Alternative titles; symbols
ORPHA: 79402;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q25.1 | Epidermolysis bullosa, junctional 5A, intermediate | 619816 | Autosomal recessive | 3 | ITGB4 | 147557 |
A number sign (#) is used with this entry because of evidence that intermediate junctional epidermolysis bullosa 5A (JEB5A) is caused by homozygous or compound heterozygous mutation in the ITGB4 gene (147557) on chromosome 17q25.
Mutations in ITGB4 also cause a syndromic form of JEB that includes pyloric atresia; see JEB5B, 226730.
Intermediate junctional epidermolysis bullosa 5A (JEB5A) is an autosomal recessive blistering disease of skin and mucous membranes. Blistering is less severe than in severe JEB (see 226700). The plane of skin cleavage is through the lamina lucida of the cutaneous basement membrane zone. Nails may be dystrophic and dental enamel defects are present. Blistering does not affect the life span of affected individuals (summary by Has et al., 2020).
For a discussion of genetic heterogeneity of the subtypes of JEB, see JEB1A (226650).
Reviews
Has et al. (2020) reviewed the clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors, and natural history of epidermolysis bullosa.
Inoue et al. (2000) studied a patient with typical features of non-Herlitz JEB without pyloric atresia who had mutation in the ITGB4 gene. The 68-year-old Japanese man had had lifelong trauma-induced skin fragility, with blisters at birth and recurrent urethral stenosis from the age of 12 years. Nails were dystrophic, and he had experienced loss of permanent dentition by age 30 years. Alopecia began in childhood and was progressive, and axillary and pubic hair were absent. He had no history of gastrointestinal symptoms or previous abdominal surgery. Histopathology showed subepidermal blister formation; transmission electron microscopy showed separation at the level of lamina lucida in some sites. In nonblistered areas, hemidesmosomes were decreased in number and were hypoplastic.
Jonkman et al. (2002) reported a 49-year-old woman with mild blistering of hands and feet from birth, dystrophy of the nails with onychogryposis, and enamel hypoplasia. She had no alopecia and no history of pyloric atresia. Electron microscopy and antigen mapping of a skin blister revealed that the level of separation was intraepidermal, extremely low in the basal keratinocytes through the attachment plaque of the hemidesmosome. Jonkman et al. (2002) pointed out that the blistering in this patient had always been confined to hands and feet. Although Jonkman et al. (2002) stated that the level of skin separation was intraepidermal (i.e., consistent with that seen in epidermolysis bullosa simplex), they pointed out that 'pseudojunctional' splits very low in the basal cells had been reported in patients with JEB with pyloric atresia carrying mutations in the ITGB4 gene (e.g., Pulkkinen et al. (1998), Mellerio et al. (1998)).
The transmission pattern of JEB5A in the family reported by Inoue et al. (2000) was consistent with autosomal recessive inheritance.
Inoue et al. (2000) reported a homozygous mutation in the ITGB4 gene (G931D; 147557.0012) in a 68-year-old male, born of consanguineous parents, with a history of congenital blisters, recurrent urethral stenosis since age 12 years, progressive alopecia since childhood, loss of permanent dentition by age 30 years, nail dystrophy, and absence of pubic and axillary hair. There was no history of gastrointestinal symptoms or previous abdominal surgery.
In a 49-year-old woman with mild blistering of hands and feet from birth, dystrophy of the nails with onychogryposis, and enamel hypoplasia, Jonkman et al. (2002) identified a heterozygous 2-bp deletion in exon 36 of the ITGB4 gene (147557.0013). Electron microscopy and antigen mapping of a skin blister revealed that the level of separation was intraepidermal, extremely low in the basal keratinocytes through the attachment plaque of the hemidesmosome. Immunofluorescence microscopy revealed absent binding of monoclonal antibody 450-11 A against the third fibronectin III repeat on the intracellular domain of integrin beta-4, whereas binding was reduced with monoclonal antibodies recognizing epitopes on amino-terminal and carboxy-terminal ends of the polypeptide. The patient was also expected to be heterozygous for a null allele, as no full-size protein was detected in vitro and the epitope 450-11 A was absent in vivo. These data showed that deletion of the third fibronectin type III repeat in the cytoplasmic domain of integrin beta-4, which is thought to interact with BP180/type XVII collagen (COL17A1; 113811), is clinically pathogenic and results in a mild phenotype. Jonkman et al. (2002) concluded that the phenotype in their patient was explained by exon 36 skipping and a 50-amino acid deletion of a less critical region the extracellular domain of beta-4: the third fibronectin repeat.
Has, C., Bauer, J. W., Bodemer, C., Bolling, M. C., Bruckner-Tuderman, L., Diem, A., Fine, J. D., Heagerty, A., Hovnanian, A., Marinkovich, M. P., Martinez, A. E., McGrath, J. A., and 10 others. Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility. Brit. J. Derm. 183: 614-627, 2020. [PubMed: 32017015] [Full Text: https://doi.org/10.1111/bjd.18921]
Inoue, M., Tamai, K., Shimizu, H., Owaribe, K., Nakama, T., Hashimoto, T., McGrath, J. A. A homozygous missense mutation in the cytoplasmic tail of beta-4 integrin, G931D, that disrupts hemidesmosome assembly and underlies non-Herlitz junctional epidermolysis bullosa without pyloric atresia? J. Invest. Derm. 114: 1061-1064, 2000. [PubMed: 10792571] [Full Text: https://doi.org/10.1046/j.1523-1747.2000.00960-3.x]
Jonkman, M. F., Pas, H. H., Nijenhuis, M., Kloosterhuis, G., van der Steege, G. Deletion of a cytoplasmic domain of integrin beta-4 causes epidermolysis bullosa simplex. J. Invest. Derm. 119: 1275-1281, 2002. [PubMed: 12485428] [Full Text: https://doi.org/10.1046/j.1523-1747.2002.19609.x]
Mellerio, J. E., Pulkkinen, L., McMillan, J. R., Lake, B. D., Horn, H. M., Tidman, M. J., Harper, J. I., McGrath, J. A., Uitto, J., Eady, R. A. J. Pyloric atresia-junctional epidermolysis bullosa syndrome: mutations in the integrin beta-4 gene (ITGB4) in two unrelated patients with mild disease. Brit. J. Derm. 139: 862-871, 1998. [PubMed: 9892956] [Full Text: https://doi.org/10.1046/j.1365-2133.1998.02515.x]
Pulkkinen, L., Kim, D. U., Uitto, J. Epidermolysis bullosa with pyloric atresia: novel mutations in the beta4 integrin gene (ITGB4). Am. J. Path. 152: 157-166, 1998. [PubMed: 9422533]