Course:MEDG550/Student Activities/ Dystrophic Epidermolysis Bullosa

Dystrophic Epidermolysis Bullosa (DEB) is a genetic condition and one of the main types of Epidermolysis Bullosa. It is distinct from other forms as it is caused by a change and/or multiple changes in a collagen (COL7A1) gene. Young patients with this condition, along with its sub-types, are sometimes referred to as the "butterfly children" as the skin tears and blisters with minimal friction or force. DEB is found to cover a large spectrum of severities and has classified into 13 subtypes. The most common sub groups are: Dominant Generalized DEB [DDEB-Gen], Severe Generalized Recessive DEB [RDEB-Sev Gen] and Recessive-Other DEB [RDEB-O]. There is currently no cure for DEB, but there is medical management. Genetic testing is available for this condition, and genetic counselling is recommended.

DEB subtype chart data collected from "Inherited Epidermolysis Bullosa"

Signs and Symptoms

The clinical features of DEB are generally appear during the neonatal stage, with absence of skin on arms and legs. Both main types of DEB are recognized by their extremely fragile skin, where generalized blistering of the skin is caused by minimal trauma. Depending on the type of DEB the blistering is found at different levels of severity and localization. Overall for all forms of DEB there is abnormal or complete absence of toe/ finger nails, throat (esophageal) narrowing and blistering, progressive difficulty swallowing (dysphagia), and small cysts under skin (mila).

The Diversity of Clinical Features

Dominant Generalized DEB (DDEB-Gen)

Severity

• less severe type
• may diminish with age

Usual Blister Localization

• hands
• feet
• knees
• elbows

Less Common Blister Localization

• backs of the knees and the insides of the armpits, elbows and groin (flexural areas)
• body trunk

Recessive DEB (RDEB)

All forms of RDEB have an increased risk of failure to thrive, growth delay, severe anemia, early infant mortality, and risk of squamous cell carcinoma that are not characteristic features of DDEB.

Severe Generalized Recessive DEB (RDEB- Sev Gen)

[Previously known as the Hallopeau–Siemens]

Severity

• Most severe type effecting multiple organ systems

Usual Blister Localization

• hand/ foot blistering that causes debilitating hand and foot deformities ("mitten deformities"; pseudosyndactyly)
• full body
• stomach and intestines (gastrointestinal tract)
• urinary (genitourinary) tract
• kidneys
• heart
• mucous membranes [oral, genital, anal, and eye (ocular)]

Other Symptoms

• progressive and often disfiguring scarring of the skin
• Severe tied tongue (ankyloglossia) and small mouth opening (microstomia)
• tooth deterioration
• develop at least one cutaneous squamous cell carcinoma
• hair is typically sparse
• constipation
• osteoporosis
• kidney inflammation (glomerulonephritis) and protein build up in kidney

Recessive DEB- Other (RDEB- O)

[Previously called non- Hallopeau–Siemens]

Severity

• similar to RDEB-Sev Gen but less severe skin involvement
• much lower risk of esophageal narrowing, eye (corneal) blisters
• no hand or foot deformities

Usual Blister Localization

• Varied from widespread disease to primarily limb involvement

Other Symptoms

• significant risk of developing squamous cell carcinomas
• tooth deterioration
• Severe tied tongue (ankyloglossia) and small mouth opening (microstomia)
• hair is typically sparse

Causes

Skin Layers

COL7A1 Gene

Both the recessive and dominant forms of DEB are due to changes in a gene called COL7A1.

This gene is responsible for the formation of collagen VII which plays an important role in holding the top layer of skin (epidermis) tightly to the rest of the skin (dermis). Changes in this gene weaken the bond between these two skin layers causing the separation of the layers and the formation of blisters and open sores.

Currently there are over 700 unique changes in this specific COL7A1 gene that are known to cause DEB.

Diagnosis

DEB patients are diagnosed and classified based on the structural appearance of the blisters (skin biopsy), inheritance pattern, clinical features, and genes involved (genetic testing).

Skin biopsy is used to determine the depth of tissue separation and thus the type of EB. Immunofluorescence mapping (IFM) and transmission electron microscopy (TEM) are the two lab tests that can be done to determine the tissue separation level.

Genetic testing gives the most accurate subtypes by determining the specific change that is causing the DEB which helps support the prognosis, genetic counseling, and prenatal diagnosis.

Management and Treatment

This condition effects multiple organ groups so a multidisciplinary approach to management is recommended. Some team members may include pediatricians, dermatologists, internal medicine specialists, dermatologic surgeons, dentists, nutritionists, physical therapists, psychologists, and other specialists depending on the type and severity of the DEB.

Management

Therapies focus on clinical DEB symptoms and are the mainstay of clinical management. Treatment mainly focuses on pain reduction, blister healing, reducing the formation of new blisters, and avoiding infection.

Pain Reduction

• systemic pharmacologic therapy should be adapted to treat both acute and chronic forms of skin pain
• for chronic pain management cognitive behavioral therapy (CBT) can be affective
• during dressing changes anxiety (anxiolytics) and pain (analgesics) medications are recommended

Additional targeted treatments are also recommended for any other symptoms the individual with DEB has, and can be addressed by a health care provider.

Blister Healing

• draining of blisters with sterile large-bore needles while keeping top of blister intact
• application of ointment and non stick dressing to blisters
• increased caloric and protein intake is recommended to support wound healing

Reducing Formation of New Blisters

• adhesive and compressive dressings must be avoided as they induce new blisters

Avoiding Infection

• dressings should be changed daily after skin cleansing
• application of topical antibiotics and antimicrobial dressings (only used if wound fails to heal to reduce chance of antibiotic resistance)

Treatment

There are no definitive treatments that have been established for DEB, although there are some clinical trials currently taking place. Recent studies have looked into using stem cell therapy and gene therapy to correct the specific change in the COL7A1 gene; Although there is no treatment currently available the in vitro cell and in vivo animal studies look promising.

Population Frequency

DEB occurs in all races and effects both males and females equally.

Around 6.5 in every 1 million people develop one type of DEB, where less than 1 in every 1 million people develop RDEB.

Genetic Counselling

Inheritance Patterns

An inheritance pattern shows how a genetic condition moves from one generation to another. These patterns can therefore help predict the recurrence risk for the condition. For DEB it can follow either a Autosomal Dominant inheritance or an Autosomal Recessive inheritance pattern.

Autosomal Dominant Inheritance

When a single change in one of the two copies of the COL7A1 gene is enough to cause the DEB phenotype it is called Autosomal Dominant.

• DDEB-Gen

The single gene change that causes the condition is inherited from the affected parent. Since an individual gets one copy of the gene from their mother and one from their father there is a 50% chance that a child will get the changed gene from the affected parent and develop DDEB. There is also a 50% chance that the child will get the unchanged copy from the affected parent and be unaffected. The majority (70%) of individuals with DDEB have inherited the changed gene, while the remaining affected individual (30%) have a new change that occurred only in them during conception.

Autosomal Recessive Inheritance

When a single change in both of the two copies of the COL7A1 gene is needed to cause the DEB phenotype it is called Autosomal Recessive.

• RDEB- Severe Generalized
• RDEB- Other

The change in both copies of the gene that causes the condition are usually inherited from two carrier (unaffected) parents. Since an individual gets one copy of the gene from their mother and one from their father both parents carry one change in the COL7A1 gene. There is a 25% chance that a child will get the changed gene from both of their parents and develop DDEB. There is a 25% chance that the child will get the unchanged copy from both of their parents and be unaffected. Additionally there is a 50% chance that the child will get the unchanged copy from one parent and a changed copy from the other and be a carrier like the parents.

Genetic Testing

An individual can undergo genetic testing for many reasons, a few are listed below:

1. To provide a definitive diagnosis. By looking at the specific gene change the caused of the condition can be found. This diagnosis can lead to more affective and target treatments.
2. To help family with family planning. Once the specific genetic change is determine individuals can chose to test their pregnancies, or undergo preimplantation genetic diagnosis (PGD) to test embryos before implantation with IVF (In Vitro Fertilization).

Types of Tests Available

Gene-Targeted Testing

• Single Gene Testing

This test only looks at the COL7A1 gene to determine the specific location of the genetic change. It is not used to classify the type or subtype of DEB.

• Epidermolysis Bullosa (EB) Pannel

This test looks at multiple genes associated with EB including COL7A1 gene. This test is used to help classify the type of EB when no definitive diagnosis has been made.

Comprehensive Genomic Testing

These tests look at either the exome (every gene) or genome (all genetic material). Both tests are used when there is uncertainty if the patient has EB or a different inherited disorder which displays EB like symptoms.

• Whole Exome Sequencing (WES)

• Whole Genome Sequencing (WGS)

Patient Resources

• Dystrophic Epidermolysis Bullosa Research Association of America (DEBRA of America)
• Dystrophic Epidermolysis Bullosa Research Association International (DEBRA International)
• Epidermolysis Bullosa Medical Research Foundation (EBMRF)
• My46 Trait Profile