Interstitial lung disease , nephrotic syndrome and integrin alpha-3 Mutation Q82.8

Has C et al. 2012

Very rare (<10 patients described) autosomal recessive, very severe multisystem disease involving skin, kidneys, and lungs. Life-limiting is congenital interstitial lung disease with recurrent respiratory infections and congenital nephrotic syndrome (Okamoto T et al. 2021). Skin fragility usually takes a back seat to the severity of symptoms in this clinical picture.

Homozygosity for a 1-bp deletion in the ITGA3 gene (605025.0001) was detected in an Italian boy with congenital interstitial lung disease, nephrotic syndrome, and mild epidermolysis bullosa who died of a lung infection at 7.5 months of age.

Analysis of the ITGA3 gene in two similarly affected unrelated girls revealed homozygosity for a splice site and a missense mutation (605025.0002 and 605025.0003). The results suggest that the mutation causes impaired post-translational processing of ITGA3 (Yalcin et al. 2015).

Transmission electron microscopy shows a thin lamina densa discontinuous between hemidesmosomes.Keratin filaments, desmosomes, hemidesmosomes, and anchoring fibrils are described as normal.

Immunofluorescence mapping shows a focal disruption of the dermal-epidermal boundary with cleavage within the basement membrane.

Skin cleavage occurs within the lamina lucida of the basement membrane. Evidence of subepidermal blisters (Has et al. 2012).

The cases known so far were lethal within the first two years of life due to fatal lung involvement. Therapeutically, organ transplantation (kidney, lung) is the only life-prolonging option.

1. Has C et al (2012) Integrin alpha-3 mutations with kidney, lung, and skin disease. New Eng J Med 366: 1508-1514.
2. Okamoto T et al (2021) Successful kidney transplantation in a patient with neonatal-onset ILNEB. Pediatr Transplant 25:e13971.
3. Yalcin E G et al (2015) Crucial role of posttranslational modifications of integrin alpha-3 in interstitial lung disease and nephrotic syndrome. Hum Molec Genet 24: 3679-3688.