Novel nicastrin mutation in hidradenitis suppurativa–Dowling–Degos disease clinical phenotype: more than just clinical overlap?

Abstract

DEAR EDITOR, In familial hidradenitis suppurativa (HS), mutations in the genes encoding three subunits of the gamma secretase complex, presenilin-1 (PSEN1), presenilin enhancer (PSENEN) and nicastrin (NCSTN), have pointed to impaired Notch signalling as a pathogenic disease mechanism. 1 Dowling-Degos disease (DDD; MIM 179850, 615327 and 615696), a rare reticulated pigmentary disorder, has also been

Pleiotropic Role of Notch Signaling in Human Skin Diseases

“…Therefore, co-manifestations of DDD and HS were reported for these patients that develop reticulate pigmentation, comedones, follicular hyperkeratosis, nodules and scars [ 105 ]. In our recent study, we also described a patient with familial HS and concomitant DDD harboring a novel nonsense mutation in NCSTN gene associated with a reduced quantity of subunits of γ-secretase [ 106 ].…”

Comorbid acne inversa and Dowling–Degos disease due to a single NCSTN mutation: is there enough evidence? Reply from the authors

“…The science and rationale of arriving at the correct drug and dosimetry of griseofulvin, fluconazole, terbinafine and itraconazole in superficial dermatophyte infections: an important step before a pragmatic trial DEAR EDITOR, While India faces the issue of recalcitrant dermatophytosis, 1 we would like to focus on the scientific rationale of drug dosimetry based on background microbiological data and existential serum/skin-level data that should pre-date a clinical trial (Figure 1). 2 The first step is based on the minimum inhibitory concentration (MIC) data derived from antifungal susceptibility testing (AFST). 1 The data from studies in India performing…”

“…DEAR EDITOR, We thank Hermasch et al for their comments 1 on our paper describing the novel nicastrin R583* mutation associated with familial acne inversa (FAI) in an Italian family, where the proband was also clinically diagnosed with Dowling-Degos disease (DDD). 2 In our report, we drew attention to this particular patient subset with comorbid FAI and DDD, emphasizing the connection between autoinflammatory-keratinization disorders and genetic reticulated pigmentary disorders. Based on our findings, we think that there is enough evidence to claim that the R583* nicastrin mutation is associated with DDD and FAI.…”

Comorbid acne inversa and Dowling–Degos disease due to a single NCSTN mutation: is there enough evidence?

“…DEAR EDITOR, In their recent publication in the BJD, Garcovich et al suggested that a nonsense mutation in the nicastrin gene (NCSTN), NP_056146Á1; p.R583*, would underlie comorbid familial acne inversa (FAI; synonymous with familial hidradenitis suppurativa) and Dowling-Degos disease (DDD) in a 54-year-old patient. 1 NCSTN codes for the homonymous protein in the c-secretase endoprotease complex that consists of three further transmembrane protein subunits: presenilin-1/2 (PSEN1/PSEN2), Presenilin-enhancer-2 (PEN-2), and anterior pharynx-defective 1a/b (APH-1a/APH-1b). 2 Mutations in NCSTN underlie autosomal dominant FAI, a chronically relapsing inflammatory disorder affecting the hair follicle and sebaceous and sweat glands.…”

“…Secondly, Garcovich et al also detected two missense variations in KRT5. 1 As they did not provide a mutation designation, an evaluation of their frequency and putative pathogenicity was not possible. In this context, we also wonder whether a single database can suffice to claim with certainty that the variation is 'benign'.…”