sign in sign up
<<
Home , Marker chromosome, Ring chromosome 22

J Med Genet 1999;36:237–241 237 Ring 22 duplication/ mosaicism: clinical, cytogenetic, and molecular characterisation J Med Genet: first published as 10.1136/jmg.36.3.237 on 1 March 1999. Downloaded from

Jill K Frizzley, Mark J Stephan, Allen N Lamb, Patricia P Jonas, Roger M Hinson, Donald R MoYtt, Dana L Shkolny, Heather E McDermid

Abstract fied as the product of a 3:1 non-disjunction A patient with several features consistent of a balanced carrier with a t(10;22) with duplication of 22q11.2 (cat eye (q26.2;q12.1).7 Thus, the patients had only syndrome or CES) was found to be three copies of the CES region. Two cases of for a dicentric double ring chro- 22q11.2 interstitial duplication with features of mosome 22 on postnatal karyotyping of CES confirm that three copies of the CES peripheral blood. The initial region can produce a CES phenotype.34 A was 46,XX,r(22)(p12q13) [46]/46,XX,dic child with a supernumerary double r(22) and r(22)(p12q13; p12q13)[4]. The amount of all major features of CES has also been material duplicated in the dic r(22) was reported.8 However, this proband’s phenotypi- determined to include and extend beyond cally normal father and grandfather each had a the CES critical region into 22q13.3. single supernumerary r(22), indicating that However, karyotyping of lymphocytes and having three copies of the region does not nec- fibroblasts, at 27 and 13 months of age essarily produce the CES phenotype. respectively, showed no dic r(22) present We report an unusual patient with some phe- in any of the cells examined. We suggest notypic features of CES and a neonatal periph- that the CES features in this patient, and eral blood karyotype of 46,XX,r(22) (p12q13) potentially in other ring cases with CES [46]/46,XX,dic r(22)(p12q13; p12q13)[4]. The phenotypic features, might result from a patient is deleted for part of 22q13.3 in all cells, high level of mosaicism for a dic r(22) but in cells with the dic r(22) there are also three during early fetal development. Usually copies of 22q11.2-22q13.3. We suggest that a this unstable dic r(22) is subsequently lost high level of cells with the dic r(22) during from most cells. development might account for the CES fea- (J Med Genet 1999;36:237–241) tures seen in this patient.

Keywords: 22; duplication; deletion; Case report

An infant female with a birth weight of 3580 g, http://jmg.bmj.com/ length 51 cm, and head circumference 35 cm Duplication of 22q11.2, known as cat eye syn- (all 75th centile for gestational age) was born to drome (CES), is a rare human condition that healthy, non-consanguineous parents after an derives its name from its association with ocu- uncomplicated term pregnancy. The couple Department of lar coloboma, involving the iris or retina or had one normal daughter and a history of one Biological Sciences, both.1 Other common phenotypic features first trimester spontaneous abortion. The 37 University of Alberta, include anal atresia (with or without fistula), year old mother had two normal sons and a Edmonton, Alberta, heart defects (most often total anomalous pul- on October 1, 2021 by guest. Protected copyright. Canada T6G 2E9 first trimester spontaneous abortion from a J K Frizzley monary venous return), urogenital defects, previous marriage. There was no family history D L Shkolny preauricular skin tags and pits, facial dysmor- of chromosomal aberrations, birth defects, or H E McDermid phism (usually hypertelorism and downward mental retardation. The proband (fig 1) slanting palpebral fissures), and mild to presented with several clinical features of CES: Department of moderate mental retardation. This syndrome is right iris coloboma, bilateral chorioretinal Pediatrics, Madigan extremely variable both in frequency and Army Medical Center, colobomata with optic nerve involvement, a Tacoma, WA 98431, severity of these features, including ocular right preauricular pit, broad nasal bridge, a USA coloboma. The most common cytogenetic small patent ductus arteriosus, and a renal M J Stephan finding is the presence of a supernumerary bi- defect. The patient showed additional clinical P P Jonas satellited .12 The CES chro- features that have not been associated with R M Hinson mosome is an isodicentric composed of the CES. There were bilateral linear ear lobule DRMoYtt short arm and proximal long arm of chromo- creases, a small oral alveolar cleft, aberrant pal- Division of some 22 (idic 22pter-22q11.2), resulting in the mar creases, generalised that inter- , presence of four copies of this region. However, fered with feeding, thin ribs, and spina bifida Genzyme Genetics, features of CES have also been seen in a small occulta of C6. She developed hypoglycaemia, Sante Fe, NM 87505, number of patients with other chromosome hyperbilirubinaemia, and a transient supple- USA 22q abnormalities, including interstitial tan- mental oxygen requirement. Bacterial and viral A N Lamb dem duplication of 22q11.234 and various cultures of cerebrospinal fluid and bacterial Correspondence to: chromosomal translocations involving proxi- cultures of blood and urine were negative. Dr McDermid. mal 22q.56 A family with two cases of CES Head ultrasound was unremarkable. MRI of associated with a supernumerary chromosome the central nervous system at 4 months of age Received 4 November 1997 5 Revised version accepted for was described by Buhler et al. The marker showed normal brain anatomy with a possible publication 14 July 1998 chromosome in these patients was later identi- delay of myelination of the motor cortex. A 238 Frizzley, Stephan, Lamb, et al J Med Genet: first published as 10.1136/jmg.36.3.237 on 1 March 1999. Downloaded from http://jmg.bmj.com/ on October 1, 2021 by guest. Protected copyright.

Figure 1 Facial features of proband. Newborn. Note broad forehead, broad nasal bridge (A), and right preauricular pit (B). (C) Aged 12 months. Note epicanthic folds and right iris coloboma. (D) Aged 17 months. Facial profile. (Photographs reproduced with permission.)

horseshoe kidney and a small subcapsular Biopsy of the bronchial mucosa showed normal hepatic cyst were noted by abdominal ultra- cilia ultrastructure by electron microscopy. sonography. Oesophageal pH study, endo- Serum levels of immunoglobins G, A, and M scopy, and upper GI contrast study were and IgG subclasses were normal for age. White normal. Because of poor feeding, a gastrostomy blood cell arylsulphatase A assay and quantita- tube was placed for nutritional supplementa- tive plasma amino acid assay were normal. tion. At 13 months of age she was noted to have The postnatal course was significant for mildly asymmetrical soft tissue growth of her chronic interstitial pulmonary opacification extremities, the right larger than the left. and recurrent upper respiratory infections with Abdominal and renal ultrasonography studies chronic purulent rhinitis and otitis media, per- were unchanged. Ophthalmological examina- sistent mild tachypnoea, wheezing, and râles. tion at 16 months showed searching nystagmus Bronchoscopy performed at 1 year of age and profound visual impairment with slight showed an anteriorly displaced larynx, mild fixation preference with the right eye. Interpu- distal tracheomalacia, and left bronchomalacia. pillary distance measured 5.0 cm (80th centile) There were purulent secretions and mucosal and inner canthal distance was 3.2 cm (>97th inflammation throughout the lower airways. centile) at the age of 18 months. Brainstem Ring 22 duplication/deletion mosaicism 239 J Med Genet: first published as 10.1136/jmg.36.3.237 on 1 March 1999. Downloaded from

Figure 2 Partial of patient showing (A) normal 22 and r(22) found in 46/50 peripheral blood cells and (B) a dic r(22) found in 4/50 peripheral blood cells (normal 22 from this cell not shown).

auditory evoked response testing showed nor- mal bilateral hearing sensitivity. At 18 months she remains hypotonic and globally develop- mentally delayed, but with normal somatic growth with gastrostomy feedings. The growth asymmetry has persisted.

Figure 4 RFLP analysis determined the extent of the duplication/deletion. The proband is heterozygous for Methods D22S95, inheriting a 15 kb paternal allele and a 20 kb Karyotypes were done using the standard G maternal allele. This sets the proximal limit for the duplication/deletion breakpoint. The proband has inherited banding protocol. Fluorescence in situ hybridi- a 1.9 kb maternal allele but no paternal allele for D22S22, sation (FISH) was performed according to setting a distal limit for the breakpoint. The 2.2 kb Oncor protocols. FISH studies used the fragment represents a non-polymorphic constant band. commercially available Oncor probes for detec- tion of DiGeorge syndrome, consisting of Results D22S75, which maps to the DiGeorge syn- Cytogenetic findings indicated that the patient drome critical region, and D22S39, which lacked the expected supernumerary CES chro- maps to the terminal region of chromosome mosome. Initial karyotyping of blood cells 22. obtained at 2 days of age showed that the patient DNA from the patient and both parents was was mosaic for a single 22 and obtained from peripheral blood samples and a dicentric double ring 22 chromosome that from the patient’s fibroblasts. Restriction frag- appeared to consist of two copies of the single ment length polymorphisms were used to ring 22: 46,XX,r(22) (p12q13)[46]/46,XX,dic determine the extent of the patient’s deletion. r(22)(p12q13;p12q13)[4] (fig 2). FISH analysis confirmed the presence of a deletion on the

The probes used in the DNA studies are from http://jmg.bmj.com/ 22q12 and 22q13 and have been previously r(22) (fig 3). D22S39, which maps to 22q13.3, described by Dumanski et al.9 The informative was present only on the single normal copy of loci were D22S22, using a 1.9 kb HindIII frag- chromosome 22. Cytogenetic analysis of skin ment which yields Ta q I alleles of 1.9 kb and 1.8 fibroblasts at 12 months of age indicated a kb, plus a 2.2 kb constant band, and D22S95, diVerent mosaic pattern, with a single r(22) in a 2.0 kb HindIII fragment which gives EcoRV 46 cells and 22 in 11 cells, while no alleles of 20 kb and 15 kb. Probes for D22S91, dic r(22) cells were observed: 46,XX,r(22)

PDGF (pSM-1), and D22S97 were unin- (p12q13)[46]/45,XX,−22[11]. A second pe- on October 1, 2021 by guest. Protected copyright. formative. ripheral blood sample at 27 months confirmed the absence of the dic r(22) in all 175 metaphase spreads examined. These findings are consistent with ring chromosome instability. Parental chro- mosomes were normal. The extent of the deletion on the ring 22, and thus the extent of the duplication on the dic r(22), was determined by examining RFLPs of the patient and both parents (fig 4). The proband was heterozygous for D22S95, identifying the upper limit of the deletion. The proband was hemizygous for D22S22, inheriting a 1.9 kb band from her mother but no allele from her father, setting the lower limit of the deletion.

Discussion With the initial clinical recognition of pheno- typic features of CES, the finding of a r(22) with 46 was unexpected. The presence of a r(22) is usually associated with a Figure 3 FISH analysis with probes for locus D22S75 in band 22q11.2 and locus 10 D22S39 in band 22q13.3. Only one probe hybridised to the r(22). Based on the G banded phenotype that is diYcult to define clinically. results, the terminal probe, D22S39, is missing. The only consistent observation with r(22) is 240 Frizzley, Stephan, Lamb, et al

moderate to severe mental retardation.11 Other duplication is considerably larger than the CES features frequently reported include muscular region. However, larger duplications of chro- hypotonia, poor coordination (unsteady gait), mosome 22 can show CES features. For J Med Genet: first published as 10.1136/jmg.36.3.237 on 1 March 1999. Downloaded from hyperactivity, , and non-specific instance, a patient with a tandem duplication of dysmorphic features.11 12 The variability of this 22q11-q12 displayed numerous CES features, phenotype is thought to be the result of the including bilateral preauricular pits, a cardiac instability of the r(22) rather than the extent of defect (total anomalous pulmonary venous the deletion at 22q13.3.13 Loss of 22q13.3 is return), absence of one kidney, various genital also seen as a simple terminal deletion. The anomalies, downward slanting palpebral fis- phenotype associated with the 22q13.3 dele- sures, hypertelorism, and developmental tion syndrome is developmental delay, normal delay.21 to accelerated growth, severe delay in expres- We suggest that mosaicism for a duplication sive speech, hypotonia, and mild dysmorphic of this region can be associated with features of features.14 Neither the r(22) nor the 22q13.3 CES. Although our patient has a deletion and deletion syndromes are associated with major is mosaic for a duplication in only a minority of malformations. Although the hypotonia seen in cells, it is the feature of the duplication that our patient can be explained by the presence of appear to predominate. Thus if the duplication a r(22) deletion, the malformations reminis- is responsible for the phenotype, the dic r(22) cent of CES cannot. It is noteworthy that the must have been more prevalent during early respiratory problems similar to those seen in embryogenesis when malformations are estab- our patient have also been reported in previous lished. The overall phenotype of this patient r(22) cases.15–17 was therefore not reflected in the predominant The presence of the dic r(22) would lead to mosaic pattern of her postnatal karyotype. duplication of the region of chromosome 22 Therefore, the formation of transient dicentric that is present on the ring chromosome. Since double ring chromosomes during development there would be three copies of the CES region may confound phenotype/karyotype correla- in such cells, in high enough numbers this tions. could be compatible with features of CES. Although the dic r(22) was present in a minor- The opinions and assertions contained herein are the views of ity (4/50) of the prenatal peripheral blood lym- the authors and are not to be construed as oYcial or as reflect- phocytes, it may have been present at a much ing the views of the United States Army or Department of Defense. We thank the University of Alberta Hospital higher frequency early in development and Cytogenetics Laboratory. This research was funded in part by a then subsequently lost by most cells. A review grant from the Medical Research Council of Canada (HEM). JKF held an Alberta Heritage Foundation for Medical Research of published cases of r(22) shows several rare summer studentship. cases with a single feature of CES, most frequently colobomata.15 18 Although no dic 1 Schinzel A, Schmid W, Fraccaro M, et al. The “cat eye syn- r(22)s were reported in these cases, it is drome”: dicentric small probably conceivable that these subjects may also have derived from a no 22 ( 22pter-q11) associated with a characteristic phenotype. Hum Genet 1981;57:148- had dic r(22)s in some cells during early fetal 58. http://jmg.bmj.com/ development. 2 McDermid HE, Duncan AMV, Brasch KR, et al. Charac- Alternatively, the dic r(22) in our patient terization of the supernumerary chromosome in cat eye syndrome. Science 1986;232:646-8. may be present perinatally owing to dynamic 3 Reiss JA, Weleber RG, Brown MG, et al. Tandem somatic mosaicism.19 This refers to the instabil- duplication of proximal 22q: a cause of cat-eye syndrome. Am J Med Genet 1985;20:165-71. ity of the ring causing continuous production 4 Knoll JHM, Asamoah A, Pletcher BA, WagstaV J. Interstitial of further chromosomal abnormalities, such as duplication of proximal 22q: phenotypic overlap with cat eye syndrome. Am J Med Genet 1995;55:221-4. dicentric double rings. Such cells do not 5 Buhler EM, Mehes K, Muller H, Stalder GR. Cat-eye syn-

drome, a partial 22. Humangenetik 1972;15:150- on October 1, 2021 by guest. Protected copyright. survive because of their more severe genetic 62. imbalance, and are lost rapidly at later cell 6 Van Hove JL, McConkie-Rosell A, Chen YT, et al. 13 Unbalanced translocation 46,XY,–15,+der(22)t(15; divisions. However, dicentric double ring 22)(q13;q11)pat: case report and review of the literature. chromosomes can be present in a high Am J Med Genet 1992;44:24-30. proportion of a person’s cells. McGinniss 20 7 Kosztolanyi G, Buhler EM. Partial - an old case et al reexamined. Hum Genet 1985;69:193-4. describe a child with a dic r(21) present in 82% 8 Mears AJ, El-Shanti H, Murray JC, McDermid HE, Patil SR. Minute supernumerary associ- of lymphocytes (patient 11). Since no fetal ated with cat eye syndrome: further delineation of the criti- karyotype of our patient is available, it is not cal region. Am J Hum Genet 1995;57:667-73. possible to prove that the dic r(22) was present 9 Dumanski JP, Carlbom E, Collins VP, et al. A map of 22 loci on human chromosome 22. Genomics 1991;11:709-19. at a high level during her development, either 10 Fryns JP, Van den Berghe H. Ring chromosome 22 in a mentally retarded child and mosaic 45,XX,–15,–22,+t(15; transiently or over a longer period of time. 22)(p11;q11)/46,XX,r(22)/46,XX karyotype in the However, the phenotype of this patient in- mother. Hum Genet 1979;47:213-16. 11 Hunter AGW, Ray M, Wang HS, Thompson DR. cludes three major malformations typical of Phenotypic correlations in patients with ring chromosome CES (malformations of the eye, heart, and kid- 22. Clin Genet 1977;12:239-49. ney) and is therefore consistent with this 12 Schinzel A. Catalogue of unbalanced chromosome aberrations in man. New York: de Gruyter, 1984:722-3. interpretation. 13 Kosztolanyi G. Does “ring chromosome” exist? An analysis To measure the extent of the duplication in of 207 case reports on patients with a ring chromosome. Hum Genet 1987;75:174-9. the cells with dic r(22), we mapped the 14 Nesslinger NJ, Gorski JL, Kurczynski TW, et al. Clinical, corresponding deletion with RFLPs. The dele- cytogenetic, and molecular characterization of seven patients with deletions of chromosome 22q13.3. Am J Hum tion breakpoint maps within the 25.5 cM Genet 1994;54:464-72. 15 Nelson R. Section of Paediatrics - cases: long-arm deletion region of deletion breakpoints in the 22q13.3 of chromosome 22, with protein-losing enteropathy. 14 Proc R deletion syndrome. Therefore the duplication Soc Med 1972;65:1081-3. 16 Salinas CF, Jastrzab JM, Cantu ES. Robin sequence associ- in the dic r(22) cells extends from the chromo- ated with karyotypic mosaicism involving chromosome 22 some 22 to within 22q13.3. This abnormalities. Am J Hum Genet 1994;55:A92. Ring 22 duplication/deletion mosaicism 241

17 Brookfield DSK, Walker S. A case of ring chromosome 20 McGinniss, MJ, Kazazian, HH, Stetten, G et al. Mecha- G22. J Med Genet 1976;13:530-2. nisms of ring chromosome formation in 11 cases of human

18 Petrella R, Levine S, Wilmot PL, Ashar KD, Casamassima ring . Am J Hum Genet 1992;50:15-28. J Med Genet: first published as 10.1136/jmg.36.3.237 on 1 March 1999. Downloaded from AC. Multiple in a patient with constitutional 21 Lindsay EA, ShaVer LG, Carrozzo R, Greenberg F, Baldini ring chromosome 22. Am J Med Genet 1993;47:184-6. A. De novo tandem duplication of chromosome segment 19 McDermott A, Voyce MA, Romain D. Ring . 22q11-q12: clinical, cytogenetic, and molecular characteri- J Med Genet 1977;14:288-32. zation. Am J Med Genet 1995;56:296-9. http://jmg.bmj.com/ on October 1, 2021 by guest. Protected copyright.