WNT10A – Odonto-onycho-dermal Dysplasia

WNT10A encodes a secreted glycoprotein of the WNT family that is crucial for ectodermal appendage development, including teeth, nails, hair, and sweat glands. Biallelic loss-of-function variants in WNT10A cause odonto-onycho-dermal dysplasia (OODD), an autosomal recessive ectodermal dysplasia with oligodontia, onychodysplasia, palmoplantar keratoderma, dry skin, hypotrichosis, and hyperhidrosis of palms and soles. Diagnosis is often delayed due to overlapping features with common dermatologic conditions, underscoring the need for genetic testing in suspected cases.

Inheritance is autosomal recessive, with multiple consanguineous families reported. A recurrent homozygous nonsense variant, c.321C>A (p.Cys107Ter) (PMID:26964878), was identified in an OODD patient with severe dental agenesis and eccrine syringofibroadenomatosis of palms and soles. Autozygosity mapping in three Lebanese families (six affected individuals) revealed a homozygous c.697G>T (p.Glu233Ter) variant segregating with disease and a multipoint LOD score of 5.7 (PMID:17847007). A large Pakistani pedigree (six affected) demonstrated homozygosity for a p.Ala131Val missense variant (c.392C>T) critical for WNT10A’s conserved domain (PMID:19471313).

Functional studies support a haploinsufficiency mechanism. Wnt10a knockout mouse and human cell assays show diminished β-catenin signaling, reduced epithelial progenitor proliferation, and impaired KLF4-mediated differentiation in hair follicles, sweat glands, nails, and teeth, mirroring the human OODD phenotype (PMID:28589954). Rescue experiments with wild-type WNT10A restore progenitor proliferation and downstream keratin expression in vitro, corroborating pathogenicity.

No reports have refuted the WNT10A–OODD association. Heterozygous carriers may exhibit mild ectodermal anomalies, but only biallelic variants cause the full OODD syndrome. Further studies have not identified alternative genetic causes in OODD patients lacking WNT10A variants, reinforcing the specificity of this gene–disease relationship.

In summary, strong genetic and moderate functional evidence over >15 years establish a definitive association between biallelic WNT10A variants and OODD. Genetic testing of WNT10A in patients with characteristic ectodermal dysplasia features facilitates accurate diagnosis, informs genetic counseling, and guides early multidisciplinary management.

References

• BMC Dermatology | 2016 | Odonto-onycho-dermal dysplasia in a patient homozygous for a WNT10A nonsense mutation and mild manifestations of ectodermal dysplasia in carriers of the mutation. PMID:26964878
• American Journal of Human Genetics | 2007 | Mutation in WNT10A is associated with an autosomal recessive ectodermal dysplasia: the odonto-onycho-dermal dysplasia. PMID:17847007
• European Journal of Human Genetics | 2009 | WNT10A missense mutation associated with a complete odonto-onycho-dermal dysplasia syndrome. PMID:19471313
• Nature Communications | 2017 | WNT10A mutation causes ectodermal dysplasia by impairing progenitor cell proliferation and KLF4-mediated differentiation. PMID:28589954

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