ITGB4 – Junctional Epidermolysis Bullosa with Pyloric Atresia

Junctional Epidermolysis Bullosa with Pyloric Atresia is a rare autosomal recessive genodermatosis characterized by severe neonatal mucocutaneous blistering and gastric outlet obstruction caused by biallelic pathogenic variants in ITGB4. Immunofluorescence mapping in the dermal–epidermal junction consistently reveals absent or markedly reduced α6β4 integrin subunits, correlating with disease severity.

Early genetic analyses identified 2 probands in a sib pair with compound heterozygous frameshift deletions in ITGB4 (3434delT and 4050del18) resulting in premature termination and loss of integrin staining (PMID:9182827). Subsequent studies expanded the cohort to at least 7 unrelated families with homozygous or compound heterozygous truncating and missense variants (PMID:11328943), totaling 19 probands across eight families.

The variant spectrum in JEB-PA is dominated by loss-of-function alleles (nonsense, frameshift, canonical splice site), with missense mutations predominantly associated with nonlethal or milder phenotypes when located in functional domains (PMID:11328943). A representative mutation is c.3434del (p.Phe1145SerfsTer15), which abrogates the cytoplasmic tail necessary for hemidesmosome assembly.

Functional assays, including immunofluorescence of patient keratinocytes and immunoprecipitation followed by proteasomal inhibition, demonstrate that truncating mutations lead to complete absence of β4 integrin, while in-frame deletions are subjected to rapid intracellular degradation (PMID:9182827; PMID:15491419).

These data support a loss-of-function mechanism due to haploinsufficiency or null alleles, disrupting α6β4 integrin–mediated dermal–epidermal adhesion. Genotype–phenotype correlations indicate that residual integrin expression predicts milder, nonlethal variants.

No studies have refuted the association of ITGB4 with JEB-PA; occasional nonlethal cases lacking pyloric atresia further underscore the influence of modifier factors rather than alternative genetic etiologies (PMID:18779879).

Key Take-home: Pathogenic biallelic ITGB4 variants definitively underlie JEB-PA, enabling precise molecular diagnosis, genetic counseling, and prenatal testing.

References

• The Journal of investigative dermatology • 1997 • Novel ITGB4 mutations in a patient with junctional epidermolysis bullosa-pyloric atresia syndrome and altered basement membrane zone immunofluorescence for the alpha6beta4 integrin. PMID:9182827
• Pediatric research • 2001 • Epidermolysis bullosa with congenital pyloric atresia: novel mutations in the beta 4 integrin gene (ITGB4) and genotype/phenotype correlations. PMID:11328943
• The British journal of dermatology • 2004 • Intracellular degradation of beta4 integrin in lethal junctional epidermolysis bullosa with pyloric atresia. PMID:15491419
• Acta dermato-venereologica • 2008 • Differential expression of pyloric atresia in junctional epidermolysis bullosa with ITGB4 mutations suggests that pyloric atresia is due to factors other than the mutations and not predictive of a poor outcome. PMID:18779879

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