J Med Genet: first published as 10.1136/jmg.20.5.396 on 1 October 1983. Downloaded from

396 Case reports complete 5p trisomy cases. The main features are References normal weight and length at birth, macrocephaly, Khodr GS, Cadena G, Le Loan K, Kagan-Hallet S. psychomotor retardation, hypotonia, postnatal Duplication (5pl3-*pter): prenatal diagnosis and review of the literature. Am J Med Genet 1982;12:43-9. growth failure, and facial dysmorphism involving 2 Leschot NJ, Lim KS. 'Complete' trisomy 5p, de novo mongoloid eye slant, epicanthus, hypertelorism, translocation t(2;5) (q36;pl 1) with isochromosome 5p. low set and dysplastic ears, and flat bridge ofthe nose. Hum Genet 1979;46:271-8. The lower extremities show short first toes and club 3 Cordero JF, Miller WA, Liberfarb RM, Atkins L, Holmes LB. Trisomy 5p: a variable phenotype. Pediatr feet. Res 1977;11:535. The three reported cases with complete 5p trisomy had seizures. In our patient most of the Correspondence and requests for reprints to main features mentioned were present but, in Dr E Orye, Laboratory of Cytogenetics, Department addition, he had a congenital heart defect, not seen in of Pediatrics, Akademisch Ziekenhuis, Rijks- the three cases reported. However, seizures were not universiteit Gent, De Pintelaan 185, B-9000 Gent, noted in our patient. Belgium.

Tetrasomy 9p confirmed by GALT

P BALESTRAZZI, G CROCI*, C FRASSI, F FRANCHI*, AND G GIOVANNELLI Department ofPaediatrics, University ofParma, 43100 Parma; and *Genetic Laboratory USL 9, 42100 Reggio Emilia, Italy.

SUMMARY We report a boy aged 12 years unremarkable and the couple's first child is in good 7 months with mental retardation, hydro- health. cephalus, dysmorphic facial features, congenital The proband was born at term by normal delivery heart disease, and skeletal and renal anomalies. after a normal pregnancy. Birth weight was 3200 g. The karyotype showed a mosaic tetrasomy 9p Asphyxia and skull asymmetry owing to a left parietal cephalohaematoma were noted at birth. http://jmg.bmj.com/ involving the secondary constriction. This result At the age of 12 years 7 months he was admitted to was confirmed by tetraplex gene dosage effect hospital because of mental retardation and for galactose-l-P-uridyltransferase (GALT). dysmorphic features. Comparing the clinical features of our case with those of previously reported patients, tetrasomy PHYSICAL EXAMINATION 9p appears to be a distinctive and clinically The following findings were present (fig 1): normal recognisable malformation syndrome. growth with a height of 157 cm (75th to 90th centile) and weight 39 kg (50th to 75th centile). He had a on October 2, 2021 by guest. Protected copyright. Tetrasomy for the short arm of chromosome 9 is a macrocephalic and asymmetrical skull, head circum- very rare condition, first described by Ghymers et al.1 ference 58 cm (>97th centile), a low anterior hairline, Since then, tetrasomy 9p has been found in eight multiple hair whorls, flat forehead, sunken eyes, additional patients with variable phenotypic expres- moderate hypertelorism, antimongoloid slants, broad sion and cytogenetic findings. This report concerns a nasal root, high nasal bridge and bulbous nasal tip, new case of tetrasomy 9p in a male aged 12 years short philtrum, down-turned corners of the mouth, 7 months. retrognathia, cup-shaped, anteriorly rotated, and protruding ears, and a short neck. There was Case report marked thoracic kyphosis and lumbar scoliosis with hyperlordosis, narrow chest widely spaced nipples, The proband is the second child of healthy, unrelated protruding abdomen, mild truncal obesity, and parents. The mother was 38 and the father 36 years narrow pelvis. There was also an incurved radius and old at the time of his birth. The family history is ulna, limited joint movements of the elbows, knees, and ankles, coxa and genu valga, narrow hands and Received for publication 14 March 1983. Accepted for publication 31 March 1983. feet, bilateral pes planovarus, and dysplasia of the J Med Genet: first published as 10.1136/jmg.20.5.396 on 1 October 1983. Downloaded from

Case reports 397

FIG 1 The proband aged 12 years 7 months. finger and toenails. The penis was small (3-2 cm in chorioretinal dystrophy, papillastaphyloma, and length) and he had palmated penoscrotal skin folds, refraction disorders. testes 8 ml in volume, and no pubic or axillary hair. CNS studies showed maturation delay of alpha There was moderate generalised muscle hypertonia, waves with generalised slow paroxysms on the EEG, ataxia of gait, and severe mental retardation (VIS moderate ventricular enlargement consistent with an was 48 and PIQ was too low to be informative at established hydrocephalus, and severe cerebellar and WISC test). The dermatoglyphic formula was: cerebral atrophy especially of the right frontal lobe http://jmg.bmj.com/ Right hand W, UL, UL, W, UL, t' 9. 7. 5. 4. on CT scan. Ac. O.O.L.O. Routine blood and urine analysis were normal. Left hand W, UL, RL, RL, UL, t 11. 9. 7. 5. GnRh and HCG tests were within normal limits for Ac. W.O.L.O. the start of puberty.

RADIOLOGICAL AND LABORATORY CHROMOSOME ANALYSIS FINDINGS Chromosome analysis (fig 2) was performed on

X-rays of the skeleton showed an asymmetrical and peripheral blood lymphocytes. Of 200 mitoses on October 2, 2021 by guest. Protected copyright. dolichocephalic skull, enlarged sella, thoracolumbar examined, 194 metaphases showed 47 chromosomes kyphoscoliosis, cleft of the posterior arc of Dl 2-LI - and six had a normal 46,XY karyotype. Using L2, incurved radius and ulna, coxa and genu valga, standard staining (R, G, and C banding methods) narrow iliac wings, wide interpubic distance, the additional chromosome was interpreted as an osteoporosis of the metacarpal and metatarsal bones, isodicentric chromosome 9 with a breakpoint at bilateral pes planus, clinodactyly of the big toes, band 9pl2. Cd banding showed that one centromere slender metatarsals 2 to 5, and delayed bone age was inactive. The proband's karyotype was therefore (11 years according to Greulich and Pyle2). 46,XY/47,XY,+ idic(9)(pter-*ql 2: :ql 2-pter). Both Intravenous pyelography and renal echotomo- parents had normal chromosomes. graphy showed both kidneys located on the right side and fused together. ENZYME ANALYSIS In the heart there was an ejection systolic click and The red cell activities of glucose-6-P-dehydrogenase, mild diastolic murmur (1-2/6) in the aortic area hexokinase, and glutathion reductase, assayed for the suggestive of aortic insufficiency. The EKG showed purpose of comparative measurements, were within mild left axis deviation (AQRS =-30°). the normal ranges. The galactose-l-P-uridyl- The eyes showed marked myopia at 00, nystagmus, transferase (GALT) assay was carried out using J Med Genet: first published as 10.1136/jmg.20.5.396 on 1 October 1983. Downloaded from

398 Case reports

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-ITG I:,B3, rI ± _ \0 00 FIG 2 (Top) Two normztal and one abnorm71al chromosomes 1X ut ^ -C 9 (RBG banding). (Bottom) Cytogenetic details of o: ti abnormal chr-omosomwe 9 (GTG, CBG, and Cd banding). o u ; '[, t°+ N+ t ess -1 11 W) 14. E E http://jmg.bmj.com/ .z !Z. . 0 t - W) 4) Beutler's method3 and showed a GALT excess (. %. cq .- 4 (35-18 IU/g Hb at 370) which, compared with the CN midparent value (16.78 IU/g Hb), demonstrated in ,.:a

the patient a tetraplex gene dosage effect (2-09). x - . ,t " F . x -; "e K+ < Discussion 0.) 0) on October 2, 2021 by guest. Protected copyright. 0- has been reported in nine . Tetrasomy 9p previously Zi ; >_>$ 4-11 1 shows the data and + patients.1 Table general 0z O z t cytogenetic findings of all subjects reported so far. ' e + + t 4: C-n The most common clinical features described in b6 O F >Q : eight out of the nine previously published papers are summarised and compared with those of our patient :z - m , :z .c E " rn r, : in table 2. The case of Eydoux et a19 has been C.) 'Z - I.. 0 0 ~~~~~~G ".. ;z 00 (1) +>i a, en .- Z >4±;I excluded because the phenotype was not described. 04) Q. V; From this comparison it appears that tetrasomy 9p -o E syndrome is a severe malformation syndrome Hz L.CZ .0 generally showing the following: moderate to severe 4i psychomotor retardation, normal to mildly deficient 7E growth, wide open sutures and fontanelles, hydro- 71 cephalus, moderate hypertelorism, epicanthic folds, -0 strabismus, enophthalmos, bulbous nose, protruding 'A and malformed ears, high arched palate or cleft lip 4) J Med Genet: first published as 10.1136/jmg.20.5.396 on 1 October 1983. Downloaded from

Case reports 399

TABLE 2 Compar-ison of clinical findings. including skin fibroblasts should be performed in all Clinicalfindings Tetrasomy 9p* Trisorny 9p patients with an apparently lymphocytic homo- Present All cases Review cf geneous tetrasomy 9p. patient 90 casest Our patient showed a tetraplex gene dosage effect for Psychomotor retardation + 9/9 galactose-l-P-uridyltransferase (GALT). This Wide open sutures and fontanelles + 5/9 result confirms the GALT locus assignment on the Hydrocephalus + 5/9 1/90 short arm of chromosome 9. It also shows that the Microcephaly 3/9 Antimongoloid slants 2/9 GALT assay can be very helpful in supporting Moderate hypertelorisnm 7/9 the cytogenetic diagnosis of 9p aneuploidy. However, Strabismus 4/9 Enophthalmos t 4/9 the GALT excess does not seem to be responsible for Epicanthic folds -- 5/9 the phenotype in this syndrome. Bulbous/beaked nose 7/9 Protruding and malformed ears 4/9 Cleft lip/palate 3/9 5/90 We are grateful to Dr G Novelli, Department of Downward slanting mouth 4/9 Human Genetics, University of Urbino, Italy, Microretrognathia 4/9 for Short neck -- 6/9 the enzyme assay and to Mr A Schianchi for his Widely spaced nipples - 3/9 valuable technical assistance. Cryptorchidism 2/5 Dysplastic fingernails 4/9 Single palmar crease 4/9 References Absence of fusion of C triradius 3/9 Clinodactyly of fifth finger 4/9 Ghymers D, Hermann Fredric Congenital heart disease 6/9 B, Disteche C, J. Tetrasomy Skeletal anomalies r 8/9 3/90 partielle du chromosome 9, A l'etat de mosaique, chez un Renal anomalies 4- 2/9 1/90 enfant porteur de malformations multiples. Humangenetik 1973 ;20:273-82. *Reported in at least two cases. 2 Greulich WW, Pyle SI. Radiographic atlas of skeletal tFrom Baccichetti et a1.12 development of the hand and *vrist. Stanford: Stanford University Press, 1970. 3 Beutler E. Red cell metabolismi. Manuial of biochemical or downward methods. New York: Grune and Stratton, 1975:411-4. palate, slanting mouth, micro- 4 Rutten FJ, Scheres JMJC, Hustinx TWJ, ter Haar BGA. retrognathia, short neck, single palmar crease, A presumptive tetrasomy for the short arm ofchromosome clinodactyly of the fifth finger, dysplastic fingernails, 9. Hum Genet 1974 ;25:163-70. congenital heart disease, and skeletal and urogenital 5 Orye E, Verhaaren H, van Egmond H, Devloo- Blancquaert A. A new case of the trisomy 9p syndrome. anomalies. Several anomalies of the face, hands and Clin Genet 1975 ;7:134-43. skeleton"1 are common to both tetrasomy and 6 Abe T, Morita M, Kawai K, et al. Partial tetrasomy 9 trisomy 9p and these findings substantiate their (9pter 9p21Ol) due to extra isodicentric chromosome. http://jmg.bmj.com/ phenotypical resemblance. Nevertheless, tetrasomy Ann Genet (Paris) 1977;20: 111-4. 7 Wisniewski L, Politis GD, Higgins JV. Partial tetrasomy 9p can easily be differentiated because it is most 9p in a liveborn infant. Clin Genet 1978;14:147-53. frequently associated with severe congenital defects 8 Moedjono SJ, Crandall BF, Sparkes RS. Tetrasomy 9p: (hydrocephalus, cleft lip/palate, congenital heart confirmation by enzyme analysis. J Med Genet 1980;17: disease, renal anomalies) which are very rare in the 227-30. state 9 Eydoux P, Junien C, Despoisse S, Chasserent J, Bibring C, trisomic (see table 2). Gregori G. Gene dosage effect for GALT in 9p trisomy

The clinical differences among tetrasomic patients and in 9p tetrasomy with an imroved technique for GALT on October 2, 2021 by guest. Protected copyright. may be the result of a different genetic background determination. Hum Genet 1981 ;57:142-4. 10 and chromosomal involvement (including a small Cuoco C, Gimelli G, Pasquali F, et al. Duplication of the short arm of chromosome 9. Analysis of five cases. euchromatic segment of the long arm of chromosome Hum Genet 1982;61:3-7. 9 in two cases6 7) as well as a variable occurrence of Garcia-Cruz D, Vaca G, Ibarra B, et al. Tetrasomy 9p: mosaicism. clinical aspects and enzymatic gene dosage expression. The mortality rate is high in the first year of life Ann Genet (Paris) 1982;25:237-42. 12 Bacchichetti C, Lenzini E, Temperani P, et al. Partial (33 % of the cases) and most probably this syndrome trisomy 9: clinical and cytogenetic correlations. Ann is viable only in the mosaic state. In fact mosaicism Genet (Paris) 1979;22:199-204. was present in the peripheral blood in two instances (our case and that of Rutten et a14) and it was found Correspondence and requests for reprints to in three additional patients in which two different Dr P Balestrazzi, Istituto di Clinica Pediatrica, tissues had been examined.1 5 10 UniversitA degli Studi di Parma, Via A Gramsci 14, For this reason exhaustive cytogenetic analysis 43100 Parma, Italy.