We would like to acknowledge the assistance of members of the debra of America Scientific Advisory Board for their kind revisions for the updated text: Dr. Alan Arbuckle, Dr. Anna Bruckner, Dr. Jo-David Fine, Dr. Anne Lucky, and Dr. Ellen Pfendner.
In addition, we thank all the members who contributed to the original website text, including: Dr. Susan B. Bayliss, Dr. Jo-David Fine, Dr. Sharon Glick, Dr. Robert Meirowitz, Dr Alan Moshell Dr. Amy Paller, Dr. Ellen Pfendner Dr. Lawrence Schachner, Dr. Daniel Siegel, Dr. Alan R. Shalita, Dr. Mary K. Spraker, as well to DEBRA UK and their EB Nurse Specialists.
Special thanks to Madeline Weiner and Kari McGrath for the preparation of the original material, Arlene Pessar, R.N., B.S.N., Founder, Dystrophic Epidermolysis Bullosa Research Association of America, Inc., and to Anne Brown, R.D., M.S., Director of Dietetics, Rockefeller University Hospital and a group of communications students from Rider College, Lawrenceville, New Jersey, for their thoughtful review and contributions to the original website text.
The following information describes a group of genetic blistering disorders of the skin that are collectively referred to as Epidermolysis Bullosa or EB. It has been written for patients, their families and friends, and health professionals to explain what we know about these disorders.
Our focus is on the inherited forms of EB, each of which range from mild to severe and can require major adjustments in the lifestyle of both the EB patient and his or her family.
EB Simplex (EBS)
EB Simplex is usually dominantly inherited, and involves mutations of the genes for Keratins 5, 14 and a structural protein called plectin. Blistering occurs within the uppermost layer of the skin within the epidermis (intraepidermal). EBS may be localized to the hands and feet or there may be a generalized distribution, with relatively mild internal involvement. Those with a subtype of EBS may develop thickened calluses on the palms and soles as they age. These same patients may also have oral blistering during infancy and develop rough, thickened fingernails/toenails at, or shortly after, birth.
Junctional EB (JEB)
Junctional EB is recessively inherited, and involves disorders of several different protein components of the junction between the epidermis and dermis such as laminin 5 (now known as laminin 332), plectin, collagen XVII, and a 6 b 4 integrin. Blisters occur between the upper and lower layers of the skin (at the level of the lamina lucida within the basement membrane zone) and skin involvement is typically generalized. There are three main subtypes of JEB: Herlitz, non-Herlitz and JEB with Pyloric Atresia.
Junctional Herlitz EB is a very severe form of EB. Death often occurs prior to the second year of life due to overwhelming infection (sepsis), malnutrition, dehydration, electrolyte imbalance or pulmonary failure secondary to internal blistering. There is a wide clinical spectrum of non-Herlitz JEB. JEB infants presenting with pyloric atresia will have trouble with feeding and abdominal distension as neonates and will require surgical intervention to treat the atresaia.
Dystrophic EB (DEB)
Dystrophic EB can be either dominantly or recessively inherited, and involves defects in Type VII collagen. Blisters occur within the lower layer of the skin (sub-lamina densa basement membrane zone separation).
Dominant Dystrophic EB (DDEB): Blistering may be localized to the hands, feet, elbows and knees or it may be generalized. Common findings include scarring, milia, mucous membrane involvement, and abnormal or absent nails.
Recessive Dystrophic EB (RDEB): Typically more generalized and severe than DDEB. In addition to the findings of DDEB, other common manifestations include malnutrition, anemia, osteoporosis, esophageal strictures, growth retardation, webbing, or fusion of the fingers and toes causing mitten deformity ( pseudosyndactyly), development of muscle contractures, malformation of teeth, microstomia and scarring of the eye. The risk of squamous cell carcinoma is greatly increased in this group as well as death from metastatic squamous cell carcinoma.
Kindler Syndrome is an extremely rare recessively inherited genodermatosis which involves mutations in the gene that codes for the structural protein Kindlin-1. The blistering can occur at any layer of the skin. Kindler Syndrome involves a generalized distribution, with internal involvement that can include colitis as well as anal stenosis. Those with Kindler syndrome may have thickened calluses on the palms and soles, photosensitization and these patients are at increased risk of developing squamous carcinoma of the oral mucosa.
EB Aquisita (EBA) is an acquired autoimmune blistering disease. EBA is not a genetic disorder.
Image used with permission from eMedicine.com, 2008
In severe EB, blisters are not confined to the outer skin. They may develop on the soft tissues (mucous membranes) inside the body such as the linings of the mouth, esophagus, stomach, intestines, lungs, bladder and genitals. The extent of tissue involvement experienced by an individual is usually determined by the severity of the disease and the subtype present.
|1.3||Additions and Changes to the EB Vocabulary|
In the last eight years, the advances in science that address the spectrum of inherited Epidermolysis Bullosa (EB) have been substantial. On May 19, 2007, 18 leading EB authorities met to review the classification system of EB and update it to reflect current knowledge. The findings of this meeting were published in the American Academy of Dermatology in June 2008 as "The classification of inherited epidermolysis bullosa (EB): report on the Third International Consensus Meeting on Diagnosis and Classification of EB." Jo-David Fine et al.
This Consensus meeting resulted in an expansion of EB’s classification to include other disorders associated with mechanical fragility of the skin. Kindler Syndrome is now classified as a fourth subtype. Kindler syndrome is an autosomal recessive disorder involving kindlin, and the cleavage plan varies in these individuals.
|Level of skin cleavage||Major EB type||Known targeted protein(s)|
|Intraepidermal (“epidermolytic”)||EBS||Keratins 5 and 14; plectin; 6β4 integrin; plakophilin-1; desmoplakin|
|Intra–lamina lucida (“lamina lucidolytic”)||JEB||Laminin-332 (laminin 5); type XVII collagen; 6β4 integrin|
|Sub–lamina densa (“dermolytic”)||DEB||Type VII collagen|
The Junctional subtype was expanded to include laryngo-onycho-cutaneous syndrome (LOC or Shabbir’s syndrome). LOC is an autosomal recessive disorder seen with increased incidence in Punjab and involves Laminin 332 (formerly Laminin 5).
The reason for the additions include:
- They have friction-induced blisters and other clinical features in common with more established forms of EB;
- They are hereditary
- The patients, especially neonates, and their families, will potentially benefit from the growing resources already available for EB patients
The Consensus group also reviewed the testing methods and findings for EB within each. DNA testing was discussed:
- mutational analysis remains a superb research tool
- gene therapy will be dependent DNA mutation identification.
- It is required so prenatal and pre-implantation diagnosis can be performed.
- At the present time it is not considered a first-line diagnostic test for EB.
|EBS, Weber-Cockayne||Change to “EBS, localized”||Lack of uniformity in original descriptions; new name has more immediate visual impact|
|EBS, Koebner||Change to “EBS, generalized other”||Inconsistency in definition even among EB experts; not associated with Koebner phenomenon|
|EB with pyloric atresia||Separate into “EBS-PA” and “JEB-PA” subtypes||Pyloric atresia may occur rarely with EBS, as well as with JEB|
|Hemidesmosomal EB||Eliminate this term||Includes only one of two JEB-nH subtypes having identical EM and clinical findings; distinction is based solely on targeted protein|
|RDEB, Hallopeau-Siemens||Change to “RDEB, severe generalized”||New term has more immediate utility for clinicians|
|RDEB, non–Hallopeau-Siemens||Change to “RDEB, generalized other”||Consistency in nomenclature|
|Transient bullous dermolysis of the newborn||Change to “bullous dermolysis of the newborn”||Not always transient; rare patients continue to blister beyond the newborn period or infancy|
The outcomes of the reclassifications of other disorders as part of the EB spectrum along with clarification in the nomenclature of EB diagnoses will result in more consistency across medical disciplines.
This is a review of only a small portion of the Classification review. The paper has summary tables about the relative findings, both cutaneous and extracutaneous, for each subtype listed within the new classification scheme. It is highly recommended that those with an interest in EB review the full article
|1.4||Prevalance and Incidence of EB (by type and subtype)|
Material is based on the NEBR study population
|EB type or subtype:||Prevalence*||Incidence**|
|EB (All types and subtypes, including unclassified patients)||8.22||19.60|
|EBS, Localized (formerly Weber- Cockayne)||3.14||6.81|
|EBS, all others||1.46||3.95|
|RDEB, severe generalized (formerly Hallopeau- Siemens)||0.42||0.41|
|RDEB, all others||0.49||1.63|
*Prevalence of EB patients per one million births (1990)
**Incidence of EB births per one million live births (1986-1990)
Fine, Jo-David and Hintner, Helmut. (2008) "Life with Epidermolysis Bullosa (EB): Etilogy, Diagnosis, Multidisciplinary Care and Therapy" Springer-Verlag/Wien, New York.
|1.5||Testing for EB|
The biggest mistake that providers make in the neonatal period is trying to determine the type and subtype of EB without the appropriate testing. Even within the same subtype of EB, with the same mutation, patients can have a different clinical presentation. When EB is suspected, an evaluation and skin biopsy should be obtained by a consulting dermatologist when one is available.
Prior to obtaining the sample, the lab should be contacted, to provide detailed instruction on sample collection. Currently, Beutner Labs, Inc., University of Colorado and Stanford University are performing diagnostic EB testing. Your consulting dermatopathologist can help guide you in the proper acquisition and processing of the tissue. Inquiring about the patient’s insurance might be necessary as well, as many times third party payers will not cover the cost of electron microscopy.
To identify exactly where the split (cleavage plane) is in the skin and which proteins are involved (absent or diminished), Immunofluorescence (IF) antigenic mapping via monoclonal antibody studies are performed. Monoclonal antibodies are used to bind to certain antigens (proteins) that are normally present in the skin. If specific antigens or proteins are missing, there will be an absence of staining, identifying the missing protein and supporting the diagnosis of the type, and sometime the subtype, of EB.
Transmission Electron Microscopy involves the use of a high powered microscope to study the sample of skin to identify specific structural defects. This is still considered the “gold standard” for diagnosis by many experts who care for patients with EB.
Upon identification of type, DNA analysis may be done to identify the specific genetic mutation and to determine the mode of inheritance .This is helpful information in regard to future family planning. Once the genetic mutation is identified in a family, prenatal diagnosis of subsequent pregnancies is possible via Preimplantation Genetic Diagnosis (PGD), chorionic villous sampling, or amniocentesis.
The sample can matched against the previously identified mutations by a genetic molecular lab. Unfortunately, these tests are very expensive and can take several weeks. However, if the patient has a new mutation (i.e. one not routinely screened by the company), testing may take longer and cost may be prohibitive for many families. Consultation with the patient’s insurance company is mandatory, because gene analysis is not always a covered service.
GeneDx (www.genedx.com) is currently performing genetic analysis for the most common known mutations of many of the forms of EB at this time in the USA.
|1.6||Genetics and How EB is inherited|
Genetic counseling provides and interprets medical information based on expanding knowledge of human genetics. A genetic counselor will work with a family to review their family history and explore the likelihood of recurrence of EB in future children and other relatives.
Genes involved in EB and their correlating chromosome locations:
The first number in the location is the chromosome, the q or p indicate the long arm (q) or short arm (p), and the numbers following that indicate the band on that arm of that chromosome
Often the genetic counselor is a physician who will participate in the diagnosis, examine family members and provide ongoing medical care. In other instances, a geneticist (someone with an advanced degree in human genetics) may work with the child's medical provider. The counselor, perhaps with close family advisors, such as a minister, priest or rabbi, can help a family make informed decisions about child- bearing and help them cope with the impact of a genetic disorder. Genetic counselors and social workers often work together to ensure that patients and families receive all the services and benefits to which they are entitled.
Modes of Inheritance:
Autosomal Dominant Inheritance: An autosomal dominant disorder is one in which one gene for the condition expresses itself in an individual. A parent with an autosomal dominant form of EB has a 50:50 chance with each pregnancy of transmitting the abnormal gene. The chance is the same whether the child is a boy or a girl, and birth order does not make a difference. A child who does not inherit the gene for EB from an affected parent will not have the condition and cannot pass it on to future generations.
Autosomal Recessive Inheritance: An autosomal recessive disorder is one in which a recessive (unexpressed) gene for the disorder is passed from each parent and the two genes are paired together, causing the disorder to be expressed in the child. If a person has one recessive EB gene paired with a normal gene, the person is “a carrier", but does not have the disorder. If parents are each carriers of an autosomal recessive gene, there is a 25 percent chance with each pregnancy that their children will have the disorder. Again, the sex of the child and the birth order do not matter. An individual with a recessive form of EB will be at risk of having an affected child only if he or she has a child with a carrier or another person with recessive EB.
Spontaneous Mutation: In some instances, neither parent has EB, but the couple has a child with an autosomal dominant form of EB. In this situation, the condition has usually been caused by a change, or mutation in the genetic material of the egg or the sperm. When a new mutation occurs, the affected individual will have a 50:50 risk of passing the gene on in his/her pregnancies, but his/her parents will not. They have no increased risk of having a child with EB in subsequent pregnancies.
For more information on the genetics of EB go to Gene Reviews at: www.ncbi.nlm.nih.gov/sites/GeneTests/review?db=genetests and search Epidermolysis Bullosa
|1.7||Prenatal Diagnosis for Epidermolysis Bullosa|
Dr. Ellen Pfendner Ph.D., Director, EB Diagnosis Program, GeneDx
In 1993 mutations in the collagen VII gene, the gene involved in dystrophic EB (DEB), were identified and the first successful prenatal diagnosis was performed for a family with a DEB child. The process has expanded as more is learned about the genetics of EB and since that time, successful prenatal diagnosis has been performed for hundreds of EB families in the US and abroad.
It is often believed that DNA mutation studies must be used to diagnose EB, but that is not their primary role. Mutation detection is a very expensive and labor intensive method. It is not always able to identify mutations in all patients. Mutation studies are most useful in determining the EB inheritance pattern in most families and to provide the basis for prenatal diagnosis in future pregnancies in a given family.
The first step to prenatal testing is confirming the subtype and the DNA mutation(s) carried in a family. Since mutation detection can take up to several months to complete, depending upon the family, it is very important to know the mutations in advance of a pregnancy.
Determining the type of EB in a particular family member can be achieved through studies of a skin biopsy taken from the affected family member. The skin sample is then sent to a laboratory where electron microscopy and/or immunofluorescence can be performed to identify the proteins missing and the level at which blister formation occurs in the skin of the patient. (See Testing for EB)
To begin mutation studies, the medical provider will arrange to have blood drawn from the patient as well as parents and sent to the diagnostic laboratory (GeneDx is the commercial lab that is doing this testing in the United States at this time). DNA will be extracted from the blood samples and from this DNA mutation studies will be performed. This process may take several months to complete and involves screening methods and direct DNA sequencing of the candidate genes in the patient and other family members. After the family mutations are identified, the risk to a future fetus can be determined.
When a pregnancy occurs, DNA taken from the fetus can be studied for the presence of these mutations, a small fetal sample can be obtained by either chorionic villus sampling (CVS) or amniocentesis, which is performed by the medical provider. After the sample is obtained, it is shipped to the diagnostic lab. DNA analysis is done to identify if the fetus carries the family’s specific genetic mutation(s).
Preimplantation Genetic Diagnosis (PGD) is done prior to pregnancy, and improves the chances of having an EB free child.
PGD is accomplished with in-vitro fertilization, in which the mother takes hormones to increase the number of eggs she produces during her monthly cycle. These matured eggs are surgically removed and then fertilized with the father’s sperm. When the fertilized egg reaches the eight cell stage, one of the cells is removed and analyzed at a special laboratory to see if it carries the EB mutations that were identified in the family. The fertilized eggs that do not carry the mutations can then be implanted. If pregnancy results from the implantation process, the child will be EB free, but may also be a carrier like the parents.
This process has been used successfully in a number of EB families. However, it is very expensive and not always covered by standard health insurance. Successful pregnancy with live birth is achieved in approximately one third of PGD cycles. As with any medical procedure, a discussion with the medical provider can determine whether PGD is right for the family.
Finally, each of the procedures discussed here involves risks. The medical provider will review these risks. Additionally, prenatal diagnosis, like any other laboratory procedure, is not 100% accurate. Very infrequently, new mutations can occur or recombination between chromosomes can lead to a faulty prediction. While there is also the possibility of laboratory error, the laboratory takes great precautions to ensure this does not happen. In general, prenatal diagnosis is a safe and effective method to determine whether the fetus has EB and has been used for many families who are coping with this devastating disease.
You may contact debra of America with questions or concerns:
staff [at] debra [dot] org
*Please note that all medical information given by debra of America 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.
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