Dystrophic epidermolysis bullosa is one of the major forms of a group of conditions called epidermolysis bullosa. Epidermolysis bullosa cause the skin to be very fragile and to blister easily. Blisters and skin erosions form in response to minor injury or friction, such as rubbing or scratching. The signs and symptoms of dystrophic epidermolysis bullosa vary widely among affected individuals. In mild cases, blistering may primarily affect the hands, feet, knees, and elbows. Severe cases of this condition involve widespread blistering that can lead to vision loss, scarring, and other serious medical problems.

Researchers classify dystrophic epidermolysis bullosa into major types based on the inheritance pattern and features of the condition. Although the types differ in severity, their features overlap significantly and they are caused by mutations in the same gene.

Recessive dystrophic epidermolysis bullosa severe generalized (RDEB-sev gen) is the classic form of the condition and is the most severe. Affected infants are typically born with widespread blistering and areas of missing skin, often caused by trauma that occurs during birth. Most often, blisters are present over the whole body and affect mucous membranes such as the moist lining of the mouth and digestive tract. As the blisters heal, they result in severe scarring. Scarring in the mouth and esophagus can make it difficult to chew and swallow food, leading to chronic malnutrition and slow growth. Additional complications of ongoing scarring can include fusion of the skin between the fingers and toes, loss of fingernails and toenails, joint deformities (contractures) that restrict movement, and eye inflammation leading to vision loss. Additionally, people with RDEB-sev gen have a very high risk of developing a form of skin cancer called squamous cell carcinoma in young adulthood. In these individuals, the cancer tends to be unusually aggressive and is often life-threatening.

Other types of recessive dystrophic epidermolysis bullosa fall along a spectrum referred to as RDEB-generalized and localized (RDEB-gen and -loc). These forms of the condition are somewhat less severe than RDEB-sev gen and are distinguished by the affected regions of the body. Blistering is often limited to the hands, feet, knees, and elbows in mild cases, but may be widespread in more severe cases. Rare forms affect specific regions of the body, such as the shins or the abdomen. Affected people often have malformed fingernails and toenails. The RDEB-gen and -loc types involve scarring in the areas where blisters occur, but these forms of the condition do not cause the severe scarring characteristic of RDEB-sev gen.

Another major type of this condition is known as dominant dystrophic epidermolysis bullosa (DDEB). The signs and symptoms of this condition tend to be milder than those of the recessive forms, with blistering often limited to the hands, feet, knees, and elbows. The blisters heal with scarring, but it is less severe than in recessive forms of this condition. 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.

Mutations in the COL7A1 gene cause all forms of dystrophic epidermolysis bullosa. This gene provides instructions for making a protein that forms the pieces (subunits) of a larger protein called type VII collagen. Collagens are proteins that give structure and strength to connective tissues, such as skin, tendons, and ligaments, throughout the body. Type VII collagen plays an important role in strengthening and stabilizing the skin. It is the main component of structures called anchoring fibrils, which anchor the top layer of skin, called the epidermis, to an underlying layer called the dermis.

COL7A1 gene mutations alter the structure or disrupt the production of the type VII collagen subunit protein. These changes affect the production of type VII collagen. Mutations that severely reduce or prevent the production of type VII collagen cause RDEB-sev gen. Mutations that allow a small amount of normal or partially functional type VII collagen to be produced lead to milder forms of the dystrophic epidermolysis bullosa. When type VII collagen is abnormal or missing, the formation of anchoring fibrils is impaired. A shortage of these fibrils disrupts the connection of the epidermis to the dermis, and friction or other minor trauma can cause the two skin layers to separate. This separation leads to the formation of blisters, which can cause extensive scarring as they heal. Researchers are working to determine how abnormalities of type VII collagen also underlie the increased risk of skin cancer seen in RDEB-sev gen.

Normal Function

The COL7A1 gene provides instructions for making a protein called pro-α1(VII) chain that is used to assemble a larger protein called type VII collagen. Collagens are a family of proteins that strengthen and support connective tissues, such as skin, bone, tendons, and ligaments, throughout the body. In particular, type VII collagen plays an essential role in strengthening and stabilizing the skin.

Three pro-α1(VII) chains twist together to form a triple-stranded, ropelike molecule known as a procollagen. Cells release (secrete) procollagen molecules, and enzymes cut extra protein segments from the ends. Then the molecules arrange themselves into long, thin bundles of mature type VII collagen.

Type VII collagen is the major component of structures in the skin called anchoring fibrils. These fibrils are found in a region known as the epidermal basement membrane zone, which is a two-layer membrane located between the top layer of skin, called the epidermis, and an underlying layer called the dermis. Anchoring fibrils hold the two layers of skin together by connecting the epidermal basement membrane to the dermis.

Health Conditions Related to Genetic Changes

Dystrophic epidermolysis bullosa

More than 700 mutations in the COL7A1 gene have been identified in people with dystrophic epidermolysis bullosa, a condition that causes the skin to be very fragile and to blister easily. These mutations alter the structure or disrupt the production of the pro-α1(VII) chain protein, which affects the production of type VII collagen. When type VII collagen is abnormal or missing, anchoring fibrils cannot form properly. A shortage of these fibrils impairs the connection of the epidermis to the dermis. As a result, friction or other minor trauma can cause the two skin layers to separate. This separation leads to the formation of blisters, which can result in extensive scarring as they heal.

Researchers classify dystrophic epidermolysis bullosa into a few major types based on the inheritance pattern and features of the condition. The recessive types of dystrophic epidermolysis bullosa (RDEB) result from mutations in both copies of the COL7A1 gene in each cell. The most severe, classic form of this disorder is known as recessive dystrophic epidermolysis bullosa severe generalized (RDEB-sev gen). Most of the COL7A1 gene mutations responsible for RDEB-sev gen result in production of abnormally short pro-α1(VII) chains that cannot form type VII collagen. As a result, little type VII collagen is available to make anchoring fibrils. This lack of anchoring fibrils disrupts the connection between the epidermis and the dermis and causes the extreme skin fragility and other signs and symptoms of RDEB-sev gen.

Somewhat less severe forms of RDEB, grouped as the generalized and localized types (RDEB-gen and -loc), are caused by other types of mutations. Many of these genetic changes alter the structure of the pro-α1(VII) chain protein such that it cannot form normal type VII collagen. As a result, anchoring fibrils are reduced in number, or they are altered and cannot function normally. The small amount of normal or partially functional anchoring fibrils accounts for the less severe signs and symptoms of RDEB-gen and -loc.

A milder, dominant form of dystrophic epidermolysis bullosa (DDEB) results from mutations in one copy of the COL7A1 gene in each cell. In many cases, these mutations alter a part of type VII collagen known as the triple helical domain. This region gives type VII collagen its usual triple-stranded structure. It is made up of a pattern of protein building blocks (amino acids) in which every third amino acid is a glycine. Mutations that substitute other amino acids for glycine in this region can disrupt the triple-stranded structure of type VII collagen. When the abnormally shaped collagen molecules are incorporated into anchoring fibrils, they interfere with the fibrils' normal function and prevent them from effectively connecting the epidermis and the dermis. Although they are most commonly associated with DDEB, mutations that substitute glycine amino acids in the triple helical domain can also cause RDEB. DDEB can also be caused by other types of mutations, particularly changes that affect the folding of type VII collagen.

It is unclear how COL7A1 gene mutations are associated with an increased risk of a certain cancer called squamous cell carcinoma in people with dystrophic epidermolysis bullosa, particularly RDEB-sev gen. Some research has suggested that abnormal forms of type VII collagen that retain a procollagen fragment called the NC1 domain may increase the risk of tumor formation. Other studies, however, have not found this association.

Other disorders

Mutations in the COL7A1 gene can also cause a rare condition called epidermolysis bullosa with congenital localized absence of skin (also known as Bart syndrome or aplasia cutis congenita type VI). Individuals with this condition have patches of missing skin at birth (aplasia cutis congenita), typically on the legs. On other parts of the body, they have the characteristic skin problems of epidermolysis bullosa. Epidermolysis bullosa is a group of conditions that cause the skin to be very fragile and to blister easily. Abnormal or absent fingernails and toenails are also common in people with epidermolysis bullosa with congenital localized absence of skin.

As in dystrophic epidermolysis bullosa (described above), COL7A1 gene mutations impair the formation of functional anchoring fibrils. A shortage of these fibrils results in skin fragility and blistering.

Some doctors believe that the aplasia cutis congenita arises from skin fragility and blisters during birth and does not signify a condition separate from epidermolysis bullosa. It is unclear why some newborns have this feature and others do not.

Other Names for This Gene

• alpha 1 type VII collagen
• CO7A1_HUMAN
• collagen type VII alpha 1
• collagen VII, alpha-1 polypeptide
• collagen, type VII, alpha 1
• collagen, type VII, alpha 1 (epidermolysis bullosa, dystrophic, dominant and recessive)
• EBD1
• EBDCT
• EBR1
• LC collagen
• long chain collagen

Genomic Location

Recessive dystrophic epidermolysis bullosa (RDEB-sev gen and RDEB-gen and -loc) is inherited in an autosomal recessive pattern. Autosomal recessive inheritance means that both copies of the COL7A1 gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs and symptoms of the condition.

DDEB has an autosomal dominant pattern of inheritance. Autosomal dominant inheritance means that one copy of the altered gene in each cell is sufficient to cause the disorder. About 70 percent of all people with DDEB have inherited an altered COL7A1 gene from an affected parent. The remaining 30 percent of affected people have the condition as a result of a new mutation in the COL7A1 gene. These cases occur in people with no history of the disorder in their family.

Doctors usually diagnose epidermolysis bullosa by:

• Asking about family and medical history, because most types of epidermolysis bullosa are inherited.
• Completing a physical exam and closely examining the skin, which can help doctors identify where the skin is separating to form blisters.
• Performing a skin biopsy and reviewing the tissue sample using special microscopic techniques, which helps doctors identify which layers of the skin are affected and determine the type of epidermolysis bullosa you have.
• Ordering genetic testing to identify specifically which gene mutations you may have. This helps doctors diagnose the specific type and subtype of the disease. People who have genetic testing should see a specialist or genetic counselor to help them understand the test results.

Epidermolysis bullosa (EB) can have either an autosomal dominant or autosomal recessive mode of inheritance in epidermolysis bullosa simplex (EBS) and dystrophic epidermolysis bullosa (DEB). Kindler syndrome and junctional epidermalysis bullosa (with the exception of one report, to our knowledge) are autosomal recessive. The mode of inheritance in a given family is usually established by analyzing the family history (pedigree analysis).

EBS in families in which only one child is affected (and the parents are unaffected) could be either autosomal dominant (as the result of a de novo gene mutation) or autosomal recessive. A de novo dominant mutation is the more likely mode of inheritance. The two modes of inheritance can usually be distinguished based on results of immunohistochemistry testing.

The only accurate method to determine the mode of inheritance in a person with DEB is molecular genetic testing to identify the responsible mutation(s). Symptoms, severity, and other types of lab results alone are not sufficient. Until recently, mutations in the responsible gene were considered 100% penetrant (meaning that all people with mutations would be affected). However in several affected families, a person with a mutation for dominant DEB had no signs of the disease.

People with questions about the inheritance of their condition and genetic risks to themselves or family members should speak with a genetics professional.

Managing EB requires a multidisciplinary team of health care providers including a dermatologist, EB nurse who specializes in wound care, occupational therapist, nutritionist, and social worker. Various other specialists may be consulted as needed. Management should be individualized for each person depending on their age, severity, symptoms, complications, and priorities.

While there currently is no specific therapy for most forms of epidermolysis bullosa (EB), extensive clinical research regarding potential treatments is ongoing. At this time, management is mostly supportive and involves wound care, pain control, controlling infections, nutritional support, and prevention and treatment of complications. Monitoring for complications with laboratory testing and imaging studies is also important, although the frequency of these tests will vary depending on the type of EB and severity in each person. Newborns with EB should be taken care of in a neonatal or pediatric unit that has the expertise, staffing, and resources necessary to manage severe skin erosions and potential complications.

Considered together, the prevalence of recessive and dominant dystrophic epidermolysis bullosa is estimated to be 3.3 per million people.