LETTER TO JMG Mild Wolf-Hirschhorn syndrome: micro-array CGH analysis of atypical 4p16.3 deletions enables refinement of the genotype-phenotype map

W olf-Hirschhorn syndrome is a multiple malformation syndrome with distinct abnormal craniofacial features, prenatal onset growth retardation, failure to thrive, microcephaly, usually severe mental retardation, seizures, and congenital heart malformations. Large variations are observed in phenotypic expression of these features, with mental retardation ranging from severe to mild. There is a one third mortality in the first two years of life. Most patients with Wolf-Hirschhorn syndrome carry 4p terminal deletions. However, the size of these deletions is variable and several phenotypic features have been tentatively mapped within the 4pter region. Further fine mapping of the different phenotypic features will ultimately lead to a functional understanding of the genes that cause these abnormal phenotypes. The minimal ‘Wolf-Hirschhorn syndrome’ phenotype was defined as the typical facial appearance, congenital hypotonia, mental retardation, growth delay, and seizures. 4 The Wolf-Hirschhorn syndrome critical region was originally confined to a region of 165 kb and nine transcripts within this region were described. A patient with a small intrachromosomal 4p deletion and a partial Wolf-Hirschhorn syndrome phenotype further refined the critical region (WHSCR1). Two genes, the WolfHirschhorn Syndrome Candidate genes 1 (WHSC1) and 2 (WHSC2), are located in the region. The expression pattern of WHSC1 colocalises spatially and temporarily with the major Wolf-Hirschhorn syndrome malformations and the gene is homologous with a Drosophila dysmorphology gene. WHSC2 is a nuclear protein with a helix-loop-helix motif that is ubiquitously expressed throughout development. 9 The identification of a Wolf-Hirschhorn syndrome patient with a terminal 1.9 Mb deletion not including this WolfHirschhorn syndrome critical region led Zollino et al to postulate a novel critical region distal to the previously defined critical region, which was termed the WolfHirschhorn critical region 2 (WHSCR2). The distal boundary of this region is located within the WHSCR1 and at least one other gene LETM1, a calcium channel gene, is located within WHSCR2. The main argument to assign a novel WHSCR was the questionable presence of the Wolf-Hirschhorn syndrome facial gestalt that delineated the distal boundary of the WHSCR1. In this report, we present six additional patients with small atypical deletions in the 4pter region, five presenting with a mild Wolf-Hirschhorn syndrome phenotype. Two of these patients had small intrachromosomal deletions and three had small terminal deletions. We defined the size of the deletion using micro-array CGH (array CGH), which enabled rapid identification of the deletion breakpoints and facilitated the genotype-phenotype correlation. MATERIALS AND METHODS Clinical examination Personal and family history was obtained from all patients. The patients were all clinically examined. Some patients were monitored over several years and follow up data were recorded.