Scrotal Dowling–Degos disease caused by a novel frameshift variant in gamma‐secretase subunit presenile enhancer gene

Abstract

We reported a Chinese pedigree with scrotal Dowling-Degos disease and evaluated the phenotypic and genotypic characteristics. In affected cases, pigmented macules were identified on the scrotum. The rashes increased, and the colour deepened progressively. No pain or pruritus were noticed, and no other skin folds were involved. Skin histopathology showed characteristic features of Dowling-Degos disease. A heterozygous PSENEN frameshift variant c.292delC(p.L98Wfs*47) was identified in affected cases. The variant was not found in dbSNP, 1000 Genomes project database and the ExAC Browser. The p.L98 and adjacent amino acids are highly conserved among species. Our cases expand the phenotypic and genotypic spectrum of PSENEN-related Dowling-Degos disease.

The Genomic Architecture of Hidradenitis Suppurativa—A Systematic Review

“…A distinctive subtype of Dowling-Degos with HS (HS-DDD) is defined by heterozygous variants in PSENEN (OMIM # 613736) on 19q13. Patients having underlying PSENEN variants but suffering from DDD exclusively have been described ( Ralser et al, 2017 ; Ren and Zeng, 2020 ). Interestingly, only obese family members harboring the pathogenic PSENEN c.62-1G > C splice variant manifested HS + DDD, whilst their lean, non-smoking relative who also harbored the same mutation manifested DDD exclusively ( Ralser et al, 2017 ).…”

“…Non-smoking, lean patients from another family having PSENEN 84_85insT variant manifested DDD without HS ( Ralser et al, 2017 ). On the other hand, the c.216delC PSENEN variant was described in non-smoking, lean patients from two separate families manifesting DDD exclusively but also in an unrelated patient with DDD-HS, whose smoking history and weight were not documented ( Ralser et al, 2017 ; Ren and Zeng, 2020 ; Theut Riis et al, 2020 ). This suggests that in the context of HS, PSENEN pathogenic variants exhibit incomplete penetrance and variable expressivity, and possibly only manifest disease in the setting of specific triggers such as obesity.…”

A loss‐of‐function NCSTN mutation associated with familial Dowling Degos disease and hidradenitis suppurativa

“…24 There was also no sign of DDD in these patients, a progressive disease that is acquired over the years . 1 In order to evaluate the impact of this SNV, ORS cells were isolated from plucked hairs of subjects II-3 (healthy control), III-2, III-5 and IV-2 (cases). A significant decrease in both NCSTN mRNA and protein level was observed by qPCR and western-blot assays in subjects carrying the heterozygous premature stop codon when compared with the unmutated individual (Figure 3).…”

“…Dowling-Degos disease (DDD) (ORPHA:79145) is a rare autosomal dominant genodermatosis characterized by slowly progressive reticulated pigmented lesions in flexural skin areas. 1 The first gene associated with DDD was KRT5. 2 Mutations in the head region of keratin 5 (KRT5) protein are found in ~1/3 of DDD patients, usually presenting an acantholytic variant named Galli-Galli Disease (GGD).…”

Dowling‐Degos disease: a review

“…Both POGLUT1 and POFUT1 play a critical role in Notch signaling, which is essential in regulating melanocyte and keratinocyte proliferation and differentiation 10,11 . Finally, PSENEN gene mutations, which also affect the Notch signaling pathway by modifying an enhancer gene that encodes a component of γ‐secretase protein complex, have recently been identified in a DDD variant associated with hidradenitis suppurativa and with DDD localized to the scrotum 14 …”