A phenotype combining hidradenitis suppurativa with Dowling-Degos disease caused by a founder mutation in PSENEN

Abstract

Dowling-Degos disease, featuring reticulate pigmentation, and familial hidradenitis suppurativa share many clinical features including autosomal dominant inheritance, flexural location and follicular defects. The co-existence of the two disorders was recently found to result from mutations in PSENEN, encoding protein presenilin enhancer gamma-secretase subunit. Here we report 4 additional families of Jewish Ashkenazi origin who presented with clinical features characteristic of both disorders. All patients were found to carry the same, heterozygous mutation in PSENEN (c.168T>G, p.Y56X). Haplotype analysis revealed that the mutation originated from a common ancestor. Dowling-Degos disease- as well as hidradenitis suppurativa-associated genes have been shown to encode important regulators of Notch signaling. Accordingly, using a reporter assay, we demonstrated decreased Notch activity in patient's keratinocytes. The present data confirm the genetic basis of the combined Dowling-Degos disease-hidradenitis suppurativa phenotype and suggest that Notch signaling may play a central role in the pathogenesis of this rare condition.

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