Split-Hand/Foot Malformation with Long Bone Deficiency (SHFLD) is a rare and severe limb deformity of variable clinical manifestations. The signs and symptoms may range from virtually no malformation to ectrodactyly and tibial hypoplasia or aplasia with or without associated anomalies. The incidence of SHFLD is estimated to be 1:1,000,000 live births.
See: United Arab Emirates > Naveed et al., 2007.
Naveed et al. (2007) presented genome wide linkage analysis of one large multigenerational Arab family with SHFLD. The majority of the family members were residing in the UAE and a few in Oman. Of the 145 individuals in the family, 14 males and nine females showed an abnormal phenotype, ranging from mild to severe defects involving upper and lower limbs. The nine affected patients included in the linkage study all had severe tibial aplasia, some with additional findings of split hand/foot, syndactyly, hypoplastic big toes, absence of middle phalanges of some toes, hypoplastic tibiae, and beaked nose. Naveed et al. (2007) identified novel genomic regions on 1q42.13-q43 and 6q14.1 harboring high-risk variants for SHFLD in the studied family. Maximum multipoint lod scores of 3.20 and 3.78 were detected for the 2 locations on 1q and 6q, respectively, with the use of an autosomal dominant mode of inheritance with reduced penetrance. Haplotype analysis with informative crossovers enabled mapping of SHFLD2 to a region on 6q14.1 between single-nucleotide polymorphisms rs623155 and rs1547251. Phenotypically unaffected or affected parents who had affected haplotypes produced affected children with affected haplotypes form chromosomes 1 and 6. Therefore, the loci on both chromosomes were essential for the phenotypic expression. Also, five individuals were observed with no manifestation of the phenotype and they carried the two disease-related haplotypes. This can be explained by reduced penetrance at each locus. The haplotype data supported the autosomal dominant mode of inheritance in the family. On the other hand, the observed ten consanguineous marriages suggested the possibility of pseudodominance in the family due to the high frequency of mutant alleles.