Split hand foot malformation (SHFM): An introduction

Some 360 million years ago, the first animal crawled out of the sea and onto the land. Ahlberg et al. very recently demonstrated that this animal, Ichthyostega, might not have actually crawled but rather inched its way over the land probably dragging its hind legs and long tail behind [Ahlberg et al., 2005]. This creature with very short legs and long tail may have propelled itself by arching its spine andpropelling itself forward like an inchworm. Nonetheless, Ichthyostega possessed the already ancient tetrapod body form. Limb development has been shown to depend upon the key roles played by gradients of signaling molecules in three spatial planes: proximo-distal or shoulder-finger, anteroposterior or thumb-little finger direction, and dorso-ventral or back of hand-palm direction. The successful formation of limbs also requires the interaction of the signaling centers for each axis. The zone of polarizing activity (ZPA) via Shh signaling directs antero-posterior patterning, nonridge ectoderm via the transcription factors En1 and Wnt7a determine dorsal-ventral patterning, and the apical ectodermal ridge (AER) through the influence of the Fgf family plays a major role in proximal-distal patterning. Limb malformations occur in approximately 1:1,000 neonates. There are currently two clinical classifications: the Temtany and McKusick [1978] classification based on clinical description and the Winter and Tickle [1993] classification based on a combination of clinical and embryologic criteria. A better understanding of underlying genetic basis for these anomalies now permits a genetic classification. SHFM is a limb malformation involving the central rays of the autopod (hand/foot). The incidence of SHFM is estimated to be approximately 1:18,000 [Czeizel et al., 1994]. It has been known by a number of other terms including cleft hand, oligodactyly, central oligodactyly, central ray deficiency, and lobster-claw malformation. It is most commonly used synonymously with ectrodactyly, a term first utilized in 1832 by Saint-Hilaire [1832] to describe a two-fingered condition. Ectrodactyly is derived from the Greek ‘ektroma’ or aborted ‘dactylos’ or finger. The Human Genome Nomenclature Committee determined that split-hand/split-foot malformation should be symbolized SHFM in 1994 [Elliott et al., 2005]. SHFM is highly variable in its severity ranging from mild digital changes to monodactyly, and can occur in isolation or as part of more than 75 syndromes. Associated non-limb anomalies are found in approximately 40% of cases of SHFM. Five SHFM loci have been identified, four autosomal and one X-linked. In this issue, Basel et al. explore the contribution of murine phenotypes of SHFM and their contributions to themolecular pathologyof SHFM.The functioning of Dlx homeobox genes in limb development in the mouse is explored by Kraus and Lufkin. Everman et al., describe the role of chromosomal rearrangements including duplication at 10q24 in syndromic and non-syndromic SHFM3. Lyle and associates suggest that the overexpression of two genes, BTRC and SUFU, in the duplicated region may be the cause of SHFM3 via b-catenin signaling. Genotype–phenotype correlations are difficult to delineate in the SHFM disorders because of the complexity of the