Identification of a novel DLX5 mutation in a family with autosomal recessive split hand and foot malformation.

BACKGROUND: Split hand and foot malformation (SHFM) refers to a genetically heterogeneous developmental disorder of the hands and feet that presents as median ray deficiency of varying severity. 7q21.3 (SHFM1) is one of six loci described to date, and although DLX5 and DLX6 are compelling candidates in that locus, no intragenic mutations have been described in either of these genes. METHODS: The authors combined autozygome analysis and exome sequencing to study a consanguineous family with a highly unusual SHFM phenotype, where there is associated dorsalisation of the hands. RESULTS: A novel missense mutation in a highly conserved residue of the homeobox domain of DLX5 was identified. Unlike previously reported position effect mutations in SHFM1, this first documented intragenic DLX5 mutation is also accompanied by abnormal dorsal-ventral patterning. CONCLUSION: This study identified the first intragenic DLX5 mutation in SHFM and raises interesting possibilities about a dual role for DLX5 in limb development.

The Erlenmeyer flask bone deformity in the skeletal dysplasias.

Erlenmeyer flask bone deformity (EFD) is a long-standing term used to describe a specific abnormality of the distal femora. The deformity consists of lack of modeling of the di-metaphysis with abnormal cortical thinning and lack of the concave di-metaphyseal curve resulting in an Erlenmeyer flask-like appearance. Utilizing a literature review and cohort study of 12 disorders we found 20 distinct disorders were associated with EFD. We interrogated the International Skeletal Dysplasia Registry (ISDR) radiographic database (1988-2007) to determine which skeletal dysplasias or syndromes were highly associated with EFD, whether it was a uniform finding in these disorders, and if forms of EFD could be differentiated. EFD was classified into three groups. The first catogory was the typical EFD shaped bone (EFD-T) resultant from absent normal di-metaphyseal modeling with relatively normal appearing radiographic trabecular bone. EFD-T was identified in: frontometaphyseal dysplasia, craniometaphyseal dysplasia, craniodiaphyseal dysplasia, diaphyseal dysplasia-Engelmann type, metaphyseal dysplasia-Pyle type, Melnick-Needles osteodysplasty, and otopalatodigital syndrome type I. The second group was the atypical type (EFD-A) due to absence of normal di-metaphyseal modeling with abnormal radiographic appearance of trabecular bone and was seen in dysosteosclerosis and osteopetrosis. The third group was EFD-marrow expansion type (EFD-ME) in which bone marrow hyperplasia or infiltration leads to abnormal modeling (e.g., Gaucher disease). Further, radiographic review determined that it was not always a consistent finding and that there was variability in both appearance and location within the skeleton. This analysis and classification aided in differentiating disorders with the finding of EFD.