Terminal deletion of 11q in two brothers: Clinical, cytogenetic, molecular genetic and counseling issues

Abstract

The 11q- syndrome (Jacobsen syndrome) involves characteristic but variable features including trigonocephaly, facial dysmorphism, psychomotor retardation, cardiac defects, digital anomalies and thrombo-or pan- cytopenia. Most cases of 11q- syndrome are de novo. and involve terminal or interstitial deletions at 11q23 and distal. Molecular studies of deletion breakpoints have delineated a phenotypte map for some of the major features. Expression of a rare folate-sensitive cytogenetic fragile site at 11q23.3, FRA11B, has been attributed to expansion of a CCG repeat in the region. A few cases of de novo terminal deletions of 11q apparently result from breaks at the FRA11B site in offspring of individuals with fragility and/or CCG expansion. We report here the first case, to our knowledge, of recurrent terminal deletion of 11q in two brothers. Both boys presented at birth with thrombocytopenia and mild dysmorphic features including epicanthal folds, broad depressed nasal bridge, hypertelorism. brachycephaly. and undescended testes. The propositus, at 10 months, was referred to Genetics clinic for evaluation of developmental delay. His older brother, evaluated elsewhere, was mosaic for 11q-. Chromosome studies on the propositus and a repeat study on his older brother revealed a del(11)(q24). The older brother had normal 11's in 12% of cells at 30 months of age FISH with the MLL probe at 11q23 and the subtelomeric probe for 11q showed that the breakpoint in these patients is distal to MLL, and that the telomeric probe is deleted from one homolog in all cells of the propositus and most cells of his brother with mosaicism. Parental chromosomes are normal, and FRA11B was not observed in cells grown in folate-deficient media. Molecular studies are in progress to: 1) determine the number of triplet repeats at FRA11B; 2) more precisely determine the breakpoint and parental origin of the deletion; 3) attempt to elucidate the cause for the familial recurrence and 4) counsel the family for reproductive options.