WNTs are secreted glycoproteins that are involved in signalling pathways critical to organ development and tissue regeneration. Of the 19 known WNT ligands, one member of this family, WNT10A, appears to have specific relevance to skin, its appendages and teeth. This review focuses on how variants in the WNT10A gene have been associated with various ectodermal disorders and how such changes may have clinical relevance to dermatologists and dentists. Germline mutations in WNT10A underlie several forms of autosomal recessive ectodermal dysplasia in which heterozygous carriers may also display some lesser ectodermal anomalies. Within the general population, multiple heterozygous variants in WNT10A can cause skin, hair, sweat gland or dental alterations, also known as ectodermal derivative impairments. WNT10A variants have also been implicated in hair thickness, male androgenetic alopecia, hair curl, acne vulgaris, lipodystrophy, keloids, wound healing, tooth size, tooth agenesis, hypodontia, taurodontism and oral clefting. Beyond dermatology and dentistry, WNT10A abnormalities have also been identified in kidney fibrosis, keratoconus, certain malignancies (particularly gastrointestinal), and neuropathic pain pathways. In this review, we detail how WNT10A is implicated as a key physiological and pathological contributor to syndromic and non-syndromic disorders, as well as population variants, affecting the skin and teeth, and document all reported mutations in WNT10A with genotype-phenotype correlation.

Background Discovering the genetic basis of inherited skin diseases is fundamental to improving diagnostic accuracy and genetic counselling. In the 1990s and 2000s, genetic linkage and candidate gene approaches led to the molecular characterisation of several dozen genodermatoses, but over the past decade the advent of next‐generation sequencing (NGS) technologies has accelerated diagnostic discovery and precision. Objectives This review examines the application of NGS technologies from 2009 to 2019 that have (a) led to the initial discovery of gene mutations in known or new genodermatoses and (b) identified more than one contributing pathogenic gene involvement in individuals with complex Mendelian skin disorder phenotypes. Methods A comprehensive review of the PubMed database and dermatology conference abstracts was undertaken between January 2009 to December 2019, collated and cross‐referenced with OMIM. Results We identified 166 new disease‐gene associations in inherited skin diseases discovered by NGS. Of these, 131 were previously recognised, while 35 were brand new disorders. Eighty‐five were autosomal dominant (with 43/85 mutations occurring de novo ); 78 were autosomal recessive; and 3 were X‐linked. We also identified 63 cases harbouring multiple pathogenic mutations, either involving two co‐existing genodermatoses (n = 13) or an inherited skin disorder in conjunction with other organ system phenotypes (n = 50). Conclusions NGS technologies have accelerated disease‐gene discoveries in dermatology over the last decade. Moreover, the era of NGS has enabled clinicians to split complex Mendelian phenotypes into separate diseases. These genetic data improve diagnostic precision and make feasible accurate prenatal testing and better‐targeted translational research.

For disorders of keratinization, topical treatment alone may be ineffective, and systemic retinoid therapy may be indicated. Treatment with systemic retinoids (acitretin, isotretinoin and alitretinoin) has been shown to be effective in reducing disease severity; however, potentially rare adverse effects (AEs) may occur, including hyperostotic skeletal changes. The true prevalence of this AE in adult patients administered life-long therapy is unknown. We identified 3 of 127 (2.4%) patients (with ichthyosis or Darier disease) who had been prescribed isotretinoin with or without acitretin, and who developed radiological signs and clinical symptoms of hyperostosis and ligamentous ossification. This clinical review highlights the significance of retinoid-induced skeletal hyperostosis in patients prescribed long-term, high-dose retinoid therapy for disorders of keratinization. Patients commencing systemic retinoid therapy, particularly women of childbearing age, should be counselled about this important and potentially serious AE, especially if long-term treatment is indicated.

Genetic hair disorders, also known as genotrichoses, are characterized by abnormalities of hair structure, growth or differentiation, giving rise to a spectrum of phenotypes such as hypertrichosis, hypotrichosis and atrichia. These disorders may present as isolated phenotypes or be part of more complex phenotypes including abnormalities in skin or other organs. Genetic discoveries for hair disorders have been recently augmented with the advent of next-generation sequencing (NGS) technologies. We reviewed the literature and summarized disease–gene associations for inherited hair disorders, as well as genodermatoses presenting with hair abnormalities discovered by NGS technologies. We identified 28 nonsyndromic hair disorders, involving 25 individual genes and four unidentified genes. We have also discovered that approximately 30% of all the genodermatoses that were identified by NGS approaches demonstrated hair abnormalities as part of their phenotype. This review underscores the huge impact of NGS technologies in disclosing the genetics of hair disorders and the potential these discoveries provide for future translational research and new therapies.