Diffuse reticulated skin hyperpigmentation in dystrophic Epidermolysis bullosa.

Dear Editors, A 20-year-old male presented to our clinic with widespread, deep brown patches on his limbs and buttocks. These lesions first appeared as red patches on the extensor surfaces of his elbows when he was one month old. Over time, the patches enlarged and thickened, worsening during summer and occasionally developing blisters after friction. Previous treatments, including topical tretinoin ointment and herbal baths, were ineffective. The patient had no significant medical history, but there was a family history of similar skin conditions in his mother and grandmother. On examination, patchy deep brown keratotic lesions were noted on the extremities, buttocks, and both ears (Figures a, b). A tense blister with the size of 1 cm was observed on the extensor aspect of the left knee joint (Figure c). Genetic testing of peripheral blood identified a probably pathogenic mutation in the COL7A1 gene (c. 5964₅965delCCinsA) in both the patient and his mother (Figure d). This indel mutation causes a frameshift within codon for Pro1990, leading to the incorporation of incorrect amino acids and introducing a premature stop codon 15 amino acids downstream (p. Pro1990Glnfs*15). The mutation has not been reported before, and the finding confirmed a diagnosis of dystrophic epidermolysis bullosa (DEB). Epidermolysis Bullosa (EB) is a rare genodermatosis with heterogeneous manifestations. The most common clinical presentation of EB is mechanical fragility of epithelial tissues following minimal trauma, resulting in blister formation. Dystrophic EB (DEB) is the second most common form of EB, representing approximately 30% of all cases. The estimated disease prevalence of DEB is approximately 6–8 per million births. 1 Dystrophic EB is caused by mutations in the COL7A1 gene. This disease can be inherited in either an autosomal-dominant or autosomal-recessive manner. The COL7A1 gene encodes type VII collagen, a critical component of anchoring fibrils that secure the epidermis to the dermis. Type VII collagen is a homotrimer comprised of three proα1 (VII) chains, containing a central collagenous triple-helical domain flanked by non-collagenous domains. The ultrastructural hallmark of DEB is skin cleavage below the lamina densa, which can be visualized by transmission electron microscopy. 2 Dominant dystrophic EB (DDEB) typically results from heterozygous glycine substitution mutations within the collagenous domain, producing a dominant negative effect on collagen assembly. In DDEB, approximately 1/8 of type VII collagen trimers are normal, while 7/8 are disrupted by the abnormal protein, explaining the dominant inheritance pattern despite the presence of one normal allele. 3 Most COL7A1 mutations are family-specific. Recurrent glycine substitution mutations, such as G2043R and G2055A variants, have been identified across different populations with DDEB. 4, 5 Some recurrent mutations show geographical patterns. For instance, in recessive DEB, R578X and R2814X are common in British populations, whereas 5818delC and E2857X are frequently found in Japanese cohorts. 6 Clinical manifestations of DDEB are generally less severe than recessive forms. Major clinical subtypes of DEB include localized, intermediate pruriginosa and self-improving types. DDEB typically presents with blistering limited to trauma-prone areas, resulting in scarring, milia formation, and nail dystrophy. 7 Mucosal and teeth involvement is relatively uncommon. The blistering usually begins at birth or shortly thereafter, though disease activity often diminishes with age. Skin pigmentation changes in EB have received limited attention. Kindler epidermolysis bullosa and EB simplex with mottled pigmentation (EBS-MP) are two subtypes characterized by prominent pigmentary alterations. Kindler epidermolysis bullosa typically presents with progressive poikiloderma, especially on the hands and neck. EBS-MP is marked by mottled or reticulate macular hyperpigmentation and hypopigmentation on the neck, trunk, and extremities. 1 Skin pigmentation changes have rarely been reported in DEB. In our patient, skin hyperpigmentation was the primary clinical manifestation, presenting as diffuse brown patches on the limbs. These lesions were predominantly distributed around the joints. Blisters occur occasionally and not always prior to skin hyperpigmentation. The exact pathogenesis of this phenotype is unknown. Diagnosis requires clinical evaluation, skin biopsy, immunofluorescence staining, and transmission electron microscopy when feasible. 8 Analysis of the COL7A1 gene using Sanger sequencing or next-generation sequencing provides insight into the molecular pathogenesis. Treatment remains primarily supportive, focusing on wound care, blister prevention, and management of complications. 9 Non-adherent dressings, pain management, and prevention of secondary infections constitute the cornerstone of management. Emerging therapeutic strategies include allogeneic fibroblast injections, recombinant protein therapy, gene-based approaches, and mesenchymal stem cells cell therapy. 10 Progress in understanding the molecular pathogenesis of DDEB, together with international collaborative registries, may accelerate research and provide new therapies for this challenging genodermatosis. None. National High Level Hospital Clinical Research Funding 2022-PUMCH-A-161. Peking Union Medical College Hospital· Public Welfare Project for Rare Disease Service Improvement. The Fundamental Research Funds for the Central Universities 3332024006.