Epidermolysis Bullosa

Epidermolysis Bullosa (EB) is a group of genetic skin conditions characterized by fragile skin and easy blistering. The skin is so fragile in people with EB that even minor rubbing may cause blistering. At times, the person with EB may not be aware of rubbing or injuring the skin even though blisters develop. In severe EB, blisters are not confined to the outer skin. They may develop inside the body, in such places as the linings of the mouth, esophagus, stomach, intestines, upper airway, bladder, and the genitals.

A diagrammatic sectional view of the skin (magnified). Source: Grey's Anatomy, 1918.

Types

EB can be acquired or inherited.

Aquista

The single type of aquired EB is EB Aquista (EBA). EBA is a rare autoimmune disorder where the body attacks its own anchoring fibrils with antibodies, the special proteins that help fight and destroy foreign substances that invade the body. In a few cases, it has occurred following drug therapy for another condition; in most cases, the cause is unknown. This form of the condition has been associated with Crohn's Disease, an inflammatory bowel disease. ^[1]

Simplex

In this type, blisters form in the epidermal layer of the skin. Symptoms usually begin in infancy or early childhood.

• The mildest form of epidermolysis bullosa simplex, known as the Weber-Cockayne type, is characterized by skin blistering that begins anytime between childhood and adulthood and is usually confined to the hands and feet. Later in life, skin on the palms and soles of the feet may thicken and harden (hyperkeratosis).
• In the Koebner type of EB simplex, blisters appear at birth or in early infancy and are more widespread. Another form of the disorder, called epidermolysis bullosa simplex with mottled pigmentation, is characterized by patches of darker skin on the trunk, arms, and legs that fade in adulthood. This form of the disorder also involves skin blistering from early infancy, hyperkeratosis of the palms and soles, and abnormal nail growth.
• The Dowling-Meara type is the most severe form of epidermolysis bullosa simplex. Extensive, severe blistering can occur anywhere on the body, including the inside of the mouth, and blisters may appear in clusters. Blistering is present from birth and tends to improve with age. Affected individuals also experience abnormal nail growth and hyperkeratosis of the palms and soles.
• Researchers have identified another skin condition characteristic of epidermolysis bullosa simplex, which they call Ogna type. It is caused by mutations in a gene that is not associated with the other types of epidermolysis bullosa simplex. It is unclear whether Ogna type is a subtype of epidermolysis bullosa simplex or represents a separate form of epidermolysis bullosa.

Junctional

This type of EB occurs in the basement membrane at the level of the lamina lucida. It usually begins at birth and is usually a more severe form of the disease. Death tends to occur early as a result of blistering of the internal organs. Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally around the trachea. Blisters generally heal with no significant scarring. There are two types of JEB: ^[2]

• In Herlitz (or lethal) JEB, the classic severe form of JEB, blisters are present at birth or become apparent in the neonatal period. Congenital malformations of the urinary tract and bladder may also occur.
• In non-Herlitz (non-lethal) JEB, the phenotype may be mild with blistering localized to hands, feet, knees, and elbows with or without renal or ureteral involvement. Some individuals never blister after the newborn period. Additional features shared by JEB and the other major forms of epidermolysis bullosa (EB) include congenital localized absence of skin (aplasia cutis congenita), milia, nail dystrophy, scarring alopecia, hypotrichosis, pseudosyndactyly, and other contractures.

Dystrophic

Dystrophic or dermolytic EB occurs in the deeper tissue under the basement membrane at the level of the lamina densa or upper dermis and often causes scarring. Considered together, the incidence of all types of dystrophic epidermolysis bullosa is estimated to be 6.5 per million newborns in the United States. The severe autosomal recessive forms of this disorder affect fewer than 1 per million newborns. ^[3] There are three types of dystrophic EB:

• Autosomal recessive dystrophic epidermolysis bullosa, Hallopeau-Siemens type (RDEB-HS) is the most severe type. Infants may be born with blistering and raw skin resulting from the birth process. Blisters may occur throughout the body, including the mouth and digestive tract. In addition, scarring can affect the fingers and toes, causing difficulties with ambulation and painful scarring and contracture. Eye inflammation can cause visual problems. Adults with this type of EB are at an increased risk of squamous carcinoma of the skin. ^[4]
• A second type of autosomal recessive dystrophic epidermolysis bullosa is the non-Hallopeau-Siemens type (non-HS RDEB). This form of the condition is somewhat less severe than the classic type and includes a range of subtypes. Blistering is limited to the hands, feet, knees, and elbows in mild cases, but may be widespread in more severe cases. The fingernails and toenails may be disformed. Non-HS RDEB involves scarring in the areas where blisters occur, but this form of the condition does not cause the severe scarring characteristic of RDEB-HS.
• The final type of dystrophic epidermolysis bullosa is known as the autosomal dominant type (DDEB). The signs and symptoms of this condition tend to be milder than those of the autosomal recessive forms. Blistering may only occur on the hands, feet, knees, and elbows. Scarring may occur, but it is usually not severe. Most affected people have malformed fingernails and toenails, and the nails may be lost over time. In the mildest cases, abnormal nails are the only sign of the condition.

Hemidesmosomal

Researchers have proposed an additional type — hemidesmosomal epidermolysis bullosa — one form of which is associated with muscular dystrophy, an inherited disease that involves progressive weakening of muscles. ^[5]

Signs and Symptoms

Signs and symptoms of epidermolysis bullosa may include:

• Blistering of the skin — severity varies depending on type.
• Deformity or loss of fingernails and toenails
• Internal blistering, possibly involving the throat, esophagus, upper airway, stomach, intestines and urinary tract
• Skin thickening on palms and soles of the feet (hyperkeratosis)
• Scalp blistering, scarring and hair loss (scarring alopecia)
• Thin-appearing skin (atrophic scarring)
• Tiny white skin bumps or pimples (milia)
• Dental abnormalities, such as tooth decay from poorly formed tooth enamel
• Excessive sweating
• Difficulty swallowing (dysphagia)

Causes

Most people with EB have inherited the condition through faulty genes they receive from one or both parents. Genes are located in the body's cells and determine inherited traits passed from parent to child. They also govern every body function, such as the formation of proteins in the skin. More than 10 genes are known to underlie the different forms of EB. Genes are located on chromosomes, which are structures in each cell's nucleus.

In an autosomal dominant form of EB, the disease gene is inherited from only one parent who has the disease, and there is a 50% (1 in 2) chance with each pregnancy that a baby will have EB. In the autosomal recessive form, the disease gene is inherited from both parents. Neither parent has to show signs of the disease; they simply need to "carry" the gene, and there is a 25% (1 in 4) chance with each pregnancy that a baby will have EB. EB can also be acquired through a mutation (abnormal change) in a gene that occurred during the formation of the egg or sperm reproductive cell in a parent. Neither the sex of the child nor the order of birth determines which child or how many children will develop EB in a family that has the faulty gene.

Although EB Simplex can occur when there is no evidence of the disease in the parents, it is usually inherited as an autosomal dominant disease. In EB Simplex, the faulty genes are those that provide instructions for producing keratin, a fibrous protein in the top layer of skin. As a result, the skin splits in the epidermis, producing a blister.

In Junctional EB, there is a defect in the genes inherited from both parents (autosomal recessive) that normally promote the formation of anchoring filaments (thread-like fibers) or hemidesmosomes (complex structures composed of many proteins). These structures anchor the epidermis to the underlying basement membrane. The defect leads to tissue separation and blistering in the upper part of the basement membrane.

There are both dominant and recessive forms of Dystrophic EB. In this condition, the filaments that anchor the epidermis to the underlying dermis are either absent or do not function. This is due to defects in the gene for type VII collagen, a fibrous protein that is the main component of the anchoring filaments.

Diagnosis

Dermatologists can identify where the skin is separating to form blisters and what kind of EB a person has by doing a skin biopsy (taking a small sample of skin that is examined under a microscope). One diagnostic test involves use of a microscope and reflected light to see if proteins needed for forming connecting fibrils, filaments, or hemidesmosomes are missing or reduced in number. Another test involves use of a high-power electron microscope, which can greatly magnify tissue images, to identify structural defects in the skin.

Recent techniques make it possible to identify defective genes in EB patients and their family members. Prenatal diagnosis can now be accomplished by amniocentesis (removing and examining a small amount of amniotic fluid surrounding the fetus in the womb of a pregnant woman) or sampling of the chorionic villus (part of the outer membrane surrounding the fetus) as early as the tenth week of pregnancy.

Treatment

There is no cure for EB, however, complications can be avoided through prevention and early intervention for skin problems. Treatment is mainly supportive and consists of protection of the skin against trauma, attention to nutritional deficiencies and dietary complications, prevention of infection, treatment of deformities and contractures, and psychological support, if needed. Some patients may have mild disease and not require much treatment while others may need a great deal of intervention.

Medications

The most common use of medication in EB is antibiotics, for treatment of skin infection, and pain medicines when needed.

Therapies

Physical therapy may be helpful in increasing the range of motion caused by scarring of the limbs.

Surgical treatment may be necessary in some forms of EB. Individuals with the severe forms of dystrophic EB whose esophagus has been narrowed by scarring may require dilation of their esophagus for food to travel from the mouth to the stomach. Other individuals who are not getting proper nutrition may need a feeding tube that permits delivery of food directly to the stomach. Also, patients whose fingers or toes are fused together may require surgery to release them.

Prevention

In many forms of EB, blisters will form with the slightest pressure or friction. This may make parents hesitant to pick up and cuddle young babies. However, a baby needs to feel a gentle human touch and affection, and can be picked up when placed on a soft material and supported under the buttocks (bottom) and behind the neck. A baby with EB should never be picked up under the arms.

A number of things can be done to protect the skin from injury. These include:

• Avoiding overheating by keeping rooms at an even temperature
• Applying lubricants to the skin to reduce friction and keep the skin moist
• Using simple, soft clothing that requires minimal handling when dressing a child
• Using sheepskin on car seats and other hard surfaces
• Wearing mittens at bedtime to help prevent scratching

Living with Epidermolysis Bullosa

Persons with mild forms of EB may not require extensive treatment. However, they should attempt to keep blisters from forming and prevent infection when blisters occur. Individuals with moderate and severe forms may have many complications and require psychological support along with attention to the care and protection of the skin and soft tissues. Patients, parents, or other care providers should not feel that they must tackle all the complicated aspects of EB care alone. There are doctors, nurses, social workers, clergy members, psychologists, dietitians, and patient and parent support groups that can assist with care and provide information and emotional support.

Caring for Blistered Skin

When blisters appear, the objectives of care are to reduce pain or discomfort, prevent excessive loss of body fluid, promote healing, and prevent infection.

The doctor may prescribe a mild analgesic to prevent discomfort during changes of dressings (bandages). Dressings that are sticking to the skin may be removed by soaking them off in warm water. While daily cleansing may include a bath with mild soaps, it may be more comfortable to bathe in stages where small areas are cleaned at a time.

Blisters can become quite large and create a large wound when they break. Therefore, a medical professional will likely provide instructions on how to safely break a blister in its early stages while still leaving the top skin intact to cover the underlying reddened area. One technique is to pat the blister with an alcohol pad before popping it at the sides with a sterile needle or other sterile tool. The fluid can then drain into a sterile gauze that is used to dab the blister. After opening and draining, the doctor may suggest that an antibiotic ointment be applied to the area of the blister before covering it with a sterile, nonsticking bandage. To prevent irritation of the skin from tape, a bandage can be secured with a strip of gauze that is tied around it. In milder cases of EB or where areas are difficult to keep covered, the doctor may recommend leaving a punctured blister open to the air.

A moderately moist environment promotes healing, but heavy drainage from blister areas may further irritate the skin, and an absorbent or foam dressing may be needed. There are also contact layer dressings where a mesh layer through which drainage can pass is placed on the wound and is topped by an outer absorbent layer. The doctor or other health care professional may recommend gauze or bandages that are soaked with petroleum jelly, glycerin, or moisturizing substances, or may suggest more extensive wound care bandages or products.

Treating Infection

The chances of skin infection can be reduced by good nutrition, which builds the body's defenses and promotes healing, and by careful skin care with clean hands and use of sterile materials. For added protection, the doctor may recommend antibiotic ointments and soaks.

Even in the presence of good care, it is possible for infection to develop. Signs of infection are redness and heat around an open area of skin, pus or a yellow drainage, excessive crusting on the wound surface, a red line or streak under the skin that spreads away from the blistered area, a wound that does not heal, and/or fever or chills. The doctor may prescribe a specific soaking solution, an antibiotic ointment, or an oral antibiotic to reduce the growth of bacteria. Wounds that are not healing may be treated by a special wound covering or biologically developed skin.

Treating Nutritional Problems

Blisters that form in the mouth and esophagus in some people with EB are likely to cause difficulty in chewing and swallowing food and drinks. If breast or bottle feeding results in blisters, infants may be fed using a preemie nipple (a soft nipple with large holes), a cleft palate nipple, an eyedropper, or a syringe. When the baby is old enough to take in food, adding extra liquid to pureed (finely mashed) food makes it easier to swallow. Soups, milk drinks, mashed potatoes, custards, and puddings can be given to young children. However, food should never be served too hot.

Dietitians are important members of the health care team that assists people with EB. They can work with family members and older patients to find recipes and prepare food that is nutritious and easy to consume. For example, they can identify high-caloric and protein-fortified foods and beverages that help replace protein lost in the fluid from draining blisters. They can suggest vitamin and mineral nutritional supplements that may be needed, and show how to mix these into the food and drinks of young children. Dietitians can also recommend adjustments in the diet to prevent gastrointestinal problems, such as constipation, diarrhea, or painful elimination.

Genetic Counseling

Epidermolysis bullosa is a difficult, sometimes painful, and often disfiguring disease. Most adults with signs of EB or who know they carry the gene would like to spare future generations, including their own potential offspring, from this condition. With the knowledge of specific gene mutations that cause EB, it is now possible to determine the specific gene mutation in the family and then to conduct prenatal tests on pregnant women with a fetus at risk of EB to determine the status of the fetus. Specific laboratories, such as the one affiliated with the Dystrophic Epidermolysis Bullosa Research Association (DebRA), can test for gene mutations. Also, a genetic counselor can provide information on the likelihood of passing the gene for EB to children and provide advice on future childbearing. Genetic counseling can be a crucial step in helping families make decisions about their family planning.

Chances of Developing Epidermolysis Bullosa

According to the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) ^[6], it is estimated that 2 to 4 out of every 100,000 people, or up to 12,000 people in the United States, have some form of EB. It occurs in all racial and ethnic groups and affects males and females equally. The disease is not always evident at birth. Milder cases of EB may become apparent when a child crawls, walks, or runs, or when a young adult engages in vigorous physical activity.

Related Problems

• The risk of dental caries (cavities) is greatly increaed in EB patients, particularly the dystrophic and junctional types, likely due to disease involvement of the soft tissues of the mouth and enamel of the teeth. ^[7]
• Eye complications (blisters, etc) are also common in dystrophic and junctional EB. ^[8]
• Growth problems (failure to thrive) may occur if blisters are present in the mouth or digestive tract or if scarring is present in the esophagus. Diligent nutritional management may be required to maintain a healthy weight and to help the body fight infection.

Clinical Trials

• A list of ongoing clinical trials is available at ClinicalTrials.gov: epidermolysis bullosa trials.
• Stanford University will be starting an EB gene trial study. Information is available on the University School of Medicine, Dermatology web site. Information about Epidermolysis Bullosa (EB).
• The University of Minnesota has an ongoing clinical trial regarding stem cell therapy for recessive dystrophic epidermolysis bullosa, available at the University of Minnesota Center for Translational Medicine. Stem Cell Therapy for Recessive Dystrophic Epidermolysis Bullosa.

Research

• A recent study showed that congenital localized absence of skin, called Bart syndrome, may occur with any of the three major types of EB, rather than primarily with dominant dystrophic EB, as previously thought. ^[9]
• Cardiomyopathy is an uncommon complication of inherited EB, and may be fatal. ^[10]
• A stem cell research center in Italy plans the first phase I/II gene therapy clinical trial for junctional EB. ^[11]
• Therapeutic options for Epidermolysis bullosa acquisita (EBA), the only autoimmune type of EB, were discussed in a recent study. Colchicine, dapsone, photophoresis, infliximab and intravenous immunoglobulin. ^[12]

Interesting Facts

Famous people

The Emmy-award winning 2004 documentary, The Boy Whose Skin Fell Off, was based on the life of Johnny Kelly, a 36 year old man who died of skin cancer and had dystrophic epidermolysis bullosa. The film generated a great deal of attention and raised a great deal of money for the cause of epidermolysis bullosa. It can be viewed in installments on YouTube.

References

1. ↑ Raab B, Fretzin DF, Bronson DM, Scott MJ, Roenigk HH Jr, Medenica M. Epidermolysis bullosa acquisita and inflammatory bowel disease. JAMA. 1983 Oct 7;250(13):1746-8. Abstract
2. ↑ Pfendner E, Lucky A. Gene Reviews web site. Junctional Epidermolysis Bullosa
3. ↑ Genetics Home Reference web site. Dystrophic epidermolysis bullosa
4. ↑ Weber F, Bauer JW, Sepp N. Squamous cell carcinoma in junctional and dystrophic epidermolysis bullosa. Acta Derm Venereol. 2001 Jun-Jul;81(3):189-92. Abstract
5. ↑ Gache Y, Chavanas S, Lacour JP. Defective expression of plectin/HD1 in epidermolysis bullosa simplex with muscular dystrophy. J Clin Invest. 1996 May 15;97(10):2289-98. Abstract | PDF
6. ↑ National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) web site. Epidermolysis Bullosa
7. ↑ Wright JT, Fine JD, Johnson L. Dental caries risk in hereditary epidermolysis bullosa. Pediatr Dent. 1994 Nov-Dec;16(6):427-32. Abstract
8. ↑ Tong L, Hodgkins PR, Denyer J, et al. The eye in epidermolysis bullosa. Br J Opthamol. 1999 Mar;83(3):323-6. Abstract | Full Text
9. ↑ Medenica L, Lens M. Recessive dystrophic epidermolysis bullosa: presentation of two forms. Dermatol Online J. 2008 Mar 15;14(3):2. Abstract
10. ↑ Fine JD, Hall M, Weiner M, Li KP, Suchindran C. The risk of cardiomyopathy in inherited epidermolysis bullosa. Br J Dermatol. 2008 Jun 28. (Epub ahead of print) Abstract
11. ↑ Ferrari S, Pellegrini G, Matsui T, Mavilio F, DeLuca M. Towards a gene therapy clinical trial for epidermolysis bullosa. Rev Recent Clin Trials. 2006 May;1(2):155-62. Abstract
12. ↑ Remington J, Chen M, Burnett J, Woodley DT. Autoimmunity to type VII collagen: epidermolysis bullosa acquisita. Cur Dir Autoimmun. 2008;10:195-205. Abstract

External Links

Dystrophic Epidermolysis Bullosa Research Association of America, Inc. (DebRA)

Epidermolysis Bullosa Medical Research Foundation