Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare, inherited genetic skin condition that causes the skin and mucous membranes to be extremely fragile. Even minor friction or trauma can lead to severe blistering and open wounds. This condition is one of the major forms of epidermolysis bullosa (EB), a group of disorders characterized by easily blistering skin. RDEB impacts the daily lives of affected individuals, as their skin is as delicate as a butterfly’s wings, earning them the nickname “butterfly children”.
The Genetic Roots of RDEB
RDEB arises from mutations within the COL7A1 gene, which is located on chromosome 3. This gene provides instructions for producing a protein known as type VII collagen. Type VII collagen is a large, rope-like protein that forms structures called anchoring fibrils.
These anchoring fibrils are located in the epidermal basement membrane zone, a specialized area between the epidermis (the outermost layer of skin) and the dermis (the underlying layer). Their function is to firmly connect these two layers. When mutations in the COL7A1 gene lead to defective or absent type VII collagen, these anchoring fibrils cannot form properly.
The impaired connection between the epidermis and dermis means that even slight rubbing or pressure can cause the skin layers to separate, resulting in the characteristic blistering seen in RDEB. RDEB follows an autosomal recessive inheritance pattern, meaning an individual must inherit a mutated copy of the COL7A1 gene from both parents to develop the condition. Parents who carry one mutated gene copy do not exhibit symptoms themselves.
How RDEB Affects the Body
RDEB affects various parts of the body. The most prominent feature is chronic blistering and open wounds on the skin, resulting from minimal friction. These wounds often heal with significant scarring and milia, which are small white cysts. Babies with RDEB may be born with large areas of missing skin, particularly on their feet and legs, due to trauma in the womb or during birth.
Beyond the skin, RDEB affects various internal linings of the body, which are also composed of epithelial tissue. The mouth and esophagus are frequently involved, leading to blistering, scarring, and narrowing (strictures) that make eating and swallowing difficult. This can result in nutritional deficiencies and slow growth. Blistering and scarring can also occur in the eyes, potentially causing corneal erosions and vision loss.
The hands and feet are particularly susceptible to severe blistering and scarring, which can lead to early contractures, restricting movement. Anemia is a common occurrence due to chronic blood loss from widespread wounds. The severity of RDEB varies among individuals, influenced by the specific COL7A1 gene mutations and the amount of type VII collagen the body can produce.
Different subtypes of RDEB exist, such as RDEB-severe (previously known as Hallopeau-Siemens type) and RDEB-generalized intermediate. RDEB-severe is the severe form, characterized by widespread blistering from birth and a complete absence of collagen VII. In contrast, intermediate forms may have some collagen VII present, leading to less severe blistering and a better prognosis, though still involving fragile skin and potential scarring.
Understanding Major Complications
Over time, RDEB can lead to severe, progressive complications that impact quality of life and lifespan. Repeated blistering and scarring on the hands and feet can cause the fingers and toes to fuse, resulting in “mitten deformities” (pseudosyndactyly). These deformities severely limit hand and foot function, making everyday tasks challenging.
Scarring around joints throughout the body can also lead to contractures, restricting movement and causing chronic pain. Individuals with RDEB face an elevated risk of developing aggressive squamous cell carcinoma (SCC), a type of skin cancer, often at a young age. This cancer typically arises in chronic wounds and scars and is a major factor affecting life expectancy, with a lifetime risk exceeding 90% in severe cases.
Chronic pain and itching are persistent issues for many individuals with RDEB. The severe involvement of the esophagus and chronic inflammation from widespread wounds often contribute to poor growth and malnutrition. In severe cases, RDEB can also lead to renal complications, including glomerulonephritis and renal amyloidosis.
Managing RDEB and Future Therapies
Current management of RDEB focuses on supportive care to alleviate symptoms and prevent complications. Meticulous daily wound care is crucial, involving specialized dressings to protect fragile skin and prevent infections. Pain management is also a regular component of care.
Nutritional support is often necessary due to difficulties with eating and swallowing; many individuals require feeding tubes, such as gastrostomy tubes. Physical and occupational therapy are important in maintaining mobility, preventing joint contractures, and improving overall function. Surgical interventions may be performed to separate fused fingers or toes, dilate esophageal strictures, or remove cancerous growths.
The field of RDEB treatment is evolving, with promising therapeutic avenues under investigation. Gene therapy aims to introduce a healthy COL7A1 gene into a patient’s cells to restore functional type VII collagen production. One autologous cell-based gene therapy, prademagene zamikeracel (pz-cel), was recently approved by the FDA for treating RDEB wounds, demonstrating wound healing and pain reduction. This therapy corrects the COL7A1 gene defect in a patient’s own skin cells, expanding them into sheets for surgical application to chronic wounds.
Cell-based therapies use healthy skin cells, such as fibroblasts or stem cells, to deliver collagen VII to affected areas. Injections of allogeneic fibroblasts have shown variable improvements in wound healing, potentially by enhancing the recipient’s own collagen VII production or through direct secretion. Protein replacement therapy is another approach, focusing on directly providing functional type VII collagen to the patient. Additionally, researchers are exploring drug repurposing and molecular therapies to improve collagen production, reduce inflammation, or enhance wound healing.