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Dowling-Degos disease (DDD) is a rare autosomal dominant reticulate genodermatosis characterized by progressive and disfiguring flexural hyperpigmentation in adulthood. Clinically, patients present with brown to black macules arranged in a reticular pattern, most notably in axillae, groin, neck, and trunk. Histopathology shows irregular elongation of rete ridges with increased basal cell pigmentation and occasional small follicular cysts, distinguishing DDD from related disorders such as Galli-Galli disease and Darier disease.
Genetic linkage and mutation analyses in two large German pedigrees (LOD 4.42 at θ = 0.0) and six unrelated probands established KRT5 as the predominant gene for DDD. Heterozygous loss-of-function variants in KRT5 segregate with disease in extended families, consistent with haploinsufficiency ([PMID:16465624]).
Segregation data include two multigenerational families (n = ~8 affected relatives) demonstrating complete co-segregation of truncating KRT5 alleles with DDD phenotype. Individual case reports further support this association, including isolated adult-onset cases with similar histology and family history ([PMID:20332593]; [PMID:40667493]).
The variant spectrum in KRT5 for DDD is dominated by frameshift and nonsense alleles leading to premature termination. A recurrent frameshift, c.817del (p.Phe272_Val273insTer), has been reported in multiple affected individuals and likely results in nonsense-mediated decay of the mutant transcript.
Functional studies of KRT5 haploinsufficiency demonstrate disrupted keratin filament assembly, impaired melanosome transport, and altered keratinocyte adhesion, providing mechanistic concordance with the pigmentary and structural skin abnormalities observed in DDD.
Together, robust genetic segregation, multiple unrelated probands, and mechanistic functional data satisfy criteria for a Strong gene-disease association. KRT5 mutation testing has clear diagnostic utility for DDD and informs genetic counseling for this autosomal dominant pigmentary disorder.
Key Take-home: Heterozygous loss-of-function mutations in KRT5 cause autosomal dominant Dowling-Degos disease via haploinsufficiency, supporting genetic testing for accurate diagnosis and family counseling.
Gene–Disease AssociationStrong8 probands across 2 families with segregation and concordant functional data Genetic EvidenceStrong8 loss-of--function variants in unrelated probands with familial segregation under AD inheritance Functional EvidenceModerateHaploinsufficiency impairing keratin filament assembly and melanosome transport |