414 Uncovering the cause of early lethality in generalized severe junctional epidermolysis bullosa

Abstract

Generalized severe junctional epidermolysis bullosa (JEB-GS) is a lethal and incurable autosomal recessive blistering skin disease, caused by null mutations in genes (LAMA3, LAMB3 & LAMC2) encoding for laminin-332, a heterotrimeric skin adhesive protein. Early lethality is a key feature of JEB-GS with an estimated mean age of survival of 5.8 months, however remains unexplained. In view of the high prevalence of sepsis and respiratory difficulties in these patients, we explored the possibility of defects in these organs in a new born JEB-GS patient. The male patient was the fourth child born to a consanguineous Syrian family, wherein one affected sibling died at 4 months of age due to sepsis. At birth, generalized skin blisters,hoarse cry, peri and subungual granulation were present. Immunofluorescence microscopy of skin biopsy showed complete absence of laminin-332 and mutational analysis revealed a homozygous mutation in LAMA3 gene (c.6745C>T; p.Gln2249*), confirming the diagnosis of JEB-GS. Computed tomography of chest showed an abnormal and remarkable reduction in thymic volume at 1 month of age (5750 mm3) as compared to an age matched control (31.7 cm3) and inconclusive lung abnormalities like ground glass opacities, volume loss and thickening of the interlobular septae. Flow cytometric analysis of cord (at birth) and peripheral blood (1 month age) showed apparently normal B and T cell subsets, except for a lowered absolute number of CD8+ T cells (0.24x109/L) as compared to control (0.55 x109/L). No further investigations were done as the parents preferred only comfort care at home. Later, the clinical condition worsened with extensive blisters, infections and respiratory difficulties leading to death at 4 months of age. These observations along with historical post-mortem reports strongly support the idea that laminin-332 is crucial in tissues beyond the skin, like thymus and lung. Regular screening for structural and functional defects in such organs is important for better understanding of the lethality of JEB-GS.