Genes provide clues to cardiocutaneous desmosome disorders

Key Points

"Genetic disorders of skin integrity are the Western world's equivalent of the olden days' leprosy in that most of them are incurable and unsightly. And the patients who have these disorders are often shunned in society even though they are not contagious," says Dedee F. Murrell, M.D., chair of dermatology, St. George Hospital, Sydney, Australia.

Although many of these disorders are rare "orphan" diseases caused by genetic defects affecting essential proteins that hold the skin together, "Much more is understood about their pathogenesis. An understanding of the diseases is the first essential step toward confirming a genetic diagnosis and enabling, where desired, prenatal diagnosis," Dr. Murrell tells Dermatology Times.

In particular, cardiocutaneous desmosome genetic diseases stem from genetic abnormalities in desmosomes - the "glue" that holds cells in heavily stressed tissues together, Dr. Murrell says.

The cardiocutaneous desmosome genetic disease with the highest profile may be arrhythmogenic right ventricular cardiomyopathy (ARVC). This autosomal dominant condition results from a mutation in plakophilin 2 (a desmosomal component that usually resides in the conduction tissue of the heart, and not the skin or hair).

In this condition, Dr. Murrell says, "Usually the parents are normal, but when the embryo is developing, genetic mistakes can develop and no one knows why. So the baby is born with a mutated gene" that by early adulthood can cause unexpected, sudden heart damage that ultimately proves lethal in apparently fit young athletes.

In the past year, researchers also have discovered that another desmosome gene defect - in desmoglein 2 - can cause similar problems. Like plakophilin 2, desmoglein 2 is only expressed in the heart, unlike desmogleins 1 and 3, which physicians recognize in the skin, Dr. Murrell says.

"So if one gets a problem with desmoglein 2 genetically, it's going to cause a heart disease rather than skin or hair disease," she says.

Conversely, desmosome genetic diseases that present to dermatologists include Naxos disease, which stems from a mutation (tail truncation) in the gene encoding plakoglobin, which is expressed in the heart, skin and hair. Naxos disease symptoms include cardiomyopathy, late onset palmoplantar keratoderma (PPK) and woolly hair, she says.

"Naxos disease was discovered on the Greek island of Naxos. People on this island inbred for generations," she says, giving rise to a cluster of cases of this recessive condition in which heterozygous parent carriers appear normal.

Its most worrisome manifestations include heart arrhythmias, sudden death and endomyocardial fibrous and fatty replacement, she adds.

The discovery of tail truncation in plakoglobin (Lancet. 2000 Jun 17; 355(9221):2119-2124) is "useful to know because it allows one to predict whether an embryo someone is carrying is affected before birth" through now-standard chorionic villus sampling (CVS) tests at 10 weeks' gestation, she says. However, each affected family has its own distinct mutation(s) which needs to be detected before the particular CVS can be offered.

Cutaneous presentations

On the other hand, striate PPK may occur, usually in adults, in linear patterns on the fingers and toes as a result of any of three desmosomal gene defects - desmoplakin haplotype insufficiency or problems with desmoglein 1 or keratin 1 - she says.

"It's dominant," Dr. Murrell adds, "so it's usually present in one parent who passes it down to their children" with 50-50 odds. "Or it can develop as a mistake in utero, as a new dominant condition that can be passed on. It's very uncomfortable and annoying," but it does not impact the hair or heart.