BACKGROUND: At least five distinct loci have been implicated in split hand foot malformation (SHFM). Establishing genotype/phenotype correlations at the chromosomal level may elucidate responsible developmental genes and improve patient management. In our analysis of previously published genetically mapped SHFM cases, preaxial hand involvement was a significant discriminating variable, most commonly seen at the SHFM3 locus (OMIM 600095) at 10q24. Of the 47 SHFM3 patients analyzed, 15 (31.9%) had triphalangeal thumb (TPT), a limb finding not reported at any other locus. METHODS: The association of TPT/split foot, in particular, prompted us to review the literature for similar cases. RESULTS: We ascertained a number of unmapped familial and sporadic cases with TPT/split foot, including a group of patients with triphalangeal thumb-brachyectrodactyly syndrome. Certain trends were similar in both SHFM3 and these unmapped literature cases. With respect to gender, 7/12 (58%) of mapped SHFM3 cases with TPT/split foot were male whereas 5/12 (42%) were female, compared with 22/50 (44%) males and 28/50 (56%) females among unmapped cases (P = 0.3715). Individuals in both groups usually had bilateral involvement, with 67 and 60% showing bilateral TPT among mapped and literature cases, respectively (P = 0.6714). Bilateral involvement of the feet was even more striking (83% of SHFM3 patients and 96% of literature cases; P = 0.0808). CONCLUSIONS: Patients with TPT/split foot may in fact represent SHFM3 cases and should be evaluated for genomic rearrangements at 10q24. TPT may be identified only by radiographic analysis, emphasizing the importance of imaging these patients and their family members. Birth Defects Research (Part A) 2007. © 2006 Wiley-Liss, Inc.
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