Refinement of the deletion in 7q21.3 associated with split hand/foot malformation type 1 and Mondini dysplasia.

S plit hand/foot malformation type I (SHFM1, OMIM *183600) is an autosomal dominant developmental disorder of limb formation that results in the absence of the central digital rays, deep median clefts, and syndactyly of the remaining digits. Patients with SHFM1 harbour deletions, translocations, and inversions in chromosomal region 7q21–q22. The deletions at 7q21–q22 encompass different genomic regions and probably result in a contiguous gene syndrome that includes growth impairment, microcephaly, craniofacial manifestations, hernias, hearing loss, and mental retardation. 3 Cases with translocations do not show this broad pattern of abnormalities but are associated with hearing loss in most cases. 5 Split hand/foot malformation type I is the only form of split hand/foot malformation associated with sensorineural hearing loss, and it has been designated SHFM1D (OMIM *605617). 6 Recently, SHFM1D was shown to result from Mondini dysplasia in a boy with a de novo deletion of about 8.9– 17 cM of the paternal chromosome 7q21.1–q21.3. So far, microdeletions at 7q21.3 have been described in only two cases: one in a boy with split hand/foot malformation plus mild mental retardation, growth retardation of post-natal onset, and hypotonia and another in a patient with ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome. 9 Mapping of the deletion and translocation breakpoints in several patients showed a critical interval of about 1 Mb for the SHFM1 locus at 7q21.3. This interval included a 500 kb region that spanned five of seven known translocation breakpoints. In this region, the candidate genes DLX5 and DLX6 (human homologues of the Drosophila distalless homeobox gene family) and DSS1 (deleted in the split hand/split foot SHFM1 region) were identified. No mutations were detected in patients with sporadic split hand/foot malformation with translocations or two families with split hand/foot malformation, sensorineural deafness, and normal chromosomes who showed linkage to 7q21. 9 10 Haploinsufficiency through interruption of the gene’s regulatory elements was considered therefore to be the cause of SHFM1. Recently, an animal model of human SHFM1 has been produced in mice by targeted inactivation of Dlx5 and Dlx6 candidate genes. 12 In this mouse model, the Dlx5/ Dlx6 genotype resulted in inner ear and severe limb malformations and craniofacial and axial skeletal defects.