LONDON – have come in understanding this debilitating group of genetic skin diseases, but also how far there is still to go towards improving the management of those affected.
Sara Freeman/MDedge News
Dr. Christina Has
Previous criteria issued in 2014 represented “important progress” and “built on the achievements of several generations of physicians and researchers who described the phenotypes, the level of skin cleavage, developed and characterized antibodies, and discovered EB-associated genes,” Cristina Has, MD, said at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA).
Dr. Has, a senior dermatologist and professor of experimental dermatology at the University of Freiburg (Germany), observed that prior criteria had “introduced genetic and molecular data in a so-called onion-skin classification of EB, and removed most of the eponyms,” which had been maintained in the latest update.
“What is new, and probably the most important change, is making the distinction between classical EB and other disorders with skin fragility,” she said, noting that the revised classification criteria for EB included minor changes to the nomenclature of EB. Six new EB subtypes and genes have also been added, and there are new sections on genotype/phenotype correlations, disease modifying factors, and the natural history of EB. Furthermore, supporting information included a concise description of clinical and genetic features of all EB types and subtypes.
The updated criteria are the result of an expert meeting held in April 2019 and have been accepted for publication. The expert panel that developed the criteria think that the revised classification criteria will be “useful and, we hope, inspiring and motivating for the young generation of dermatologists, pediatricians, and for the researchers who work in this field,” Dr. Has said.
“The term EB has been used in the last years for many new disorders, and this is the reason why we thought we have to somehow control this, and to make the distinction between classical epidermolysis bullosa due to defects at the dermal junction and other disorders with skin fragility where the anomalies occur within other layers of the epidermis or in the dermis,” Dr. Has explained.
There are still 4 main types of classical EB: EB simplex (EBS), dystrophic EB (DEB), junctional EB, and Kindler EB, but there are now 34 subtypes, slightly fewer than before. The updated criteria distinguish between the types and subtypes according to the level of skin cleavage, the inheritance pattern, the mutated gene, and the targeted protein, Dr. Has said.
As for peeling disorders, these have been classified as being erosive or hyperkeratotic, or as affecting the connective tissue with skin blistering. Similar to classical EB, these disorders are associated with fragility of the skin and mucosa and share some pathogenetic mechanisms. Moreover, as “the suffering of the patient is similar,” Dr. Has said, “we’d like to consider them under the umbrella of EB.” Most of the disorders she listed were inherited via an autosomal recessive mechanism, with intraepidermal disorders inherited via an autosomal dominant mechanism. New genes are being identified the time, she added, so these groupings will no doubt be subject to future revisions.
Minor changes to nomenclature were made to avoid confusion among clinicians and those living with the condition. As such, Kindler EB replaces Kindler syndrome, names of some subtypes were simplified, and a new “self-improving” type of DEB was introduced to replace the term “transient dermolysis of the newborn.” Altogether, there are now 11 subtypes of DEB. A distinction was also made between syndromic and nonsyndromic EB. “We all know that EB can be a systemic disorder with secondary manifestations within different organs,” Dr. Has told conference attendees. Anemia and failure to thrive can be associated, but it still remains a nonsyndromic disorder, she said. By contrast, “syndromic EB is due to genetic defects, which are also expressed in other organs than the skin or mucosal membranes, and lead to primary extracutaneous manifestations, such as cardiomyopathy, nephropathy, and so on.”
There are fewer subtypes of EBS and “we think they are better defined,” Dr. Has stated. “EB simplex is the most heterogenous EB type, clinically and genetically, and includes several syndromic disorders,” and the new classification criteria should be useful in helping categorize individuals with EBS and thus help target their management.
One of the six new subtypes of EB included in the revised classification criteria is “syndromic EBS with cardiomyopathy” caused by the KLH24 mutation. This gene was discovered in 2016 and more than 40 cases have so far been identified, 50% of which have been sporadic de novo mutations.
Other new EB subtypes are:
- “EBS with localized nephropathy” caused by a mutation in the CD151 gene.
- An autosomal recessive EBS linked to the KRT5 gene.
- A new phenotype that manifests with oral mucosal blisters linked to the DSG3 gene. (Although only a single case has been reported to date, it was felt worthy of inclusion.)
- Another linked to DSG3 that leads to skin fragility and hypertrichosis.
- A new dystrophic EB subtype linked to mutations in the PLOD3 gene.
In an interview, Dr. Has reiterated the importance of keeping classification criteria updated in line with current research findings. She emphasized that there were many types of EB and how important it was to refine how these were classified based on the underlying genetics.
“We brought much more genetic data into the paper, because we are in the era of personalized medicine,” she said. “There are specific therapies for mutations and for different subtypes and that’s why we think that, step by step, we have to bring in more and more data into the classification.”
There are many people with EBS, she observed, and while these individuals may not have such a dramatic clinical presentation as those with recessive DEB, for example, the effect of the condition on their daily lives is no less. “These people are active, they have jobs, they have to work, and they have pain, they have blister,” Dr. Has said.
While the criteria are intended only for classification of EB, they might help in practice. Dr. Has gave an anecdotal example of a woman that has been misdiagnosed as having a type of DEB with a high risk of squamous cell carcinoma but in fact had a different form of EB with no risk of developing SCC. “That’s why criteria are important,” she said.
Dr. Has had no conflicts of interest to disclose.