Synpolydactyly: clinical and molecular advances

Abstract

Synpolydactyly (SPD) is a rare limb deformity showing a distinctive combination of syndactyly and polydactyly. Of the nine non-syndromic syndactylies, it is clinically and genetically one of the most heterogeneous malformation. SPD families may show clinical features consistent with the Temtamy and McKusick criteria as well as additional phenotypic variants, which vary from case to case. In certain instances, these variants predominate in a given family, while the typical SPD features remain less explicit. We have reviewed all the clinical variants occurring in well-documented SPD families. We conclude that typical SPD features can be delineated from minor clinical variants. Then, we propose to lump all the phenotypic variants, manifesting themselves in SPD families into three categories: (i) typical SPD features, (ii) minor variants, and (iii) unusual phenotypes. Next, we discuss the likely reasons for the occurrence of minor variants and the obvious lack of penetrance in SPD families. Finally, we show that for the SPD phenotype associated with HOXD13 mutations, a straightforward genotype-phenotype correlation is weak. Our lumping and splitting scheme for SPD phenotypic variants could be useful for the understanding of this interesting malformation.

Syndactyly: phenotypes, genetics and current classification

“…The hallmark features of SPD are cutaneous/bony fusion of third and fourth fingers and second and third toes with partial or complete reduplication of a digital ray within the syndactylous web ( Figure 1). 27 It is the only syndactyly type with a mesoaxial superfluous finger. The extreme phenotypic heterogeneity in SPD families has led to the lumping of all clinical variants (B18 types) into three categories: (A) typical SPD features; (B) minor variants; and (C) unusual phenotypes.…”

“…The extreme phenotypic heterogeneity in SPD families has led to the lumping of all clinical variants (B18 types) into three categories: (A) typical SPD features; (B) minor variants; and (C) unusual phenotypes. 27 SPD segregates as an autosomal dominant entity with reduced penetrance. Three SPD loci have been discovered (SPD1-3), however, these entities have not yet been clinically delineated (Table 2).…”

Unfoldomics of Human Genetic Diseases: Illustrative Examples of Ordered and Intrinsically Disordered Members of the Human Diseasome

“…Three genetically distinct SPD malformations are now known and have been designated as SPD1, SPD2 and SPD3. The phenotype of SPD1 is associated with the expansion mutations in the polyalanine repeat of the HOXD13 transcription factor [68]. Weyers acrodental dysostosis is an autosomal dominant skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly and dysplastic nails and teeth that is caused by the mutations in the collapsin response mediator protein 1 (CRMP1), which is one of the CRMP family members that mediates signal transduction of axon guidance molecules [69].…”

Mutant Hoxd13 induces extra digits in a mouse model of synpolydactyly directly and by decreasing retinoic acid synthesis

“…Duplications of digits are frequently associated with cutaneous or osseous webbing of the adjacent fingers, resulting in syndactyly, hence the name synpolydactyly (SPD) for these conditions (15). One type of SPD has been shown to be caused by mutations in homeobox d13 (Hoxd13), the most 5′ homeobox (Hox) gene of the D cluster.…”