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Dear Editors, Dowling-Degos disease (DDD) and Galli-Galli disease (GGD) are rare autosomal dominant genodermatoses classified within reticulate pigmentary disorders.1 GGD is distinguished by the additional histopathologic finding of suprabasal nondyskeratotic acantholysis,1 and occasionally presents with erythematous papules or coalescing plaques.2 Historically, GGD has been considered a variant of DDD due to their shared diagnostic features.1, 3, 4 Both DDD and GGD are also categorized into localized forms, affecting flexural areas, and generalized forms, with widespread distribution, including non-flexural areas.5 Despite the growing number of identified causal genes, the extensive overlap in features among these conditions poses a challenge for establishing clear genotype-phenotype correlations.5 Reports of intrafamilial variability, with phenotypes ranging from generalized DDD to GGD,6 further complicate this issue. Advances in molecular diagnostics offer an opportunity to enhance our understanding of these disorders. This report describes a patient with a heterozygous keratin 5 gene (KRT5) c.T2C variant exhibiting generalized GGD, with varying phenotypes of the same variant among her siblings. The proband was a 40-year-old otherwise healthy woman with diffuse asymptomatic small hypopigmented macules on the trunk and extremities that had been present for over fifteen years. Additionally, pruritic erythematous papules had appeared on her neck, chest, and abdomen every summer for the past three years (Figure 1a). Her mother had similar skin manifestations, while her two brothers displayed numerous brown macules on the face, neck, and chest (Figure 1b). Histopathologic analysis of an abdominal erythematous papule on a hypopigmented background revealed atrophic epidermis with elongated rete ridges and suprapapillary thinning in the peripheral area. The central erythematous papular lesion exhibited acantholytic cells in the upper epidermis and mixed perivascular inflammation in the superficial dermis (Figure 2a). A diagnosis of generalized GGD was established. Whole exome sequencing of genomic DNA extracted from the blood of the proband and oral mucosa of two affected siblings revealed a germline heterozygous KRT5 variant c.T2C, which was subsequently confirmed by Sanger sequencing (Figure 2b). The c.T2C variant alters the translation initiation codon (ATG to ACG), preventing the formation of the start methionine – a molecular mechanism that has been previously recognized as pathogenic in KRT5-related disorders.4, 7 DDD and GGD have traditionally been categorized as reticulated hyperpigmentation of flexural areas. However, atypical cases now include generalized hypopigmented and hyperpigmented variants. Linking genotypes to phenotypes in these disorders is challenging due to the overlap of genotypes with multiple phenotypes and vice versa.5 Hanneken et al. demonstrated that the KRT5 c.418dupA variant was present in both localized DDD and GGD and highlighted the retrospective identification of underreported acantholysis in cases of DDD.1 This supports the concept that GGD may be a subset of DDD rather than a distinct entity. Given that KRT5 c.418dupA can cause both localized DDD and GGD, we investigated whether a single gene variant could lead to both localized and generalized forms of the disorder. Previously, KRT5 c.T2C was initially identified in patients with localized GGD exhibiting flexural reticulate hyperpigmentation,4 and it was also observed in a Chinese family with generalized DDD presenting both hyper- and hypopigmented lesions.7 Our findings contribute to the literature by showing that the phenotypic spectrum associated with KRT5 c.T2C includes generalized GGD. We also demonstrate familial phenotypic heterogenicity resulting from the same variant. Recently, variants in the protein O-glucosyltransferase 1 (POGLUT1) gene have also been implicated in GGD,8 suggesting a more complex genetic landscape. Histopathologic confirmation remains essential, especially when acantholysis is focal. Biopsies from multiple sites are recommended, as single samples may not capture the diagnostic features.9 GGD must also be differentiated from Grover disease (GD), which may show overlapping features like acantholysis and elongated rete ridges. Emerging research has identified ATP2A2 variants in some GD cases,10 whereas KRT5 variants, characteristic of GGD, have not been found in GD. Therefore, genetic testing plays a vital role in differentiating GGD from similar conditions like GD and should be integral to diagnosis. There are no standardized treatment guidelines for DDD and GGD, and most available therapies demonstrate variable efficacy. Both conditions may benefit from minimizing friction and sun exposure. Topical agents typically offer limited effectiveness. In GGD, vitamin A derivatives and Er:YAG laser have shown some potential as treatment options.8 In DDD, treatment with Er:YAG laser and a combination of Q-switched Nd:YAG and fractional CO2 lasers has led to improvements in pigmentation.5 However, no existing therapies address the underlying genetic causes. In conclusion, the KRT5 c.T2C variant can manifest in various phenotypes, including generalized hyper- and hypopigmented lesions, reticulate hyperpigmentation confined to flexural areas, and erythematous papules. These findings reinforce the notion that DDD and GGD exist along a disease spectrum influenced by shared molecular pathways. Improved understanding of the genetic basis and broader phenotypic presentations will aid in refining diagnostic criteria, promoting early detection, and guiding future therapeutic strategies. We thank the Genomic Medicine Core Laboratory at Chang Gung Memorial Hospital, Linkou, and the Genomics and Proteomics Core Laboratory at the Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, for their technical assistance, next-generation sequencing, bioinformatics analyses, and ongoing support. None.