Academic journal article Genetic Counseling

DISTAL 11q MONOSOMY SYNDROME: A REPORT OF TWO EGYPTIAN SIBS WITH NORMAL PARENTAL KARYOTYPES CONFIRMED BY MOLECULAR CYTOGENETICS

Academic journal article Genetic Counseling

DISTAL 11q MONOSOMY SYNDROME: A REPORT OF TWO EGYPTIAN SIBS WITH NORMAL PARENTAL KARYOTYPES CONFIRMED BY MOLECULAR CYTOGENETICS

Article excerpt

Summary: Distal 11q monosomy syndrome: a report of two Egyptian sibs with normal parental karyotypes confirmed by molecular cytogenetics: Jacobsen syndrome is a rare disorder, caused by segmental monosomy for the distal end of the long arm of chromosome 11 with variable phenotypic expressivity. We report on the first male (6 years old) and female (3 years old) sibs with clinical and cytogenetics characterization of Jacobsen syndrome. Their karyotypes showed deletion 11q23.3-qter. Patients presented with growth and psychomotor retardation, facial dysmorphism, eye anomalies, and congenital heart disease (variable degrees of septal defect). Family history revealed a clinically similar brother, who died at 2 months old from cardiac anomalies in the form of single ventricle without being subjected to further investigations. Chromosomal analysis of the parents was normal. Karyotyping for the 2 patients and their parents was confirmed by fluorescence in situ hybridization analysis (FISH) using whole chromosome painting probes for 11 (WCP 11). Relevant investigations for both sibs showed mild thrombocytopenia with normal platelets morphology and striking periventricular demyelination on neuroimaging. Inguinal small testicles as well as focal epileptiform dysfunction were recorded in the male patient only. Abdominal ultrasound, hearing test, and DEXA scan were normal in both patients. Due to of the presence of apparently 3 affected offspring and normal parental karyotypes, an inherited predisposition was highly suspected. The large size of the distal deleted 11q segment in our patients support the recent hypothesis, that Jacobsen syndrome is a chromosomal deletion syndrome with genetic predisposition, due to expansion of p(CCG)n trinucleotide in the folate-sensitive fragile site FRA11B, at breakpoint 11q23.3. In conclusion, identification and further delineation of more similar patients will contribute to understanding the genetic basis of the 11q phenotype.

Key-words: Jacobsen syndrome - Distal 11q deletion - Molecular cytogenetics

INTRODUCTION

The 11q terminal deletion disorder, also called Jacobsen syndrome (JBS: MIM 147791), is a contiguous gene disorder. It was first described by Jacobsen and his co-workers in 1973 (8). Since then, over 120 cases have been reported in the literature presenting a wide range of phenotypes of varying severity (1, 4, 5, 22). Different organ systems can be affected in JBS. The main cause of early infant death is severe cardiac anomaly (5). Common clinical findings are growth retardation starting intrauterine, psychomotor delay, facial dysmorphism, congenital heart defects, digital anomalies (camptodactyly, syndactyly, clinodactyly), thrombocytopenia, genitourinary anomalies, gastrointestinal and ophthalmological problems (12, 13, 19). Facial dysmorphism includes prominent forehead, hypertelorism, downslanting palpebral fissures, broad nasal bridge with short nose, thin upper lip and low-set malformed ears. Eye abnormalities consist of strabismus, ptosis, atrophy of optic nerve, and coloboma of the eyelid or iris (11). The incidence of distal 11q deletions is estimated to be 1 in 100000, while the male to female ratio is 1:3 (1,23).

Based on karyotype analysis, the breakpoints arise typically in subband 11q23.3 with deletions extending to the telomere. Most cases arise from de novo deletion or rarely as an unbalanced segregation from a balanced carrier (15). Voullaire et al. (21) suggested that the origin of Jacobsen syndrome was a familial folate-sensitive 11q23.3 fragility carried by one of the parents. They hypothesized, that the fragile chromosome 11 was transmitted to the embryo and subsequently broke at the site of fragility, producing a predominant cell line with deleted chromosome 11q23.3-qter. Molecular studies of the deletion breakpoints led to the identification of one subset of 11q terminal deletions (9). In this subset, the deletion was caused by expansion of a CCG - trinucleotide repeat at the site of the deletion breakpoint and consequent expression of the folate-sensitive fragility site (FRA11B) in 11q23. …

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