weight. He was noted at ysis did confirm the presence of a t(5;8) transloca- hospitalization to be developmentally delayed. He rolled at tion. However, when stimulated peripheral blood was 4-5 mo, sat at 10 mo and took some steps at 14 mo. analyzed, we found a 46,XX,t(5;8) karyotype in her At evaluation, he was noted to be a small active, socially normal lymphocytes. She was therefore a t(9;22) CML responsive child who showed curiosity about the interviewing without any additional leukemic induced transloca- room and the toys. He had relatively large ears, deep-set tions and was treated with a standard CML chemo-reg- eyes, highly-arched eyebrows, saddle-like nose with up-turned imen. A second patient was referred to our lab to nares, full lips and very short fifth fingers. His mother rule out CML. Cytogenetic evaluation of bone marrow had similar facial features and hands. cells revealed a 46,inv(16)(pl3.l;q22.l) karyotype. Chromosome studies on child and mother showed an identical Cytogenetic evaluation of stimulated peripheral microdeletion of chromosome 9 long arm from bands 31.2-32, blood revealed a normal 46,XY karyotype. The inver- with loss of band 31.3. ted 16 is usually associated with the M4 subset of Maternal grandparents were healthy and had apparently acute myelomocytic leukemia and the patient diagno- normal learning ability; neither had facial features similar sis was revised. A third patient was referred with to their daughter and grandson. Chromosome studies were AML. Cytogenetic analysis revealed an unusual not permitted. t(l;ll)(p36;ql4.2) translocation in his bone marrow Further evidence for a de novo event in the mother was cells and a normal 46,XY karyotype in his stimulated the finding of at least two normal cells. blood cells. Thus, in this case, the unusual trans- location was associated with the leukemia and not of germline origin. We recommend that in leukemic cases with unusual translocations, stimulated perip- heral blood should be examined to verify the leuke- mic origin of the translocations. A82 Clinical Cytogenetics

(0315) 9.6 (0316) 1.171

Detection of Y Chromosome Specific Fragments in Turner Severe mental retardation and mild dysmorphism: association Syndrome Subjects Using Polymerase Chain Reaction Amplifica- with an uncommon interstitial deletion of chromosome 4. M. tion. K. Maness" V. Hannig', M. Summar', V.G. Dev', J.A. J. Mascari, P. N. Mowrey, J. C. Ramer and R. L. Ladda. Phillips III', D.W. Bianchi¾ and U. Muller Vanderbilt Univ. PA State Univ., Col. of Med., Hershey. School of Medicine, Nashville, TN' and Harvard Medical School, Chromosomal abnormalities which are rarely reported in Boston, MA2. the literature present a difficult challenge to geneticists Turner Syndrome (TS) is associated with a variety of karyo- in providing prognostic information. We describe a 14-year- typic abnormalities including 45,X/46,XY mosaicism and 46,X old girl with a de novo interstitial deletion of the long + Y chromosomal fragments. The presence of an intact Y or arm of chromosome 4, specifically 46,XX,del (4)(ql3q21). certain Y chromosomal fragments in TS subjects is associated Although our patlent exhibited severe mental retardation with increased risk for the development of gonadoblastoma. (I.Q. 20-30) in addition to multiple behavioral difficulties, Conventional cytogenetic techniques have limitations in the only mild dysmorphism was apparent. detection of low levels of 45,X/46,XY mosaicism as well as in On physical examination, height was 2.5 standard devia- verification of certain Y chromosome derived fragments tions below the mean for age. Both weight and head circum- especially in the quinacrine-negative regions Ypter-Yql. To ference were at the 60th percentile. Our cutaneous detect mosaicism for Y-containing cells as well as the examination revealed multiple atrophic regions over the presence of non-quinacrine-staining Y chromosomal fragments, arms, legs and abdomen from self-abusive picking of the skin. we studied DNA from a cohort of 13 previously identified TS In addition, multiple xanthomas were noted over the lower subjects, including 3 found to be mosaic for chromosomal frag- eyelids bilaterally. Craniofacial features were consistent ments. DNA was isolated from peripheral blood samples, and with both parents and overall dimensions were within the 500 ng aliquots from each subject were amplified using normal range. Eye examination was significant for hyperopia polymerase chain reaction (PCR). The 23 base oligonucleotide with astigmatism. The oral examination revealed multiple primers used were derived from the Y156 sequence which maps caries with enamel defects. The remaining findings included to Yp, is specific for males, and is present in z 10 copies. enhanced lordotic positioning of the spine and somewhat Following PCR amplification, the predicted 222 bp fragments shortened fingers and toes. were detected by ethidium bromide staining of 5% polyacryl- Our patient represents an uncommon interstitial deletion amide gels. PCR from 3 male controls and 1 of the 13 subjects of chromosome 4 associated with severe mental retardation consistently yielded 222 bp fragments. The subject whose DNA and mild dysmorphism. The deleted segment includes 3 G- amplified had a 45,X/46,X + fragment karyotype. This fragment positive and 3 G-negative bands at the 550 band level was quinacrine negative and Southern blot analysis of the which constitutes approximately 1% of the haploid genome. subject's DNA confirmed the presence of Y chromosome specific A review of the literature identified only a few cases with sequences. The chromosomal fragments from the remaining 2 similar but non-identical breakpoints, which manifested both subjects were documented cytogenetically to be derived from concordant and discordant phenotypic features. Our patient the X chromosome. Using serial dilutions of male DNA and further illustrates the importance of publishing case female DNA we determined the lower limit of sensitivity of reports in the literature to assist in providing prognostic this method to be 1 part male in 59,999 parts female DNA. information. These results indicate that PCR amplification enables more sensitive and rapid detection of Y chromosome mosaicism and certain Y fragments than current cytogenetic techniques.

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Counter enhanced DA/DAPI staining of restriction t(2;13) in a deaf individual: implications for endonuclease ALUI resistant chromatin of human mapping genes involved in hearing. chromosomes. T.Mathews, M.J. Macera and R.S. Verma M.W. McAfee. K.S. Arnos. K.E. Toomey and C.C. Long Island College Hospital-SUNY Health Science Morton. Harvard Medical School, Boston, MA, and Center at Brooklyn, N.Y. Gallaudet University Genetic Services Center, The past two decades have witnessed a revolution Washington, D.C. and Saint Christopher's Hospital in our understanding of the human genome. Prolifer- for Children, Philadelphia, PA. ation of newer staining techniques have facilitated Genes responsible for deafness disorders and our understanding of the structural organization of syndromes have not yet been isolated although chromosomes. When chromosomes are stained by DA/ several loci have recently been identified by DAPI, the secondary constriction regions of chromo- linkage analysis using restriction length somes 1, 9, 16, the proximal short arm of chromosome polymorphisms. As a part of an effort in our 15 and the distal long arm of the Y chromosome show laboratory to begin to identify and isolate genes bright fluorescence. In addition, some pericentric involved in hearing, we performed a karyotype regions of other chromosomes also show fluorescence analysis of peripheral blood lymphocytes derived of various intensities. Slides treated with restri- from a 21 year old male college student with ction endonuclease ALUI produce banding patterns profound bilateral sensorineural hearing impairment characteristic of the C-heterochromatic regions of who was diagnosed at three months of age. In the genome. The chromatin which is resistant to addition to deafness, physical examination revealed ALUI treatment can be seen clearly when stained with bilateral ptosis, small palpebral fissures, broad Giemsa. When ALUI treated slides are then counter and prominent nasal root and asymmetric facies. stained with DA/DAPI, ALUI resistant chromatin reg- GTG-banding revealed a chromosome rearrangement ions clearly show an enhanced fluorescence pattern. involving chromosomes 2 and 13. Reverse-banding A parallel relationship exists between the staining with CA.,/DA was used to rule out an insertion and to profile obtained by these stains. i.e. there is no establish the breakpoints of the translocation as ALUI chromatin on chromosomes 2, 8, 11, 12 and these 2p24 and 13q21. Karyotypes of the proband's parents regions did not show any DA/DAPI positive areas. were normal. This de novo cytogenetic aberration What is also intriguing is that areas that are nega- may be responsible for physical abnormalities and/or tive when DA/DAPI is used alone are positive when for deafness in this individual. Of special counter stained after ALUI digestion. DA/DAPI is an interest to us, the 2p24 and 13q21 breakpoints may intercalating dye and after ALUI digestion those indicate regions of the genome which contain genes ALUI resistant regions have undergone a conforma- involved in hearing. This case demonstrates the tional change, thus providing additional DA/DAPI potential value of karyotyping deaf individuals to staining areas. The clinical implication of this focus a molecular genetic approach to hearing. approach is discussed. Clinical Cytogenetics A83

(0319) 1.173 (0320) 1.174

Tetrasomy 8p in a 4yr.old boy evaluated because of Evaluation of a mosaic marker chromosome with Y- speech delay. D.J.McCorguodale, K.R. Tanaka, J.E. Specific DNA probes and monoclonal H-Y antibody. C.M. Holan, T.W. Kurezynski, and M.M.McCorquodale. Meyers, V. Jaswaney. S. Demas, A. TharapIL L P. Medical College of Ohio, Toledo Ohio, and Harbor- Shulman, PK anning* J. L. Simpson, S. Wachtel, S UCLA Medical Center, Torrance Calif. 90502. Elias. Univ. of Tennessee, Memphis, and Lakeside A case of tetrasomy 8p was discovered in a 4 yr. Hospital, New Orleans, LA.* old boy evaluated because of speech delay. Parents Females with a Y chromosome are at increased risk of first became concerned about possible language and developing malignant gonadal tumors. We studied a 24- gross motor delays when the child was 15 months of year-old female, initially evaluated for primary age. Physical examination at 4 years revealed only amenorrhea. She was phenotypically normal except for mild dysmorphic features. The patient's head bilateral "streak ovaries" observed at laparoscopy. A circumference was 51.1 cm (5th percentile), height 45,X/46,X,-X,+mar complement was assigned after giemsa was 401 in.(25th percentile). He had several naevi and quinacrine staining of blood lymphocytes (1:2 ratio) on his face and his head was relatively narrow with and cultured skin fibroblasts (3:2 ratio). Parental a prominent forehead. The incisor teeth showed gaps chromosomes were normal. Because of the high but the palate was normal. Extremities showed frequency of gonadal neoplasia in females with a Y- normal palmar creases in the digits except for the chromsome, we sought to determine whether the presence of excessive flexion at the inner phalan- fragment was Y-derived. Serological H-Y ("male") geal joints. Toenails were deep set and the fifth antigen was estimated in blood lymphocytes with toenails were hypoplastic bilaterally. Neurologic monoclonal H-Y antibody gw-16 and FITC-conjugated examination was within normal limits. Chromosomal goat anti-mouse IgG in an EPICS V flow cytometer; in analysis showed 47 chromosomes with a metacentric each of three separate trials, 104 cells were screened for marker chromosome which was interpreted to be an label and the results compared with those obtained with iso-8p chromosome. The identity of this chromosome cells from male and female controls. The subject was was confirmed by showing a gene dosage effect for typed H-Y-. Concurrently, Hind III digests of DNA from glutathione reductase which is located on the short blood lymphocytes were challenged with arm of chromosome #8. It is noteworthy that the pericentromeric Y-probes Y- 156 and Y- 190 (courtesy of child displays only mild dysmorphic features while U. Muller, Boston). These would be expected to hybridize 8p trisomy causes a variety of congenital malfor- if pericentromeric Y-chromosome material were mations and dysmorphic stigmata. This is probably present, but not if Y-pericentromeric material were due to the fact that the majority of 8p trisomies absent. No hybridization was observed on Southern blot are also partially monosomic for other chromosomes analysis. On the basis of these results, we infer that the involved in a parental translocation. Features which fragment is not Y-chromosome derived. Laparotomy our patient shares with 3 other cases of "pure" 8p for gonadectomy was thus avoided in this patient duplication are: numerous vascular naevi or hemangi- because H-Y serology and Y-probe analysis indicated omas, hyperlaxity of the interphalangeal joints and absence of Y-sequences. We conclude that these frontal bossing. More reports are needed on patients techniques are useful in determining the necessity for with "pure" duplications within the short arm of prophylactic gonadectomy in patients having chromosome 8 to determine whether 8p duplications chromosome fragmcnts of uncertain etiology. can be distinguished as a separate clinical entity. (NIH Grant AI-23479)

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Complex malformations in del (21)(q22.1). B. A. Moglia, Genu recurvatum in a trisomy 18 infant. M. A. Morey P. N. Mowrey, J. C. Ramer, M. J. Mascari and R. L. Ladda. and R. R. Hiaains. Children's Mercy Hospital, Kan- PA State Univ, Col. of Med., Hershey. sas City, Missouri. We have followed the development of a child with complex A 39 week, 2770 gm. infant was delivered by malformations who was recognized in early infancy to have a Caesarean section to a 30 year old woman. The del (21)(q22.1). She was small for gestational age and head was in the vertex position. The infant's out- developed feeding difficulties with cyanosis in the newborn standing presenting features were severe bilateral period. She was examined in the first week of life and had genu recurvatum and hips in flexure contraction. an abundance of hair over the neck and back with low Diastasis recti was present. Upslanted, short, and hairlines and extra skinfolds around the neck. Craniofacial narrow palpebral fissures; disorganized eyebrows; profile showed scaphocephaly with a large anterior hirsute forehead, arms and legs; small mouth and fontanelle. Frontal area showed bossing with downturning of jaw; abnormal ears; curved index and small fingers, the orbital ridges, and a prominent nasal bridge. Gingival bilaterally; syndactyly of toes 3 and 4; and redun- margins were wide and irregular but nonsegmented. Eye exam- dant neck, legs and buttocks' skin suggested a ination revealed disconjugate gaze with large corneal chromosome abnormality. Chromosome analysis showed diameters and corneal clouding. Diagnosis of bilateral a trisomy 18 female (47,XX,+18). glaucoma was followed up with both medical and surgical Abdominal wall defects, with or without treatment. Ears were small and cup-shaped. A prominent diastasis recti, and limited hip abduction are fre- systolic murmur was noted with atrial septal defect and quent in trisomy 18. Equinovarus, rocker bottom pulmonic stenosis diagnosed by echocardiogram. Prominent feet, syndactyly of toes 2 and 3 are relatively diastasis recti was associated with a small umbilical hernia. frequent. Genu recurvatum seems not to have been Club foot deformity was present with bilateral hip dis- reported in a trisomy 18 patient. Chromosome ab- location. Thorax was bell shaped and vertebral bodies normalities associated with genu recurvatum are re- were flattened; cervical spine had fusion anomalies. Cranial viewed. An infant presenting with genu recurvatum ultrasound indicated absence of septum pellucidum. Over should have cytogenetic analysis. the course of the first two years of life, severe psychomotor and developmental delay was apparent. Review of the literature identified at least 15 cases with various degrees of partial monosomy 21, but all had larger deleted segments than in our case. CNS and ocular anomalies, particularly microphthalmia, occur with high frequency. Glaucoma has not been reported in other cases. A84 Clinical Cytogenetics

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Familial mental retardation, growth deficiency, Multiple marriages yield high frequency of liveborns with craniofacial abnormalities and imperforate anus: chromosome 2 imbalance and previously unappreciated digital a new syndrome? C. A. Morris and K. M. Farwiq anomalies. P. N. Mowrey, J. C. Ramer, M. J. Mascari and R. University of Nevada School of Medicine, Las Vegas. L. Ladda. PA State Univ., Col. of Med., Hershey. A family was evaluated; the mother and her three Four matings to a presumed dir ins (6;2)(ql5;q31q33) living children had mental retardation, hypernasal carrier have produced a high frequency of abnormal speech, and distinctive facial features. Cranio- individuals. Four children born with the der (2) are facial abnormalities included brachycephaly, a high karyotypically del (2)(q31q33). The phenotype includes pre- nasal root, broad nasal bridge, thick and notched and postnatal growth retardation, developmental delay, alae nasi, epicanthal folds, bitemporal narrowing, seizures, limb anomalies and low hairlines. Patient II-3 and thick overfolded helices. One son had a bifid had facial hirsutism, midfacial hypoplasia, hypospadius nasal tip. The children had postnatal growth and undescended testes. Patient III-7 had respiratory deficiency. One son died at age six weeks; he had distress, CHF and died at day 15. Our cases are similar to the same facial features and an imperforate anus. previously reported cases, including poor growth, significant One daughter had an anteriorly placed anus. There developmental delay, abnormal ear shape and minor facial were no congenital anomalies of other organ systems. dysmorphism. Cleft palate was reported in 4/7 previous Chromosome studies were normal. The facies had some cases; none of our cases were affected. Our cases had resemblance to Tricho-rhino-phalangeal and Langer- numerous hand and foot anomalies. Combining all cases: Giedion Syndromes, but there were no skeletal or 6/11 had syndactyly; 11/11 had minor malformations (clino- digital anomalies. Autosomal dominant or X-linked dactyly, camptodactyly, brachydactyly). inheritance is possible. Published risks for a translocation carrier to have a child with a chromosomal imbalance range from 5-20%. Our pedigree contains 5/15 (33%) individuals with del (2)(q31q33) (including an elective abortion) and 3 (20%) carriers of a balanced dir ins. The deleted segment includes 2 G-positive and 3 G-negative bands (550 level) constituting about 1% of the genome. Individual II-1 and possibly II-2 had dup (2) (q31q33) not previously reported in the medical literature. E.

C

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Exclusion of the CAD locus from 2p2101->p23.3 using 2p interstitial Is there an association of cerebro-oculo-facial-skeletal (COFS) deletions from patients with holoprosencephaly. syndrome phenotype with a pericentric inversion of chromosome 6? M. Muenkel, D.M. Sosnosk1, W. G. wM2, E. R. Wassma3, J N. R.S. Muneer, A. Garnica, L. Thompson, F. Bates, J. Shissler, D. Hopcus andOa M. Rennert. Department of Pediatrics, Division of Davidson4, D. Patterso5, and R.L. Nussbauml. lHoward Hughes Cytogenetics, University of Oklahoma Health Sciences Center and Medical Institute, Univ. of Pennsylvania, Philadelphia, 2Univ. of Children's Hospital of Oklahoma, Oklahoma City, Oklahoma. Virginia, Charlottesville, 3Institute for Genetics, Pasadena, CA, We report an interesting American Indian family in which four 4Univ. of Kentucky, Lexington, 5Univ. of Colorado, Denver. members, the father and all the three children are heterozygous for Holoprosencephaly (HP) is a midline defect with malformations of a pericentric inversion of chromosome 6. This inversion involved brain and face. The etiology of HP is heterogeneous with evidence less than one-half of chromosome 6, with the break points at 6p2 1 for non-genetic and genetic forms due to non-random chromosome and and 6q21. abnormalities: trisomy 13, del(18p)! dup(3p), del(7q). parents are now 21 years We have described 3 patients with HP and an overlapping 2p The family history is remarkable. Both deletion: del(2)(p21->p22.2) [MUnke et al., Am J Med Genet 30:929, of age, and the mother previously had one miscarriage. Of the 1988], del(2)(p21 1->2109) [Shanks et al., Am J Hum Genet 43:A122, three children, the oldest is a phenotypically normal 6 year old boy. 1988], and del(2)(p21->p23.3) [Grundy et al., Am J Med Genet, in The other two siblings, a boy and a girl are 3 years and 7 months press]. The smaflest of these deletions consists of part of chromo- old, respectively. They are profoundly handicapped with multiple some band 2p21 which comprises 0.2% of the haploid genome and common may approximate 6000 kb or less. We hypothesize that a gene in- congenital malformations in with the COFS syndrome volved in early embryonic brain development is located within this phenotype. They both were born 3-6 weeks prematurely and had region. severe feeding problems in infancy. Their clinical examination As an initial step towards isolating sequences from within this revealed the following features: All growth parameters below 5th deletion and generating a long range restriction map from 2p21, we percentile; microcephaly, hypotelorism, widely open anterior have hybridized the CAD gene, previously mapped to 2p21->p22 by fontanelle, dysmorphic skull; micrognathia, posteriorly rotated in situ hybridization [Chen et al., Hum Genet 82:40, 1989], to DNA from 2 patients with HP and del(2p), a cell line with yet a different low-set ears, high arched palate; cubitus valgus, rocker bottom feet 2p deletion, a 48,XXXX cell line [GM14161, and normal male and with hallucal malleus; hypotonia; widely-spaced hypoplastic female controls. Dosage blots and analysis of the autoradiograms by nipples; unusual dermatoglyphic with simian crease; and agenesis scanning densitometry demonstrated the presence of 2 copies of the of corpus collosum. The testes are in the inguinal canal bilaterally, CAD-specific fragments in each cell line when compared to the with hypospadias and hypoplastic scrotum. expected copy number of X-specific fragments. Thus, we could The comparative, clinical feature of both affected infants in exclude the CAD gene from del(2)(p210i->p2lO9), del(2)(p21->23.3) and del(2)(p23.3->p25.1) [GM09216]. In combination with the data of relation to chromosomal, HLA antigen and other studies will be Chen et al. [1989] our results suggest a location of CAD either in sub- presented. band 2p23.3 or more likely on 2p proximal to 2p2lOl. The CAD gene encodes a mu tifunctional protein for the first 3 steps of the pyrimidine biosynthesis and is defective in the mutant CHO cell line, Urd-A. Thus, Urd-A has selectively retained human chromosome 2 after fusion to human cells [Patterson and Carnright. Somat Cell Genet 3:483, 1977]. In order to separate the normal from the deleted chromosome 2 in the HP patients, we have obtained somatic cell hybrids between Urd-A cells and cells with del(2)(p2101->2109) and del(2)(p23 .3->p25.1), respectively. Furthermore, we are in the process of generating hybrids from Urd-A and human cells from balanced translocation carriers with cytogenetic breakpoints proximal, distal, and within 2p2l. Clinical Cytogenetics A85

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X chromosome bends in variant Turner syndrome patients. C.A. Paternally inherited paracentric inversion of chrcsone 6. Munn, S.L. Wenger and M.W. Steele. Div. Genetics, Dept. R.L. Neu*, A.L. Zaslav, H.O. Shah, M. Williams, Pediatrics, Univ.and Children's Hospital of Pittsburgh, PA. L. Trinchitella, W.T. Brown and B.A. Pletcher. North Shore The inactive X chromosome has been associated with bends Univ. Hospital-Cornell Univ. Medical College, Manhasset, NY. at the Xql3-21 site. We studied 57 cases with X chromosome *Vivigen, Santa Fe, New Mexico. aneuploidy and 14 cases with X chromosome structural Paracentric inversions of chrccosome 6 are rare. Only one abnormalities for frequency of X bends. All individuals report of this anomaly has been cited in the literature (De with one normal Xql3-21 region (XY, X, XYY, and Novo and Starberg, 1988). This is a second report of an X,del(X)(ql2)) had ". 2% cells with bends. Presumably this inversion of chrcmsce 6. represents background unassociated with X inactivation. The A 26 year old wonan was referred for amniocentesis because frequencies of cells with X bends in individuals with 2 or of a history of Down syndrcm in her husband's niece. 3tintact Xql3-21 inactivation regions are seen in the table: Pregnancy history was significant for a healthy 4 year old son and one spontaneous abortion at three months gestation. Karyotype # PTs # Cells % K Bends* Cytogenetic analysis revealed a male fetus with a paracen- 46,XX 100 2902 10.1 tric inversion of one nurber 6 chrcmsace, 46,XY,inv(6) (p21 47,XXY 23 2200 9.4 p25). Peripheral bloods fran both parents were evaluated to 48,XXXYt 2 108 9.3 determine whether this inversion was inherited or a de navo 46,X,i(Xq)t 6 562 13.1 event. Wile the mother had a normal karyotype, 46,XX, the 46,X,del(X)(p22) 3 211 6.6 father was found to have the same inversion as the fetus, 46,X,del(X)(q26) 2 177 4.5 46,XY,inv (6) (p21p25). Therefore, the parents were counseled 46,X,inv(X)(ql2q27) 1 100 5.0 that this chrcmosace variation most likely had no clinical *% cells with bend on one or more X chromosomes significance for the fetus since the father was a phenotyp- ically normal male. The frequency of cells with X bends in the 6i(Xq) cases The breakpoints described in the 1988 report were (3 intact Xql3-21 inactivation regions) was similar to that 6(pll.2p21.1). This inversion was also paternally inherited of subjects with 2 or 3 structurally normal X chromosomes. and there was also a history of a single previous spontaneous However, the 6 cases with X chromosome structural abortion. As with other inversions, these two reports of abnormalities but only 2 intact Xql3-21 inactivation regions chrcnoscmn 6 paracentric inversions suggest that phenotype- had significantly fewer cells with X bends than the normal ically normal carriers may be at increased risk for spontan- 46,XX subjects (X =10.4;df=3;p<0.025). Four of these 6 eous abortions or birth of abnormal offspring resulting fran cases had congenital abnormalities and/or mental retardation crossing over within the inversion during Meiosis. not usually associated with either gonadal dysgenesis or Turner syndrome. Grompe et al (AJHG 43:A53,1988) suggested that such unusual pathology might result from alteration in the inactivation pattern of an abnormal X chromosome. Presumably this could either allow expression of harmful X- linked recessive genes or cause dosage imbalances for X- linked genes in general. Our data support the latter.

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Familial inversion of chromosome 7 (pl5.lq36)mat leading to Paternal inheritance of the deleted chromosome 5 in most cri du offspring with deletion and duplication of terminal segments. chat syndrome patients. L. Overhauser*, G.-T. Lee-Chen#, T. H. J. Noack, P. N. Mowrey, R. L. Ladda, J. C. Ramer and M. McMahan#. J. Wasmuth#. S. Oberlender*. M. E. CarlinA. and E. J. Mascari. PA State Univ., Col. of Med., Hershey. Niebuhr**. *Thomas Jefferson University, Philadelphia, The proband, karyotyped as 46,XX,rec(7),dup p, inv (7) (pl5.lq36)mat, presented at 4 years 7 months of age with #University of California, Irvine, AUniversity of Miami/ multiple congenital anomalies including hydrocephalus and Mailman Center for Child Development, **University Institute interspinal cyst with bilateral clubbed foot deformity. At of Medical Genetics, Copenhagen, Denmark. 12 years of age, height and weight were below the 1st Cri du chat syndrome is associated with a deletion in the percentile and severe psychomotor delay was apparent with short arm of chromosome 5. The amount of chromosomal functional level estimated at 2 years. Craniofacial features included brachycephaly and prominent frontal bossing with material can vary from a cytogenetically undetectable deletion, to midfacial hypoplasia associated with hypoplasia of the loss of almost the entire short arm, with the majority having zygomatic and maxillary processes. Philtrum was long and large deletions. A preponderance of paternal origin of deletions simplistic with carp shaped mouth. Micrognathia was have been observed in microdeletion syndromes which include prominent with a deep dimple below the lower lip. Ears were Prader-Willi syndrome, Miller-Dieker Syndrome, and low set by standard criteria and posteriorly rotated with retinoblastoma. We have looked at the parental origin of prominent folding of the helices. She had experienced deletions in cri du chat patients to investigate if a large deletion recurrent vomiting with gastroesophageal reflux and abdominal pain, probably related to severe constipation. Chronic syndrome would also show a preference for a paternal origin of nasal drainage and challazion were also troublesome. the altered chromosome. The family history revealed multiple losses of pregnancy RFLPs previously localized to the short arm of in 3 generations with 8 individuals reported to have died chromosome 5 were used to determine the origin of the deleted in early childhood with multiple congenital anomalies. A chromosome. In cases where only one parent was available, maternal aunt with multiple anomalies lived to 19 years and somatic cell hybrids derived from the cri du chat patient were died of respiratory failure. Seven carriers of the inversion (7)(pl5.1q36) were identified. Medical records used in conjunction with RFLP analysis to determine parental were not available on all affected individuals, but all origin. In 20/25 cases, the deleted chromosome 5 was shown to individuals with early death had severe hydrocephalus. be of paternal origin. Thus, a chromosomal syndrome resulting in large deletions also shows a preponderance for paternal origin of the deleted chromosome as seen in microdeletion syndromes. A86 Clinical Cytogenetics (0331) 1.178 (0332) 1.179 Molecular analysis of three Down syndrome patients Regionalization of the Y-absent and Y-present cell with a 'mirror' duplication of chromosome 21. lines in the short and long legs of an asymmetric C.Pangalosl2. D. Theophile13. P.M. Sinet3. D. male with 45,X/46,ZY mosaicism. P.R. Papenhausen. Abazis2. Z. Chettouh3. M.O. Rethor6l, M. Prieurl. C. J.F. Salazar. O.T. Mueller and T. A. Tedesco. Verelen4. J. Leieunel and J.M. Delabar3. Department of Pediatrics, Univ. of South Florida, lInstitut de Progonbse, 45 rue des Saints Tampa. Peres,75270,Paris,France. 2 Genetic Center ,86 A karyotypic analysis of peripheral blood and Vassilissis Sophias Ave.,11528,Athens, Greece.3 URA skin fibroblasts obtained from the back and both the CNRS 1335, Lab. Biochimie Ghnetique, Hop. thighs and calves were performed on a 13 1/2 year Necker,75743,Paris,France.4 Centre de Genetique, old boy, with a 5 cm growth deficit in one leg, UCL,Av.Monier,1200,Brussels,Belgium. small penis size, and normal endocrine parameters. Phenotypic,cytogenetic and molecular analysis were Cytogenetic results were: performed in three patients: AL, TY and LI. All had 45,X 46,XY the phenotypic features of Down syndrome. In patient count (%) count (%) TY, two signs were discordant: ears with a large Blood lymphocytes 14 (36) 25 (64) unfolded helix and post-natal hypertonia. In the 3 Back 8 (30) 19 (70) patients, karyotypic analysis by high resolution R Right thigh (short) 25 (100) 0 (0) banding showed a 'mirror'duplication of chromosome Right calf (short) 32 (80) 8 (20) 21: 46, XX or XY, -21, + psu dic(21)t(21;21)(q22.3; Left thigh (normal) 0 (0) 25 (100) q22.3). The evaluation of the copy number of Left calf (normal) O (0) 40 (100) chromosome 21 single-copy sequences was performed by a slot blot method. In patient AL, SODI, D21S15, Confirmation of the deficit of Y bearing cells in PFKL and CD18 were all found in 3 copies. In patient the right leg was obtained using densitometric TY, the copy number for SOD1, D21S15 and CD18 was estimation following DNA hybridization with two Y- respectively 3, 3 and 1. In patient LI, the copy specific probes at the DYZ1 and DYZ4 loci. The number for D21S15, BCEI and CD18 was respectively 3, fibroblast culture derived from the right thigh 3 and 1. These results indicate that: 1- the biopsy had Y-specific sequences at about 5% of translocation leading to "mirror' duplication of normal, whereas the culture derived from the right chromosome 21 lies within 21q22.3 as showed by the calf demonstrated about 30% of normal Y specific cytogenetic analysis; 2- the location of the levels. The cell cultures from the left calf and translocation breakpoint is variable: distal to CD18 thigh both had apparently normal amounts of Y DNA. in patient AL, proximal to CD18 in patients TY and Evidence that the X and Y chromosomes carry genes LI; 3- this type of chromosome rearragement may lead that influence height is clear from phenotypes to partial deletion of 21q22.3. As patient TY shows observed in cases of both Turner syndrome and sexual some clinical features not usually encountered in polysomy. The segregation of the 45,X and the 46,XY trisomy 21, further molecular analysis of these and cells into different legs with considerable growth other patients with 'mirror' duplication of differences may be indicative of the local influence chromosome 21 may be relevant to phenotype-genotype these cells have on bone growth. The bone itself correlation studies in Down syndrome. may demonstrate the same discrepancy in Y bearing cells although this has not been examined.

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Prenatal detection of two cases of familial satellited Yq (Yqs) chromosomes. Premature meopause in a female with an X/autoscme J. P. Park. E. F. Rawnsley. and D. H. Wurster-Hill. Dartmouth-Hitchcock translocaticn, 46,X,t(X;8)(q21;q24.3). U. Patel, L. Medical Center, Hanover, N. H. Riddle, A. Babu, V.B. Penchaszadeh, and N. Szlachter. We present the 20th and 21st cases of a Yqs chromosome arising either de Divisicr of Medical Genetics, ard Department of CB/GYN, novo (Turleau et al, 1978) or of familial origin (all remaining cases). Such Beth Israel Medical Center, New York, New York. translocations involving part or all of the short arm of an acrocentric We report cn the Me findings of a 24 year old chromosome and the long arm of the Y are believed to be reciprocal. The female with premature ovarian failure. Menarchia had acrocentric chromosomes most often involved are No. 15 and 22. occurred at 12 years of age and menstrual cycles were Homologous DNA sequences are known to be present in the constitutive ncrmal until 15 years of age after which they were heterochromatin of the short arms of these acrocentrics and the long arm of reduced in frequency (2-3 times a year). Regular cycles the Y and, at interphase, these regions are arranged in close spatial contact. ensued with pogestercne therapy, but disapeared upon Both of our cases were detected following amniocentesis for increased risk of disccntinuaticc of treatment at 22 years of age. trisomy 21 based on maternal serum AFP (case 1; risk of 1:260, case 2; no Abdminal MRI showed very small ovaries and a small cyst increased risk after recalculation based on corrected maternal age). The Yqs on the right ovary. The physical exanination was chromosome was also observed in the father in each case. The Yqs was otherwise normal. Cybogenetic analysis revealed an X;8 characterized by G, C, and Q banding in both cases and no discernible loss of translocaticn with breakpoints at q21 and q24.3, the C, Q positive heterochromatin band was observed. Active Yqs NOR's respectively, karyotype: 46,X,t(X;8)(q21;q24.3). were demonstrated in both cases by AgNOR staining. Satellite/NOR iranmecme analysis of the parents were normal. Ihe associations between the Yqs and acrocentrics were not uncommon. Case 2 breakpoint co the X chraecme is located within the came to term after an uneventful pregnancy with the birth by Ceasarian section critical region Xql3-Xq27. Studies of the X replication of a phenotypically normal, 61b, l3oz apgar 9 male. The pregnancy of case 1 pettemis in peripheral blood lymphocytes showed the proceeds without complication. The lack of phenotypic abnormalities rxrnal X dnu"Iso to be inactive in all cells. associated with the segregation of these rearranged chromosomes is best Patients with X/autoseme translocaticrs with a demonstrated by the case of Genest (1973) where the Yqs has been breakpoint in the critical region of Xq present usually transmitted in patrilineary fashion for 11 generations. The case of de novo with gcradal dysgenesis and primary anenrrhea. Our Yqs was associated with multiple phenotypic anomalies which could be patient, however, dsmstrates that this ch0a0sm9 coincidental to the rearrangement or attributable to consanquinity of the rearrangement can be the basis of premature ovarian parents (first cousins). A recent case of a deleted Yq in the sterile offspring of failure without ary samatic stigmata. a man with familial Yqs (Chandley et al, 1989) represents the first reported case of a secondary Yq lesion in such a family. The presence of Yqs has been associated with nondisjunction involving trisomy 21 (2 cases) and 47,XXY. While most of the reported cases of Yqs involve the actual visualization of satellites, it is possible that translocations involving acrocentrics with no discernible satellites may go undetected in the absence of routine use of AgNOR techniques. Our cases of prenatally diagnosed familial Yqs taken in the context of other reported cases, and given the possibility that many such cases go undetected, suggest that Yqs represents a structural rearrangement without deleterious phenotypic effect. Clinical Cytogenetics A87

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Prematurecentrm eric separation in an obligate heterozy- Distinct Clinical Discrepancies Between Prenatally gote for Rderts-SC phocxelia syrdrcie. Paulson. C.. land Postnatally Diagnosed Casey of 45,X/47,XYY. Mann. E.. Rabin. A.. Marion. R.. Nitcwskw. H.. Schmidt. R. M. J. Pettenati, M Wheeler, D . J. Bartlett, I Albert Einstein, Bronx, New York, Metpath laboratory Ine., Subrt, 1B.K.Burton. lBowman Gray School of Medicine, Teterboro, New Jersey. Winston-Salem, NC; 2University of Colorado Health Roberts-C (IRS) phoccmelia syrdrcme is an autosnal Sciences Center, Denver, CO; tEast Anglian Regional recessive disorder dharacterized cytogenetically by a Genetics Service, Cambridge, ENG; Institute for localized puffirg of the heterohrcuatin of the sister the Care of Mother and Child, Prague, CZ. circnatids and early separation of the entroeres. Prenatal detection of sex chomosome mosaicism Phenotypic variability includes pre- and postnatal growth poses problems in terms of accurately predicting retardation, limb reduction defects and various craniofa- phenotypic outcome and possible associated problems cial abnormalities. We report a case of Roberts-SC since individuals with abnormal sex characteristics phocomelia and demonstrate premature centromeric and sex chromosome mosacism show variable phenotypic separation (PCS) in a normal appearing obligate features. Recently two of our centers each heterozygote of the RS phocamelia syndrcme as well as in prenatally detected a sex chromosome mosaicism of the affected newborn. Sonogram at 33 weeks gestation by 45,X/47,XYY with the outcomes resulting in IMP revealed a fetus with apparently hypoplastic or absent postnatally confirmed phenotypically normal males. lirbs. A pelvic x-ray confirmed the abeee of ex- 45,X/47,XYY mosaicism is a rare sex chromosome tremities. The family ancestry was significant for the mosaic disorder with clinical information limited to biological parents being first cousins once removed. The 7 literature cases. Thus predicting prenatally a newborn male of 36 weeks gestation had tetra-amelia, phenotypic outcome and prognosis is poor. Two micrognathia, midline cleft palate and enlargement of the additional 45,X/47,XYY mosaics were located with phallus. Post-mortem examination revealed cryptorthidism, clinical and cytogenetic information. Both were bilateral punonary agenesis, and absent pulmonary females, diagnosed postnatally because of phenotypic arteries. cytogenetic analysis by G- aid C- bardirn on abnormalities. the infant's peripheral blood dsistrated PCS in the Clinical summary of the 11 cases of 45,X / 47,XYY majority of matapsases examine; whereas a few of the mosaicism showed that 5 are phenotypically male. The obligate heterozygote's cells demonstrated this cytogene- 3 postnatally diagnosed males have variable clinical tic feature. It has been widely accepted that the RS phenotypes. The 6 females identified postnatally phocamlia syndrcme represents a single genetic entity have some phenotypic features of Turner syndrome. (Krassikoff et al., Am. J. Hum. Genet. 39, 618-630, 1986) There was no apparrent correlation between the with varying phenotypes as a consequente of multiple percent mosaicism and the phenotypic sex. alleles or variable expression. The dearstration of a These clinical findings suggest that the significantly lower fraction of PCS in the obligate phenotype of prenatally diagnosed X/XYY mosaicism heterozygote is consistent with an hypo- thesis of can be quite different from postnatally detected cytogenetic variation resulting frum variable expression cases. It does appear that there is a likelihood of a recessive mutant gene. We propose that many of the that a fetus identified with a sex chromosome mild phenotypic variants of RS phocomelia syndrcme may in mosaicism 45,X / 47,XYY will be a phenotypic fact be heterozygotes. normal male. The long term clinical outcome of these 45,X/47,XYY mosaics is not known.

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Greig Syndrome associated with an interstitial deletion of 7p: Confirma- Partial trisomy for distal long arm of chromosome 6: A clinically recognizable tion of the localization of Greig syndrome to 7pl3. A.L. Pettigrew, F. syndrome. EXK Pivnick. J.B. Summitt. A. T. Tharapel and R.S. WKiy University Greenber, D.H. Ledbetter and CI.T Caskey. Baylor College of Medicine, of Tennessee, Memphis. Houston, Texas. A derivative chromosome which is usually inherited from a reciprocal Greig cephalopolysyndactyly syndrome is an autosomal dominant disor- translocation heterozygote contributes to partial trisomy for one chromosome der characterized by craniofacial defects, polysyndactyly of the hands and and partial monosomy for a second. In effect, such patients represent double feet and typically, normal intelligence. The majority of cases have been chromosome syndrome. We present an exception to this condition where pure familial. We report a sporadic case of an 11 month old infant with typical trisomy 6q23.3-qter was seen in a patient. The trisomic segment was features of the disorder including mazrocephaly, frontal bossing, syndac- translocated to the short arm of a chromosome 15. The proband was a tyly, postaxial polydactyly of the hanis and preaxial polydactyly of the newborn, genetically evaluated for dysmorphic features and congenital feet. On formal developmental testing, she demonstrated mild delays. anomalies. Physical examination revealed intrauterine growth retardation, Skull X-rays did not demonstrate craniosynostosis. A CT scan of the brain brachycephaly, anterior webbing of the neck, hypertelorism, downward slanting showed mild prominence of the ventricles, and presence of the corpus cal- palpebral fissures, carp-shaped mouth, micrognathia, joint contractures, heart losum was noted. High resolution chromosome analysis showed a murmur (critical valvular pulmonary stenosis), bilateral clubfoot deformation and 46,XX,del(7)(pl3pl4)pat chromosome pattern. Parental chromosomes were retracted foreskin. Chromosomal analysis of the proband revealed: normal. Cytogenetic analysis of polymorphisms of the heterochromatin in 46,XY,-15,+der(15),t(6:15)(q23.3;p12). The father and the paternal the pericentromeric region determined the deleted chromosome to be of grandfather were carriers of the balanced translocation. paternal origin. This is the first report of an interstitial deletion associated Including the present case, 21 patients have been reported with partial with Greig syndrome and confirms the localization to 7p13 first suggested trisomy for the distal long arm of chromosome 6. In the 21 cases reported 16 by two reports of familial Greig syndrome segregating with balanced trans- were due to maternal translocation, two due to paternal translocation, two due locations involving 7p13 [t(3;7) and t(6;7)]. It is also consistent with to maternal balanced insertion and one due to maternal pericentric inversion. preliminary studies showing linkage ) the epidermal growth factor recep- Based upon the clinical picture of these patients we have delineated the tor cDNA probe pHER-64-1 which maps to 7pl2-13 and to the T- s characteristic phenotype of partial trisomy 6q. Major malformations confirmed receptor locus which maps to 7pl5. Reports of chromosome analyses in were as follows: Greig syndrome are rare, but have been abnormal in three of eight cases (includin) this patient). Cytogenetic analysis should be performed in all Microcephaly 17 Club foot 14 cases pal ticularly those that are sporadic, atypical or associated with Down slanting palpebral Genitourinary unusually stvere mental retardation. This case demonstrates that the Men- fissures, hypertelorism 1 8 abnormality 11 delian disorder of Greig syndrome can be caused by a chromosomal dele- Carp-shaped mouth 19 Heart defect or murmur 9 tion and sleat deletions of differing size and location may explain some of Anterior webbed neck 19 Growth retardation 10 the variability in phenotypic expression. This heterogeneity could include Micrognathia 16 Mental retardation the Schinzel acrocallosal syndrome wnich shares numerous features with Joint contractures 16 in older patients 10/10 Greig syndrome, but differs in that there is severe mental retardation, ab- sence of the corpus callosum and only rarely syndactyly. The acrocallosal From the phenotypic analysis of these patients we conclude that partial syndrome may be allelic to Greig syndrome or represent a physically con- trisomy 6q is truly a clinically distinguishable entity. When the presenting tiguous locus. A lymphoblastoid cell line established on this patient will be phenotype includes cranial anomalies, facial dysmorphia, anterior webbing of the instrumental in identifying DNA markers and expressed sequences in the neck, joint contractures, and mental retardation (in older patients), partial trisomy region ard, perhaps, in clarifying the relationship between Greig syndrome for the distal long arm of chromosome 6 must be considered. and the acrocallosal syndrome. A88 Clinical Cytogenetics (0339) (0340)

Partial trisomy lq and partial monosomy 14q resulting from a A longitudinal evaluation of thyroid function and growth in maternal balanced translocation. B.A. Pletcher, H.O. Shah and young children with trisomy 21. J. C. Ramer, M. J. Mascari, M. Shaham. Department of Pediatrics, North Shore University P. N. Mowrey and R. L. Ladda. PA State Univ., Col. of Med., Hospital, Cornell Univ. Medical College, Manhasset, New York Hershey. and MediGene Inc., Elmford, New York. Sixty-three children under the age of 60 months with A 28 year old profoundly retarded male presented to our trisomy 21 had yearly evaluation of thyroid function (T4,TSH) office for diagnostic work-up. He was born at term weighing and growth beginning at twelve months of age. Four individ- 61b 5oz. Prior to his birth another male child was born with uals (6%) had significantly decreased T4 and elevated TSH a large hemangioma on his lower back and died at 4 months of values requiring hormonal replacement and seventeen (27%) had age from complex congenital heart disease. at least one elevated TSH (>6.0 iiu/mL) level with a normal Medical history was significant for multiple T4 value for a total of twenty-one (33%) children with hospitalizations early in life for respiratory infections. A possible thyroid dysfunction. Six of the children with cardiac murmur noted in the past was not evaluated. Parents initial elevated TSH levels had a later normal TSH; three denied a history of seizures. had persistently elevated values and eight have not as yet On physical examination this patient was found to have been reevaluated. The TSH elevations were mild (range mild microcephaly, cranial asymmetry, low anterior and 6.5-19.4 pu/mL) and tended to occur during significant posterior hairline, antimongolian palpebral slant, low set illnesses. and cupped ears, pectus carinatum, significant kyphoscoliosis Growth, including height, weight, head circumference and and arachnodactyly. Cardiac examination revealed a Grade mid-facial measurements, was no different in the group with II/VI systolic murmur without clubbing or cyanosis. The either persistent or transient elevation of TSH compared to right pupil was non-reactive to light and a cataract was the children with normal thyroid function. The six children noted. A right cortical thumb was seen with lateral with initially elevated TSH values had no change in growth displacement at the DIP joint. Metatarsal shortening of toes rate when the TSH level returned to normal. 3,4 and 5 was evident. Gait was broad-based and awkward. Chromosome analysis of this patient showed 46,XY, inv(9) (pllql3),-14,+der(14)t(1;14)(q31;32.3)mat. His mother had a balanced reciprocal translocation with 46,XX, inv(9)

(pllql3) ,t (1; 14) (q31;q32 . 3). Features in our patient similar to others with partial trisomy lq include: downslanting palpebrae, flat nasal bridge, possible cardiac defect, long hyperextensible fingers and cryptorchidism. Features similar to ring 14 include facial dysmorphology, scoliosis and ataxic gait, but a seizure disorder was not present.

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Hits after misses: the value of rekaryotyping. Failure to thrive and developmental delay associated K.W. Rao. N.P Callanan. S. Wilson. W.G. Talley. and with the translocation of an active nucleolar A.S. Aylsworth. Departments of Pediatrics and organizer from chromosome 14 to the long arm of Pathology, The University of North Carolina at chromosome 21. D.Riffner, E.S. Ruppert, T.W. Chapel Hill. Kurczynski, and M.M. McCorquodale. Medical College Roughly 4 years ago our laboratory adopted the of Ohio, Toledo Ohio, 43699. newer methods of increasing chromosome length, and A 2 yr. old female was seen in developmental cli- changed our routine chromosome banding method from nic for failure to thrive and developmental delay. Q-banding to G-banding. Since then, we have At the time of evaluation her weight was below the rekaryotyped 43 patients who were studied initially 5th percentile, and her length and head circumfer- either in our laboratory or at other facilities. ence were at the 25th percentile. There were no For 13 of these 43 patients (30.2%) the original dysmorphic features, but developmental assessment diagnosis was significantly altered. In 8 cases was at an 18 month level with expression language previously diagnosed as chromosomally normal, a at 6 months. Laboratory studies included normal structural abnormality was found; in 5 cases with CBC, thyroxine, blood chemistries, and amino acids. earlier "abnormal" diagnoses, the interpretation of Chromosomal analysis showed 46 chromosomes with ex- the karyotype changed. New diagnoses include 7 tra material on the long arm of chromosome 21, some- deletions, 3 derivative chromosomes, a dicentric Y what separated from the rest of the chromosome. Sil- chromosome, and a paracentric inversion. Six of ver staining identified the extra material as an ac- the 13 patients with altered diagnoses were tive nucleolar organizer region. Chromosome #14 was originally studied with Q-banding and two were noted to be telocentric, with no NOR-region present. originally karyotyped at prenatal diagnosis. For Since the child had no antimongoloid features, we comparison, a total of 37 chromosome abnormalities assume that no 21q material was missing. NOR trans- (16.7%) were found in 221 patients with a similar locations into non-acrocentric regions of chromo- range of phenotypes referred for their first somes are rare. A genetically benign insertion of peripheral blood karyotype during 1987-88. an active NOR into the short arm of chromosome 12 We have adopted the policy of rekaryotyping has been reported in 3 generations of one family. any patient whose original karyotype was normal, We suspect that our insertion is not benign as the but whose phenotype or family history strongly proposita's mother has a history of mental illnesses suggests a chromosome abnormality and who meets one and 2 sibs are delayed. The grandfather, who cares or more of the following conditions: A) the for the proposita, has not yet consented to testing original study was done with Q-banding; B) the of other family members. original study was a prenatal karyotype; C) the original study was performed 5 or more years ago; or D) the original study was performed at another laboratory and karyotypes or prints are not available for review. Our experience suggests that it is at least as efficient to rekaryotype patients who meet these criteria as it is to perform initial karyotypes on newly ascertained patients. Clinical Cytogenetics A89

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Absence of Prader-Willi Phenotype in a Carrier of a Cytogenetic evidence for a putative hotspot for recombination Reciprocal Translocation (13;15) and 15q Mrnoscry. within the pseudoautosomal region of the X-chromosome. J. Rinsky, J. Rabin, A. Shanske. Queens Hospital Center Affiliation, Long Island Jewish Medical Center, Jamaica, N.Y. J. Rosendorff and R. Bernstein*. MRC Human Ecogenetics Individuals with partial mmnoscnies often exhibit Research Unit, Dept. Human Genetics, South African Institute specific abnormalities which are useful in delineating chrcooscne deficiency sydrcxmes and mapping new loci. We for Medical Research and Univ. of the Witwatersrand, Johannes have identified an infant with a unique rearrangement in- burg, South Africa. (*Present address: Department of herited as a result of malsegregation of a 13/15 trans- location. Pediatrics, University of California, Irvine), a month infant who was the 2845 K.B. (GM10329) is 6 gram We describe three siblings, one male and two females, who product of a 42 week gestation acmplicated by substance abuse delivered by primary section to a 19 year old with a have a duplication deficiency X-chromosome defined as rec(X) strong family history of early fetal loss. He was noted (Xqter-*X26.3 Xp22.3-*Xqter), inherited from their mother at birth to be microcephalic (H.C. 33 an), to have a Greek helmet profile without a defined nasal bridge, bilateral who carries a pericentric inversion X-chromosome with the cup-shaped pinna, long digitalized thumbs and multiple breakpoints p22.3and q26.3. This rec(X) has previously been digital contractures. Subsequently he was demonstrated to have an ASD. He has generalized hypertonia and mild molecularly proven to be a true duplication - deficiency developmental delays. A factor XII assay was 32% (NL 50-150) chromosome. The rec(X) was nonrandomly inactivated in the and a factor X assay was 34% (NL 50-150). Cytogenetic studies revealed an unbalanced male karyotype female siblings of the proband, while the inv(X) was randomly from 45,XY,-13,-15,+der(13)t(13;15) (q31;ql5) mat inherited inactivated in the mother. The duplicated region (Xq26.3+ his mother as a result of 3:1 segregation. This karyotype is monoscinic for 13q31 *q ter and 15 pter -*.q15. Xqter) differs from previously investigated X-chromosome The clinical observations noted thus far are all con- abnormalities described in male individuals. The family sistent with 13q3 monosany. Our patient lacks any of the specific features associated with partial 15q monoscmy or described appears unique in that the same rec(X), ascribed the Prader-Willi syndrcue. We have also demonstrated a to meiotic crossing over within an inversion loop, was gene dosage effect consistent with 13q3 monosaoy by ob- serving markedly reduced production of factors VII and detected in three siblings. The findings in this family X terminal linked to 13q. illustrate that the sequence involved in the maternal inv(X),

within the pseudoautosomal region on Xp, may be regarded as a hotspot for meiotic recombination.

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Sequential meiotic nondisjunction resulting in First detailed clinical description of a 2q deletion in region 49,XXXXY and 48,XXYY: Confirmation using RFLPs. 2ql: Further evidence of a possible 2q deletion syndrome. L.J. Russell, M. Bialer and T.E. Kelly. Univ. T. J. Rutherford, T. W. Kurczynski, E. G. Brookfield, K. J. of Virginia, Charlottesville. Brown, and M. M. McCorquodale. Albert Einstein Hospital, The 49,XXXXY and 48,YXXYY karyotypes are rare Philadelphia, PA., Medical College of Ohio and the Toledo sex chromosome aneuploidies associated with the Hospital, Toledo, Ohio Klinefelter phenotype and thought to arise from We report a case involving a de novo interstitial deletion sequential nondisjunction, first in meiosis I and of the proximal region of chromosome 2. Dysmorphic features then in meiosis II. Previous studies utilizing included: micrognathia, high arched palate, thin lower lip, genotyping by the Xg blood group have shown that rotated and low set ears, short neck with increased skin all four Xs in several informative cases of the folds, antimongoloid eye slant, flattened face, sacral dimple, 49,XXXXY syndrome are maternal in origin and that anterior anus, hypoplastic toenails, complete and partial syn- one X and both Ys in the 48,XXYY syndrome are dactyly of the toes, a large cleft between the first and sec- paternal in origin. ond toes, and pectus excavatum. Cardiac evaluation revealed We have genotyped one patient each with the a small VSD and a large PDS which was surgically ligated. Ul- 49rXXXXY and 48,XXYY syndromes and their parents trasound and CT of the head showed slight symmetrical dilata- using a variety of X-linked RFLPs. All four Xs in tion of the ventricles. An MRI showed delayed myelination and the individual with the 49,XXXXY syndrome were less prominent gyri with prominent ventricles. At 8 months of maternal in origin while one X and both Ys in the age she is feeding well (weight - 6,648g and length = 63.5cm), person with the 48,XXYY syndrome were paternal in smiles, sits alone, grasps but does not transfer. She is origin. Therefore, these results confirm those of currently felt to have mild developmental delay and a recent earlier studies utilizing genctyl;ing with the Xg BAER test shows a sensory-neural deficit. Chromosome analysis blood group and are consistent with sequential revealed an interstitial deletion in region one of chromosome nondisiunction in reiosis. Use of RFLPs for 2 involving the two small dark bands 14.1 and 14.3. High genotyping has the advantage that a much higher resolution analysis suggested that the fine dark band 21.2 is percentage of families is informative. still present defining the breakpoint at 2ql3 and 2q21.3. Chromosome studies on both parents were normal but 5% of the mother's cells showed a fragile site at 2q33. There are 19 patients reported with 2q deletions and their clinical feat- ures vary depending upon the location of the deletion. Our patient is only the second patient reported with a deletion in region 1 and displays some features outstanding in patients with deletions in other regions - syntactyly, cleft between first and second toe, heart defect, low set ears, abnormali- ties of the palate, antimongoloid slant to the eyes, and hypo- plastic nails. Interestingly 16 of the 19 del 2 patients are females. A90 Clinical Cytogenetics

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The incidence of hemorrhagic endovasculitis is in- Tetrasomy 9p: Prenatal Diagnosis and Delineation creased in cases of both liveborn and stillborn of the Phenotype. G. B. Schaefer. D. B. Domek. R. S. trisomy 21. C.M. Salafia, J.P. Burns, and P.S. Muneer. S.F. Johnson and M.A. Morgan. University Danbury Hospital, Danbury, CT and The Univ- of Oklahoma College of Medicine, Oklahoma City, ersity of Connecticut School of Medicine, Farming- Oklahoma. ton. Tetrasomy 9p is a very rare condition; only 12 10 cases of trisomy 21 delivered between weeks reports of any form of this condition appear in 16 and 40 at Danbury Hospital between July 1984 and the literature. Of these 12 cases only 1 May 1988. All 4 liveborn infants had hemmorhagic documents "pure" tetrasomy 9p i.e. no mosaicism endovasculitis; in 2 cases the lesion was focal, and no inclusion of any segment of 9q. We report and in 2 cases, large areas of the placenta were the prenatal diagnosis of a subsequently stillborn involved. In the remaining 6 cases, 4 demonstrated infant with tetrasomy 9p. This is the first hemorrhagic endovasculitis; in 3 cases, the lesion report of prenatal diagnosis of tetrasomy 9p and was focal, and in 1 case the lesion was widespread. only the second documented case demonstrating no The incidence of hemorrhagic endovasculitis in our mosaicism in multiple tissues and no involvement normal population is less than 5% (vs. 80% in cases of any portion of 9q. Comparisons between the in trisomy 21). Hemorrhagic endovasculitis has been reported clinical features of the mosaic versus suggested to indicate either the presence of con- non-mosaic cases and those cases with inclusion genital viral infection, maternal-fetal immunopath- of segments of 9q versus those without begin to ology, or the effects of hemodynamic instability. delineate a unique phenotype associated with this While it is possible that these data reflect a aneuploidy. Major features include early infant spurious coincidence of congenital viral infection death (non-mosaic) or psychomotor retardation with trisomy 21, they may suggest two alternative (mosaic); hypotonia; open cranial sutures/wide hypotheses: (1) maternal-fetal immune recognition fontanelles; bulbous, beaked nose; hypertelorism; in pregnancy may be abnormal when trisomy 21 is ear malformations; cleft lip/palate; skeletal present, leading to placental immunopathologic anomalies (especially hypoplastic or absent bones, lesions; (2) trisomy 21 may be associated with articular dislocations, short neck, shortened primary placental dysfunction leading to hemo- hands and feet); sacral dimple; genitourinary dynamic instability. Either of these mechanisms may anomalies; dysplastic nails and redundant skin. contribute to the natural selection process against Common features include microcephaly, fetuses with trisomy 21. Hemorrhagic endovasculitis hydrocephaly, enopthalmus, epicanthal folds, has also been associated with longterm neuro- strabismus/myopia, downward slanting mouth, logical outcome. The presence of this placental retromicrognathia, and congenital heart disease. lesion in certain cases may explain some of the variance in intellectual performance observed in this syndrome.Additional cases to July 1989 will be presented.

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DNA analysis of a case of incomplete testicular Normal fertility in females of two successive feminization with 47,XXY karyotype. N.R. Schneider generations with an X/Y translocation (1), U.H. Nuller(2). G.N. Wilson(l). (1) Univ. of [der(X)t(X;Y)([22.3;ql2)]. M. Schwartz, D.P. Morejon, Texas Southwestern Medical Center at Dallas (2) A. Babu and V.B. Penchaszadeh. Divisicon of Medical Children's Hospital and Harvard Medical School, Genetics, Beth Israel Medical Center, New York, New Boston, MA. York. Androgen-insensitivity disorders including com- An abnormal X was detected through the plete and incomplete forms of testicular femin- family study of a 9 year old female proband with severe ization (TF) are inherited as X-linked recessive growth stunting, dysnorhic features, mental traits. Persons with TF and 2 X chromosomes must retardation and seizures. The analysis of thus have a mutant gene on both X chromosomes. Non- the proband was apparently rmal 46, XX. The patient disjunction at meiosis II in a heterozygote could died shortly thereafter and rn specific syrnmrcnic produce a gamete with 2 X chromosomes, each diagrnsis was made. C2rosome analysis of the mother carrying a mutant gene for TF. Only 3 previous and maternal grannther revealed an abrxrmal X instances of testicular feminization with 47,XXY chdnosme (Xp+), karyotype 46,XXp+. The additicnal karyotype have been reported. We report another material on the abnormal X chrmscme stained uniformly case and demonstrate for the first time that the dark with GIG banding. Subsequent analysis using nondisjunction occurred in maternal meiosis II. An multiple banding techniques showed that the extra 11-year old prepubertal girl with bilateral material was brillantly fluorescent with QFQ and inguinal testes, clitoromegaly, and absent uterus DA/DAPI, and stained darkly with CBG. This region was and ovaries by ultrasound was found to have a found to be uniformly late replicating by RHG in all 47,XXY karyotype in 50 lymphocytes and 50 skin the cells. The staining profile ccnfirmed the extra fibroblasts. Five Y-chromosome-specific DNA probes, material to be of Y origin, as a result of a four of which derive from the testis-determining translocatiao between the X and Y chrcmssemes, region of Yp, failed to reveal a Y chromosome 46,X,der(X)t(X;Y)(p22.3;ql2). Both individuals were deletion. Probe St14-1 (kindly provided by J.L. phenotypically normal except for significant short Mandel), which detects a DNA polymorphism on Xq, stature. Analysis of the family history dtastrated was informative and showed absence of the paternal normal fertility patterns in both translocation allele in the girl, indicating maternal origin of carriers: the grandmother had four full-term live both of her X chromosomes. A VNTR probe, offsprings between the ages of 16 and 27, while the M27B(DXS255) (kindly provided by I.W. Craig), which mother had the proband and a boy with ventricular maps between Xpll.3 and the centromere, was also septal defect at the ages of 15 and 16 respectively. informative, showing that nondisjunction at These observations confirm that carriers of an X;Y maternal meiosis II was highly likely, resulting in translocation involving the Y heterochrcmatic segment homozygosity (uniparental disomy) for at least a may have nrmal fertility. portion of a single maternal X chromosome in the girl. This maternal X chromosome presumably carries a mutation of the androgen-receptor gene (which, like DXS255, maps to the pericentromeric region of X). Androgen-receptor studies are planned. Clinical Cytogenetics A91

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An unusual mosaic karyotype detected through prenatal diagnosis with Diagnostic elevations of G2/G1 phase ratios in Fanconi duplication of lq and 19p and associated teratoma development. L anemia and their normalization by caffeine. Schwartz. L.J. Raffel. C.-C.J. Sun. R. Chisum. University of Maryland Helga Seyschab, Gisela Bretzel, R. Friedl, D. Schindler, School of Medicine, Baltimore. M. Nenadov4, A. SchinzeV2 and H. Hoehn. Univ. of Wirzburg, FRG, 4tUniv. of Lausanne and 2Univ. of A 39 year old white female underwent amniocentesis for advanced Zurich, Switzerland. maternal age at 15.4 weeks gestation. In situ cultures were harvested on Cultured cells frcm patients with coverslips at 8-12 days and chromosome analysis of cells representing 30 Fanconi anemia (FA) primary clones demonstrated two distinct cell lines. Three clones revealed exhibit a specific cell cycle defect (prolonged transit a balanced translocation involving chromosomes I and 19 through and arrest within the G2 phase) which is thought [46,XX,t(l;l9XplI;q I1)]. The karyotype of the remaining 27 clones (modal to reflect their inability to properly remove DNA lesions number - 47) contained both the balanced translocation and an additional caused by ambient oxygen (1 ,2). -In 8 FA patients, the derivative chromosome, yielding a karyotype that was trisomic for both Iq G2/G1 ratios of cycling lymphocytes ranged from 1.5 to 2.2 and 19p [47,XX,t(l;l9Xpl l;ql l)+der(l)t(l;l9Xql l;ql 1)]. The father had (mean 1.91±1.05), whereas 32 non-FA controls showed a mean a normal karyotype; however, the mother carried the balanced translocation. G2/G1 ratio of 0.45±0.32 (p<0.001). Among 11 siblings of Amniotic fluid alphafetoprotein level was elevated and an a single family with one clinically affected child, we was detected. acetylcholinesterase band observed a trimodal distribution of G2/G1 ratios, sugges- Level II ultrasonography at 17 weeks revealed several abnormalities ting the pre-symptcmatic detection of two further affected including a large facial cleft and a probable facial teratoma. An additional siblings and the possibility of heterozygote detection in teratoma was thought to be present in the brain. A second ultrasonogram at 24 weeks revealed rapid growth of the intracranial tumor, with marked that particular family. -In an attempt to resolve the endo- enlargement of fetal head size. Autopsy following pregnancy termination genous cell cycle lesions of FA cells, FA lymphocyte cul- confirmed the presence of an oral pharyngeal teratoma (epignathus) with tures were exposed to 0.25 - 3.0 mM concentrations of intracranial extension. Histologically, the tumor was an immature teratoma. caffeine during 22 to 72 h after PHA stimulation. Exposure Also present were hepatomegaly and multiple abnormalities of the distal to 1.5 to 3.0 mM caffeine reduced their spontaneously elev- extremities, including syndactyly and flexion deformities of the fingers. G2/G1 ratios to control levels by causing G2 phase arrested Chromosome evaluation of 106 metaphases from tissue samples of both the FA cells to enter the subsequent G1 phase. In contrast, epignathus and the intracranial teratoma revealed a predominance of the cell X-ray induced G2 phase arrests of control lymphocytes were 47 chromosomes In 100 metaphases non- line with (100/106 94.3%). from reduced by only 20% as opposed to a 55% reduction observed teratoma tissue (skin and lung), only the balanced karyotype (2n = 46) was in FA cells after exposure to caffeine. latter detected. The finding suggests that a different molecular mechanism may account This case represents the earliest prenatal detection of a fetal epignathus. for the G2 phase arrest seen Chromosomal mosaicism in the fetus arose via mitotic nondisjunction of a in FA cells and that induced in normal cells by exposure rearranged chromosome from a reciprocal translocation. This chromosomal to X-rays. (1) Schindler D, imbalance appears to be instrumental in the etiology of the teratoma since Hoehn H, Am J Hum Genet 43:429, 1989 (2) Hoehn H et al, it was present only in the tumor cells. This is the second teratoma in which in: Fanconi Anemia, TM Schroeder-Kurth et al (eds.) p 161, a involving the arm of chromosome No. I has been rearrangement long Springer-Verlag, Berlin Heidelberg, 1989. detected, suggesting the possible localization of genes associated with the organization, growth, and development of these tumors.

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Meiotic Non-Disjunction in a Carrier of a Reciprocal Trans- Fragile X syndrome and inv dup (15) in a 12 year old female. location (13;15). A. Shanske, R. Kazi, H. Lightman, D. Vine. G.abhikora, A.L Zaslav, I.E. Fox, and J. Stamberg. Schneider Queens Hospital Center Affiliation, Long Island Jewish Children's Hospital, Long Island Jewish Medical Center, New Hyde Medical Center, Jamaica, N.Y. (A.S., R.K.); Hospital for Park, NY. Joint Diseases, Orthopedic Institute, N.Y. N.Y. A 12 year old female was referred for genetic evaluation The clinical features seen in unbalanced translocation because of a severe learning disability. At age 9.5 years carriers help to delineate new partial trisany and monosacy psychoneurological evaluation revealed a verbal IT of 80,(low syndromes. We have observed what to our knowledge is a average), a performance IQ of 65,(mentally deficient) and a full patient with a unique rearrangement, 47, X, t(13;15) (q31;q22), scale 1Q of 71, (borderline). Her speech, hearing, and vision were -der(15,t(13;15) (q32;q22) pat. normal. The patient developed seizures at age 10 years. Physical K.D. (@110274) is a 7 month old infant who was the examination at age 12 years revealed height at the 5%; weight at the 7 lb. 1 oz. product of a term, uneventful pregnancy noted 25% and head circumference at the 2%. She had a long face, and at birth to have bilateral preaxial hexadactyly, bilateral her ears were of normal shape and position and were at the 50% in inferior colobcnmas and a prominent nevus flammeus of the length for age. The only other remarkable finding was increased forehead and nasal bridge. Subsequently, she has been laxity of the joints. The patient's maternal uncle also exhibited a noted to have a VSD (confirmed echocordiographically), significant learning disability. hepatosplenomegaly and bilateral hydronephrosis. Her A fragile X study was performed on the proband, and a fragile psychomotor development has been markedly delayed though tip at the Xq long arm was found in 5.3% of cells (confirmed with she continues to thrive. two blood samples). In addition, 66% of the cells had a G-size Cytogenetic studies revealed an unbalanced reciprocal marker chromosome, resembling a partial number 15 chromosome, translocation inherited frcm her father. Her karyotypic which appeared to be dicentric. Studies using G and C banding, and abnormalities resulted fran alternate segregation during NOR and DA-DAPI staining were performed to identify the meiosis I followed by non-disjunction of der (15) at fragment. The marker had two centromeres, active NOR's at one terminus, and miosis II. Alternatively, but much less likely, the super- positive bands on DA-DAPI staining, identifying this numerary derivative 15 could have arisen through marker as an mv dup (15). Thus, the patient's karyotype is mitotic non-disjunction and the loss of the monosanic line. 46,X,fra(X)(q27)/47,XX,+inv dup (15)(pter->q13::q13->pter). Peripheral blood samples were Our observations are consistent with the clinical obtained on both parents to features of 13q3 triscny (colobomas, hexadactyly and establish fragile X carrier status and/or balanced translocation carrier status. No marker chromosome, abnormality of chromosome hemangiama) and triscrny (15) (pter * q22) (mental re- 15 or fragile X tardation and VSD). No Prader-Willi syndrome features chromosome was identified in either parent. Polymorphisms were been this uninformative for parental origin of the have observed. The karyotypic features of marker. The family declined further testing. patient are reminiscent of those seen in the partial This patient's phenotype appears to resemble a of trisany 22 syndrcme where there is an apparent increased combination the 15q trisomy and the fragile X syndromes. of incidence of non-disjunction in a translocation involving A karyotype 46,fra(X)(q27)/47,XX,+inv dup (15) must be extremely rare, an acrocentric chromosome. because, to our knowledge, there are no published reports ofinv dup (15) concomitant with the fragile X syndrome. A92 Clinical Cytogenetics

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Apparent duplication 8p22 in three generations. Sommer, A. and Trisomy 15 in a mosaic, doubly aneuploid two year old. Stallard, R. The Ohio State Univ. and Children's Hospital R. Stallard and A. Sommer. Children's Hospital and The Ohio Columbus. State Univ., Columbus. Carriers of chromosomal imbalances are ususually affected Z.R. was referred for genetic evaluation because of mild phenotypically. We report an abnormal #8 chromosome in a white failure to thrive and developmental delay. He was the product female with developmental delay, hypermobile joints, hypotonia of a normal pregnancy of a 23 year old G2 P2 mother and a 29 and mottling of the skin and in her normal mother and grand- year old father and had a birth weight of 3.18 kgs and a father. length of 46.25 cms. There were no immediate neonatal compli- She was born after an entirely normal pregnancy, labor and cations, but the patient was a very poor feeder and slept ex- term delivery to a G2 P2 SAB2 mother. Birth weight was 2.72 cessively. Because of slow growth and poor weight gain, he was kgs and length was 47.5 cms. She was mildly cyanotic at birth further evaluated. The family history revealed that both par- and later developed neonatal jaundice. Developmental delay ents and the older brother were healthy and there were no soon became evident. Both parents were 28 and healthy at the known hereditary diseases. At six mo., the patient was found time of delivery; a healthy older brother was unremarkable. At to be in the 30th percentile for height, weight and head cir- 10 mo. she had normal growth parameters, but severe hypotonia, cumference. He was not yet sitting up, but transferred and myopathic facies, a somewhat elongated calvarium with a high rolled over. Mild craniofacial dysmorphism consisted of slight forehead, mild hypotelorism and a high nasal bridge with a ly course facies, prominent eyebrows, epicanthic folds, a squared-off root. Her palate was high-arched and she had a broad nasal bridge with an upturned nasal tip, a long philtrum pectus excavatums deformity. There were no other dysmorphic and hypertrophic lateral palatine ridges resulting in a high, features. A complete work-up revealed no metabolic or struc- narrow palate. He had a lcm non-draining mass in the midline tural CNS abnormalities and included normal electrolytes, of the anterior neck. There were no other abnormalities inclu- blood gases, aminoacids, thyroid studies and a CT-scan of the ding normal male genetalia with bilaterally palpable gonads. brain. The patient achieved sitting at 12 years and crawled When 100 leukocytes from two cultures were 45,X and when 22 and pulled to standing at 2 yrs. skin fibroblasts were also 45,X, an HCG stimulation test was Although all her symptoms could be explained as a disorder performed. His testosterone level rose from a baseline of less of neuronal migration, chromosomal studies were ordered be- than 5 ng/dl to 325.7 ng/dl indicating the presence of func- cause she had significant unexplained delay in gross and fine tioning testicular tissue. An exploratory laparotomy did not motor skills as well as in development of language. Karyotypes reveal any internal female reproductive structures, but only of the proband, her mother and grandfather were without demon- two normal appearing testes in their normal positions. The strable structural abnormality, at high resolution, except for testes were biopsied and found to contain only normal infant- an apparent duplication of 8p22 and a minute segment of either ile testicular tissue on microscopic examination. Fibroblasts 8p21.3 or 8p23.1. The segmental imbalance was about 8.5% of a from the right testis were 45,X(13/15) and 47,Xy,+15(2/15); #8 and less than 0.5% of a haploid autosomal length. The mo- those from the left were 45,X(15/20) and 47,XY,+15(5/20). ther and grandfather were phenotypically normal and function- Considering the patient's failure to thrive and developmen- ing at normal intellectual levels. tal delay, we think that the mosaicism for trisomy 15 may be The proband's phenotype, therefore, seems unrelated to the more extensive and present in other untested sources. Hereto- karyotypic abnormality. Additional reports of family studies fore, trisomy 15 mosaicism has been considered incompatible are needed to establish the significance of such primarily with postnatal development. This case suggests the need for GTG-positive additions to the standard chromosomal complement. caution in interpreting trisomy 15 in prenatal diagnoses.

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The Xg,STS,ZFY and ZFX loci in a dysmorphic male infant with Down syndrome children have a decreased reverse triiodothyro- an inherited X;Y translocation. M.W. Steele, S.L. Wenger nine level. and J.H. Cummins. Division of Genetics, Dept. Pediatrics, C.Stoll, Y.Alembik, B.Dott and Univ. of School of Children's Hospital Pittsburgh The introduction of routine screening for thyroid disea- PA. Medicine, se in the newborn population has shown that infants with Down We report here a newborn male infant whose karyotype is syndrome (DS) have an increased incidence of thyroid dysfunc- Like several other such cases in 46,Y,t(X;Y)(p22.3;qll.l). tion : other studies have shown that, apart from the well- our had somatic abnormalities the literature, patient described autoimmune hypothyroidism of adolescence and post- including here dysmorphic facies, agenesis of corpus adolescence there is also an increased incidence of thyroid callosum and Dandy-Walker cyst. His genitalia seemed to be dysfunction in the infant or child with D.S. The thyroid func- normal male except for bilateral hydrocoels. Karyotypes on tion was investigated in patients with DS, all the cases were patient's mother and his sister were each trisomy 21: 47,XX or XY,+21. All were home reared and in good 46,X,t(X;Y)(p22.3;qll.1) and both were physically normal health. A propective study of 100 patients with DS (mean age albeit somewhat short and the mother had cubitus valgus. 5 years 7 months, age range 2 months to 15 years) was performed The patient's mother received the t(X;Y) from her normal Conventional, clinical laboratory procedures were used for de- as a new cell mutation since 46,XY father presumably germ termining the thyrotropin (TSH), the total and free tetraiodo- The she did not inherit her father's Xg blood group. thyronine (T4 and FT4), the total and free triiodothyronine patient did not have an Xg (courtesy Gamma (TB and FT3) and the reverse T3 (rT3)uptake ratios. The levels Biologicals,Houston) or a STS locus (courtesy Dr. L. of these parameters were compared to those of a control group Shapiro, Torrence, CA) but had both the ZFX and the ZFY loci of the same age as the patients. All the children were screened (courtesy D. Page, Cambridge, MA). His mother was ZFX for the presence of antithyroglobulin (AT) and antimmicrosomal our will positive, ZFY negative. Presumably patient develop (AM) antithyroid antibodies. Growth parameters (head circumfe- ichthyosis. This report confirms once again that: the Xg rence, height, weight) and bone age were compared with normal and STS loci are both distal to Xp22.3; ZFX is proximal to infants. Growth was retarded in DS children and 38 of them had Xp22.3,ZFY is not on distal Yq, replacement of one distal Xp a delayed bone age. None of the DS child had hypothyroidism or by a distal Yq in females does not necessarily cause hyperthyroidism (1 of them had AT, 1 other had AM antithyroid significant somatic abnormalities or prevent fertility. antibodies and 1 other had both antibodies (controls 1 and 1). In the DS group there was a trend for TSH values to increase and for T4 values to decrease (mean TSH 3.49 ± 1.37 uU/ml, controls 2.69 ± 1.14 but the difference was not statistically significant. Mean T4 8.62 - 2.48 ,ug/dL, controls 9.46 - 2.31 Mean T3 was 7.61 ± 1.73 pmol/L in the DS children and 7.98 - 1.81 in the controls (not significant). However rT3 was signi- ficantly lower in the DS children than in the controls (302.48 - 32.56 pg/mL vs 406.32 - 118.40). The decrease of the ratio rT3/TSH (106.42 in DS children, 208.24 in controls) was highly significant, p (0.01. These results suggest that rT3 which level is decreased in the DS children, may play a major role in the thyroid dysfunction of the DS patients. Clinical Cytogenetics A93

(0359) 9.10 (0360) Chromosomal basis for Waardenburg's Acrocephalo- Pigmentary abnormalities and mosaicism for chromosomal syndactyly (ACS) syndrome (deletion of 13q). K.E. aberration: A recognized association with clinical features Toomey and H.H. Punnett. St. Christopher's Hospital for similar to hypomelanosis of Ito. V. P. Sybert, R. A. Pagon, Philadelphia, M. Donlan, C. Bradley. Children's Hospital & Medical Center Children, Temple Univ. School of Medicine, Univ. of Washington School of Medicine, Seattle; and Pa. and In 1934, Waardenburg described an infant with Deaconess Hospital, Spokane, WA. of Congenital disturbances in skin pigment are associated multiple congenital anomalies the most striking which were: hypertelorism toe and finger anomalies with a variety of syndromes, including single gene disorders, abnormalities, and disorders of unknown cause. resembling those of the Afeiffer syndrome, low-set chromosome eyes. This Both hyper- and hypo- pigmentation may occur in the same malformed ears and severe dysgenesis of the of these conditions are characterized by syndrome was called the Acrocephalosyndactyly syn- individual. Many a chromo- structural malformations and mental retardation of varying drome though Waardenburg postulated that severity. Following the report of Thomas and Frias (Am J some abnormality was no doubt present. In the instant case, an infant presented with Human Genet 1986;A84(285)) of eight patients with pigmentary hypertelorism, downward slanting palpebral fissures, abnormalities and mosaicism for chromosomal abnormalities, we medially deviated great recalled our patients who carried a diagnosis of hypo- severe microphthalmia, broad palmar creases melanosis of Ito, a disorder of uncertain etiology toes, spatulate fingers, horizontal characterized by mental retardation, malformations, and bilaterally, absence of the mid-phalanx of the fifth swirly hypopigmentation of the skin. Peripheral lymphocytes digits, hypoplastic toes, hypotonia, partial agenesis of the corpus callosum, mild kidney hypoplasia, low set and skin fibroblasts were karyotyped when possible. Both deafness. light and dark areas of skin were biopsied and karyotyped malformed ears and bilateral sensorineural studies, a when permission was given. These evaluations were also Prior to the completion of cytogenetic performed in all patients with pigmentary abnormalities and tentative diagnosis of ACS was made. developmental disabilities who presented to our clinic Chromosome preparation revealed a deletion of the subsequent to the Thomas and Frias report. Seven of twelve long arm of chromosome 13 with break points at q22 and feature q32 or 33. Parental karyotypes are normal. A review of patients had abnormal karyotypes. No single clinical that substantial deletions of was associated with chromosome imbalance. Cytogenetic the literature reveals and foot anomalies as findings included: a balanced de novo X-autosome trans- distal 13q result in similar hand location; ring 10; 45,X/46,Y,+ring (peripheral blood); mosaic well as severe anomalies of the eyes. del 13q11 (fibroblasts); mosaic triploidy (fibroblasts); mosaic tetrasomy 12p (fibroblasts); and mosaic for a balanced 15;22 translocation (peripheral blood). Many of these patients fit the clinical description of hypomelanosis of Ito, a condition for which autosomal dominant and X-linked dominant inher- itance have been suggested, but not confirmed. We believe hypomelanosis of Ito is an etiologically heterogeneous disorder and recommend karyotyping of multiple tissues in all patients with this diagnosis.

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Thyroid antibodies as a risk factor for non-disjunction. C.P. An XY phenotypic female with Down syndrome and Torfs. B.J. van den Berg. F.W. Oechsli. CA Birth Defects probable gonadal dysgenesis. L. Trinchitella, Monitoring Program, Emeryville, CA and Child Health & A.L. Zaslav, H.O. Shah, P. Fort, F. Lifshitz, Development Studies, Berkeley, CA. W.T. Brown and B.A. Pletcher. Dept. of Pediatrics, Previous studies have reported a higher prevalence of serum North Shore Univ. Hospital-Cornell Univ. Medical thyroid antibodies (TAB) in mothers of children with Down College, Manhasset, New York. syndrome (DS) than in age-matched controls (Fialkow et al. A one month old female infant was referred for 1970, 1979). It was then suggested that the presence of TAB in evaluation because she had a number of stigmata of maternal or paternal serum was a risk factor for non- Down syndrome. On examination she was noted to disjunction (Flannery et al., ASHG, 1985, 1986). Confirmation have typical facial and somatic features of Down of this association would have important consequences for syndrome. A cardiac murmur was heard and echo- prenatal screening, particularly in younger women. If TAB are cardiography revealed a small secundum atrial a risk factor for non-disjunction, then they should be present septal defect. External genitalia were that of a in a parent at the time of conception of a child who will be normal prepubertal female without evidence of trisomic. We tested this hypothesis in two populations, the masculinization. Child Health & Development Studies (CHDS) and the Collaborative Chromosome analysis using G and Q banding Perinatal Project (CPP), totaling about 70,000 births. Maternal techniques revealed the following karyotype: 46,XY, blood samples had been drawn prospectively, usually at the -21,+ t(21q21q), a male with a translocation beginning of pregnancy, and stored for future research. We between the long arm (q) of two number 21 chromo- identified all cases of trisomies (115) born in the CHDS and somes. Parental karyotypes were both normal (46,XX CPP; 9 cases did not have available maternal sera and were and 46,XY). A three year old female sibling was excluded. Of the 106 remaining cases, 100 had DS and 6 had unavailable for chromosome analysis. other trisomies. Three controls per case, matched for sex, Family history was negative for females with hospital of birth, and age and race of both parents were amenorrhea or infertility. Baseline testosterone randomly selected. We tested maternal sera for both level was less than 20 ng/ml and did not rise after antimicrosomal (AMA) and antithyroglobulin (ATA) antibodies. three doses of HCG. This, and the presence of a The prevalence of either AMA or ATA was 16.04% in the cases and hypoplastic uterus on pelvic sonogram, suggested 16.67 % in the controls. The lack of association was evident in the diagnosis of gonadal dysgenesis rather than both populations and in all parental races and age groups. In testicular feminization. the subgroup of Caucasian mothers over 30 years of age the Familial and sporadic occurrence of XY females prevalence of AMA was non-significantly higher in the cases with gonadal dysgenesis are relatively rare. Down than in the controls (OR=1.87, p=0.16). In the CHDS population, syndrome resulting from a D:G or G:G translocation paternal bloods were also available; 0% of 44 cases and 11.4% is seen in only 4% of individuals with features of of 132 controls had TAB. We conclude that TAB are not a trisomy 21. To the best of our knowledge, this is significant risk factor for non-disjunction. Differences the first report of an XY female with both gonadal between some of our findings and those from other studies could dysgenesis and Down syndrome. It is possible that result from differences in methods of selection of cases and children with Down syndrome may be at risk for more controls, in the timing (before birth) of the testing, or in significant defects in gonadal development than the the number of cases and controls. (Supported by NIH grant hypogonadism described primarily in males. HD21113) A94 Clinical Cytogenetics

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Somatic mosaicism in Rothnund-Thomson syndrome: A step in the Incidence of chromosomal abnormalities detected by process of cancerous change? M. Vekemans, J.J. McGill, H.R. chorionic villus sampling. A comparison with amnio- Kopleman, S. Lavall6. G.V. Dunbar, and V.M. Der Kaloustian. centesis and abortion data. R. S. Verma. Long Divisionof Cytoetics, Department of Pathology; Divisions Island College Hospital-SUNY Health Science Center of Medical Genetics and Gastroenterology, Department of at Brooklyn, N.Y. Paediatrics; Montreal Children's Hospital; and McGill Centre Prevention of genetic diseases by prenatal diag- for Human Genetics, McGill University, Montreal, Canada. nosis has gained universal appeal in the contempor- Somatic chromosomal mosaicism has been reported in several ary practice of modern medicine. Amniocentesis is conditions in which there are dermatological manifestations. an established approach utilized to diagnose various Skin biopsies were taken from a 3 year old boy in whom the genetic diseases however, chorionic villus sampling diagnosis of Rothmund-Thomson syndrome was based on his is rapidly gaining popularity. An attempt has been characteristic facies; short stature; osteoporosis; and the made to compare the incidence of chromosomal abnorm- dermatological features of poikiloderma, varying degrees of alities found in fetuses obtained by various approa- atrophy, areas of hypo- and hyper-pigmentation, and telangiec- ches. The information is based upon 100,000 cases tasia. The fibroblast karyotype from an area of poikiloderma of amniocentesis, 10,000 cases of CVS and 10,000 was: 46,XY,-17,+t(2;17) (qll;p13) in 44 of 56 cells examined cases of abortuses. In general, the number of abnor- from 3 flasks cultured from the first trypsinization of the malities observed in CVS is higher as compared to explant. These results indicate that the translocation amniocentesis data. Many unusal chromosomal abnorm- originated in vivo. The normal karyotypes are presuned to be alities are seen by CVS which are not observed by from islands of normal skin within the area of poikiloderma. amniocentessis. Obviously, if CVS was not performed The fibroblast karyotype from an area of normal pigmentation the majority of these abnormalities would have abor- was: 47,XY,+8 in 45 of 57 cells examined from 2 flasks cul- ted spontaneously due to in utero selection. Never- tured from the first trypsinization of the explant and theless, a higher incidence of chromosomal abnormal- 47,XY,i(2q) in 28 of 34 cells examined from the fourth tryp- ities in the first trimester of pregnancy has advan- sinization of the explant. The patient has no clinical tages over amniocentesis, including major medical features of mosaic trisomy 8 syndrome and we interpret these and psychological benefits. However, the higher results to represent in vitro changes. Blood karyotypes from risk of abortion associated with CVS procedure needs the patient (50 cells examined) and his parents were all further evaluation. normal. Rothmund-Thomson syndrome has been associated with osteo- sarcoma and skin cancer. We postulate that the unbalanced translocation found in this patient may be an early step in the process of cancerous change. Further studies are planned to assess if a degree of chromosomal instability, similar to that found in Werner syndrome, is present in this condition.

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A FAMILY WITH A SATELLITED Yq CHROMOSOME. B.T. A Unique Phenotype Associated With a Pericentric Inversion Wang. C.H. Rubin and J. Williams. The Prenatal of Chromosome 6 in Three Generations. K.D. Wenstrom, Diagnostic Center of So. Ca., Beverly Hills. A.C. Muilenburg, S.R. Patil, J.W. Hanson, Univ. of Iowa, Iowa A family with an unusual satellited Yq (Yqs) City, Iowa chromosome has been identified throughout three We generations. A 36 year old woman underwent describe a previously unreported unusual phenotype in transcervical chorionic villi sampling (CVS) at three generations of one family. BS, a 40-year-old gravida 11.3 weeks gestational age. Fourteen milligrams of one female, presented for genetic counseling and amniocente- normal appearing villi were obtained. sis at 15 weeks' gestation. She, two brothers age 45 and 34 Cytogenetic analysis of both direct slide (GE and RE), and their 77 year old father (EE) had multiple preparations and cultured chorionic villi cells medical problems including the following: revealed a satellited Yq chromosome in all cells. BS GE RE EE Fetus Subsequent cytogenetic study of blood lymphocyte Congenital Cataracts X X X X X cultures was carried out by standard methods with Hearing Loss X X X X confirmation of the Yqs in other male relatives Dental Anomalies X X X including the fetus's father, paternal grandfather, Ear Anomalies X X X X uncle and first cousin. Giemsa, Quinacrine, C- Premature Graying X X X banding, Silver staining as well as DA/DAPI staining were performed on the cultured cells. The Unilateral Strabismus X X presence of satellites attached at the end of the Mild Mental Retardation X X long arm of the Y chromosome was evident in G-, Q- Coloboma X and C-banded metaphase cells. Silver staining for EE reported that his mother, now deceased, was born with the study of nucleolar organizing regions (NORs) congenital cataracts. There was no family history of proved that the long arm of the Y chromosome infertility, spontaneous abortions, stillbirths, or neonatal contained a NOR. DAPI staining revealed a bright demise. region extending all the way to the attached Chromosome analysis by G-banding of BS, GE, RE, EE, and satellites. the 15 week fetus revealed that all had the identical peri- Satellites on the long arm of the Y chromosome centric inversion of are rare and usually are not associated with chromosome 6 [46, XX or XY, inv(6) phenotypic abnormality. Although de novo (p23q23.1)]. The karyotypes of two unaffected siblings and ocurrances have been reported, a satellited Yq can the spouses of BS and EE were normal. usually be traced back to a common ancestor. The The fetus was delivered uneventfully at term. The 2905 DAPI staining finding in the present report gram male was noted to have ear anomalies, a small left suggested that the satellited Yq chromosome facial pit, anterior polar cataracts, and a small mandible. probably involves a translocation between Y and the The association of this phenotype with the same pericen- short arm of chromosome #15. However, DNA probe tric inversion in three generations suggests a causal studies are required to confirm such cytogenetic relationship. The clinical manifestations of this rearrange- findings. To the author's knowledge, this is the ment may be due to a submicroscopic deletion at the site of first case of satellited Yq diagnosed by CVS. exchange, a position effect, or a gene mutation at the chro- mosome break point(s). Molecular studies would be necessary to confirm any of these possibilities. Clinical Cytogenetics A95

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Disomic balanced reciprocal translocation-first Balanced chromosome 12/13 translocation in mother and fetus observation in humans. P.L. Wilmot, A.C. with situs abnormalities in the fetus: Transection of a mater- Casamassima, L.R. Shapiro, and R.V. Scott. New York nal effect gene regulating early pattern? G. N. Wilson, J. P. Medical College and Westchester County Medical Stout, N. R. Schneider, S. M. Zneimer, L. C. Gilstrap, C. S. Center, Valhalla, New York. Richards. Univ. of Texas Southwestern Medical Center and Gene- Complete disomy of a balanced reciprocal trans- Screen Laboratories, Dallas. location has not been reported previously. This Studies in lower organisms have identified genes expressed one month old male was evaluated because of infant- in oocytes or early zygotes which are critical for pattern for- ile seizures. Examination revealed a lethargic in- mation. Mutations in these genes may exhibit maternal effect-- fant with hypotonia and myoclonic jerks. No signif- they cause abnormalities in the fetus only when present in the icant dysmorphic features were present. An MRI scan mother. We report an inherited translocation which may illus- revealed decreased size of the left frontal lobe. trate maternal effect on human topogenesis. A 35-year-old Chromosome analysis revealed 46 chromosomes with Asian G5 P2 Ab2 female requested amniocentesis for maternal age. a male sex chromosome constitution and two identi- She has 7 normal siblings and two normal children in addition cal balanced reciprocal translocations involving to the spontaneous abortions. The fetal karyotype of 46, XX, the short arm of both #3 chromosomes and the long t(12;13)(ql3.1;pl3) was also found in maternal peripheral blood, arm of both #16 chromosomes [46,XY,t(3;16)(3;16) suggesting a low risk for fetal abnormality until ultrasound (p25;q13p25;q13)]. The parents were phenotypically revealed hypoplastic left heart. Elective abortion at 22 weeks normal second cousins once removed whose chromosome yielded a 422 g female fetus with complex cardiac malformations, analyses each revealed identical balanced recipro- bilateral trilobar lungs, asplenia, and abdominal heterotaxia cal translocations [t(3;16)(p25;q13)]. consistent witha pathologic diagnosis of Ivemark syndrome. An Although the reciprocal translocations are ap- 8-10% risk for fetal anomalies is associated with de novo parently balanced, crossing over may have resulted translocations, but detection of the translocation in a normal in differences of some loci on the translocation parent is usually reassuring. While abnormality in this case chromosomes; however, many loci would still be homo- may be coincidental, a more compelling explanation would be zygous. Also, it is possible that in the formation transection of a maternal effect locus which can be rescued by of the translocation chromosomes, one or more genes a normal fetal genome. Children of this mother who inherit the may have been deleted. While of no consequence in translocation will have the same altered locus with consequent the hemizygous state, a homozygous deletion could anomalies of early pattern. The grandmother, with 8 normal result in clinical abnormality, such as the central children and no abortions, presumably does not carry the trans- nervous system abnormality and the infantile seiz- location. Characterization of the translocation breakpoints is ures in this patient. Thus, the disomy of the underway to substantiate this hypothesis. Of note are the Hox 3 balanced translocations not only results from but and int-1 loci in the 12ql region and a potential junction with is an indicator of parental consanguinity. There- ribosomal DNA on 13p. Human maternal effect mutations will fore, in addition to the possibility of various un- simulate Mendelian or maternal inheritance according to their balanced translocations, the consequences of con- mechanism of action. Their expression may include female sanguinity, as manifested by the disomic transloc- sterility, multiple miscarriages, heterotaxy, and selected ation, should be considered in reproductive midline malformations. decisions.

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Analysis of a family with multiple siblings with chromosome 5 Terminal deletion of chromosome 13q34: Clinical deletions caused by chromosomal breakage at the site of a and cytogenetic findings in a rare case. W. Wilson*. A. Geddis*. M. E. Carlin#, D.R. Witt, E. Oleskowicz and M. Boswell. Genetics paternal translocation. Dept., Kaiser Permanente Medical Group, San Jose, and T. Overhauser.*Thomas Jefferson University, Philadelphia; CA. #University of Miami/Mailman Center for Child Development, An eight month old boy was evaluated for Miami. microcephaly and developmental delay. He was A family was studied in which two children had generally healthy except for eczema and asthma. cytogenetically detectable deletions at 5p15.1. The karyotype of Physical examination revealed weight <3%, height both parents appeared to be normal. To determine if an 3%, OFC <<3%. He had epicanthal folds, slightly protruberant ears, tented nares and mild gross in one of the undetectable chromosomal rearrangement parents motor delay. There were no major malformations. was the cause for multiple affected offspring, molecular analysis The family history was significant for small head was performed. Through repeated quantitative blot size in his father ( 10%) and three year old hybridizations, it was found that both children had deletion brother (3%). breakpoints in the same location in chromosome 5. Parental Leukocyte chromosome analysis using G and R origin of the deleted chromosome was determined to be of banding revealed deletion of the terminal band q34 of chromosome 13: 46,XY,del(13)(pter -* q33:). use RFLPs. Somatic cell paternal origin through the of hybrids There was no evidence for a translocation. where isolated which carried either of the father's chromosomes Chromosome studies of both parents revealed normal 5 and analysis of the chromosome 5 material present in each of karyotypes including both chromosome 13 homologues the cell hybrids demonstrated that one of the paternal with no evidence for a translocation. homologues had chromosome 5 material deleted. The location To our knowledge this is the first reported of the translocation breakpoint appeared to be located in the case of a pure deletion limited to band 13q34. Studies of patients with larger deletions of same on chromosome 5 as the deletions seen in the two region distal 13q have shown a variety of abnormalities offspring. These results conclude that the father is a carrier of a including microcephaly, developmental delay and balanced translocation that is undetectable using high resolution minor and major malformations. The milder cytogenetics, and in two cases, the derivative chromosome 5 was clinical phenotype in this patient appears to be unstable during meiosis, resulting in inheritance of a deleted correlated with the smaller amount of deleted chromosome rather than a translocation. In situ hybridization is material. to the other chromosome involved in the The genes for coagulation factors VII and X being used identify have been mapped to band 13q34. Dosage studies to original translocation event. In addition, chromosome walking corroborate the cytogenetic finding' are pending. experiments are underway to localize the chromsomal breakpoint in order to determine the reason for its instability during gamete formation. (Supported by a grant from the W.W. Smith Foundation) A96 Clinical Cytogenetics

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An inherited 18p duplication, ascertained prenatally, associated with a Terminal deletion 8p23.1 associated with microcephaly and normal phenotype. D.W. Wolff. M. Ferre. L.J. Raffel. M.G. Blitzer and S. developmental delay. A.Wong, E. Menard, M. Vekemans, V. Der Schwartz. Division of Human Genetics, University of Maryland School of Kaloustian. Montreal Children's Hospital and Centre for Human Medicine, Baltimore. Genetics, McGill University, Montreal, Quebec Canada.

1 Direct two-generational transmission of an unbalanced 8p+ was We report here a 14 year-old boy with a history of develop- revealed following amniocentesis. Neither the mother nor the child mental delay. He was born after an uneventful pregnancy and exhibited any overt physical malformations or mental impairment, although by a normal vaginal delivery at 42 weeks of gestation. a significant amount of DNA was present in triplicate. The physical examination did not reveal A 25 year old black female underwent amniocentesis at 18 weeks dysmorphic features gestation because of repeated elevated maternal serum alpha fetoprotein other than microcephaly, small palpebral fissures and anti- (MS-AFP) values (3.5 and 3.8 MOM). The amniotic fluid AFP value was mongoloid slant of the eyes. normal. Cytogenetic analysis of amniocytes revealed a 46, XX, dup High resolution chromosome analysis of peripheral blood cells (18)(pll.l-pter) fetal karyotype. GTG banding showed both G-positive in cultures showed a very small terminal deletion of the short and G-negative bands in the duplicated material, indicative of additional arm euchromatic and heterochromatic DNA. C-banding demonstrated that the of chromosome 8. The karyotype is 46,XY del (8) (p23.1). abnormal chromosome was not an 18ph+ variant, but rather a whole arm Chromosome analyses of the parents are normal. 1 duplication of 8p. Molecular analysis utilizing the DNA probe, B74, which The clinical findings of this boy are compared with those of maps to 18pI 1, is in progress to verify the origin and extent of duplicated others reported monosomic for a portion of the short arm of material. Parental karyotypes revealed that the mother had an identical duplication, while the father was normal. chromosome 8. In addition, the cells from this patient provide a a Only I I previous cases of duplication 1 8p have been reported and these good opportunity to establish detailed physical map for exhibited either a normal phenotype or mild and inconsistent physical the coding sequences of the gene products located in this abnormalities. Intelligence was normal in 4 individuals, mildly retarded in region i.e. cathepsin B lipoprotein lyase, glutathione reduct- 6 cases, and I proband exhibited moderate retardation. In 10 of the cases, tase, luteinizing hormone releasing factor and DNA probes such a balanced reciprocal translocation involving 18p was found in one parent, as D8S7 and D8S11. These provide also a unique opportunity to the karyotypically abnormal child resulting from chromosomal study the mechanism of origin of terminal deletions and to I I malsegregation. In the th case, the parent carried one normal 18, an 18p- examine the nature of telomeric DNA sequences. and an isochromosome 18p. This case is of interest for several reasons: (I) it constitutes the only report of parent to child transmission of an unbalanced duplication of 18p; (2) it provides further support that duplication of 18p yields few or no phenotypic abnormalities; and (3) prenatal detection of this specific chromosomal abnormality has not been reported previously. One can appreciate the counseling dilemmas created by this finding due to the small number of cases reported and no apparent phenotype-karyotype correlation.

(0373) 1.201 (0374)

A Sex chromosome anomalies detected prenatally in one of a twin pair distinct phenotype associated with partial trisamy15p. resulting from in vitro fertilization. J.L.Zackowski. L.J. Raffel. A.L. Zaslav, R. Sobel, L. Trinchitella, H.O. Shah, W.T. Brown B.A.Bernhardt*. and S.Schwartz. Division of Human Genetics, University and B.A. Pletcher. North Shore Univ.Hospital-Cornell Univ. of Maryland School of Medicine; Medical Biotechnology Center of the Medical College, Manhasset, NY. Maryland Biotechnology Institute, Baltimore, MD; and Sinai Hospital, A new born female infant with dysmorphic features was Baltimore, MD. referred for chranosmal analysis. She was the 2650 gram 36 weeks product born to a 23-year-old G3P1011 female by A patient with a twin pregnancy, achieved through in vitro Cesarean-section for breech presentation. On examination the fertilization (IVF), underwent amniocentesis because of advanced infant was noted to have a flat occiput, bilateral epicanthal maternal age. The amniotic fluid alpha-fetoprotein concentration of folds, malar hypoplasia, redundant posterior nuchal fold, both twins was normal. Routine GTG chromosomal analysis of Twin A diastasis recti, a left palmar crease revealed mosaicism consisting of 45,X (11.5%) and 46,X+mar (88.5%). transitional and All 20 metaphases from Twin B demonstrated a normal 46,XX erate hypotonia. Unilateral hydronephrosis was present. G karyotype. The parents elected to continue the pregnancy, having banding techniques revealed a female karyotype with additional initially considered selective termination of the affected twin. However, material on the short arm (p) of one nunber 15 hcmlog, 46,XX, significant intrauterine growth retardation of Twin A became apparent as -15, + der (15). The parental karyotypes were both normal the pregnancy progressed, with fetal demise at 38 weeks gestation. (46,XX and 46,XY) indicating a de novo event had occurred. Autopsy at the time of delivery, seven days later, revealed a growth The abnormal number 15 hcmslog contained 3 C-bands, one at the retarded female fetus with no apparent gross external or internal centrcmere and 2 on the short arm. NOR-staining revealed a anomalies. Significantly, the heart and reproductive organs were normal. double structure of the satellites on the abnormal number 15 Tissue samples from the fetal placental membrane obtained at the time of chrcrmscse. autopsy also demonstrated the 45,X/46,X+mar karyotype (60%/40%). It appeared that the additional material on Cytogenetic studies to better define the marker chromosome of Twin this chrauo- was 15p in origin. confirm this A included C- and Q-banding. C-banding revealed the presence of a scsm To possibility the DA- centromere; no brilliant Q-fluorescence, characteristic of Yq, was DAPI staining technique which identifies the heterochrcoatic observed. Molecular techniques were usedto further characterize the regions of chromoscmes1,9,16,Y and the short-arm of chrdmD- marker chromosome. It failed to hybridize in situ with the biotinylated scm 15 was employed. All abnormal 15 chrcoscrms in all probe Y- 190, a 3.5 kb fragment specific for repeated sequences in the cells evaluated were DA-DAPI positive. This indicated that short arm Y chromosome. it is unlikely that the marker of the Thus, the additional material on the short arm of this chrcmsosme In hybridization with pSV2neoX- derives from the Y chromosome. situ was 15p in origin. 5, a probe that hybridizes to alphoid sequences mapping tothe X The additional material on this e could have chromosome centromere, is planned. chrmoscm resulted from a duplication or translocation of15p material This case is of interest since: 1) it represents another instance of a resulting in an individual with partial 15. A chromosomal abnormality following humanIVF; 2) the detection of this trisomy number of clinical reports describing inverted anomaly presented complex counseling issues, including the expected duplications of 15 occurring as an extra C-sized phenotype and probable survival of the fetus, and the possibility of chrctsose have been published. selective termination; and 3) it reinforces the utility of molecular The clinical features in this patient were distinctly differ- techniques in the detailed characterization of chromosomal abnormalities. ent than those described byinv dup (15). To our knowledge, this is the first report of partial triscny 15p occurring as additional material directly on the short arm of chrcsansc 15. The distinct phenotypic features in association with the unusual karyotype of the patient suggests that this represents a new chrcmsusasl syndrome. Clinical Cytogenetics/Cytogenetics A97

(0375) Some interesting karyotypes found in 621 cases for genetic counseling. I.G.Zhou Q .Q .Zhan X .Z.LA..X. .Li and B.L.Wu. Division of cytogenetiesNational Center of Genetic Medicine ,Shanghai ,P.R.China. All cases studied are divided into two categories. One is 552(88.9%) cases which have indication for cytogenetic diagnosis and other 69(11.1%) for genic disorders and so on.Among 552 cases,habitual abortion is 244(44.2%>),azoospermia 79(14.3%),poor obstetric history 76(13.8%),mental retardation 64(11.6%),ame- noorhea 26(4.7%),infertile IOtI.8%),external genital anomalies 19(3.4%),multiple malformation 15(2.7%*) and autosomal trisomy 1( 3.5%).By cytogenetic analy- ses 50(9.6%) cases were found to be abnormalities in- volving chromosomal number,27(4.9%) cases abnormali- ties with chromosomal structure and 112(20.3%) cases polymprphism.10 kinds of balanced translocation were found in 10 families.9 of them show no phenotypic ef- fect in all carriers except one family.In that family dauther and son have a karyotype of 46,XX(or XY),rcp (14;16)(q22;q24) and similar anomalies of the digital bones.But their mother seems to be normal even with same abnormal translocation as her children.It is not clear whether or not this kind of translocation might be responsible for the malformation in the digital bones.A girl with secondary amenoorhea has a karyo- type of 45,X/46,X,del(X)(p27.1-2).The site of break- point in the deleted X chromosome locates in or near those of MIAO gene.A boy with X-linked ichthyosis shows an abnormal X/14 translocation.His karyotype is.45,Y,-X,-14,+der(X),t(X;14) (p22.3;qll.2).This de- rivative chromosome in the patient 's karyotype must be from his mother whose karyotype is 46,X,rep(X;14) (p22.3;q1 1.'2).In Brdu-acridine fluorescent prepara- tions of the mother the normal X chromosome appeared to be early and the abnormal X/14 translocation late replicating.It seems that the site of breakpoint in the abnormal X chromosome may locate to be exact one which STS gene occupied.

Cytogenetics

(0376) 1.202 (0377) In situ hybridization with dopamine-beta-hydroxylase on Cytogenetic effects of radiation syrwcty with a rearranged chromosome 9. P.W. Allderdice, B. White dysprceiiu165. A. Babu and V.B. Penchaszadeh. and S.F. Craig. Memorial Univ. St.John's Nfld. and Divisicr of Medical Genetics, Beth Israel Medical Genetics Laboratory, Univ. of Oxford U.K. Center, New York, New York. Individuals with a paracentric insertion of Radiatimn sye is an established treatment for chromosome 9: inv ins 9(q22.1q34.3q34.1) have previously persistent rhxinatoid synovitis of the knee joint. been described (Allderdice et al. 1983 Am.J.Hum.Genet. Erly att ts using radiocolloids such as gold-198 35:1009-1019). We now report on the use of in situ and yttritua90 (90Y) proved to be hybridization to confirm the cytological observations. therapeutically effective bit were found to induce The cDNA for dopamine-beta-hydroxyl ase, previously significant levels of cc c damage. An localized by in situ hybridization to 9q34 (Craig et al. alternative approach has been to use the radiois e 1988 Cytogenet. Cell Genet. 48:48-50) was provided by dysprcsiu 165 (165 y) that has a auch shorter half- Drs. Mallet and Lamouroux, CNRS, Gif-sur-Xvette, France. life (2.3 hours) with 94% beta Micra. In addition, The 2.4kb probe was nick translated with 3H dCTP to a the isotope is carried by ferric hydroxide macro- specific activity of 7.4x10 dpm/ug and hybridized in aggregates (FOM4) in larger size particles (1-5 un Si" to replication banded metaphase chromosomes diameter) compared with the previously used colloids, prepared from whole blood. A clear signal was seen on which significantly reduces leakage into surr ng both the normal chromosome 9 and the rearranged 9. Of tissues. Previous clinical trials of 165Dy..HMA 238 grains scored in 44 cells, 24 (10%) were localized s oecy in natod arthritis have sown marked to 9q34 on the normal 9, confirming previous ingrovuaent in patients diti. The present localization of the probe. A similar proportion of investigation was undertaken to examine cytetic grains i.e. 22 (9%) were observed in the centre of the effects of 165Dy .pA sycoe y. Patients were long arm of the rearranged 9. This supports the treated with a single intra-articular dose of 270-300 cytological observation of paracentric insertion of millicuries of 1655yF after which the joint was 9q34. Additional probes for 9q are being employed to immibilized in full extesi for 24 hours. Blood confirm and extend these observations. sarples for c Roee studies were drawn prior to treatment and 24 hoirs, 3 mEnths and 6 months after treatment. Cro me preparations fran PHA stimulated lymphocytes, cultured for 48 hours, were assessed for damage by scoring the rubber of chrcmatid and ChraecsOs aberrations described in ISAN (1985). Preliminary data on 40 patients have indicated no overall increase in hreca aberrations in any of the post-treatment samples when compared to correspcding pre-treatment sample. This study indicates that 165Dy-E sysnvectoy does not cause any detectable chraicMe damage uxxer the therapeutic caxditics described.