Beneath the surface: delineating the subtypes of Dowling-Degos disease

Dowling-Degos disease (DDD) is a rare, genetically heterogeneous pigmentation disorder with an autosomal dominant pattern of inheritance. While DDD shows wide clinical variability, a defining feature is reticulate hyperpigmentation, which typically emerges after puberty and worsens progressively thereafter. Additionally, affected individuals may experience symptoms such as itching, burning and/or inflammatory changes to the skin. DDD also shows histopathological diversity. However, hallmark features include thinning of the suprapapillary epidermis and elongation of the rete ridges with melanin deposition in the basal layers. While early researchers assumed that DDD was attributable to a single disease gene, and predominantly affected the flexural areas, over the last 20 years understanding of DDD has expanded substantially. To date, five causal genes have been identified: KRT5, POFUT1, POGLUT1, PSENEN and GLMN. Each gene is associated with frequently recurring phenotypic characteristics. In terms of hyperpigmentation, pathogenic variants in KRT5, POFUT1 and POGLUT1 primarily affect intertriginous regions, acrogenital areas and the extremities, respectively. Pathogenic PSENEN variants increase susceptibility to hidradenitis suppurativa, particularly in predisposed individuals, while GLMN variants may be associated with a distinctive clinical feature, namely glomuvenous malformations. Despite advances in our understanding of the genetic architecture of DDD, no causal treatment is yet available. While symptomatic therapies such as ablative laser treatment have shown promise in terms of reducing pigmentation, potential risks have also been identified, including postinflammatory hyperpigmentation. This review outlines the path that led to current understanding of the complex genetic basis of DDD. On the basis of this, we propose an approach for clinical subphenotyping in patients with suspected DDD, which will facilitate targeted genetic analysis based on observed genotype-phenotype correlations. Furthermore, the review addresses key issues of DDD, including the debated term 'Galli-Galli disease', the psychosocial impact and treatment of DDD, as well as emerging insights into Notch signalling as a pathogenic mechanism.