Junctional Epidermolysis Bullosa with Renal and Respiratory Involvement: Integrin α[Alpha]3 Mutations

Skin

Clinical features

Blisters, nail dystrophy, sparse hair

Immunomapping

Focal disruption of the dermo-epidermal junction, cleavage within the plane of the basement membrane

Transmission electron microscopy

Thin lamina densa, discontinuous between the hemidesmosomes

Kidney

Clinical and laboratory findings

Congenital nephrotic syndrome, peritoneal dialysis

Histology

Globally atrophic glomeruli, segmental glomerulosclerosis, diffuse interstitial fibrosis and tubular atrophy, renal dysplasia, focal segmental glomerulosclerosis

Transmission electron microscopy

Focal mesangial hyperplasia, podocyte effacement, lamellation of the basement membranes

Lung

Clinical features

Respiratory distress, oxygen dependency, aspiration pneumonia, recurrent respiratory infections

Chest radiograph

Interstitial reticulonodular changes

Computed tomography

Consistent with interstitial lung disease

Histology

Overinflation and mild-to-moderate simplification of airspaces, chronic pneumonitis, interstitial fibrosis

Transmission electron microscopy

Reduplicated and irregular alveolar basement membrane, abnormal lamellar bodies in the alveolar cells

All patients survived the neonatal period but died of multiorgan failure between the age of 4 and 19 months. Although the respiratory and renal features dominated the clinical picture, it was the investigation of the skin fragility that gave the clue to the diagnosis.

39.4 Integrin Α[Alpha]3 Mutations

Thus far, four ITGA3 mutations have been disclosed in patients with junctional EB with renal and respiratory involvement: one small deletion c.1173_1174del, p.Pro392ValfsX2, one splice site mutation c.1538–1G>a, and two missense mutations c.1883G>C, p.Arg628Pro and c.1045G>T, p.A349S [3, 12]. All were found in a homozygous state in the patients, whereas the parents were heterozygous carriers. The deletion mutation led to mRNA decay and absence of integrin α[alpha]3 expression. The missense mutations altered the posttranslational modification of mutant integrin α3 subunits [12, 13].

39.5 Morphological Analyses of the Skin, Kidney and Lung

Integrin α[alpha]3-negative human skin was atrophic and exhibited detachment of basal keratinocytes from the basement membrane, i.e. junctional cleavage of the skin. In contrast to the classical subtypes of junctional EB, in which the signal for laminin-332 is located at the base of the blister [14], in this case laminin-332 was present both at the base and the roof of the blister (Fig. 39.1). The basement membrane-associated collagens IV and VII demonstrated irregular and disorganised staining patterns at the dermo-epidermal junction. Transmission electron microscopy of the skin was consistent with a severely disrupted cutaneous basement membrane, with a thin lamina densa that was discontinuous between the hemidesmosomes [3].

Fig. 39.1

Morphology of the skin in junctional EB with renal and respiratory involvement: (a) H&E staining shows a subepidermal skin split. (b) Immunofluorescence staining of control (left) and patient’s (right) skin with an antibody to the laminin β[beta]3 chain. It demonstrates a positive signal for the laminin β[beta]3 chain at both the blister base and the blister roof in the patient’s skin; this indicates disorganisation and disruption of the basement membrane. (c) Infant with erosions on the lower legs and a biopsy site (courtesy Dr Lisa Weibel, Kinderspital Zürich).

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