ORPHA: 79403;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q31.1 | Epidermolysis bullosa, junctional 6, with pyloric atresia | 619817 | Autosomal recessive | 3 | ITGA6 | 147556 |
A number sign (#) is used with this entry because of evidence that junctional epidermolysis bullosa-6 with pyloric atresia (JEB6) is caused by homozygous or compound heterozygous mutation in the ITGA6 gene (147556) on chromosome 2q31.
Junctional epidermolysis bullosa-6 with pyloric atresia (JEB6) is an autosomal recessive blistering disease of skin and mucous membranes. Pyloric atresia is usually evident within a few days of life. Full thickness skin loss (aplasia cutis congenita) may also occur. The plane of skin cleavage is through the lamina lucida of the cutaneous basement membrane zone. JEB5B is usually lethal within the first few weeks of life despite surgical correction of pyloric atresia (summary by Has et al., 2020).
Another form of junctional epidermolysis bullosa with pyloric atresia (JEB5B; 226730) is caused by mutation in the integrin-beta-4 gene (ITGB4; 147557).
See also epidermolysis bullosa simplex with pyloric atresia (EBS5C; 612138), which is caused by mutation in the PLEC1 gene (601282).
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.
Ruzzi et al. (1997) reported a female infant, born of clinically normal Moroccan parents, with junctional epidermolysis with pyloric atresia (JEB-PA) and mutation in the ITGA6 gene. She had cutaneous aplasia of both legs, feet, hands, and both sides of the scalp. Blisters and erosions were present over the trunk and extremities. Pinnae of both ears were small and malformed. Severe esophageal stenosis as well as pyloric atresia was present. Eruption of new cutaneous and mucosal blisters and multisystem failure led to death at 23 days of age. Immunofluorescence analysis showed no staining for the alpha-6-integrin subunit and strongly reduced staining for beta-4-integrin (ITGB4; 147557). Staining for type VII collagen (COL7A1; 120120), laminin-5 (see 150292), and hemidesmosomal components BPAG1 (DST; 113810) and BPAG2 (COL17A1; 113811) were comparable to those of controls. Ultrastructural analysis revealed skin cleavage plane within the lamina lucida and reduced numbers of hemidesmosomes that lacked a subbasal dense plate.
Allegra et al. (2003) reported a male infant, born of unaffected consanguineous Emirate Arabian parents, with JEB-PA and mutation in the ITGA6 gene. Aplasia cutis congenita involving the legs, feet, nose, right jaw, and both pinnae, as well as microtia, were present at birth. Blistering of skin and mucosa consequent to friction occurred shortly after birth. Pyloric atresia was detected by radiology, and pyloric ablation was performed at 4 days of age. At 10 days of age, aspiration pneumonia consequent to nasojejunal feeding caused general deterioration. Death occurred at age 26 days due to septicemia resulting from widespread blistering of skin and oral mucosa concomitant with thrombocytopenia and neutropenia.
Schumann et al. (2013) studied a 3-month-old Turkish boy (patient 8) with lethal JEB-PA and mutation in the ITGA6 gene. The patient had generalized blistering and severe skin fragility from the time of birth. Pyloric atresia was surgically corrected and feeding maintained by gastrostomy. Stridor developed in the first weeks of life, and a tracheostomy was placed for mechanical ventilation. Urinary stasis, with dilated pelvis and ureter, and hematuria developed. Ultrasound examination revealed thickened bladder walls, cholestasis, irregular inner surface pattern, and significantly reduced inner lumen.
Masunaga et al. (2017) reported a female infant, born of nonconsanguineous Japanese parents, with lethal JEB-PA and mutation in the ITGA6 gene. The patient presented at birth with several blisters and erosions distributed over the trunk, extremities, and oral mucosa. Pyloric atresia and patent ductus arteriosus were also detected. The patient died at 96 days of life with disseminated intravascular coagulation.
The transmission pattern of JEB6 in the family reported by Ruzzi et al. (1997) was consistent with autosomal recessive inheritance.
In a female infant with JEB-PA, Ruzzi et al. (1997) detected homozygosity for a single-base deletion in the ITGA6 gene (791delC; 147556.0001). The clinically normal parents were heterozygous for the mutation. ITGA6 was selected as a candidate gene for the disorder based on reduced expression of ITGA6 mRNA in cultured keratinocytes from the proband's parents, because paucity of biopsy material from the proband prevented expression studies.
In a male infant with JEB-PA born of unaffected consanguineous Emirate Arabian parents, Allegra et al. (2003) identified homozygosity for a ser47-to leu mutation (S47L; 147556.0002) in the beta-propeller domain of ITGA6. Functional studies indicated that the S47L mutation triggers instability of alpha-6 integrin that was at least partially mediated by the lysosomal degradation pathway.
Schumann et al. (2013) studied 8 epidermolysis bullosa patients with alpha-6/beta-4 mutations, 7 with homozygous or compound heterozygous mutations in ITGB4 and 1 with homozygous mutation in ITGA6 (147556.0003). This patient had pyloric atresia and a severe phenotype.
In a Japanese infant with lethal JEB-PA, Masunaga et al. (2017) detected compound heterozygosity for splicing mutations in the ITGA6 gene (147556.0004 and 147556.0005). Both mutations resulted in exon skipping, with in-frame deletion or premature termination of the protein.
Allegra, M., Gagnoux-Palacios, L., Gache, Y., Roques, S., Lestringant, G., Ortonne, J. P., Meneguzzi, G. Rapid decay of alpha-6 integrin caused by a mis-sense mutation in the propeller domain results in severe junctional epidermolysis bullosa with pyloric atresia. J. Invest. Derm. 121: 1336-1343, 2003. [PubMed: 14675179] [Full Text: https://doi.org/10.1111/j.1523-1747.2003.12625.x]
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]
Masunaga, T., Ogawa, J., Akiyama, M., Nishikawa, T., Shimizu, H., Ishiko, A. Compound heterozygosity for novel splice site mutations of ITGA6 in lethal junctional epidermolysis bullosa with pyloric atresia. J. Derm. 44: 160-166, 2017. [PubMed: 27607025] [Full Text: https://doi.org/10.1111/1346-8138.13575]
Ruzzi, L., Gagnoux-Palacios, L., Pinola, M., Belli, S., Meneguzzi, G., D'Alessio, M., Zambruno, G. A homozygous mutation in the integrin alpha-6 gene in junctional epidermolysis bullosa with pyloric atresia. J. Clin. Invest. 99: 2826-2831, 1997. [PubMed: 9185503] [Full Text: https://doi.org/10.1172/JCI119474]
Ruzzi, L., Gagnoux-Palacios, L., Pinola, M., Belli, S., Meneguzzi, G., Zambruno, G., D'Alessio, M. A homozygous mutation in the gene encoding integrin alpha6 in junctional epidermolysis bullosa with pyloric atresia. (Abstract) Medizinische Genetik 9: 13-14, 1997.
Schumann, H., Kiritsi, D., Pigors, M., Hausser, I., Kohlhase, J., Peters, J., Ott, H., Hyla-Klekot, L., Gacka, E., Sieron, A. L., Valari, M., Bruckner-Tuderman, L., Has, C. Phenotypic spectrum of epidermolysis bullosa associated with alpha-6-beta-4 integrin mutations. Brit. J. Derm. 169: 115-124, 2013. [PubMed: 23496044] [Full Text: https://doi.org/10.1111/bjd.12317]