Polydactyly: phenotypes, genetics and classification

Abstract

Polydactyly is one of the most common hereditary limb malformations featuring additional digits in hands and/or feet. It constituted the highest proportion among the congenital limb defects in various epidemiological surveys. Polydactyly, primarily presenting as an additional pre-axial or post-axial digit of autopod, is a highly heterogeneous condition and depicts broad inter- and intra-familial clinical variability. There is a plethora of polydactyly classification methods reported in the medical literature which approach the heterogeneity in polydactyly in various ways. In this communication, well-characterized, non-syndromic polydactylies in humans are reviewed. The cardinal features, phenotypic variability and molecular advances of each type have been presented. Polydactyly at cellular and developmental levels is mainly a failure in the control of digit number. Interestingly, GLI3 and SHH (ZRS/SHH enhancer), two antagonistic factors known to modulate digit number and identity during development, have also been implicated in polydactyly. Mutations in GLI3 and ZRS/SHH cause overlapping polydactyly phenotypes highlighting shared molecular cascades in the etiology of additional digits, and thus suggesting the lumping of at least six distinct polydactyly entities. However, owing to the extreme phenotypic and clinical heterogeneity witnessed in polydactyly a substantial genetic heterogeneity is expected across different populations and ethnic groups.

Human Malformation Syndromes of Defective <b><i>GLI</i></b>: Opposite Phenotypes of 2q14.2 (<b><i>GLI2</i></b>) and 7p14.2 (<b><i>GLI3</i></b>) Microdeletions and a GLIA/R Balance Model

“…Actually, the cases with point mutations and the cases with contiguous deletions manifest highly overlapping phenotypes, and it is not easy to distinguish these 2 conditions. Specifically, GLI3 is particularly important for finger development [Malik, 2014], and a deficiency of GLI2A, which is an activator form of GLI2, especially affects pituitary and midface development [Gregory et al, 2015]. The fact that GLI2 and GLI3 gene mutations exhibit different phenotypes in humans indicates that each GLI gene became functionally differentiated through evolution, and GLI2 and GLI3 proteins play different roles during embryonic development.…”

CYLD – a deubiquitylase that acts to fine-tune microtubule properties and functions

“…Recently, two independent studies using different mouse models have shown that CYLD is required for ciliogenesis. We have found that Cyld-knockout mice exhibit polydactyly, a cilium-associated symptom (Malik, 2014), and defective ciliogenesis in multiple organs, including the skin, kidney, trachea and testis (Yang et al, 2014b). Transmission electron microscopy showed that CYLD is required for the anchorage of the basal body and proper organization of the basal body and axoneme (Fig.…”

Identity-by-descent refines mapping of candidate regions for preaxial polydactyly II /III in a large Chinese pedigree

“…It is one of the most common congenital deformities [2]. The worldwide incidence of PPD is 1 in 3000 births [3].…”

“…The prevalence rate of polydactyly in Chinese ranks third in birth defects after congenital heart diseases and central nervous system diseases [4]. Polydactyly has genetic and clinical heterogeneity [2]. The mainstream treatment is resection for excess digits.…”