SG08 Pathogenic variants in the PSENEN and NCSTN genes cause ‘follicular’ Dowling–Degos disease: report of five unrelated Indian families

Abstract

Follicular Dowling–Degos disease (DDD) is a rare clinically and histologically distinct genodermatosis. Not much is known about its genetic basis. We aimed to describe the clinical and histological features and the mutational spectrum of follicular DDD. This ­single-centre observational study included patients with follicular DDD who visited the All India Institute of Medical Sciences, New Delhi, India. Clinical and histological features were recorded. Whole-exome sequencing on venous blood of probands and their family members was done, and the results validated by Sanger sequencing. We saw 10 Indian patients (7 male and 3 female) from 5 unrelated families, products of nonconsanguineous marriage, with pedigree charts suggestive of autosomal dominant inheritance in four families. All patients presented with open comedones, small follicular keratotic papules, and fine pitted and shallow crateriform scars predominantly on the face, back and flexural sites. In addition, five patients from three families had brownish hyperpigmented macules on the flexures, typical of classical DDD, while one patient had discrete hypopigmented macules on the back and lower limbs. None of the patients or family members has developed hidradenitis suppurativa (HS) to date, with a follow-up duration of 4–6 years. Skin biopsy showed follicular plugs along with downward elongation and branching of pigmented rete ridges confined to the follicular infundibulum. Whole-exome sequencing revealed three distinct variants in the PSENEN gene, one novel (c.65G>A, p.Gly22Glu, likely pathogenic) and two previously reported (c.194T>G, p.Leu65Arg, pathogenic and c.62–1delG, pathogenic). Another two novel variants were identified in the NCSTN gene (c.1493T>C, p.Leu498Pro, likely pathogenic and c.1060_61insTGCAGTTA, p.Val354fs, pathogenic). Our study identifies PSENEN and NCSTN gene mutations as the genetic basis of follicular DDD. PSENEN and NCSTN gene mutations, earlier reported in patients with HS as well as those with DDD–HS overlap, may potentially explain the predominantly folliculocentric phenotype of follicular DDD.