Epidermolysis bullosa simplex with mottled pigmentation (EBS-MP) or with migratory circinate erythema (EBS-MCE) are rare clinical subtypes, typically associated with KRT5 pathogenic variants. A clinical and molecular analysis was conducted on 49 patients from 21 unrelated families in Argentina with suspected EBS-MP or EBS-MCE. Forty-eight individuals carried KRT5 variants, with the most frequent being c.1649del, found in 44 patients from 16 families. All affected individuals inherited the variant from one parent, and shared ancestry was traced to a restricted region in northeastern Argentina. Clinical data showed early-onset blistering, followed by generalized mottled pigmentation, and progressive nail dystrophy. Migratory erythema was observed in 18 patients, resolving by age 4 in most cases. Strikingly, 3 families showed intra--familial phenotypic variability: some individuals developed only MP, while others exhibited early MCE that later evolved into MP. This suggests a dynamic phenotypic spectrum potentially influenced by modifier factors. Additionally, a novel pathogenic variant in KRT14 and a large KRT5 exon 8 deletion were identified. This study represents the first report on the molecular epidemiology of EBS-MP in a South American population with an uncharacterized genetic background, contributing novel insights into genotype-phenotype correlations and natural history of EBS-MP and EBS-MCE.

Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin (and mucosal epithelia in some instances) that results in non-scarring blisters and erosions caused by minor mechanical trauma. EBS is distinguished from other types of epidermolysis bullosa (EB) or non-EB skin fragility syndromes by the location of the blistering in relation to the dermal-epidermal junction. In EBS, blistering occurs within basal keratinocytes. The severity of blistering ranges from limited to hands and feet to widespread involvement. Additional features can include hyperkeratosis of the palms and soles (keratoderma), nail dystrophy, milia, and hyper- and/or hypopigmentation. Rare EBS subtypes have been associated with additional clinical features including pyloric atresia, muscular dystrophy, cardiomyopathy, and/or nephropathy. The diagnosis of EBS is established in a proband by: the identification of a heterozygous dominant-negative variant or biallelic loss-of-function variants in KRT5, KRT14, or PLEC; a heterozygous pathogenic variant in KLHL24; or biallelic pathogenic variants in CD151, DST, or EXPH5; and/or presence of characteristic findings on examination of a skin biopsy using transmission electron microscopy and/or immunofluorescent mapping. Treatment of manifestations: Supportive care to protect the skin from blistering; use of dressings that will protect the skin and promote healing of wounds. Encourage activities that minimize trauma to the skin; appropriate footwear and physical therapy to preserve ambulation; lance and drain without unroofing new blisters. Dressings consist of three layers: a primary nonadherent contact layer; a secondary layer that provides stability, adds padding, and absorbs drainage; and a tertiary layer with elastic properties. Aluminum chloride (20%) applied to palms and soles can reduce sweating and therefore minimize blister formation in some individuals with EBS. In addition, botulinum toxin, cyproheptadine (Periactin®), tetracycline, erythromycin, diacerein, sirolimus, apremilast, cannabidiol oil, and gentamicin have all been reported to be beneficial. Keratolytic agents for palmar and plantar hyperkeratosis may reduce skin thickening and cracking. Topical and/or systemic antibiotics or silver-impregnated dressings or gels can be used to treat skin infection or reduce bacteria colonization, thereby promoting wound healing. Identification and management of specific causes of pain and itching; management with a pain specialist as needed. Management of fluid and electrolyte imbalance in severely affected infants may be critical during the postnatal period. Nutritional support including vitamin and mineral supplementation, feeding via gastrostomy tube, guided feeding therapy, and Haberman feeder may be necessary for infants and children with oral manifestations of EBS. Iron supplementation for those with anemia as a result of chronic inflammation from blistering and wounding. Weight management and treatment of obesity in older individuals. Standard treatment for basal cell carcinomas in individuals with severe EBS. Psychosocial support when needed. Standard treatments for additional features reported in rare subtypes including pyloric atresia, muscular dystrophy, cardiomyopathy, and nephropathy. Surveillance: Dermatologic assessment for blisters, oral disease, hyperkeratosis, hyperhidrosis, signs and symptoms of wound infection, as well as pruritus and pain. At each visit, assessment of hydration status, growth, nutrition, weight, motor development and mobility, and psychosocial well-being. Consider serum B-type natriuretic peptide (BNP) and creatinine kinase in those with EBS, intermediate with cardiomyopathy; serum renal function studies and urinalysis for those with nephropathy; and neurologic assessment for those with muscular dystrophy as needed. Agents/circumstances to avoid: Excessive heat exposure may exacerbate blistering and infection. Avoid poorly fitting or coarse-textured clothing/footwear and activities that traumatize the skin. Avoid adhesives from regular medical tapes or Band-Aids®. EBS is typically inherited in an autosomal recessive or an autosomal dominant manner. Autosomal recessive EBS is associated with either biallelic loss-of-function variants in KRT5, KRT14, or PLEC or biallelic pathogenic variants in CD151, DST, or EXPH5. Autosomal dominant EBS is associated with either a heterozygous dominant-negative variant in KRT5, KRT14, or PLEC or a heterozygous pathogenic variant in KLHL24. In rare instances, EBS is caused by the presence of heterozygous pathogenic variants in both KRT5 and KRT14 and is inherited in a digenic manner. Autosomal recessive EBS. If both parents are known to be heterozygous for an EBS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Autosomal dominant EBS. In families with autosomal dominant inheritance, each child of an affected individual has a 50% chance of inheriting the pathogenic variant and (most likely) being affected with EBS (penetrance appears to be <100% for known heterozygous dominant-negative KRT5 and KRT14 variants). Once the EBS-related pathogenic variant(s) have been identified in an affected family member, molecular genetic testing for at-risk family members and prenatal and preimplantation genetic testing are possible.