Alternative titles; symbols
ORPHA: 79403; DO: 0060733;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q25.1 | Epidermolysis bullosa, junctional 5B, with pyloric atresia | 226730 | Autosomal recessive | 3 | ITGB4 | 147557 |
A number sign (#) is used with this entry because of evidence that junctional epidermolysis bullosa 5B with pyloric atresia (JEB5B) is caused by homozygous or compound heterozygous mutations in the integrin-beta-4 gene (ITGB4; 147557) on chromosome 17q25.
Junctional epidermolysis bullosa 5B with pyloric atresia (JEB5B) is an autosomal recessive blistering disease of skin and mucous membranes. Severity of skin involvement ranges from extensive full thickness skin loss (aplasia cutis congenita) to mild epidermolysis bullosa that improves with age. The plane of skin cleavage is through the lamina lucida of the cutaneous basement membrane zone. Pyloric atresia is usually evident within a few days to weeks of life. Atresia may occur at other gastrointestinal sites including the esophagus and duodenum. JEB5B is usually lethal within the first few weeks of life despite surgical correction of pyloric atresia. Milder, non-lethal forms with less skin blistering have been reported (summary by Has et al., 2020).
Another form of junctional epidermolysis bullosa with pyloric atresia (JEB6; 619817) is caused by mutations in the integrin-alpha-6 gene (ITGA6; 147556).
See also epidermolysis bullosa simplex with pyloric atresia (EBS5C; 612138), which is caused by mutations 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.
In a study involving 265 cases of junctional or hemidesmosomal EB, Varki et al. (2006) reviewed the clinical and molecular heterogeneity of these subtypes of EB, discussed exceptions to the general rules on genotype-phenotype correlations, and noted unusual phenotypes and genetics observed in patients and families with EB.
Traditionally, EB-PA has been classified as a form of junctional epidermolysis bullosa. Uitto et al. (1997) and Pulkkinen and Uitto (1998) proposed reclassification of the disorder as a 'hemidesmosomal' variant because ultrastructural findings can indicate cleavage in the hemidesmosomal region of the skin. However, in subsequent reports of consensus conferences, Fine et al. (2000, 2008) eliminated the term 'hemidesmosomal' because it added undue confusion. The disorder is considered to be a form of junctional EB because skin cleavage occurs within the lamina lucida. Hemidesmosomes may be abnormal because the integrins span this region.
Bull et al. (1980, 1983) reported a sister and brother with epidermolysis bullosa and pyloric atresia at birth. Both died in early infancy of complications related to the skin disorder. An older stillborn sister was probably affected. Both sibs also had bilateral stenosis at the ureterovesical junctions with bilateral pyelonephrosis; this feature was present in an earlier-reported case. Electron microscopic studies of skin biopsy specimens disclosed findings consistent with a diagnosis of epidermolysis bullosa letalis, or the Herlitz form of JEB (see 226700). The authors found 10 previously reported cases and 2 instances in which sibs were affected, suggesting autosomal recessive inheritance.
Similar cases were reported by Adashi et al. (1980) and Berger et al. (1986). Death usually occurred in the first few months of life despite surgical management of the pyloric abnormality.
Carmi et al. (1982) described 2 sibs from consanguineous Bedouin parents with extensive aplasia cutis congenita. Only 1 had pyloric atresia. Elevated amniotic fluid alpha-fetoprotein was noted by Carmi et al. (1982) and by Leschot and Treffers (1975). Carey et al. (1983) described a pair of dizygotic twins, a boy and girl, with extensive skin changes similar to the changes observed in the patients of Carmi et al. (1982). Carey et al. (1983) suggested that the designation 'aplasia cutis congenita' was inappropriate because it usually entails involvement of the scalp predominantly or exclusively; they suggested the eponymic designation Carmi syndrome. One of the twins had axillary pterygia and bilateral lower lid ectropion, whereas the other showed esophageal atresia.
Toriello et al. (1983) reported affected brother and sister, and Leschot (1983) called attention to the similar case reported by Leschot et al. (1980). Frieden (1986) reported arthrogryposis and ear and nose deformities.
Egan et al. (1985) described 2 male sibs with pyloric atresia and junctional epidermolysis bullosa confirmed by electron microscopy. Cutaneous erosions and blisters were present in various locations in both; both had dystrophic nails. Surgical correction of pyloric atresia was performed in both, but death occurred at 12 weeks of age in one sib and at 32 days of age in the other. Autopsy in the first sib revealed marked esophageal erosions, interstitial nephritis with hyaline droplet change of the tubules, and submucosal hemorrhage and areas of calcification in the bladder.
Vivona et al. (1987) described a sister and brother with lethal congenital cutis aplasia. Only 1 had esophageal atresia with complete absence of the pyloris. In the view of Vivona et al. (1987), the similarity between their cases and those of Carmi et al. (1982) strongly supported the existence of a unique EB-like mutation, i.e., an autosomal recessive disorder with variable involvement of skin, nails, and mucosa, with variable effects on the digestive system.
Rosenbloom and Ratner (1987) reported premature sibs with lethal epidermolysis bullosa associated with congenital pyloric atresia. A review of other cases indicated that it is usually a lethal condition with death due to the septic complications of EB.
Ishigami et al. (1990) described congenital pyloric atresia in a female infant with junctional EB who, despite successful early surgical correction of the obstruction, died from intractable diarrhea and protein-losing gastroenteropathy at the age of 4.5 months.
Lacour et al. (1992) described a case of lethal JEB in a newborn girl who also had pyloric stenosis. Immunohistologic and electron microscopic studies showed cleavage through the lamina lucida of the digestive basement membrane, as for the localized skin blisters. There was normal immunostaining of the laminin glycoprotein BM600 at the dermoepidermal junction.
Vidal et al. (1995) reported an infant with JEB and mutation in the ITGB4 gene who presented at birth with pyloric atresia and cutaneous aplasia of the left hand. Perioral blistering and erosions of the mucosa of the mouth, upper esophagus and cornea were noted shortly after birth. Gastric erosions were found later. The infant died at the age of 8 months as the result of infection of skin blisters and generalized infection.
Pulkkinen et al. (1998) described an 18-month-old boy with mild epidermolysis bullosa and pyloric atresia and mutation in the ITGB4 gene. Pyloric atresia was diagnosed at birth and surgically removed at 3 days of age. Following the operation skin blistering was noted at sites exposed to mechanical trauma; blisters healed without apparent scarring, milia, or pigmentary changes. With age, only occasional blisters developed, mostly at the sites of trauma such as knees and toes, and dystrophy of some toenails developed. At the time of the report the patient was mostly free from blisters, and mucous membranes were not involved.
Chavanas et al. (1999) reported a patient with JEB-PA and mutation in the ITGB4 gene who represented a rare instance in which JEB-PA showed improvement with age. The proband was a 14-year-old boy, the child of nonconsanguineous parents, who at birth presented all the hallmarks of severe JEB-PA, including extensive skin blistering, pyloric atresia, and urethrovesical occlusion. However, as the child grew, the blistering tendency decreased and his skin and epithelia acquired resistance to trauma. At the age of 14, induction of blisters required prolonged rubbing of the skin.
The transmission pattern of JEB5B in the family reported by Vidal et al. (1995) was consistent with autosomal recessive inheritance.
Lestringant et al. (1992) found that the GB3 monoclonal antibody, which reacts to laminin-5 subunits, was normally expressed in skin biopsies from 3 of 3 cases of JEB-PA, thus excluding it as a form of Herlitz JEB, which is due to mutations in genes encoding laminin-5 subunits. Lestringant et al. (1992) concluded that the pyloric atresia/epidermolysis bullosa association represents an autosomal recessive entity of JEB, and that pyloric atresia is a primary manifestation rather than a scarring process secondary to JEB. The authors noted that patients with JEB-PA often have erosions and/or subepithelial cleavage in the respiratory, gastrointestinal, and urinary tracts. Obstruction of the ureterovesical junction and a high incidence of a peculiar form of aplasia cutis congenita were considered to be additional features.
Maman et al. (1998) provided detailed clinical and histopathologic information on 8 cases of the triple syndrome epidermolysis bullosa/pyloric atresia/aplasia cutis congenita (EB-PA-ACC). The affected individuals were members of the extended Bedouin family first described by Carmi et al. (1982). All affected infants were found to have mixed skin lesions, including blisters and patchy lack of skin. In 7 of the 8, intestinal obstructions, especially pyloric atresia or stenosis, were found. Skin lesions involved all layers with marked dystrophic changes. The intestinal obstruction was the result of overproliferation of connective tissue. In view of the clinical and histopathologic findings, Maman et al. (1998) postulated that the condition is caused by an autosomal recessive mutation affecting the integrity of the basement membrane and hemidesmosomes and the control of the normal process of fibrosis occurring during wound healing. The sequence of events appeared to be initiated by the separation of the epidermis or the intestinal mucosal layer. An inflammatory reaction then takes place and proceeds with massive fibrosis penetrating the deep layers and causing damage to skin and obstruction of the intestinal lumen. Maman et al. (1998) postulated a mutation in one of the integrin genes.
Prenatal Diagnosis
Nazzaro et al. (1990) made the prenatal diagnosis of JEB-PA by ultrastructural demonstration of dermal-epidermal separation at the lamina lucida level in fetal skin obtained at 18 weeks of gestation. Fetal ultrasound showed marked gastric dilatation, and light microscopy of pyloric tissue obtained after termination showed that the pyloric lumen was replaced by loose connective tissue with no inflammatory reaction. Skin biopsy studies showed a positive reaction with the GB3 antibody, thus excluding the Herlitz form of JEB. In the family studied, 2 previous children had died during the first months of life of the same disorder despite surgery for the pyloric abnormality.
Although AFP and skin biopsy had been used for prenatal diagnosis of this condition, Achiron et al. (1992) found normal levels of amniotic AFP at 16 weeks' gestation in a woman at risk for this disorder in her fetus. However, 10 weeks later, ultrasonography showed hydramnios, dilated stomach, deformed external ear, and contracted fisted hand, all of which were confirmed postnatally.
In an infant with junctional epidermolysis bullosa with pyloric atresia (JEB5B), Vidal et al. (1995) demonstrated compound heterozygosity for 2 mutations in the integrin beta-4 gene (147557.0001, 147557.0002).
In a patient with nonlethal JEB-PA and survival until 14 years of age, Chavanas et al. (1999) found compound heterozygosity for 2 splice site mutations in the ITGB4 gene (147557.0007 and 147557.0011).
In members of the original inbred Bedouin kindred from southern Israel with EB-PA-ACC described by Carmi et al. (1982) and Maman et al. (1998), Birnbaum et al. (2008) identified a homozygous 2,279-bp in-frame deletion in exons 27-30 of the ITBG4 gene (147557.0016). They stated that this was the largest deletion in the ITBG4 gene to date and included the first pair of fibronectin III repeats.
Pulkkinen et al. (1998) identified novel lesions of both ITGB4 alleles in the probands of 5 families with JEB-PA, 2 of them with lethal and 3 of them with nonlethal variants of the disease. Of the 2 patients with lethal JEB-PA, one was a compound heterozygote for premature termination codon mutations, and the other was homozygous for a missense mutation involving a cysteine residue (C61Y; 147557.0005). The 3 patients with nonlethal JEB-PA had missense mutations on both alleles.
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Adashi, E. Y., Louis, F. J., Vasquez, M. An unusual case of epidermolysis bullosa hereditaria letalis with cutaneous scarring and pyloric atresia. J. Pediat. 96: 443-446, 1980. [PubMed: 7359240] [Full Text: https://doi.org/10.1016/s0022-3476(80)80695-0]
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