A fine regulation of adhesive contacts between cells underlies many crucial processes during ectodermal tissues morphogenesis, renewal and maintenance. Ectodermal Dysplasias (EDs) are genetically heterogeneous genodermatoses affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and sweat glands. Clinically overlapping EDs occur as the result of defects in cell adhesion molecules (CAMs) or in their regulatory transcription factors (TFs).
Here we report a family with two sibs from healthy parents affected by hair defects with alopecia, nail dysplasia, cutaneous syndactyly variably affecting fingers and toes and palmoplantar hypercheratosis. Such
combination of features is diagnostic of nectinopathies caused by mutation in either PVRL1 (nectin-1) or PVRL4 (nectin-4) genes, but molecular analysis of these genes was negative in this family.
By Whole Exome Sequencing, we identified two variants in RIPK4 gene predicted to be pathogenic and not previously reported in the literature. The RIPK4 serine/threonine kinase is a major modulator of epidermal
differentiation and is altered in two distinct genetic disorders with multiple pterigia, cleft lip/palate and other ectodermal defects known as Bartsocas-Papas and CHAND (Curly Hair-Ankyloblepharon-Nail Dysplasia)
syndromes.
Given the strong overlap between phenotypes resulting from nectins and RIPK4 alterations, we propose the existence of a functional link between RIPK4-mediated phosphorylation and CAMs playing a role during ectodermal morphogenesis and epidermal differentiation. Our results consolidate and expand the role of RIPK4 in epidermal development, differentiation and renewal, pinpointing the complex basis of EDs pathogenesis.

Novel biallelic RIPK4 mutations cause ectodermal dysplasia with cutaneous syndactyly