Nonbullous ichthyosiform erythroderma

Epidermolytic hyperkeratosis

Epidermolytic hyperkeratosis, also known as Bullous Ichthyosis or bullous congenital ichthyosiform erythroderma Brocq is a rare skin disease in the ichthyosis family affecting around 1 in 250,000 people.

Presentation

At birth, affected babies are called "enfant brûlée", from the French for "burned child", because they look red and have a fragile top layer of skin which easily forms blisters and wounds. Such injury can be caused by diapers, or just by touching the baby. The wounds should be properly cared for, otherwise they are at risk from infection.

The skin is stressed by birth. It gets better after some weeks and fewer blisters are formed. Some months later the skin starts scaling; this is caused by hyperkeratosis. There is a fairly large variation in the degree and extent of the scaling and the blisters.

In particular, some patients have scaling and blisters on the palms and soles of the feet, whereas others do not. Usually scaling is seen on the rest of the body, often concentrated around the joints.

Additionally, the skin develops blisters (hence the bullous part of the name). Typically these will be more common in children than in adults. Sufferers of the disease may also experience ectropion, palmoplantar keratoderma with or without ainhum, frequent superimposed infections, and foul odor. The quality of life for afflicted individuals was poor until the advent of treatment with oral retinoids.

Genetics

This is a dominant genetic condition caused by mutations in the genes encoding the proteins keratin 1 or keratin 10.

  • Keratin 1 is associated with the variants affecting the palms and soles.
  • Keratin 10 is associated with the variants in which these are unaffected.

Key findings

  • skin: generalized redness; thick, generally dark, scales that tend to form parallel rows of spines or ridges,especially near large joints; the skin is fragile and blisters easily following trauma; extent of blistering and amount of scale is variable
  • nails: thickening or dystrophy of one or more nails (common)
  • hair: often sparse; no shaft abnormalities

Treatment

Oral retinoids have proven effective in treating this disease. Examples are etretinate, acitretin, isotretinoin

Gene Therapy

Gene Therapy is really the only true therapy on the horizon for sufferers of EHK.

Over the past 10 years since the first EHK mouse model was developed, many ideas have been discussed about how best to cure EHK. Back as far as 1994 researchers were discussing new promising ideas such as topical lotions that would deliver ribozymes in a liposom cream. Ribozymes are a small piece of synthetic RNA which can act like a knife. When all cells decide to make a protein from a gene on a chromosome sitting in the nucleus, the gene is first copied as a piece of RNA. This RNA is then decoded into a protein or enzyme. Ribozymes can be designed to specifically destroy a piece of RNA bearing an evil mutation. In theory, this will stop the production of a bad protein or enzyme, so that the other normal 50% can work without interference. This sounded like a promising theory however virtually no research funding has been applied to this idea over the past 10 years.

Luckily other new ideas have moved to the foreground that are even more promising. Successful gene therapy solutions have been recently achieved on mouse models by Jiang Chen M.D., a post-doctoral fellow in the laboratory of Dennis Roop, Ph.D., in the Center for Cutaneous Molecular Biology at Baylor College of Medicine's departments of molecular and cellular biology and dermatology in Houston.

In 1998 they developed an inducible mouse model for epidermolysis hyperkeratosis which is viable, due to the fact that the expression of a mutant K10 allele can be restricted to a focal area of the skin. "Once the mutant K10 allele is activated in epidermal stem cells by topical application of an inducer, these stem cells continuously give rise to defective progeny that form hyperkeratotic lesions which persist for the life of the mouse. It was observed that partial suppression of the mutant K10 gene may be sufficient to eliminate the disorder."

To test this observation, Dr. Chen and his team of researchers developed siRNAs that target the mutant K10 genes for degradation, without affecting normal K10 genes. Dr. Chen observed that under these conditions, an efficient knock-down of mutant, but not normal, K10 genes could be achieved. The results allowed the normal K10 genes to function properly building healthy skin tissues. He claims that these results may prove to be a very vital step forward in forging a novel gene therapy and possible permanent corrective therapy for this debilitating skin disease.

Next Steps...

Larger animal models are the next step required to determine the safety and efficacy of novel in vivo therapies before testing in human subjects. A spontaneously occurring large animal model has been identified as the recessive dystrophic EB in golden retrievers where type-VII collagen is absent. This disease has successfully been corrected using retroviral vectors and ex vivo gene transfer. Norfolk Terriers have been identified as having epidermolytic hyperkeratosis naturally. Once these cases have been cured as the golden retrievers have been cured for EB, EHK will be ready for human clinical trials. If anyone is aware of this next critical step being worked on, please post details about it here.

Maintenance

Until gene therapy solutions finally become reality, EHK sufferers must treat their fragile skin carefully. Most have learned that taking regular extended baths allows patients to care for their fragile skin and keep it manageable. Baths that include sea salt seem to improve the process of softening and removing the thickened skin. Occasionally adding bleach to the bath water helps to reduce the risk of skin infections and reduces blistering. The first step in a successful bath is to remove topical oils with soap to allow the water to penetrate the skin layers. Sometimes, a pre-bath shower with body jels (detergents) helps to remove the topical oils from the skin. This keeps the soaps out of the bathwater that can irritate the fragile skin. Once the oils have been removed, soaking the skin in the bath can begin. The skin will whiten and soften up after 20-30 minutes of soaking. Various textures of pumice stones work better for different parts of the skin to remove the thickened layers. Rough skin removing creams such as "Pretty Hands & feet" also work well at this point to help remove the thickened skin from delicate areas. Once the skin has been buffed down to a normal thickness it will be more flexible and less likely to crack under motion. This fragile skin needs to be immediately be protected after getting out of the bath. Regular skin lotions do not work effectively in protecting skin that is this fragile. EHK skin needs to have the moisture locked in to keep it flexible. Using a thick petroleum oil (Vaseline) works best to protect the skin and to seal in valuable moisture. The generic petroleum jelly is actually thicker and works better. These daily bathing rituals, while time consuming, can allow EHK patients to live relatively normal lives.

See also

References

  • Barker, Jonathan; McGrath, John Cell Adhesion and Migration in Skin Disease (Cell Adhesion and Communication). Boca Raton: CRC Press.
  • Traupe, Heiko (1989). The Ichthyoses A Guide to Clinical Diagnosis, Genetic Counseling and Therapy. Berlin: Springer Verlag.

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