Genotype, Clinical Course, and Therapeutic Decision Making in 76 Infants with Severe Generalized Junctional Epidermolysis Bullosa

Abstract

Severe generalized junctional epidermolysis bullosa, a lethal hereditary blistering disorder, is usually treated by palliative care. Allogeneic stem cell transplantation (SCT) has been proposed as a therapeutic approach, yet without clinical evidence. Decision making was evaluated retrospectively in 76 patients with severe generalized junctional epidermolysis bullosa born in the years 2000-2015. The diagnosis was based on the absence of laminin-332 in skin biopsies. With an incidence of 1 of 150,000, severe generalized junctional epidermolysis bullosa occurred more often than published previously. Eleven as yet unreported mutations in the laminin-332 genes were detected. Although patients homozygous for the LAMB3 mutation c.1903C>T lived longer than the others, life expectancy was greatly diminished (10.8 vs. 4.6 months). Most patients failed to thrive. In two patients with initially normal weight gain, the decision for SCT from haploidentical bone marrow or peripheral blood was made. Despite transiently increasing skin erosions, the clinical status of both subjects stabilized for several weeks after SCT, but finally deteriorated. Graft cells, but no laminin-332, were detected in skin biopsies. The patients died 96 and 129 days after SCT, respectively, one of them after receiving additional skin grafts. Treatment of severe generalized junctional epidermolysis bullosa by SCT is a last-ditch attempt still lacking proof of efficacy.

Attenuation of Severe Generalized Junctional Epidermolysis Bullosa by Systemic Treatment with Gentamicin

“…Mean survival of the five infants reported here was 8.1 months, not significantly higher than that of other patients with severe generalized JEB who lived for 5.8–6.5 months on average [7, 31]. The main therapeutic principle for this fatal disorder should be to offer comfort and company to the patient and his family, rather than aggressive therapies [13, 31].…”

“…Since more than 90% of the patients with severe generalized JEB carry nonsense mutations in one of the three laminin-332 genes, most of which are in-frame PTCs [6, 7], PTC read-through remains a therapeutic approach that clearly deserves further investigation. Other substances such as PTC124 or amlexanox have become available that are known to induce read-through with lower risks of inadvertent effects than described for aminoglycosides [16, 29, 30].…”

“…Laminin-332, a heterotrimer consisting of an α3-, β3-, and γ2-chain encoded by the genes LAMA3 , LAMB3 , and LAMC2 , respectively [1-5], is undetectable in most of these patients. More than 90% of them carry homozygous or compound-heterozygous premature termination codons (PTCs) in one of the three genes [6, 7], resulting in complete absence of functional laminin-332 and thus in a devastating clinical course with widespread erosions of the epidermis and mucous membranes, loss of protein, fluids, and iron, compromised wound healing, excessive formation of granulation tissue, respiratory complications, infections, and death within the first years of life [2, 4, 7]. Despite elaborate therapeutic approaches, including allogeneic stem cell transplantation, protein replacement therapy, and gene therapy, which has not yet been evaluated in clinical trials [7-12], severe generalized JEB cannot be cured so far.…”

An overview of the genetic basis of epidermolysis bullosa in Brazil: discovery of novel and recurrent disease‐causing variants

“…Attempts to correlate genotype and phenotype in JEB have been addressed by several studies . JEB‐generalized severe is commonly associated to variants leading to premature termination codons (PTC), such as nonsense, insertions/deletions, and specific splice‐site mutations, in both alleles of LAMB3 , LAMA3 or LAMC2 , which lead to a truncated and non‐functional laminin 332 .…”

Gene Therapy for Epidermolysis Bullosa

“…Of the seven patients who initially entered the trial, one died before receiving a transplant, likely due to cyclophosphamide cardiotoxicity, and another died after transplantation from infections associated with graft failure (Wagner et al, 2010). Bone marrow replacement was unable to favorably affect two patients with severe generalized JEB, with each patient dying between 3 and 5 months after therapy (Hammersen et al, 2016). Thus, the challenge remaining with this mode of therapy is to further reduce the serious risks it poses to patients.…”