Pathogenesis and clinical features of alopecia in epidermolysis bullosa: A systematic review.

BACKGROUND: Epidermolysis bullosa (EB) is a group of rare genetic skin diseases characterized by the gene mutations encoding adhesion proteins within the skin. These adhesion proteins are also present in normal hair follicles. Anecdotally, there have been reports of scalp alopecia as a complication of EB and there are scattered cases in the literature, but alopecia has generally been overlooked in severe blistering diseases because it is regarded as a cosmetic issue. Therefore, there is no consensus about the natural history and clinical manifestations of alopecia in EB to allow potential intervention. OBJECTIVES: To review the current literature detailing the pathogenesis and clinical presentations of alopecia in EB patients. METHODS: Relevant human studies were searched in Medline, PubMed, and EMBASE electronic databases up to October 2018. RESULTS: Only 15 reports detailed 29 EB patients with demographic and clinical manifestations of alopecia. Vertical biopsy sections were the most common method of alopecia diagnosis, and the most common pattern was patchy scalp alopecia (45%) followed by diffuse alopecia (41%). The most robust finding was nonspecific scarring alopecia in all dystrophic EB (DEB) patients and nonspecific nonscarring alopecia in most patients with EB simplex (EBS). CONCLUSIONS: Hair abnormalities observed in EB are of variable severity despite there being no universal validated alopecia scoring system, with alopecia occurring secondary to blistering, or in areas prone to trauma.

Keratin mutations of epidermolysis bullosa simplex alter the kinetics of stress response to osmotic shock.

The intermediate filament cytoskeleton is thought to confer physical resilience on tissue cells, on the basis of extrapolations from the phenotype of cell fragility that results from mutations in skin keratins. There is a need for functional cell assays in which the impact of stress on intermediate filaments can be induced and analyzed. Using osmotic shock, we have induced cytoskeleton changes that suggest protective functions for actin and intermediate filament systems. Induction of the resulting stress response has been monitored in keratinocyte cells lines carrying K5 or K14 mutations, which are associated with varying severity of epidermolysis bullosa simplex. Cells with severe mutations were more sensitive to osmotic stress and took longer to recover from it. Their stress-activated response pathways were induced faster, as seen by early activation of JNK, ATF-2 and c-Jun. We demonstrate that the speed of a cell's response to hypotonic stress, by activation of the SAPK/JNK pathway, is correlated with the clinical severity of the mutation carried. The response to hypo-osmotic shock constitutes a discriminating stress assay to distinguish between the effects of different keratin mutations and is a potentially valuable tool in developing therapeutic strategies for keratin-based skin fragility disorders.

[Keratin diseases]. / Keratinsygdomme.

The rapid development in human genome research has resulted in a tremendous increase in our understanding of the molecular basis of many genetic skin diseases. One outstanding example of this is diseases caused by mutations in keratin genes, which comprise several disorders of the epidermis, as for example the different types of epidermolysis bullosa simplex. In this respect, the most important questions have been to 1. Define the molecular defect. 2. Unravel the pathophysiological mechanisms that lead to the characteristic phenotype and 3. Design of new therapeutic strategies. Molecular research has contributed significantly to the first two issues whereas a therapeutic break-through has yet to appear.

Disease severity correlates with position of keratin point mutations in patients with epidermolysis bullosa simplex.

Keratins are the major structural proteins of the epidermis. Recently, it was discovered that point mutations in the epidermal keratins can lead to the blistering skin diseases epidermolysis bullosa simplex (EBS) and epidermolytic hyperkeratosis (EH), involving epidermal cell fragility and rupture upon mechanical stress. In this study, we demonstrate a correlation between disease severity, location of point mutations within the keratin polypeptides, and degree to which these mutations perturb keratin filament structure. Interestingly, of the 11 EBS or EH mutations thus far identified, 6 affect a single highly evolutionarily conserved arginine residue, which, when mutated, markedly perturbs keratin filament structure and keratin network formation. This site also appears to be a hot spot for mutation by CpG methylation and deamination. In the four epidermal keratins, there are several other CpG dinucleotides that exist at codons within the highly conserved ends of the keratin rod. To elucidate why mutations at these sites have not been detected in severe cases of EBS, we engineered 7 of these C-->T transitions in K14 and tested their ability to perturb keratin network formation and keratin filament assembly in vitro. The effects of these mutants on keratin filament network formation were significantly less severe than the EBS/EH arginine mutation, suggesting that the high incidence of mutations of the residue in EBS and EH patients is a result of both a special sensitivity of filament structure to perturbations in this residue and its susceptibility to mutagenesis.