Epidermolysis Bullosa

What is Epidermolysis Bullosa?

Epidermolysis bullosa (EB) is a type of skin disorder that exists within a set of rare and inherited conditions. People with this condition have very fragile skin due to structural issues where the outermost and second layers of skin meet. This can make the skin more prone to damage. Normal levels of physical contact and pressure can cause it to blister, erode, or ulcerate. This condition can lead to an increased risk of infections, damage due to heavy scarring and severe skin cancer in some cases. These risks can sometimes result in an early death. The severity and effects of the disorder can range widely: In some people, it might only affect specific parts of the body that bear weight or pressure, while in others, it might affect a larger area, including organs outside of the skin. Some subtypes of EB can lead to high levels of sickness (morbidity) and several other issues due to its effects on multiple body systems.

Thirty different subtypes of epidermolysis bullosa have been identified, and they affect sixteen different genes. The subtypes vary in terms of the severity of their effects, how much they lead to sickness and death, and their specific genetic causes. There are four major groups of subtypes based on which layer of the skin the disorder impacts:

• Epidermolysis Bullosa Simplex (EBS): This type accounts for approximately 70% of all epidermolysis bullosa cases. It mostly affects the outermost layer of the skin and is usually inherited from one parent.
• Junctional Epidermolysis Bullosa (JEB): About 5% of cases fall into this group, which specifically impacts the “lamina lucida” or middle layer of the skin. This disorder is inherited from both parents.
• Dystrophic Epidermolysis Bullosa (DEB): This kind makes up roughly 25% of cases and can be inherited from either one or both parents. It affects the “lamina densa” at the basement level of the skin.
• Kindler Epidermolysis Bullosa (KEB): This type is the rarest of the four main types, also inherited from both parents. It influences any layer of the skin where the outermost and second layers of the skin meet. There have been about 400 reported cases globally.

It’s important to highlight that inherited epidermolysis bullosa is different from a non-inherited skin disorder known as epidermolysis bullosa aquisita, where the immune system produces antibodies against type VII collagen, another protein essential to the skin’s health.

What Causes Epidermolysis Bullosa?

Epidermolysis bullosa is a skin condition caused by problems in the area where the top layer of skin (epidermis) connects to the lower skin layer (dermis). This area is known as the dermo-epidermal junction, and it’s important to understanding how this disease develops.

Imagine your skin as a layered stack: the top part is the epidermis and underneath it lays the dermis. In between these two skin layers, you can find the basement membrane zone. This zone is like a skin’s multitasking powerhouse: it holds the epidermis to the dermis, provides a structure for cells to move and stick to, and serves as a model for the growth, repair, and replacement of skin cells.

The basement membrane zone has two layers: the lamina lucida that’s just under the basal epidermis and the lamina densa that’s below the lamina lucida.

These layers all work together and depend on each other. Their positions and function relies heavily on protein structures. In epidermolysis bullosa, some of those proteins are either missing or don’t work due to genetic mutations. This means that the harder it is for these proteins to do their jobs, the more severe the symptoms of epidermolysis bullosa would be.

Unfortunately, one of the outcomes of this malfunction in the dermo-epidermal junction is fragile skin. Even some everyday events like bumping your skin can make it blister, erode, or develop ulcers. And these wounds hang around, make it easy for infections to set in, cause itching and pain, and generally affect the patients’ quality of life.

Risk Factors and Frequency for Epidermolysis Bullosa

Epidermolysis bullosa, a group of skin diseases, mainly consists of four types. Of these, epidermolysis bullosa simplex accounts for about 70% of all cases. Dystrophic epidermolysis bullosa makes up around 25%, and junctional epidermolysis bullosa accounts for the remaining 5%. The rarest type is Kindler epidermolysis bullosa, with only about 400 cases reported across the globe.

Even though diagnosing epidermolysis bullosa can be challenging in areas with fewer resources, comprehensive studies agree that its prevalence is about 10 in every one million people, with around 20 new cases for every one million live births. The disease does not disproportionately affect one gender over the other. However, some studies in Scottish and Middle Eastern populations have pointed out a geographical bias. This bias can be due to a smaller variety of genes in small geographical areas and social and cultural factors that encourage marriage between relatives.

Signs and Symptoms of Epidermolysis Bullosa

Epidermolysis bullosa is a condition that usually starts showing signs at birth or during early childhood. The symptoms include fragile skin which easily gets blistered, and wounds that don’t heal as they should. People with this condition often feel a lot of pain and itchiness. The blisters usually appear more on parts of the body that frequently experience friction or pressure like the hands, feet, buttocks, and knees. In babies and children, the diaper area is also commonly affected.

This condition is genetic, meaning it’s inherited from one or both parents. This also means it varies greatly; some people might have it worse than others. The exact type of epidermolysis bullosa one has determines how severe the symptoms are and where they appear on the body.

A specialized examination, including high-powered microscopy and genetic testing, may be needed to confirm the diagnosis and subtype of epidermolysis bullosa. Here are some common types:

• Localized epidermolysis bullosa simplex: causes blisters and thickened skin, mainly on the hands and feet.
• Severe epidermolysis bullosa simplex: leads to hard, thick skin on the palms of the hands and the soles of the feet, along with grouped blisters that resemble a cold sore.
• Junctional epidermolysis bullosa: suspected in babies who have a hoarse cry and show excessive tissue growth around their mouth, neck, and armpits, as well as a defect in tooth enamel.
• Severe dystrophic epidermolysis bullosa: causes severe scarring, narrowing of the mouth opening, loss of tongue bumps, finger contractions, and webbed fingers and toes.
• Kindler epidermolysis bullosa: unique by causing sensitivity to light and skin discolouration and thinness.

In some cases, complications can also affect areas inside the body. These problems vary greatly and depend heavily on the specific genetic type of epidermolysis bullosa. It shows the importance of a detailed medical history and physical examination. It will guide doctors to the best treatment plan for each person with this condition.

Testing for Epidermolysis Bullosa

For a suspected case of a skin condition known as epidermolysis bullosa, which is known to cause blistering, certain tests are recommended using a biopsy, a procedure where a small sample of skin is removed for examination. These tests, called transmission electron microscopy and immunofluorescence antigen mapping, are typically performed on non-blistered skin that’s been slightly rubbed in order to trigger the early signs of blistering. These tests are preferably done on non-blistered skin because the repair process that takes place in blistered skin could potentially lead to a misleading diagnosis.

After the biopsy, the transmission electron microscopy and immunofluorescence antigen mapping are important for identifying detailed features of the skin and the level at which it’s impacted. The transmission electron microscopy test provides a closer look at the exact location and the various tiny structures within the skin (like desmosomes, hemidesmosomes, anchoring filaments, fibrils, sub-basal dense plates, basal keratin filaments), which all help in diagnosing the exact type of epidermolysis bullosa. However, conventional light microscopy, a more common and simpler microscope, doesn’t yield these fine details and is, therefore, not very useful in diagnosing this skin condition.

Immunofluorescence antigen mapping and transmission electron microscopy are especially crucial as they can help to identify and measure the amount of specific proteins called antigens that are involved in epidermolysis bullosa. This is important because the number of these antigens play a huge role in telling us how severe the condition is.

However, it’s important to note that despite the high degree of accuracy and detail that these tests provide, they are time-consuming, expensive, and require a high degree of expertise to perform and interpret. This can therefore pose a challenge in places with limited resources.

Apart from these tests, genetic screening is also helpful in diagnosing epidermolysis bullosa. A technique called next-generation sequencing has now become more common as it is less expensive, faster, and more efficient in screening multiple genes simultaneously, than the old technique known as Sanger sequencing. These genetic tests are not only useful in confirming a diagnosis, but they can also provide critical information for genetic counseling and planning future pregnancies, especially for families with a history of this condition.

Treatment Options for Epidermolysis Bullosa

Epidermolysis bullosa (EB) is a skin condition that doesn’t currently have a cure. As such, doctors focus on offering care that supports the patient, controls symptoms, and prevents complications which can range from mild to severe. Specific care strategies also depend on the type of EB that a patient has.

In EB, blisters can be prevented by limiting exposure to physical damage. For newborns, this means that health providers need to avoid practices that cause skin injury, such as heel prick tests and the use of plastic patient ID bands or cord clamps. Heat and humidity can worsen skin fragility. Protective bandages placed over parts of the body where pressure or friction occurs can also help to prevent blisters. Any blisters that do form may be safely punctured with sterile needles and drained, while the skin covering the blister is left in place to help reduce pain and prevent infection. Broken skin can be treated with special non-sticking foams and bandages.

Antiseptic washes and creams can be used to further prevent infection. Antibiotics should be used only when an infection is confirmed, or in cases of severe skin or bloodstream infections. They may also use corticosteroids to manage the overgrowth of wound tissue.

People with EB are particularly at risk of a serious type of skin cancer called squamous cell carcinoma. It is a common cause of early death in some types of EB. Doctors recommend surgery to remove the cancer, but it can still be aggressive and spread rapidly. In a severe type of EB, the chances of dying due to this cancer increase significantly with age, and survival is usually around 5 years after the initial diagnosis. For patients with this cancer, radiation therapy, chemotherapy, and newer immune therapy treatments may be used to relieve symptoms.

Pain is a major symptom of EB, and it can affect the skin as well as other parts of the body. Furthermore, wound care activities, such as changing dressings or bathing, can also cause pain. Pain can be managed with the help of a pain management team and psychological support, which can greatly improve patients’ quality of life. Skin itch and pain that isn’t resolved by moisturizers, topical corticosteroids, and antihistamines can be managed with medicine designed to treat nerve pain.

Recently, two new treatments for EB have been approved. One of them, called beremagene geperpavec or ‘B-VEC’, is a form of gene therapy that’s applied to the skin. It is designed to help treat a type of EB known as dystrophic EB. The other treatment is an herbal gel made from birch tree extract called Oleogel-S10. This has been approved for the treatment of wounds in certain types of EB.

What else can Epidermolysis Bullosa be?

When it comes to newborn babies, there are a variety of conditions that need to be considered and ruled out. These include:

• Pompholyx Eczema: This condition causes blisters that are itchy and usually appear on the hands and feet. Someone with this condition might also have a past experience with atopic diseases. Tests to identify allergens might be needed.
• Porphyria: This condition is characterized by scarring, small white bumps (milia), and sensitivity to light. It could also involve excessive growth of hair. Skin biopsies and tests for a type of chemical called porphyrin might be necessary.
• Bullous Pemphigoid: This condition causes large, tense blisters and itching. A clinical exam and a skin biopsy can confirm the condition.
• Bullous Systemic Lupus Erythematosus: This stage of lupus results in tense fluid-filled sacs (vesicles), blisters, and shallow sores, often on areas of skin exposed to the sun. Tissue studies and fluorenscent tests can identify this condition.
• Bullous Tinea Pedis: This foot condition, also known as athlete’s foot, results in blisters, often with skin maceration between toes. Cultures from skin scrapings can diagnose the condition.
• Palmoplantar Keratoderma: This condition results in thickening skin on the hands and feet, often paired with abnormal nails. Genetic testing might be needed, though this condition could also be linked to internal cancers, thyroid abnormalities, inflammatory skin conditions like lichen planus, and certain medications.
• Epidermolysis Bullosa Acquisita: This autoimmune disease can present symptoms similar to dystrophic epidermolysis bullosa but later in life. Biopsy and fluorescence studies on the skin are usually carried out to confirm.
• Ehlers-Danlos Syndrome: This condition has symptoms like skin that can easily be extended, movable joints, and easy bruising with skin fragility. Diagnosis can be done by skin biopsy and genetic testing.
• Incontinentia Pigmenti: This condition is signified by the presence of vesicles following a certain pattern, forming skin growths and areas with excessive pigment.

Each of these conditions have their unique presentations and distinct tests to accurately diagnose them.

What to expect with Epidermolysis Bullosa

The outlook for people with epidermolysis bullosa can greatly vary. This largely depends on the specific type of the condition one has and the complications that can develop from skin and other symptoms. In milder types of epidermolysis bullosa, life expectancy isn’t significantly affected.

On the other hand, for more severe types, mortality amongst infants and children can be quite high. For instance, most infants with a severe type known as junctional epidermolysis bullosa often do not live past 2 years of age. Additionally, persons with a severe form called recessive dystrophic epidermolysis bullosa may possibly die between their 30s and 50s due to an aggressive form of skin cancer known as squamous cell carcinoma.

Possible Complications When Diagnosed with Epidermolysis Bullosa

After diagnosing a patient with certain skin complications, it’s important to involve all healthcare professionals in deciding their treatment plan.

Oral and Gastrointestinal Issues

Frequent blisters, cuts, ulcers, and scars inside the mouth due to defective proteins may lead to smaller mouth opening, a tied-up tongue, or loss of a deep fold in the mouth lining. Some may also experience defective tooth enamel. These issues, combined, could make tooth decay more likely due to difficulties in maintaining proper oral hygiene. The treatment might include dental scaling, root planning, and antibiotics.

• Problems with mouth
• Defective tooth enamel
• Increased risk of tooth decay
• Dental treatment

Eating issues are influenced by all these mouth issues and stomach problems too. Blisters in the oesophagus can make swallowing hard, affecting nutrition. To ease this, pain relief, eating soft foods, and sometimes, inhalable steroids, might be used. The oesophagus becoming narrow or scarred may also interfere with eating due to swallowing problems and reflux symptoms. Gentle stretching and drugs to decrease stomach acidity could be the treatment choice. In infants, if there is a blockage in the exit of the stomach, surgery is necessary straight away to allow nutrition. Long term, a dietitian’s support and placing a feeding tube may be needed.

• Swallowing difficulties
• Possible treatments
• Necessary surgery for infants with stomach blockage
• Long-term solutions including dietician help and feeding tube

Poor nutrition, combined with skin and gastrointestinal losses, may lead to a type of anaemia where the red blood cells are smaller or normal-sized but in fewer numbers. Iron supplements can be added to the diet, and in case of iron deficiency, an intravenous iron transfusion may be necessary. Constipation in patients can be caused by regular painkillers, poor dietary fibre and water intake, and blisters in the anus. Changes in the diet and prescribing a stool softener can help manage this.

• Anemia
• Iron supplementation
• Constipation and its causes
• Diet changes and stool softeners

Musculoskeletal Disease

Patients with skin blisters have an increased risk of developing bone loss due to reduced mobility, unresolved inflammation, lack of Vitamin D, delayed puberty, and chronic use of opioids. Along with Vitamin D supplements, physiotherapy, and measures to attain puberty could be considered for managing bone health. Frequent blistering might lead to contracture of joints and fusion of fingers and toes affecting the movements, which may require surgery if preventive measures fail.

• Risks of bone loss
• Vitamin D supplements, physiotherapy, puberty induction
• Joint contracture and finger fusion
• Possibility of surgery

Eye Issues

While a detailed eye examination is recommended for complications, it is advised to use eye lubricants for prevention. Some patients with a specific subtype of skin blistering may lose their eyesight due to eye complications.

• Eye complications
• Need for detailed eye examination
• Use of eye lubricants
• Possibility of blindness

Genitourinary Issues

Complications might include narrowing of the urethra, which if unresolved could make the tubes carrying urine from kidneys to bladder swollen and filled with fluid. Surgical stenting may be needed. Women might encounter narrowing of the vagina as a complication. In some, kidney diseases such as IgA nephropathy, post-streptococcal glomerulonephritis, and renal amyloidosis might require dialysis or kidney transplantation.

• Narrowing of urethra and its implications
• Surgical stenting
• Vaginal narrowing
• Possibility of dialysis and kidney transplantation

Cardiovascular and Respiratory Involvement

Some mutations causing dilated and hypertrophic heart diseases require a visit to a heart specialist. Involvement of lung disease leading to small spaces in the lung tissue could carry a bad prognosis. Involvement of the voice box requires immediate management of the airway.

• Heart and lung involvement
• Need for heart specialist
• Importance of immediate airway management

Mental Impact

Having skin blisters is frequently a disabling disease with no cure and could have a considerable mental impact. Chronic wounds, pain, itchiness, reduced ability to move, and difficult social exchange can lower the quality of life significantly. All these can financially affect the caregivers, especially relatives. Thus, mental support may improve the emotional well-being of patients and caregivers.

• Potential mental impact
• Quality of life issues
• Financial strain on caregivers
• Importance of mental support

Preventing Epidermolysis Bullosa

Epidermolysis bullosa, a skin disease which is passed down through families, can be determined through genetic counseling, prenatal testing, and preimplantation screening. These methods can provide information about the likelihood of a future child inheriting the disease. Genetic counseling can provide a plan for possible inheritance, and the chances of passing on epidermolysis bullosa to your child.

Prenatal testing makes use of techniques like chorionic villus sampling or amniocentesis. These tests are conducted during pregnancy to assess the genetic health and risk of inherited diseases in an unborn child. However, it’s important to note that chorionic villus sampling carries a higher risk of miscarriage, even though it is an effective screening method.

Preimplantation screening and haplotyping are techniques used to identify genetic mutations in embryos and oocytes (eggs) respectively. This helps promote the chances of fertilization with genetically sound cells, thus ensuring the child will not be impacted by the disease.