RHBDF2 – Palmoplantar Keratoderma–Esophageal Carcinoma Syndrome

Tylosis with esophageal cancer (TOC) is an autosomal‐dominant disorder characterized by palmoplantar keratoderma and high risk of esophageal carcinoma. Four unrelated probands from UK, US, Germany and Finland harbor heterozygous missense variants in RHBDF2 clustering in the N‐terminal cytoplasmic domain, establishing RHBDF2 as the causative gene for palmoplantar keratoderma–esophageal carcinoma syndrome ([PMID:22638770]).

Genetic evidence includes four distinct missense variants—c.475G>A (p.Asp159Asn)—segregating with disease in four families with at least two additional affected relatives in the Finnish kindred ([PMID:22638770]). All variants are absent from population databases and co‐segregate with disease in multiple generations, consistent with autosomal‐dominant inheritance and a gain‐of‐function mechanism.

The variant spectrum is restricted to missense changes within a narrow N‐terminal region; no loss‐of‐function alleles have been reported. Recurrent sites include codons Ile186, Asp188 and Pro189 in independent families, suggesting a mutational hotspot specific to TOC ([PMID:22638770]).

Functional assays in patient keratinocytes and transfected cell lines demonstrate that TOC‐associated iRhom2 mutants increase ADAM17 maturation and activity, leading to elevated shedding of EGF‐family ligands and hyperactivation of EGFR signaling. These alterations correlate with aberrant desmosome processing, epidermal hyperkeratosis, and enhanced resistance to bacterial infection, recapitulating human epidermal pathology ([PMID:24643277]).

Mouse models corroborate these findings: cub (N‐terminal deletion) and toc (knock‐in TOC mutation) alleles of Rhbdf2 augment amphiregulin secretion via ADAM17, driving epidermal hyperplasia and accelerated wound healing without spontaneous tumorigenesis. Genetic ablation of Areg normalizes skin architecture in toc mice, confirming AREG as the key mediator of the GOF phenotype ([PMID:24825892], [PMID:28655741]).

Integration of genetic and functional data supports a Strong ClinGen classification for the RHBDF2–TOC association, with definitive diagnostic utility and implications for targeted therapy via modulation of EGFR or AREG pathways.

References

• Familial cancer • 2012 • Analysis of a Finnish family confirms RHBDF2 mutations as the underlying factor in tylosis with esophageal cancer. PMID:22638770
• Human molecular genetics • 2014 • iRHOM2-dependent regulation of ADAM17 in cutaneous disease and epidermal barrier function. PMID:24643277
• Proceedings of the National Academy of Sciences of the United States of America • 2014 • Rhbdf2 mutations increase its protein stability and drive EGFR hyperactivation through enhanced secretion of amphiregulin. PMID:24825892
• Biology open • 2017 • Genetic deletion of amphiregulin restores the normal skin phenotype in a mouse model of the human skin disease tylosis. PMID:28655741

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