EB Simplex

What is the cause of EB Simplex?

Through research it is now known that the genes that carry the instructions necessary to produce the proteins in the top layer (keratins) are faulty. This results in incorrectly formed keratins, deeming them unable to perform their normal role as a 'scaffolding' for the top most layer of skin. It appears as though there is a mutation (a change in the genetic material) within Keratin genes K5 or its partner K14. So as a result, the top layer of skin falls apart, resulting in a blister. Although EB Simplex is considered a non-scarring form of EB, secondary infection may cause scarring.

How is EB Simplex Inherited?

EB Simplex is usually inherited as an autosomal dominant condition. One parent of an affected person will usually also have the condition, though it is possible for EB simplex to appear 'sporadically' (to appear for the first time in a person who has no other affected family member). Anyone who has EB simplex whether male or female, can pass the condition on to his or her children. Each time a pregnancy occurs, there is a 1 in 2 chance that the child will inherit EB simplex.

Some precipitating factors that may cause an outbreak of blistering may include the following:

• Physical stress
• Emotional stress
• Warmer climates
• Infections
• Sexual maturation

Even though some forms of EB Simplex are localized it is important to know that all skin cells are affected. Therefore, all skin surfaces are prone to develop generalized blistering.

Weber-Cockayne Subtype of EB Simplex:

This form is also termed localized EB simplex. This disorder usually presents in childhood or adolescence. It may also occur in an infant or adult life. In many instances it presents itself in infancy from friction induced by shoes and starting to walk.

People with Weber Cockayne EB Simplex develop blisters on their feet and hands, (usually palms and soles) in response to friction. These wounds usually heal without scarring. Walking even short distances is often enough to cause blisters. They may experience thickening of the skin (keratoderma) on the soles of the feet. This type of EBS usually does not involve nails or mucous membranes. Most individuals seem to be more prone to blisters in warmer climates and during periods of strenuous activity such as jogging, marching or walking. With trauma or friction rarely the blistering can be (generalized) or appear on other parts of the body.

Mutations are in the genes encoding K5 or K14.

Koebner Subtype of EB Simplex:

This is a form of generalized EB simplex. This disorder usually presents at birth or infancy. Blisters are noted to be widespread over the body's surface. Though it is not a common feature of this type of EB to scar on rare occasions it does happen. There may be mild involvement of mucous membranes. Fingernails and toenails are sometimes involved. Localized thickening of the skin (keratoderma) on the soles of the feet and the palms of the hands may occur especially as one gets older.

Mutations are in the genes encoding K5 or K14.

Dowling Meara Subtype of EB Simplex:

EBS-DM is a generalized form of EB simplex. This type of EB is probably the most severe form of EB Simplex.

Infants are often born with widespread grouping of blisters on the face, trunk and limbs. Blisters on hands and feet often eventually cause confluent keratoderma (thickening of the skin). In many cases these calluses form complete thickening of the palms and soles. If the thickening is severe enough it may limit the range of motion of a joint. In such cases, consultation from a surgeon may be necessary to determine the best course of treatment.

Heat may exacerbate blistering. Milia (tiny cysts on skin) may be present after blisters have healed. Nail thickening and discoloration is a common feature.

Blistering in Dowling Meara EBS can involve organs including the oral cavity, gastrointestinal tract and rarely, the upper respiratory tree.

Electron microscopy shows clumps of keratin filaments, which are not seen in other forms of EB simplex.

Mutations are usually in the genes encoding K5 or K14.

Since EBS-DM is the most severe form of EBS, the widespread blistering may lead to death in infancy. However, blistering tends to become smaller and less problematic for most patients as they grow older.

*Since EB varies in severity these manifestations may or may not be experienced by the individual affected.

Common Manifestations of EBS:

• Blisters
• Keratoderma - Thickened skin on palms of hands and soles of feet. Confluent keratoderma in EBS-DM.
• Nail dystrophy - The presence of rough, thickened or absent finger or toenails.
• Problems with the soft tissue inside the mouth.

Uncommon Manifestations of EBS:

• Milia - Tiny skin cysts.
• Atrophic scarring - Depressions in skin as a result of thinning in epidermis or dermis.
• Anemia - A reduced amount of red blood cells, volume of red blood cells, amount of hemoglobin. Hemoglobin is the oxygen carrying portion of the red blood cell. The heme aspect of hemoglobin, is the iron compound that makes up the pigment part of the hemoglobin molecule. Anemia is more common in the severely affected individual.
• Growth retardation. This is more common in a severely affected individual.
• Gastrointestinal tract - Involvement of the GI tract may include blisters in mouth, esophagus and/or anal margins.

Rare Manifestations of EBS:

• Granulation tissue - The appearance of red fleshy tissue which is capillary formation during tissue healing This would be a rare occurrence in a person affected with EBS. This is more commonly seen in a person severely affected with Junctional EB.
• Dental caries (cavities) - This is more common in people affected with RDEB or JEB however, if mouth care is not performed regularly it will increase chances of cavities.
• Ocular (eye) involvement is more commonly seen in people with RDEB or JEB however, it has been reported in some forms of EBS.
• Pseudosyndactyly - Fusion of fingers and/or toes. This manifestation is more commonly seen in RDEB. In rare instances it has been reported in EBS-DM.
• Enamel hypoplasia - Underdeveloped enamel upon the teeth. This is more prevalent in patients with JEB.
• Respiratory tract involvement. Rare occurrences have been noted in the more severely affected individual.
• Genitourinary tract involvement. Rare occurrences involving the GU tract have been reported in some forms of EBS.

There is no evidence that people with EBS are at a higher risk for developing squamous cell carcinoma or malignant melanoma, however, suspicious wounds/lesions should always be evaluated by your dermatologist.

Other Subtypes of EB Simplex include:

EB Simplex Superficialis, EB Simplex with Mottled Pigmentation and Kallin’s Syndrome.

There is a recessively inherited simplex that accompanies Muscular Dystrophy which appears to be a mutation in the Plectin gene.

Junctional EB

What is the cause of Junctional EB?

Through research it is now known that mutations in the genes encoding alpha 6, beta 4 integrin, collagen XVII or one of the three chains of Laminin 5 contribute to defects in the formation of hemidesmosomes or anchoring filaments.

Defects within any of those components of the skin allows for the separation of tissue and blister formation whenever there is friction or trauma to an area. In many instances blistering can occur spontaneously.

There are three major sub-types of Junctional EB. Herlitz, non-Herlitz and Junctional EB with associated Pyloric Atresia. Though Junctional EB is considered a non-scarring form of EB, tightening and thinning of the skin does occur. In many instances residual atrophic scarring occurs.

How is Junctional EB Inherited?

JEB is an autosomal recessive condition. This means both parents are healthy carriers. Healthy carriers are non-symptomatic and will never develop the illness. When each parent has a copy of the altered gene, there is a 25% or 1 in 4 chance the child will be affected by Junctional EB. Unfortunately, there is no test to detect carriers for JEB. We are made aware that the parents are carriers after the child is born.

Junctional Herlitz EB:

Junctional Herlitz EB is a very severe form of EB. These infants often die during infancy due to overwhelming infection (sepsis), malnutrition, dehydration, electrolyte imbalance or complications resulting from blistering in the respiratory, gastrointestinal or genitourinary tract.

Some babies develop a hoarse cry and breathing difficulties which indicates internal involvement as well. These infants often fail to gain weight. These are usually symptoms of the severe form of Junctional EB.

Blistering is usually present at birth, however, there have been instances of infants being discharged to home, with a small blister on the finger or lip. After they are home, the blistering becomes more apparent warranting a visit to the physician. Skin blistering and ulcerations can occur spontaneously on the arms, hands, finger tips, back of the head, neck, shoulders, trunk, buttocks, legs and feet and toes (generalized distribution). Nails may be ulcerated or dystrophic. Warmer climates can exacerbate blistering. Blistering is noted on perioral (around the mouth) and mucosal surfaces as well. Oral lesions may affect eating causing weight loss.

Electron microscopic evaluation of the structure of the skin in a patient affected with JEB-H usually shows skin separation in the lamina lucida within the basement membrane zone. Absent or reduced amounts of hemidesmosomes may also be apparent.

Junctional Herlitz EB mutations are present on the genes encoding one of the three chains of Laminin 5.

Junctional non-Herlitz EB:

Generalized blistering and mucosal involvement may be evident at birth or soon after. Blistering may be mild to severe. Erosions on finger and toenails, nail dystrophy or absence of nails may be evident. Erosions and loss of hair (alopecia) upon the scalp may occur. Granulation tissue around mouth and nares may be seen. There may be some scarring and thinning of the skin on affected areas (atrophic scarring). Warmer climates can exacerbate blistering. Though laryngeal involvement (hoarse cry) may be experienced in early infancy, respiratory distress is a rare occurrence in this type of Junctional EB.

The infant may suffer complications such as infection, dehydration, electrolyte imbalances, respiratory, gastrointestinal, and/or genitourinary tract involvement. These complications may lead to death.

Electron microscopic evaluation of the structure of skin in a patient affected with JEB-nH shows skin separation at the level of the lamina lucida of the basement membrane zone. Variable appearance of hemidesmosomes may be visualized as well.

JEB-nH mutations usually involve the genes encoding type XVII collagen also called (BP 180 ). Occasionally mutations in laminin 5 are seen.

Junctional EB with Pyloric Atresia:

Some infants are born with Junctional EB and have been observed to have pyloric atresia, in which the opening between the stomach and the intestines fails to form. Surgery is necessary to repair the anomaly.

Generalized blistering, ulcerations of skin and mucous membranes is usually evident at birth. Blistering may be mild to severe. Erosions on finger and toenails, nail dystrophy or absence of nails may be evident. Erosions and loss of hair (alopecia ) upon the scalp and granulation tissue around mouth and nares may occur. There may be some scarring and thinning of the skin on affected areas (atrophic scarring). Warmer climates can exacerbate blistering.

The infant may suffer complications such as infection, dehydration, electrolyte imbalances, respiratory, gastrointestinal, and/or genitourinary tract involvement. These complications may lead to death.

Electron microscopic evaluation of the structure of the skin of a person affected with JEB-PA reveals skin separation at the level of the lamina lucida, small hemidesmosomal plaques and reduced amount of keratin filaments with hemidesmosomes.

Mutations in JEB-PA are within the genes encoding either alpha 6 or its partner beta 4 integrin. These components of the hemidesmosome are found both in skin and the stomach, explaining the failure of formation of the first part of the intestine (the pylorus).

*Since EB varies in severity these manifestations may or may not be experienced by the individual affected.

Common Manifestations of JEB:

• Blisters/erosions
• Dystrophic nails - The presence of rough, thickened finger or toenails.
• Atrophic scarring - Depressions in skin as a result of thinning in epidermis or dermis.
• Granulation tissue is the appearance of very red fleshy tissue, which is capillary formation during tissue healing. (More apparent in the perioral region and the nares.)
• Scalp abnormalities. Presence of blisters on scalp and/or scarring alopecia (areas of scarring with absence of hair growth).
• Respiratory tract involvement. May be present in the more severely affected individual.
• Anemia - A reduced amount of red blood cells and volume of red blood cells, amount of hemoglobin. Hemoglobin is the oxygen carrying portion of the red blood cell. The heme aspect of hemoglobin is the iron compound that makes up the pigment part of the hemoglobin molecule. The globin portion of hemoglobin is made up of protein. (This is more common in the severely affected individual.)
• Growth retardation and malnourishment.
• Problems in the soft tissue inside the mouth.
• Enamel hypoplasia - The presence of underdeveloped enamel upon the teeth.
• Dental caries is the development of cavities in teeth.
• Gastrointestinal tract involvement (blisters in mouth, esophagus and/or anal margins).
• Ocular (eye) involvement.

Rare Manifestations of JEB:

• Genitourinary tract involvement may include scarring and/or urethral stenosis.
• Milia - Small skin cysts
• Pseudosyndactyly - Fusion/ webbing of fingers and/or toes. On rare instances this has been reported in JEB patients.

There is no evidence that people with Junctional EB are at higher risk for developing malignant melanoma. In rare instances squamous cell carcinoma has been reported.

Any suspicious lesions should be evaluated by a determologist.

For additional information about JEB, you can view the Revised classification system for inherited epidermolysis bullosa. On the NEBR web site: http://www.daklex.com/.

Dystrophic Epidermolysis Bullosa

What Is The Cause Of Dystrophic EB?

Through research it is now known that the genes that carry the instructions necessary to produce the proteins in the basement membrane zone of the skin, are faulty. This results in incorrectly formed anchoring fibrils, deeming them unable to perform their normal role as a 'stable interweave' between the dermal and epidermal layers of the skin.

Mutation (a change in the genetic material) occurs within the collagen VII gene, which encodes the protein of the anchoring fibril. Anchoring fibrils hold together the two layers of skin. As a result, there is a lack of adherence and disruption of the skin when any friction or trauma occurs to an area. Where the two layers separate there is a blister. Blistering in the various types of dystrophic EB causes scarring.

There are two major types of DEB:

• Dominant Dystrophic Epidermolysis Bullosa
• Recessive Dystrophic Epidermolysis Bullosa ( Major subtypes of RDEB are listed below.)

1. Recessive Dystrophic Epidermolysis Bullosa- Hallopeau Siemens
2. Recessive Dystrophic EB-non Hallopeau Siemens
3. Recessive Dystrophic EB inversa

How is Dominant Dystrophic Epidermolysis Bullosa Inherited?

DDEB is an autosomal dominant condition. One parent of an affected person will usually also have the condition. It is possible for DDEB to appear 'sporadically' (to appear for the first time in a person who has no other affected family member). Anyone who has DDEB whether male or female, can pass the condition on to his or her children. Each time a pregnancy occurs, there is a 1 in 2 chance that the child will inherit DDEB.

Electron microscopic evaluation reveals skin separation at the level of the sub lamina densa of the basement membrane zone, with normal or decreased number of anchoring fibrils.

Mutations are noted in the genes encoding collagen VII either the gene from the mother or from the father. The change that results, decreases the functioning of the anchoring fibrils, but does not eliminate the anchoring fibrils

Dominant Dystrophic Epidermolysis Bullosa :

There is usually generalized blistering noted at birth. Blistering may be generalized or appear only on the hands, feet, elbows or knees: this is usually due to mechanical trauma. Rarely does scarring cause immobility and deformity of the hands and feet. Small cysts or milia are seen at sites of scarring. There may be mild involvement of the mucous membranes, nails may be thick, dystrophic or destroyed. Some affected by this form of EB may note the presence of small, firm flesh colored or white skin elevations that appear spontaneously on the trunk and extremeties of their body, that are called albopapuloid lesions.

• Transient Bullous Dermatosis of the Newborn *(TBDN) appears to be a form of DDEB noted by blistering and skin fragility that appears from changes in the collagen VII gene. For reasons unknown the problem seems to correct itself during infancy.

How is Recessive Dystrophic Epidermolysis Bullosa Inherited?

RDEB is an autosomal recessive inherited condition. This means both parents are carriers, yet they are unaffected. When each parent has a copy of the altered gene, there is a 1 in 4 chance or 25% that the child will be affected. Unfortunately, there is no test to detect carriers for RDEB. We are made aware that the parents are carriers after their child is born.

Electron microscopic evaluation reveals skin separation at the level of the sub lamina densa, with absence of anchoring fibrils in RDEB-HS.

There are reduced or occasionally abnormal appearing anchoring fibrils in RDEB-nHS.

Mutations in RDEB are found in both the mother’s and the father’s gene encoding collagen VII.

Recessive Dystrophic Epidermolysis Bullosa:

Although in some cases this form of EB can be mild with generalized blistering, typically the recessive forms of EB tend to be more severe. Onset is usually at birth with areas of missing skin. Generalized blistering then scarring can occur on skin surfaces and mucous membranes. Scarring may limit range of motion of extremities. Fusion of fingers and toes and contractures cause deformity and loss of function.

In some cases there is relatively mild blistering on hands, feet, elbows, and knees; these cases are very similar to dominant dystrophic EB. However, recessive dystrophic epidermolysis bullosa typically is characterized as follows:

Blistering onset is at birth or soon afterwards. In some cases, nearly all skin surfaces and mucous membranes (from mouth to anus) are covered by blisters. Large areas may be devoid of skin. There is widespread scarring and deformity. Fingers and toes may become immobile. With recurrent scarring, fingers and/or toes may fuse together. Hands and arms may become fixed in a flexed position with resulting contractures. There is usually loss of the nails of the fingers and toes. Teeth may be malformed and delayed in appearing through the gums. Because routine dental care can raise blisters, many persons with RDEB have a higher than normal incidence of cavities. Blistering on the mucosal surfaces often cause scarring within the mouth and gastrointestinal tract. The ingestion of food may be limited due to microstomia (inability to fully open mouth due to scarring and contractures of the perioral region), painful swallowing, difficulty chewing, (due to poor dentition) esophageal webbing. In many cases chronic malnutrition, growth retardation and anemia may ensue. Involvement of the eyes can include eyelid inflammation with adhesions to the eyeball, as well as inflammation of the cornea or the conjunctiva (the mucous membrane covering the eyeball and the underside of the lids).

RDEB inversa is a rare subtype of RDEB, blistering is noted on intertriginous (areas where skin rubs on skin i.e. axilla and groin) Lumbosacral areas may be affected as well.

Common Manifestations of DEB:

*Since EB varies in severity these manifestations may or may not be experienced by the individual affected.

• Generalized blistering.
• Absent or dystrophic nail - Presence of a rough, thick or changed finger or toenail.
• Milia - tiny skin cysts.
• Atrophic scarring - Depressions in skin as a result of thinning in epidermis or or dermis.
• Anemia - A reduced amount of red blood cells, volume of red blood cells, amount of hemoglobin. Hemoglobin is the oxygen carrying portion of the red blood cell. The heme aspect of hemoglobin, is the iron compound that makes up the pigment part of the hemoglobin molecule. It is more common in the severely infected individual (RDEB Hallopeau Siemens). In some instances anemia may occur in (DDEB, RDEB non-Hallopeau-Siemens and RDEB inversa).
• Growth retardation is more common in a severely affected individual (RDEB Hallopeau Siemens). In some instances this may occur in (DDEB, RDEB non-Hallopeau-Siemens and RDEB inversa).
• Problems with the soft tissue inside the mouth.
• Ocular (eye) involvement is more common in severely affected individuals (RDEB-HS). In some instances this may occur in (RDEB non-HS and RDEB inversa).
• Dental caries - Presence of cavities. This is more common in (RDEB-HS and RDEB inversa).
• Gastrointestinal tract: Involvement of the GI tract may include blisters in the mouth, esophagus and/or anal margins. (Problems may exist in those with DDEB however it is more commonly seen in RDEB.)
• Pseudosyndactyly - Fusion of fingers and/or toes. This manifestation is more common in the severely affected individual (RDEB HS, RDEB non-HS and RDEB inversa).

Rare Manifestations of DEB:

• Granulation tissue - Capillary formation during tissue healing. Would be a rare occurrence in a person affected with either form of DEB. (This manifestation may be seen in a person severely affected with Junctional EB.)
• Enamel hypoplasia - Underdeveloped enamel upon the teeth. This is more prevalent in patients with JEB.
• Respiratory tract involvement. Rare occurrences have been noted in the more severely affected individual.
• Genitourinary tract involvement. Rare occurrences involving the GU tract such as urethral stenosis and/or scarring have been reported.

For additional information about DEB you can view the Revised classification system for Inherited epidermolysis bullosa (http://www.daklex.com/).

Skin Cancers and Dystrophic Epidermolysis Bullosa

It is important to note that skin cancers usually react differently in a patient with EB. The more severely affected individual (RDEB) appears to be more at risk for developing squamous cell carcinoma. These localized skin cell tumors have the ability to grow faster and spread to other areas of the body more rapidly then they would on a less compromised individual. Patients and caregivers need to examine skin carefully for any changes. It is important to perform self examinations of your skin at home. Many times it is helpful to have family members look at areas that are not often viewed by the affected individual, such as the back or upon the scalp. Mirrors can be helpful in detecting growths on the back of trunk and extremities when you are self examining.

Any suspicious lesions, moles or markings should be evaluated by a dermatologist. Yearly full body exams are usually recommended, however, in some instances your dermatologist may modify the frequency of skin exams.

• Squamous Cell Carcinoma and Recessive Dystrophic EB: The incidence of squamous cell carcinoma is more common in the severely affected individual, RDEB Hallopeau-Siemens. There have also been reports of Squamous Cell Carcinoma in patients with RDEB non Hallopeau- Siemens.
• Squamous Cell Carcinoma and Dominant Dystrophic Epidermolysis Bullosa: It is a rare occurrence for the person affected with DDEB to develop squamous cell carcinoma.
• Melanoma and Dystrophic EB: Rare occurrences of melanoma have been reported in Dominant Dystrophic EB and Recessive Dystrophic EB.
• Basal Cell Carcinoma and Dystrophic EB: Rare, but has been reported in a small percentage of individuals with Dominant Dystrophic EB.

Changes in skin that warrant visit to physician for prompt evaluation include the following:

• Chronic non-healing wound.
• Deep ulcers.
• Any unusually thick, raised and/or crusted areas.
• Make note of any changes in the pattern of healing. Although there are variations in healing rates among each wound, it is important to monitor and note any changes, especially to areas prone to blistering.
• Any change in sensation on the non-healing area.
• Any changes in size, shape, diameter and color on existing growths and development of new growths.
• Pus or foul smelling odor.

Generally biopsies are obtained to confirm the presence of skin cancer. However, if a biopsy is obtained from a suspicious growth and the results are negative, please continue to monitor the area. If the area is still not healing please notify your physician, it may be necessary to re-biopsy the area.

For helpful hints on self examination please note the following web-site for the Skin Cancer Foundation

(http://www.skincancer.org/self_exam/spot_skin_ca ncer.html)

How is EB Treated?

Because EB involves many systems of the body, parents and health professionals must take a 'team approach' , to the treatment of an EB patient. Intense and total patient care often must be provided, particularly for young and growing children. The severe forms of EB require hours of intensive nursing care that in many ways is similar to that given to burn patients. Much of this care is often provided by the parents; however, the education of all people who have contact with the patient is essential. These people may include the primary care physician (often a pediatrician), the dermatologist, the nurse, the pediatric dentist, the specialist in gastrointestinal (digestive) diseases, the dietitian or nutritionist, the plastic surgeon, the psychologist or social worker, and the genetic counselor, as well as teachers, relatives, baby sitters, and others.

So far, research has not yet found a cure for epidermolysis bullosa or a treatment to completely control any form of EB. However, many complications can be lessened or avoided through early intervention. Many persons with milder forms have minimal symptoms and may require little or no treatment.

In all cases, treatment of EB is directed towards the symptoms and is largely supportive. This care should focus on prevention of infection, protection of the skin against trauma, attention to nutritional deficiencies and dietary complications, minimization of deformities and contractures, and the need for psychological support for the entire family.

*Please note that all medical information given by DebRA is for informational purposes only. Our information is not intended to substitute the care and guidance given by a qualified physician. All regimens of care should be discussed with the patient's physician. Always check with your physician prior to starting any medications or treatment regimens.