PARTIAL TRISOMY DUE TO A DE NOVO DUPLICATION 22q11.1-22q13.1: A CAT-EYE SYNDROME VARIANT WITH BRAIN ANOMALIES

Summary: Partial trisomy due to a de novo duplication 22q11.1-22q13.1: a cat-eye syndrome variant with brain anomalies: We report a case of partial trisomy 22q with de novo duplication of chromosomal region 22q11.1-22q13.1, also confirmed by microarray comparative genomic hybridization (Array-CGH) analysis. The fetus had interhemispheric cyst and corpus callosum agenesis diagnosed by MRI which has not been reported in the literature. This novel phenotype differs from the reported cat eye syndromes by the absence of heart defects and the presence of brain anomalies. Key-words: Partial trisomy 22q - Cat eye syndrome - MRI -Array-CGH.






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Publication: Genetic Counseling
Author: Karcaaltincaba, D
Date published: January 1, 2010

INTRODUCTION

Supernumerary marker chromosomes are encountered during prenatal and postnatal cytogenetic analyses. They are defined as additional centric chromosome fragments too small to be characterized for their chromosomal origin by traditional banding techniques, but require molecular cytogenetic techniques for their identification (10). Although trisomy 22 is the second most common trisomie karyotype found in spontaneous abortions after trisomy 16 and trisomy 22, it is very rarely described in live born infants (1, 14). The phenotypes of partial trisomy 22q include the cat eye syndrome (CES) (2, 8, 1 1), the der(22) syndrome (6), the microduplication 22qll.2 syndrome (3), distal 22q duplication syndrome (4, 12), and the chromosome 22q duplication syndrome/s (7, 9).

We report a case with partial trisomy 22q, duplication between 22ql 1.122ql3.1 confirmed by microarray comparative genomic hybridization (Array-CGH) analysis. Associated findings of interhemispheric cyst and corpus callosum agenesis were seen at prenatal MRI.

CLINICAL REPORT

A-20-year old pregnant woman at 18 weeks of gestation was referred to our clinic because of increased risk at second trimester Down syndrome screening. On obstetric ultrasonography, bilateral pelvic ectasia, single umbilical artery and cranial interhemispheric cyst were noted (Fig. Ia). Fetal karyotyping was done by flask cultures of amniocytes at 550 band level with GTG banding and 46,XY, add(22)(ql3.3) karyotype was detected (Fig. 2). Karyotypes of both parents were normal. Parents decided to continue pregnancy despite poor prognosis and wanted intensive medical care. Significant intrauterine growth retardation developed during follow up. Fetal MRI demonstrated corpus callosum agenesis and cranial interhemispheric cyst at 30th week (Fig. 1b, 1c). Fetal echocardiogram was normal. The male baby was delivered vaginally at a gestational age of 41 weeks.

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There was no spontaneous breathing at the time of delivery. The baby responded resuscitation. On physical examination saddle nose, facial hemangioma, hypertelorism, low ears with preauricular tag, high palatal arch, triangular shaped pupils, coloboma of iris, hypospadias and undescended testis were present (Fig. 3). The baby died because of respiratory arrest that was unresponsive to resuscitation 18 hours after birth. SNP microarray analysis (Affymetrix GeneChip 250K Human Mapping) from cord blood demonstrated partial duplication of 23.5 MB between 22qll.l and22ql3.1 (Fig. 4).

DISCUSSION

The birth prevalence of supernumerary marker chromosomes (SMCs) was reported to be 0.043 % (10). A subset of these SMCs is derived from chromosome 22 (9 %), and may cause CES if it encompasses the proximal region of chromosome 22q, with a tri-or tetrasomy of the cat eye critical region (1, 14). Three types of cat eye syndrome have been described previously based on the localization of endpoints at 22q chromosome. CES I is duplication of 22qll.2 excluding DiGeorge critical region, CES II is duplication of ql 1 .2 including DiGeorge critical region. CES III is characterized by a breakpoint at ql2.3 at a point distal to CES I and CES II (2, 8). In our patient there was a de novo duplication of 23.5MB between 22ql 1.1 and 22q 13.1, which has not been reported before.

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Cat eye syndrome patients rarely die from multiple malformations during early infancy and in general life expectancy is not significantly reduced. Growth retardation and mental retardation are variable features. Hallmark features of cat eye syndrome are coloboma of the iris, the choroid and/or optic nerve, microphthalmia; cleft palate; congenital heart malformations, anal atresia, various renal malformations, reduction of the auricles to several tags (2, 8, 11) but duplications in distal 22q can be manifested by severe psychomotor retardation, pre and postnatal growth retardation, renal and genital anomalies, skeletal abnormalities and hypotonia. Life expectancy appears to be highly reduced, since almost half of all published patients deceased before the age of 12 years (4).

Our patient had cat eye syndrome like features including coloboma of the iris, preauricular tag, renal anomaly, hypospadias which is most likely related to involvement of cat eye syndrome critical region. In our case absence of heart defect and presence of brain anomalies differ from cat eye syndrome, which is usually associated with congenital heart malformations including anomalous pulmonary venous return and tetralogy of Fallot. The death of the baby may be due to lack of mosaicism. Usually patients with mosaicism of partial trisomy 22q survive and have a normal life expectancy (2). The proximal 22q duplications up to the 22ql2q 13 junction are usually not associated with severe mental retardation. But distal 22q duplications are usually associated with severe psychomotor delay, suggesting a relevant role of band 22ql3 in determining the more severe clinical abnormalities in the spectrum of the complete trisomy 22 phenotype (7).

Prenatal MRI findings allowed the diagnosis of corpus callosum agenesis associated with dorsal interhemispheric arachnoid cyst in our case. Corpus callosum agenesis can be associated with various congenital anomalies (5). To our knowledge it has not been shown to be associated with 22q chromosome anomalies.

Array CGH analysis is a specific, sensitive, and fast technique which allows screening of the whole genome in a single test. It has enabled high-resolution examination for identifying genetic alterations and is helpful to clarify the origin of duplicated segment which could not be assessed by routine karyotyping techniques (13). This clarification is important to detect prognosis of the cases and affects the clinician's approach.

In conclusion, partial trisomy of 22q due to addition between 22ql 1.122ql3.1 can present with intrauterine growth retardation, corpus callosum agenesis, renal anomalies, dysmorphic face and single umbilical artery during prenatal period and can have cat eye syndrome like features. Array CGH analysis and MRI findings are helpful for prenatal diagnosis with SMCs.

References:

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2. BACINO CA., SCHRECK R., FISCHEL-GHODSIAN N., PEPKOWITZ S, PREZANT T.R., GRAHAM J.M. JR. : Clinical and molecular studies in full trisomy 22: further delineation of the phenotype and review of the literature. Am. J. Med. Genet, 1995, 56, 359-365.

3. WOLLINA K., SEIDEL J, KIRCHNER M., BEENSEN V, KELBOVA C: Komplette Trisomie 22. Monatsschr. Kinderheilkd., 1993, 141, 211-213.

4. BARTSCH 0., RASI S, HOFFMANN K, BLIN JV.: FISH of supernumerary marker chromosomes (SMCs) identifies six diagnostically relevant intervals on chromosome 22q and a novel type of bisatellited SMC(22). Eur. J. Hum. Genet., 2005, 13, 592598.

5. GENTILE M., DE SANCTIS S., CARIÓLA F, SPEZZI T., DI CARLO ?., TONTOLI F, LISTA F, BUON ADONN A Al:. FISH approach to determine cat eye syndrome chromosome breakpoints of a patient with cat eye syndrome type II. Eur. J. Med. Genet, 2005, 48, 33-39.

6. MEMS M., BURFEIND P., MOTSCH S., TRAPPE R., BARTMUS D., LANGER S, SPEICHER M.R., MÜHLENDYCK E, BARTELS L, ZOLLB.: Partial trisomy of chromosome 22 resulting from an interstitial duplication of 22qll.2 in a child with typical cat eye syndrome J. Med. Genet, 2003, 40, e62.

7. FUNKE B., EDELMANN L, MCCAINN, PANDITA KK., FERREIRA J, MERSCHER S., ZOHOURI M, CANNlZURO L, SHANSKE ?., MORROW B.E.: Der(22) syndrome and velo-cardio-facial syndrome/DiGeorge syndrome share a 1.5-Mb region of overlap on chromosome 22ql 1 . Am. J. Hum. Genet, 1999, 64, 747-758.

8. ENSENAUER RE, ADEYINU A., FLYNN HC, MCHELS V.V., LINDOR N.M., DAWSON D.B., THORLAND EC, LORENTZ CR, GOLDSTEIN IL, MCDONALD M.T., SMITH W.E., SIMONFAYARD E., ALEXANDER A.A., KULHARYA A.S., KEHERUNGKP., CLARK R.D., JALAL SM: Microduplication 22qll.2, an emerging syndrome: clinical, cytogenetic, and molecular analysis of thirteen patients. Am. J. Hum. Genet, 2003, 73, 1027-1040.

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10. FEENSTRA L, KOOLEN D.A., VANDER PASJ, HAMELB.C, MELOOH, SMEETSDF, VANRAVENSWAAIJ CM.: Cryptic duplication of the distal segment of 22q due to a translocation (21;22): three case reports and a review of the literature Em J. Med. Genet, 2006, 49, 384-395.

11. GENTILE M., WUYTS W, GRHTANl S, DI CARLO A., CARIÓLA F, VERDYCK P., MARGARlL, PERNIOLA T., BUONADONNAA.L: Clinical, cytogenetic, and molecular characterization of a patient with a de novo interstitial 22ql2 duplication. Am. J. Med. Genet ?, 2004, /27?, 186-190.

12. KNOLL JH, ASAMOAH A., PLETCHER BA, WAGSTAFF J.: Interstitial duplication of proximal 22q: Phenotypic overlap with cat eye syndrome. Am. J Med. Genet, 1995, 55, 221-224.

13. FUCHS F, MOUTARD Ml., BLM G, SONIGO P., MANDELBROT L: Prenatal and Postnatal FoIlow-Up of a Fetal Interhemispheric Arachnoid Cyst with Partial Corpus Callosum Agenesis, Asymmetric Ventriculomegaly and Localized Polymicrogyria. Case Report. Fetal Diagn. Ther, 2008, 24, 385-388.

14. OOSTLANDER A.E., MEIJER GA, YLSTRA B.: Microarray-based comparative genomic hybridization and its applications in human genetics. Clin. Genet, 2004, 66, 488-495.

Author affiliation:

BY D. KARCAALTINCABA1, S. CEYLANER2, G. CEYLANER2, S. DALKlLlC3, K. KARLI-OGUZ4 AND O. KANDEMIR1

Author affiliation:

(1) Department of Obstetrics and Gynecology, Etlik Zubeyde Hanim Women's Hospital, Ankara, Turkey.

(2) Intergen Genetics Centre, Ankara, Turkey.

(3) Institute of Biotechnology, Ankara University, Ankara, Turkey.

(4) Department of Radiology, Hacettepe University School of Medicine, Ankara, Turkey.

Author affiliation:

ADDRESSFOR CORRESPONDENCE:

Serdar Ceylaner, MD.

Intergen Genetics Centre

Iran cd. 13/25 Kavaklidere

Ankara/Turkey

Phone: 90 312 428 4814; Fax: 90 312 428 2693

E-mail: serdarceylaner@intergen.com.tr

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