Interstitial Lung Disease, Nephrotic Syndrome, And Epidermolysis Bullosa, Congenital

A number sign (#) is used with this entry because of evidence that congenital interstitial lung disease with nephrotic syndrome and epidermolysis bullosa (ILNEB) is caused by homozygous mutation in the ITGA3 gene (605025) on chromosome 17q21.

Description

Mutations in the integrin alpha-3 gene are associated with disrupted basement-membrane structures and compromised barrier functions in kidney, lung, and skin. Patients exhibit a multiorgan disorder that includes congenital interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa. The respiratory and renal features predominate, and lung involvement accounts for the lethal course of the disease (summary by Has et al., 2012).

Clinical Features

Has et al. (2012) described 3 unrelated children, a boy and 2 girls, who had congenital interstitial lung disease, nephrotic syndrome, and mild epidermolysis bullosa. The index patient was a boy from southern Italy who had respiratory distress at birth requiring high-flow supplemental oxygen; chest x-ray showed severe reticulonodular changes. At 2 weeks of age, he developed renal failure and nephrotic syndrome, and peritoneal dialysis was initiated. From the age of 3 months, the infant had increasing skin fragility, with small blisters and erosions after mechanical manipulation. There was no mucosal involvement. Scalp hair, eyebrows, and eyelashes were fine and sparse. The big toenails became dystrophic, and distal onycholysis followed mild trauma to the fingernails. Renal biopsy at 1 month of age showed globally atrophic glomeruli, focal segmental glomerulosclerosis, diffuse interstitial fibrosis, tubular atrophy, and loss and immaturity of the tubules. At 5.5 months, lung biopsy showed hyperinflation and mild to moderate simplification of air spaces and mild reactive changes in the bronchioles. The infant died at 7.5 months during an episode of pulmonary infection. The second patient was a girl born to healthy consanguineous parents from Gaza, the only affected of 9 sibs, who developed respiratory distress at 2 days of life. At 6 weeks of age, chest x-ray showed bilateral infiltrates, and CT findings were consistent with diffuse interstitial lung disease. Laboratory tests showed proteinuria in the nephrotic range, and peritoneal dialysis was begun. The girl died of multiorgan failure at 2 months of age. The third patient was a Pakistani girl, born to healthy consanguineous parents, who developed fever and respiratory distress at 2 months of age; chest x-ray showed changes consistent with right upper and middle lobe pneumonia. Proteinuria in the nephrotic range was noted, and a renal biopsy at 5 months of age showed focal segmental glomerulosclerosis. Progressive renal function deterioration required peritoneal dialysis at 17 months of age. She had recurrent respiratory infections and required supplemental oxygen to maintain peripheral saturation above 90%. At 4 months of age, she developed annular erythematous skin lesions that coalesced into blisters that were consistent with epidermolysis bullosa. She died of multiorgan failure at 19 months of age.

Yalcin et al. (2015) reported a male infant, born of consanguineous parents, who presented in the first week of life with respiratory distress and cyanosis in the absence of evidence of infection with microorganisms. Lung imaging was consistent with interstitial lung disease, and biopsy showed abnormal alveolarization and poorly septated alveolar spaces. Laboratory studies showed nephrotic-range proteinuria and hypoalbuminemia associated with crossed fused renal ectopia. The patient had fine sparse scalp hair and dystrophic nails, but no overt clinical skin disease. Skin biopsy showed a junctional split. He died at age 6.5 months of respiratory infection.

Pathogenesis

Has et al. (2012) analyzed skin samples from an Italian boy who had mild epidermolysis bullosa associated with congenital interstitial lung disease and nephrotic syndrome. Light microscopy showed a flat epidermis without rete ridges, and subepidermal blisters were present. Transmission electron microscopy showed a thin lamina densa that was discontinuous between the hemidesmosomes. Keratin filaments, desmosomes, hemidesmosomes, and anchoring fibrils appeared to be normal. Immunofluorescence mapping revealed focal disruption of the dermal-epidermal junction with cleavage within the basement membrane. Has et al. (2012) noted that these changes did not correspond to any known type of epidermolysis bullosa in humans, but bore a striking resemblance to the findings described in the integrin alpha-3 (ITGA3; 605025) knockout mouse.

Molecular Genetics

In an Italian boy with congenital interstitial lung disease, nephrotic syndrome, and mild epidermolysis bullosa, who died at 7.5 months of age of a lung infection, Has et al. (2012) excluded mutation in the NPHS2 (604766) and WT1 (607102) genes as a cause of the nephrotic syndrome and also ruled out mutation in the CFTR (602421) and ABCA3 (601615) genes as a cause of the interstitial lung disease. The authors observed that patient skin samples resembled those of the integrin alpha-3 knockout mouse, and a lack of ITGA3 immunoreactivity in patient tissue samples was confirmed. Direct sequencing of patient DNA revealed homozygosity for a 1-bp deletion in the ITGA3 gene (605025.0001) that was present in heterozygosity in the unaffected parents. Analysis of ITGA3 in 2 similarly affected unrelated girls revealed homozygosity for a splice site and a missense mutation (605025.0002 and 605025.0003).

In a male infant with ILNEB, Yalcin et al. (2015) identified a homozygous missense mutation in the ITGA3 gene (R463W; 605025.0004). Studies of patient cells indicated that the mutant protein did not undergo proper processing of N-linked oligosaccharides. There was intracellular accumulation of ITGA3, lack of expression at the cell membrane, and no association with the ITGB1 (135630) subunit. The findings suggested that the mutation caused impaired posttranslational processing of ITGA3.