Dear Editors, Dowling-Degos disease (DDD) (OMIM # 615327) is a benign genodermatosis classified as a reticular pigmented dermatosis. 1 Lesions typically appear in adulthood between the second and fifth decades, on intertriginous regions, acral areas, genital areas, and the extremities, presenting as symmetric and progressive macular reticular hyperpigmentation with reddish-brown papules and plaques. 1, 2 The pathogenesis is linked to variants in specific genes, including Protein O-fucosyltransferase 1-POFUT1 (OMIM* 607491). 1 Here, we report a novel likely pathogenic variant in the POFUT1 gene identified in a family with DDD, supported by clinical, histopathological, and genetic findings. A 51-year-old healthy Turkish woman presented with asymptomatic bilateral pigmented lesions in the axillary and inguinal regions, which had developed since her twenties. Dermatological examination revealed reticular hyperpigmented macules and patches on her face, neck, axillae, inframammary folds, inguinal and genital regions, arms, dorsal hands, and pits on bilateral palms (Figure 1a–c). Seborrheic keratosis (SK) appeared on her neck and shoulder in her forties. Histopathological analysis of a hyperpigmented lesion showed elongation of the rete ridges, focal increased pigmentation at the tips of the rete. Based on the clinical and histopathological findings, a diagnosis of DDD was considered. With informed consent, genomic DNA was extracted from her peripheral blood. Whole exome sequencing (Qiagen, Germany), identified a novel heterozygous likely pathogenic POFUT1 variant, NM₀15352. 2 (POFUT1): c. 1047dup (p. Phe350LeufsTer34), (PVS1, PM2) in exon 7 that causes a frameshift, leading to a truncated and likely nonfunctional POFUT1 protein, which is related to DDD. The index patient's mother, an 81-year-old woman, developed similar reticular hyperpigmented lesions on her neck, axillae, inframammary folds, inguinal and genital regions, arms, dorsum of the feet consistent with DDD since her twenties and multiple SKs later on her forties (Figure 1d–f). The index patient's 24-year-old son did not have any lesions. With informed consent, genetic testing was conducted for the index patient's father, mother, brother, and son. Sanger sequencing was performed to confirm the presence of the variant in the patient and to assess its segregation among available family members, her son and her mother were heterozygous for NM₀15352. 2 (POFUT1): c. 1047dup variant (Figure 2b). Similar lesions were reported in eleven relatives; however, no material was available for genetic testing or segregation analysis (Figure 2a). At the 1-year follow-up of the index case, newly developed hyperpigmented lesions were noted in the perianal region. In addition, both the patient and her mother showed an increase and further darkening of hyperpigmented lesions. The genetic causes of DDD involve variants in multiple genes. Five casual pathogenic variants in keratin 5 (KRT5), POGLUT1, POFUT1, PSENEN, and GLMN have been identified in association with the disease. 1-4 In 2013, Li et al. discovered variants in the POFUT1 gene in patients with DDD. 1, 3 Functional analysis indicates that POFUT1 plays a role in melanin synthesis, transport and regulation of keratinocyte proliferation and differentiation. 1, 3 The novel heterozygous NM₀15352. 2 (POFUT1): c. 1047dup variant identified in our patients has not been previously reported in major genetic databases (NCBI, dbSNP, HGMD, ClinVar). Based on ACMG/AMP 2015 guidelines and available data, it has been classified as likely pathogenic, supported by PVS1 (predicted loss-of-function through a frameshift in a gene where haploinsufficiency is a known disease mechanism) and PM2 (absence from large population databases). 5 This frameshift variant introduces a premature stop codon, truncating the protein and disrupting its function. Its occurrence in multiple affected family members further supports its pathogenic role. Literature indicates a range of clinical findings in DDD patients linked to various gene variants. 1, 3, 4 A recent review by Kumar et al4 expanded the clinical spectrum of DDD, highlighting at least five distinct subphenotypes associated with specific genetic variants. Of particular relevance, POFUT1-associated DDD (subphenotype II) is characterized by acral and genital hyperpigmentation in addition to classical flexural involvement. In line with this evolving definition, index patient and her mother exhibited genital involvement, further supporting the concept that DDD extends beyond flexural sites. However, her son had no lesions associated with DDD, suggesting variability in the onset of clinical manifestations within the same family despite identical variants. In literature POFUT1 variants in DDD are also reported to be linked to distinct clinical manifestations, including multiple SKs, and psoriasis. 1, 6 Our patients had multiple SKs. A reported case with a deletion in the POFUT1 gene showed DDD lesions appearing in the fifth decade, multiple SKs appearing in childhood. 6 In our cases, DDD lesions appeared in the third decade followed by SKs in the fifth with a duplication in the POFUT1 gene. The identification of the novel pathogenic variant NM₀15352. 2: c. 1047dup (p. Phe350LeufsTer34) expands current knowledge of POFUT1-related pathogenic variants. Further reports may be helpful in elucidating the relationship between genotype and phenotype in DDD. None.
Solak et al. (Thu,) studied this question.