Dental and extra‐oral clinical features in 41 patients with WNT10A gene mutations: A multicentric genotype–phenotype study

Abstract

WNT10A gene encodes a canonical wingless pathway signaling molecule involved in cell fate specification as well as morphogenetic patterning of the developing ectoderm, nervous system, skeleton, and tooth. In patients, WNT10A mutations are responsible for ectodermal-derived pathologies including isolated hypo-oligodontia, tricho-odonto-onycho-dermal dysplasia and Schöpf-Schulz-Passarge syndrome (SSPS). Here we describe the dental, ectodermal, and extra-ectodermal phenotypic features of a cohort of 41 patients from 32 unrelated families. Correlations with WNT10A molecular status (heterozygous carrier, compound heterozygous, homozygous) and patient's phenotypes were performed. Mild to severe oligodontia was observed in all patients bearing biallelic WNT10A mutations. However, patients with compound heterozygous mutations presented no significant difference in phenotypes compared with homozygous individuals. Anomalies in tooth morphology were frequently observed with heterozygous patients displaying hypodontia. No signs of SSPS, especially eyelids cysts, were detected in our cohort. Interestingly, extra-ectodermal signs consisted of skeletal, neurological and vascular anomalies, the latter suggesting a wider phenotypic spectrum associated with WNT10A mutations. Indeed, the Wnt pathway plays a crucial role in skeletal development, lipid metabolism, and neurogenesis, potentially explaining patient's clinical manifestations.

WNT10A gene is the second molecular candidate in a cohort of young Italian subjects with ectodermal derivative impairment (EDI)

“…More recently, mutations in WNT10A (2q35; OMIM 606268) have been shown to be associated with EDI with both autosomal dominant and recessive inheritance . The WNT10A gene is implicated in the Wnt/beta‐catenin pathway, which together with the ectodysplasin signaling pathway plays a crucial role in tooth morphogenesis and the development of ectodermal structures …”

Turkish Ectodermal Dysplasia Cohort: From Phenotype to Genotype in 17 Families

“…XLHED is due to mutations in the EDA gene (ectodysplasin-A), which maps to Xq12q13.1 and encodes ectodysplasin ( EDA ; OMIM 300451), a member of the tumor necrosis factor (TNF) family [Bayés et al, 1998]. Autosomal dominant (AD; OMIM 129490) and autosomal recessive (AR; OMIM 224900) forms of HED/EDA are encountered less frequently and result from mutations in the EDAR or in the EDARADD genes [van der Hout et al, 2008;Plaisancié et al, 2013]. Moreover, recently, it has been shown that mutations in the WNT10A gene are responsible for a broad spectrum of autosomal recessive ED [Cluzeau et al, 2011].…”

“…In contrast, mutations in the WNT10A gene (OMIM 606268), encoding a protein that participates in the WNT/β-catenin/Lef-1 signaling pathway, have been shown to cause a highly variable phenotype, ranging from isolated tooth agenesis to ED syndromes such as odonto-onycho-dermal dysplasia (OODD; OMIM 257980) and Schöpf-Schulz-Passarge syndrome (SSPS; OMIM 224750) [Adaimy et al, 2007;Bohring et al, 2009;Cluzeau et al, 2011;Kantaputra et al, 2014]. The classic Wnt/β-catenin signaling pathway has been shown to play an essential role in odontogenesis, ectodermal development, and epidermal homeostasis [Tardieu et al, 2017].…”

Long‐term dental management of a patient with features of Schöpf–Schulz–Passarge syndrome

“…SSPS is speculated to be an autosomal recessive condition caused by mutations in the WNT10A gene, which plays roles in signaling molecule that regulates cell to cell interactions and in multiple developmental processes in embryogenesis including tooth morphogenesis . Hence, several studies have found WNT10A mutations to cause a range of phenotypes, with hypodontia being a consistent feature . However, as patients with odonto‐onycho‐dermal dysplasia and nonsyndromic hypodontia have also been reported to exhibit similar WNT10A mutations, these mutations cannot be considered to be pathognomonic of SSPS …”

“…Hence, several studies have found WNT10A mutations to cause a range of phenotypes, with hypodontia being a consistent feature . However, as patients with odonto‐onycho‐dermal dysplasia and nonsyndromic hypodontia have also been reported to exhibit similar WNT10A mutations, these mutations cannot be considered to be pathognomonic of SSPS …”