Dear Editor, Epidermolysis bullosa (EB) is a group of inherited mechanobullous disorders characterized by skin fragility and blister formation following minimal trauma. EB is classified into four primary subtypes based on the level of skin cleavage: Simplex (EBS), junctional (JEB), dystrophic (DEB), and kindler syndrome (KS). 1 In EBS, mutations occur in genes-encoding keratins 5 or 14, or plectin, whereas JEB is caused by the mutations in hemidesmosomal proteins such as laminin 332, type XVII collagen, or the α6- and β4-integrins. 1 The cleavage plane in EBS is within basal keratinocytes, while in JEB, it occurs along the lamina lucida of the basement membrane. DEB results from the mutations in the collagen VII gene, and KS is associated with autosomal recessive mutations in the kindlin gene. 1 Histopathologically, KS is distinguished by multiple cleavage planes within a single skin specimen. 1 Here, we report a distinctive clinical case of EB caused by a mutation in the LAMB3 gene. A 15-year-old male of Chinese ethnicity, born to nonconsanguineous parents as the first of two children, presented with recurrent skin blistering triggered by minor trauma beginning in the 1st week of life. The lesions spared the oral mucosa, nails, and palmoplantar surfaces, healing without milia or scarring (atrophic or hypertrophic). No systemic involvement was evident. The skin biopsy revealed diminished laminin-332 (laminin-5) and BP180. Subsequent whole exome sequencing uncovered compound heterozygous variants in LAMB3 gene: NM₀01127641. 1: c. 1978C>T (p. Arg660Ter) and NM₀01127641. 1: c. 28 + 5G>A. This finding is consistent with autosomal recessive JEB due to LAMB3 mutation. The patient exhibited significant skin fragility during childhood; however, by the age of 12 years, the fragility resolved despite ongoing participation in high-intensity sports and training, with no further blister formation Figure 1. His current primary concern is dental health, due to amelogenesis imperfecta, a known feature of JEB, which necessitated dental crowns. Figure 1: (a-d) Skin lesions without blister formation, healed with hyperpigmentationAt birth, differential diagnoses such as EBS and bullous dermolysis of the newborn were considered in light of neonatal blistering. Nevertheless, clinical evolution, biopsy/immunostaining showing diminished laminin-332 (laminin-5) and BP180, and subsequent molecular analysis supported a diagnosis of JEB. Similar clinical courses have been described previously. Kiritsi et al. reported a comparable case of a 16-year-old German female with JEB due to a LAMB3 splice site mutation, c. 1288 + 1G>T, differing from the c. 1978C>T mutation identified in our patient. 2 Functional RNA analysis and immunoblotting in their cohort demonstrated production of shortened, yet functional laminin β3 polypeptides, preserving heterotrimerization, secretion, and basement membrane assembly of laminin-332. This mechanism likely underpins the observed mild phenotype. 2 Such detailed functional studies were not feasible for our patient due to resource limitations. An alternative explanation for this phenotype is revertant mosaicism (RM), a somatic genetic correction mechanism that results in a mixture of normal and mutant cells, thereby improving skin integrity and function. 3, 4 RM can arise through various genetic events, including back mutation, intragenic crossover, mitotic gene conversion, or secondary mutations. 4 Mitotic gene conversion has been implicated in some EB cases, as described by Jonkman et al. , while Pasmooij et al. documented multiple RM mechanisms across the individuals. 5, 6 This genetic mosaicism presents potential therapeutic avenues, such as exploiting naturally corrected cells for regenerative treatment approaches. 7 Advancements in understanding the genetic basis and mosaicism mechanisms in EB are critical for developing improved management strategies across EB subtypes, including JEB. 8 Beyond that, artificial intelligence (AI) is prevalent among JEB patients, including the patient in our report. Data published in 2020 indicate that all individuals with JEB, irrespective of severity, are diagnosed with AI. 9 Furthermore, both parents presenting with isolated AI were found to carry a laminin-332 gene mutation, supporting the diagnosis among JEB patients. 10 The phenomenon of spontaneous remission of skin fragility in certain EB patients warrants further investigation. Continued genetic and molecular research in this area may elucidate underlying mechanisms and support the development of future gene-or cell-based therapy inspired by RM mechanisms, particularly for JEB. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his/her consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Ghani et al. (Mon,) studied this question.