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www.eymj.org To the Editor, Epidermolysis bullosa (EB) with pyloric atresia (PA) is an autosomal recessive form of EB subtype that affects the skin, as well as digestive and frequently urogenital tracts. EB-PA is classified as the simplex form caused by the plectin gene (PLEC) mutations and the junctional form caused by integrin α6β4 genes (ITGA6, ITGB4) mutations. However, the intracellular domain of integrin β4 interacts with other hemidesmosomal components of basal keratinocytes, including plectin. A recent review on the transmission electron microscopy (TEM) findings of EB-PA patients who showed absent expression of integrin β4 reported a consistent level of cleavage planes through concurrent low intra-basal epidermal and lamina lucida, suggesting that the loss of integrin β4 can lead to this unique ultrastructural finding. We previously reported a Korean male newborn who presented with PA with mucocutaneous blisters at birth. Widespread blisters were found on the entire body and oral mucosa, and they eventually healed without significant scarring. Nail dystrophy was observed on the right thumb. Multiple urologic abnormalities including bilateral hydronephrosis, hydroureter, and a distended trabeculated bladder were noted at 12 months of age. Immunofluorescence mapping and TEM performed at infancy revealed the localization of type IV and VII collagen to the blister base and intra-basal epidermal cleavages with tonofilaments clumping, respectively, leading to a diagnosis of EB simplex, generalized severe, formerly called Dowling-Meara type with PA and urologic abnormalities. The patient’s father, paternal brother, and sister had reported bullae without any anomalies, which had spontaneously improved. In this report, we describe compound heterozygous mutations in integrin β4 in this patient, which were not previously identified. Next-generation sequencing performed after obtaining informed consent revealed compound heterozygous missense mutations, c.113G>T (p.C38F) in exon 3 and c1274A>C (p.Q425P) in exon 11 of ITGB4 gene, which were confirmed by additional Sanger sequencing (Fig. 1A). Mutations in PLEC or keratin genes have not been detected. Missense mutation of p.Q425P has been reported in EB-PA. p.C38F in ITGB4 was reported as a codon variant, but has not been reported to be associated with EB. Two in silico tools, including SIFT and PolyPhen-2, predicted that this amino acid substitution in ITGB4 is likely pathogenic. Cutaneous symptoms improved with age, showing only blistering limited to the extremities and inguinal area at age 22 (Fig. 1B). Integrin β4 consists of an intracytoplasmic domain connected to keratin intermediate filaments via binding to plectin and type XVII collagen and an extracellular domain connected to laminin. ITGB4 mutations are the most frequent cause of EBPA, and EB-PA caused by ITGB4 mutations has been classified as a form of junctional EB, but a previous paper reported that the deletion of a cytoplasmic domain of integrin β4 causes EB simplex without PA. This indicated that mutations in the intracytoplasmic domain of integrin β4 may result in intrabasal splits, suggesting EB simplex rather than junctional EB. In this case, despite the compound heterozygous missense mutations in the Received: April 3, 2020 Revised: July 1, 2020 Accepted: July 20, 2020 Corresponding author: Sang Eun Lee, MD, PhD, Department of Dermatology and Cutaneous Biology Research Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Korea. Tel: 82-2-2019-3360, Fax: 82-2-2019-4881, E-mail: jennifer823@yuhs.ac

Compound Heterozygous Mutations with a Novel Variant in Integrin Beta4 Cause Epidermolysis Bullosa with Pyloric Atresia and Urologic Abnormalities