Genotype-phenotype correlations and clinical diagnostic criteria in Wolf-Hirschhorn syndrome

Abstract

We report on a clinical-genetic study of 16 Wolf-Hirschhorn syndrome (WHS) patients. Hemizygosity of 4p16.3 was detected by conventional prometaphase chromosome analysis (11 patients) or by molecular probes on apparently normal chromosomes (4 patients). One patient had normal chromosomes without a detectable molecular deletion within the WHS "critical region." In each deleted patient, the deletion was demonstrated to be terminal by fluorescence in situ hybridization (FISH). The proximal breakpoint of the rearrangement was established by prometaphase chromosome analysis in cases with a visible deletion. It was within the 4p16.1 band in six patients, apparently coincident with the distal half of this band in five patients. The extent of each of the four submicroscopic deletions was established by FISH analyses with a set of overlapping cosmid clones spanning the 4p16.3 region. We found ample variations in both the size of the deletions and the position of the respective breakpoints. The precise definition of the cytogenetic defect permitted an analysis of the genotype-phenotype correlations in WHS, leading to the proposal of a set of minimal diagnostic criteria, which in turn may facilitate the selection of critical patients in the search for the gene(s) responsible for this disorder. We observed that genotype-phenotype correlations in WHS mostly depend on the size of the deletion, a deletion of <3.5 Mb resulting in a mild phenotype, in which malformations are absent. The absence of a detectable molecular deletion is still consistent with a WHS diagnosis. Based on these observations a "minimal" WHS phenotype was inferred, the clinical manifestations of which are restricted to the typical facial appearance, mild mental and growth retardation, and congenital hypotonia.

Fine-grained facial phenotype–genotype analysis in Wolf–Hirschhorn syndrome

“…13 There is considerable variation in the phenotypic spectrum, and, more recently, a correlation with the size of the deletion has been recognized; children with submicroscopic deletions within 4p16.3 tend to have a milder phenotype. 14,15 Some patients with microdeletions within 4p16.3 were initially reported as having Pitt-Rogers-Danks syndrome, now considered to be within, and at the milder end of, the WHS spectrum. 16,17 We use small and large, respectively, to refer to a terminal deletion with a break point within 4p16.3, a deletion size of about 3.1 Mb or less, and one with a break point more proximal than 4p16.…”

Comprehensive analysis of Wolf–Hirschhorn syndrome using array CGH indicates a high prevalence of translocations

“…3 Sixteen of the 32 patients in our study had heart defects and four of these patients had deletion breakpoints within 4p16.3, which is distal to 4p16.2. Three of these four patients with heart defects and smaller-sized deletions had unbalanced translocations, and one of these was cryptic.…”

A double cryptic chromosome imbalance is an important factor to explain phenotypic variability in Wolf–Hirschhorn syndrome

“…11 Her psychomotor development was reasonably good until 17 months, when she suffered from repeated epileptic status, with two episodes of cardiac arrest. Therefore, the severity of mental retardation in this patient was considered secondary to severe critical episods.…”

“…Patients 1, 8, 13, 15, 44, 46 and MG (Tables 1 and 3) were reported previously. 1,11 However, the assessment of the basic genetic defect with molecular cytogenetics methods including not only chromosome 4p analysis but also all subtelomeric regions analysis, their correlation with parental origin and the clinical outcome of the newly characterized rearrangements are reported here for the first time.…”