Epidermolysis Bullosa Simplex With Pyloric Atresia
A number sign (#) is used with this entry because of evidence that epidermolysis bullosa simplex with pyloric atresia (EBSPA) is caused by homozygous or compound heterozygous mutation in the gene encoding plectin-1 (PLEC1; 601282) on chromosome 8q24.
EBS with muscular dystrophy (EBSMD; 226670), EBS Ogna type (EBSOG; 131950), and EBS with nail dystrophy (EBSND; 616487) are allelic disorders.
See also junctional EB with pyloric atresia (JEBPA), a similar disorder caused by mutation in the ITGB4 (147557) or the ITGA6 (147556) gene.
DescriptionEBSPA is an autosomal recessive genodermatosis characterized by severe skin blistering at birth and congenital pyloric atresia. Death usually occurs in infancy. In reports of 2 consensus meetings for EB, Fine et al. (2000, 2008) considered EBSPA to be a 'basal' form of simplex EB because the electron microscopy shows that skin cleavage occurs in the lower basal level of the keratinocyte, just above the hemidesmosome. There is often decreased integration of keratin filaments with hemidesmosomes.
Clinical FeaturesCowton et al. (1982) reported a female infant born with epidermolysis bullosa, aplasia cutis, and pyloric atresia. The mother had increased alpha-fetoprotein during early pregnancy. Electron microscopy of skin biopsies showed EB simplex.
Morrell et al. (2000) reported a male infant, born of consanguineous parents, with numerous and skin erosions and bullae at birth. There was extensive absence of skin on the face, trunk, and limbs. Other anomalies included malformed pinnae fused to the scalp, hypoplastic nasal alae, and joint contractures. The pregnancy was complicated by polyhydramnios. Electron microscopy of skin biopsies showed cleavage in the lowermost third of basal keratinocytes, consistent with a diagnosis of EBS. Abdominal radiographs and clinical symptoms indicated pyloric atresia, which was surgically repaired. He died at age 5 weeks of respiratory failure. Genetic analysis excluded mutations in the ITGB4 and ITGA6 genes.
Charlesworth et al. (2003) reported 3 sisters, born of consanguineous Turkish parents, with features consistent with EBSPA. Clinical features included congenital absence of the skin on the nose, skin fragility with blister formation, and dysmorphic features, including deep-set eyes, hypoplastic ears with helices fused to the skull, hypoplastic nose, and joint contractures. The pregnancies were complicated by polyhydramnios, and ultrasonographic findings suggested pyloric atresia. However, due to the religious beliefs of the family, postmortem examination and extensive studies were refused. All the girls died within hours of birth or termination. Available skin biopsies of 2 of the patients were consistent with EBS with cleavage in the lower part of basal keratinocytes.
Nakamura et al. (2005) reported 3 patients from 2 unrelated families with EBSPA. In the first family, 2 brothers were born with multiple blisters and ulcers on all areas of the body. Pyloric atresia was apparent by ultrasound during the pregnancies. Both died at ages 16 and 4 months, respectively. The proband in the second family had a similar disease course. Electron microscopy in all patients showed cleavage at the base of the basal keratinocytes and hypoplastic hemidesmosomes. Immunohistochemical studies showed decreased or absent expression of PLEC1.
Pfendner and Uitto (2005) reported 4 consanguineous families in which at least 1 member had EBSPA. All patients had extensive blistering at birth with pyloric atresia, most had aplasia cutis, and all died from complications of the disorder shortly after birth. Molecular analysis confirmed homozygous mutations in the PLEC1 gene (see, e.g., 601282.0007 and 601282.0009). Pfendner and Uitto (2005) noted that 1 of the mutations deleted a region that may be important for plectin interaction with alpha-6/beta-4 integrin, and that mutations in the latter genes result in the phenotypically similar JEB-PA. Thus, PA in all of these patients is likely related to perturbed interactions between plectin and alpha-6/beta-4 integrin within attachment structures expressed during gastrointestinal development.
Molecular GeneticsIn 3 Turkish female infants with lethal EBSPA, Charlesworth et al. (2003) identified a homozygous mutation in the PLEC1 gene (601282.0006).
In 2 unrelated patients with lethal EBSPA, Nakamura et al. (2005) identified compound heterozygous mutations in the PLEC1 gene (see, e.g., 601282.0007; 601282.0008).