Epidermolysis bullosa (EB) is most often due to a genetic mutation that makes the skin extremely fragile and prone to often severe blistering.
Genetic causes of EB include a defective gene that is inherited from one or both parents, or spontaneous mutations that can make the child the first in the family to have the disease.
Non-genetic EB is caused by the immune system wrongly attacking healthy tissue.
Genetic causes
In most cases, patients inherit the defective gene causing EB from one or both parents. Different types of EB are caused by mutations in different genes involved in the formation of skin layers — the epidermis (outer layer), the dermis (underlying layer), and the basement membrane zone, or the area where the dermis and epidermis meet.
An individual’s DNA contains coding sequences called genes, which provide the information necessary to make proteins.
The faulty genes causing EB can be inherited in two ways — autosomal recessive and autosomal dominant.
Autosomal recessive inheritance
In this case, both copies of the gene, each inherited from one biological parent, are defective. The parents are said to be carriers — they each carry one defective gene copy, but its effect is compensated or masked by the other and normal gene copy. Still,  they can pass the disease-causing mutation along to a child while they themselves do not show symptoms, and a possibly unaware of their carrier status. When both parents are carriers, there is a 25% chance of their child developing the disease.
Recessive inheritance of EB appears to associate both with the disease’s rarity and with its more severe symptoms.
Junctional EB, inherited in an autosomal recessive manner, is most commonly caused by defects in the genes that promote the formation of hemidesmosomes (structures that anchor epidermal cells to those of the underlying dermis) and anchoring fibrils, which are critical for linking the epidermis to the dermis. Among those genes are COL17A1, LAMA3, LAMB3, and LAMC2.
Kindler syndrome is another, and more rare, type of EB with autosomal recessive inheritance. It is caused by mutations in the FERMT1 gene, which gives instructions to produce a protein that has a key role in keratinocytes (a major component of the epidermis).
Autosomal dominant inheritance
Here, a mutation in one of the copies of a gene is enough for EB to develop. Since the defective gene copy dominates the effect of the normal copy, the parent carrying the faulty gene also has the disease. In autosomal dominant inheritance, there is a 50% chance that a child will develop EB.
Dominant inheritance appears to be associated with less severe disease.
EB simplex, this disorder’s most common form, is usually inherited as an autosomal dominant disease, caused by defects in genes coding for keratin proteins (a protein of the outer skin layer), typically KRT5 and KRT14.
Dystrophic EB, another major disease form, is caused by defects in the COL7A1 gene that encodes for the type VII collagen protein — a major structural component of anchoring fibrils. It can be inherited in both recessive and dominant ways.
Spontaneous mutation
EB can also be caused by spontaneous mutations that occur in the egg or sperm cells of a parent. In such a case, neither adult is a carrier of a faulty gene, but their child can still develop the disease.
Non-genetic causes
EB acquisita is an autoimmune disorder in which the body makes antibodies against the type VII collagen protein, resulting in a loss of anchoring fibrils and subsequent blistering. EB acquisita, typically diagnosed in adults and without a genetic link, has been reported in people affected by other diseases, including  Crohn’s disease, systemic lupus erythematosus, amyloidosis, myeloma, lung cancer, and lymphoma.
Last updated: July 7, 2021
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