Discrepancies in upper and lower limb patterning in split hand foot malformation

Abstract

Discrepancies in upper and lower limb patterning in split hand foot malformation. Split hand foot malformation (SHFM) is genetically heterogeneous with five loci mapped to date. Highly variable in presentation, it can occur as an isolated finding or with other anomalies. The genetic heterogeneity and clinical variability make genetic counselling of SHFM families challenging. By establishing genotype/phenotype correlations, one can provide insight into responsible developmental genes and help to direct mapping efforts and target genetic testing, ultimately providing more accurate information for family members. Preaxial involvement of the upper extremities was a significant discriminating limb-specific variable in our analysis of genetically mapped SHFM cases. This finding, which was originally identified through descriptive epidemiology, was subsequently confirmed by discriminant function analysis (p < 0.0001) to be a significant locus discriminator. Preaxial involvement of the upper extremities was most commonly seen at the SHFM3 locus mapped to chromosome 10q24 (OMIM 600095) and consisted of proximally placed thumbs and/or triphalangeal thumbs (TPT), preaxial polydactyly and/or absence of the first ray. These patients' feet, however, tended to show a classical central longitudinal deficiency without a significant preaxial component. This article discusses this discrepant clefting pattern between the upper and lower extremities and proposes potential mechanisms.

Clinical, genetic, and molecular aspects of split‐hand/foot malformation: An update

“…General correlations exist between individual loci and their associated nonsyndromal and/or syndromal SHFM phenotypes (Tables I and II), and relationships between particular loci and specific limb and non-limb manifestations have also been defined [Elliott et al, 2005;. For example, preaxial involvement of the upper extremities seems to be a significant locus discriminator, most commonly seen in patients with SHFM3 and SHFM5 (60% and 40%, respectively).…”

Triphalangeal thumb in association with split hand/foot: A phenotypic marker for SHFM3?

“…Cases were included if they had central deficiency, a large gap between digits 1 and 2, or longitudinal clefting. A detailed list of patients included in our analyses has been published previously (Elliott et al, 2005). Discriminant function analysis using SPSS for Windows of phenotypic variables in cases of SHFM mapped to four autosomal loci showed preaxial involvement to be a significant limb discriminating variable (P < .0001).…”

“…The genetic heterogeneity and clinical variability of SHFM makes targeted genetic analysis and genetic counseling challenging. In our analysis of genetically mapped SHFM cases (patients for whom the responsible genetic locus has been identified) from the literature, preaxial involvement of the upper extremities proved to be a significant discriminating variable (Elliott et al, 2005). Triphalangeal thumb (TPT), in particular, was found to be a significant preaxial variable.…”

Split-hand/split-foot malformation (SHFM)

“…In the majority of cases, SHFM is autosomal dominant with reduced penetrance and autosomal-recessive and X-linked forms are rare. [1][2][3][4][5] At least seven SHFM types (six basic from SHFM1 to SHFM6 and one additional SHFM/SHFLD) have been distinguished in the literature. Type I, the most frequent variety, is due to a mutation on chromosome 7 (rearrangements in 7q21.3-q22.1) in a region that contains two homeobox genes, DLX5 and DLX6.…”

“…It may look like lobster claw if there is absence of third digit with clefting into the proximal portion of the hand or foot and syndactyly of remaining digit on each side of cleft. [1][2][3] A large number of human gene defects can cause SHFM. The most common mode of inheritance is autosomaldominant with reduced penetrance.…”