Epidermolysis bullosa (EB) is a genetically heterogeneous skin fragility disorder. Some subtypes also involve other organs, including the pulmonary, gastrointestinal, and renal systems. One severe form, junctional epidermolysis bullosa (JEB), is characterized by cleavage within the skin layers. The rarest and most lethal spectrum of this disorder includes pyloric atresia (PA), known as JEB-PA. The number of reported cases in Thailand is limited. Using trio whole exome sequencing, we identified a Thai newborn with lethal JEB-PA caused by novel null compound heterozygous variants in ITGB4. The patient carries a known nonsense variant (c.2533C>T) and a novel frameshift indel variant (c.1614delT) in ITGB4, inherited from her parents. Both are null variants that result in a premature termination codon (PTC). A comprehensive review of existing literature was conducted to gather information on disease-causing variants and genotype-phenotype correlations in JEB-PA. We summarized 50 previously reported JEB-PA cases, detailing disease severity and ITGB4 variants. We found that nonsense and frameshift indels were predominant in lethal cases (32/62 alleles), whereas missense variants were more common in nonlethal forms (18/38 alleles). Pathogenic variants were most frequently located in the Fibronectin II-like domain (FnIII) and cytoplasmic domain (CP) for null variants and in the von Willebrand factor Type A (VWFA) domain for missense variants. We emphasize the importance of genetic testing in these heterogeneous skin disorders. Molecular results reveal the disorder's diagnosis, provide a precise prognosis, and guide the genetic counseling process for the family. Moreover, understanding pathomolecular mechanisms can lead to potential future treatments.

Epidermolysis bullosa with associated pyloric atresia (EB-PA) is a rare subtype of epidermolysis bullosa with a high mortality characterized by skin fragility, pyloric atresia, as well as renal and ureteral abnormalities. We present a unique case of EB-PA in a newborn male further complicated by esophageal atresia and nephrotic syndrome. We review the previously reported nine cases of EB-PA with esophageal atresia. However, to our knowledge, this case represents a previously unreported phenotype of EB-PA with esophageal atresia and nephrotic syndrome.

We report a case of junctional epidermolysis bullosa with pyloric atresia (JEB-PA) with minimal skin involvement but severe protein-losing enteropathy and airway involvement. Genetic analysis revealed heterozygous mutations in the ITGB4 gene encoding integrin β4 protein. Parental testing confirmed inheritance of frameshift variant (c.794dupC) as maternal and splice site variant (c.1608C>T/p.Cys536Cys) as paternal. Immunofluorescence mapping of her skin revealed a subepidermal blister with decreased and frayed integrin β4 at both the floor and the roof of the blister, while the intestinal mucosa showed complete absence of integrin β4. We review the literature and discuss the differential expression of integrins in the skin and gastrointestinal tract, as well as the role of chronic inflammation in the pathogenesis of EB.

The association of junctional epidermolysis bullosa with pyloric atresia (JEB-PA) and aplasia cutis congenita (ACC) was described by El Shafie et al. (J Pediatr Surg 14(4):446-449, 1979) and Carmi et al. (Am J Med Genet 11:319-328, 1982). Most patients die in the first weeks of life, and no curative treatment options are available so far. We describe a patient with JEB-PA and ACC (OMIM # 226730) who was treated for extensive areas of ACC by Integra®-Dermal Regeneration Template and split-thickness skin grafting (STSG). Clinically, the dermal template changed into well-vascularized neodermis, and after STSG, full take of the transplants was detected. No infections of the huge ACC areas were seen. Further studies must validate this treatment option in severe and acute cases of JEB-PA with ACC. Based on clinical findings, we postulate that placement of Integra®-Dermal Regeneration Template with STSG could be a new treatment option for patients having JEB-PA with ACC to prevent severe infection, compartment-syndrome-like conditions, and deformities. Based on literature findings, we assume that Integra®-Dermal Regeneration Template with STSG could even be able to prevent new blistering and thereby be a treatment option in cases of ACC and JEB.