Ectodermal Dysplasia-Syndactyly Syndrome with Toe-Only Minimal Syndactyly Due to a Novel Mutation in NECTIN4: A Case Report and Literature Review

Abstract

Ectodermal dysplasia-syndactyly syndrome 1 (EDSS1) is characterized by cutaneous syndactyly of the toes and fingers and abnormalities of the hair and teeth, variably associated with nail dystrophy and palmoplantar keratoderma (PPK). EDSS1 is caused by biallelic mutations in the NECTIN4 gene, encoding the adherens junction component nectin-4. Nine EDSS1 cases have been described to date. We report a 5.5-year-old female child affected with EDSS1 due to the novel homozygous frameshift mutation c.1150delC (p.Gln384ArgfsTer7) in the NECTIN4 gene. The patient presents brittle scalp hair, sparse eyebrows and eyelashes, widely spaced conical teeth and dental agenesis, as well as toenail dystrophy and mild PPK. She has minimal proximal syndactyly limited to toes 2–3, which makes the phenotype of our patient peculiar as the overt involvement of both fingers and toes is typical of EDSS1. All previously described mutations are located in the nectin-4 extracellular portion, whereas p.Gln384ArgfsTer7 occurs within the cytoplasmic domain of the protein. This mutation is predicted to affect the interaction with afadin, suggesting that impaired afadin activation is sufficient to determine EDSS1. Our case, which represents the first report of a NECTIN4 mutation with toe-only minimal syndactyly, expands the phenotypic and molecular spectrum of EDSS1.

ADAM10: Possible functions in enamel development

“…Biallelic mutations in the human NECTIN4 gene cause ectodermal dysplasia-syndactyly syndrome 1 (EDSS1). Two reports of EDSS1 had patients with associated enamel hypoplasia (Raza et al, 2015;Rotunno et al, 2021). Perhaps ADAM10 modulates NECTIN4 expression at the cell surface.…”

A novel pathogenic variant of NECTIN4 gene in a child with ectodermal dysplasia-syndactyly syndrome

“…To the best of our knowledge, the c.1117C>T variant was never described before in patients with EDSS1 and is absent in the general population genome aggregation database (gnomAD). [ 1 ] Family history of skin and genetic diseases was negative and the parents have not been tested. The patient is currently using topical treatments with emollients, urea, and other keratolytic products.…”

“…EDSS1 commonly involves hair, teeth, nails, and sweat glands with proximal cutaneous syndactyly of the fingers and/or toes. [ 1 3 6 ]…”

“…Hair morphology may also be modified with the presence of pili torti and swelling along the shafts with a great possibility of breakage. [ 1 3 6 ]…”

“…Dental abnormalities may include widely spaced teeth with peg-shaped and conical crowns, enamel defects, and hypodontia; nail dystrophy, hypoplastic nails, palmoplantar hyperkeratosis, variable sweating, and heat intolerance could also be present. [ 1 3 6 ]…”