Localized dominant dystrophic epidermolysis bullosa worsened by diabetes

Dystrophic epidermolysis bullosa (DEB) is a clinically heterogeneous blistering disease caused by pathogenic variants in the COL7A1 gene. Phenotypes range from localized to generalized and are primarily determined by the variant type, though additional modifiers influence disease severity. To characterize the molecular basis of the disease phenotype in a diabetic patient presenting with localized skin blistering and nail dystrophy. Skin biopsies were taken from the index patient for immunofluorescence mapping and keratinocyte culture. Exome sequencing was used to screen for pathogenic variants and Sanger sequencing for variant segregation in family members. COL7A1 mRNA and protein studies were performed by reverse transcriptase-PCR analysis and western blot. Advanced glycation end products in skin were analysed by confocal immunofluorescence microscopy. Molecular analysis identified a heterozygous COL7A1 splice variant, c.5053-1G>C, which resulted in both an exonic deletion and an intronic insertion with decay of the mutant transcripts, leading to about half of the normal levels of mRNA and protein in the patient's keratinocytes. Although the diabetic proband was the only family member developing recurrent skin blisters, great toenail dystrophy segregated with the variant in the offspring. Functional COL7A1 haploinsufficiency is therefore the most likely mechanism for the segregation of this mild DEB trait in the family. Increased protein glycation was detected in the proband's skin. The effects of the mutation and increased protein glycation in the proband's skin suggest a concurrent effect of diabetic dermopathy and COL7A1 pathology on skin fragility.