Cri-du-Chat Syndrome Cytogenetically Cryptic Recombination Aneusomy of Chromosome 5: Implications in Recurrence Risk Estimation

Abstract

Cri-du-chat syndrome is caused by haploinsufficiency of the genes on the distal part of the short arm of chromosome 5, and characteristic features include microcephaly, developmental delays, and a distinctive high-pitched mewing cry. Most cri-du-chat syndrome cases result from a sporadic de novo deletion that is associated with a low recurrence risk. On rare occasions, however, cri-du-chat syndrome with 5p monosomy can be accompanied by 5q trisomy. This combination is virtually always associated with parental large pericentric inversions. Among previously reported cri-du-chat syndrome cases with 5p monosomy accompanied by 5q trisomy, the aneusomy of chromosome 5 in all but one case was cytogenetically visible using G-banding. When an accompanying 5q trisomy is detected, a significant recurrence risk is expected. We here report on a patient with cri-du-chat syndrome phenotype who initially exhibited a normal karyotype on G-banding but in whom molecular analysis using multiplex ligation-dependent probe amplification and array comparative genomic hybridization revealed a 5p deletion accompanied by a 5q duplication. Parental chromosomal testing led to the identification of a very large pericentric inversion, of which breakpoints resided at the terminal regions of 5p15.31 and 5q35.1. This information was vital for counseling the family regarding the significantly high recurrence risk.

Fig. 1

Propositus at 3 years. Note the broad nasal bridge, the prominent forehead, upslanting palpebral fissures, the bulbous nose, preauricular tags, and the smooth philtrum. In addition, the patient had a bifid uvula.

Fig. 2

Results of cytogenetic studies in the propositus. a GTG-banded chromosomes 5. Although the karyotype was initially reported normal, reevaluation after the results from molecular studies were known indicated a derivative chromosome der(5)inv(5)(p15.31q35.1)del(5)(p15.31)dup(5)(q35.1). b Fluorescence in situ hybridization analysis. Metaphase spreads revealed a deletion of the subtelomere of the short arm and a duplication of the subtelomere of the long arm in one of the chromosome 5 homologs when hybridized with a 5p subtelomere probe (green signal, arrowhead) and 5q centromere probes (red signals, arrows).

Fig. 3

Results of cytogenetic studies in the parent with cryptic pericentric inversion. a GTG-banded chromosomes 5 revealing a large pericentric inversion with subtle changes in the telomeric banding pattern. b Fluorescence in situ hybridization analysis. Metaphase spreads revealed an inversion of the subtelomere of the short arm and the subtelomere of the long arm in one of the chromosome 5 homologs when hybridized with a 5p subtelomere probe (green signals, arrowheads) and 5q centromere probes (red signals, arrows).

Fig. 4

Result of array CGH analysis and schematic diagram of the extent of the deletion. Array CGH analysis revealed the 9.1-Mb terminal deletion of 5p and the 11-Mb terminal duplication of 5q (gray areas). Filled boxes represent proposed candidate regions for cat-like cry and speech delay (see text).