Correct diagnosis

The clinical descriptions of EB and the methods of establishing a correct diagnosis are dealt within other articles in this issue (see the articles by Intong and Murrell, Pohla-Gubo and colleagues, and Eady and Dopping-Hepenstal elsewhere in this issue for further exploration of this topic.). It may be several weeks until the correct diagnosis can be made, and genetic counseling may take a back seat to immediate medical needs. Parents are always certain that they are somehow responsible for their infant’s disease. Irrespective of the diagnosis, parents can be told that this is not true. Predictions of lethality may be over or understated. I have found that assurances of providing maximum support while waiting for information, despite the condition’s possible fatality, are better received than the immediate hanging of crepe. I also make it clear that despite many tools providing medical support, much of what happens is not in the physician’s or the parents’ hands, and the infants have a say too. They will determine how they will do and may not survive despite best efforts.

The correct diagnosis is required before recurrence risks can be estimated. The diagnosis of epidermolysis bullosa simplex (EBS) Koebner type (generalized) implies an autosomal dominant cause, heterozygosity for a mutation in keratin 5 ( KRT5 ) or keratin 14 ( KRT14 ), and a 50% recurrence risk to offspring of an affected person. EBS with muscular dystrophy due to homozygosity for plectin mutations can look clinically identical to EBS until the muscular dystrophy manifests. These are autosomal recessive disorders, and the risk of transmission to offspring, although higher than the background risk, is absolutely small, whereas the risk for affected siblings is 25%. If the correct diagnosis is not established, bad medicine will be practiced.

The correct diagnosis is required before molecular testing can be performed efficiently. Mostly, molecular testing does not establish the diagnosis of EB but confirms it. Molecular testing is directed by clinical acumen. If one mistakes junctional disease for dystrophic disease and tests for mutations in COL7A1 (type 7 collagen), testing will be uninformative. Junctional disease is not due to mutations in COL7A1 . If the diagnosis of dystrophic disease is correct, a negative test for COL7A1 does not rule out dystrophic disease. Sensitivity of molecular testing is almost never 100%; technologic limitations and the creative packaging of DNA can make some mutations undetectable. Allelic heterogeneity (where different versions or alterations in the same gene can cause the disorder) can also complicate molecular testing. Molecular testing may be limited to common or hotspot mutations, thus missing mutations that are due to alterations elsewhere in the gene. Locus heterogeneity (where mutations in different genes can result in clinically indistinguishable disorders) also limits the utility and accuracy of molecular testing. For simplex disease, both KRT5 and KRT14 must be analyzed. In junctional disease, mutations in the pair of 1 of at least 6 different genes ( LAMB3, LAMC2, LAMA3, COL17A1, ITGB4, ITGA6 ) may be causal, and testing needs to be performed in a stepwise fashion.

The correct diagnosis is required before a prognosis can be generated and is necessary to determine the likely natural history for the condition. It is not enough to tell affected individuals or parents what the diagnosis and recurrence risks are and whether prenatal diagnosis is available and appropriate. They need to know about the disorder, how to care for the skin, what to expect, and how to manage complications. All this is also part of genetic counseling. Parents of babies with severe junctional EB need to know about the possibility of respiratory arrest. They should know that no matter how vigilant they are, the infants may slough their respiratory mucosa and succumb. If they want to learn how to resuscitate, we need to teach them. But they need to understand that even the most vigorous of interventions may fail. We should address pain control, blister care, and feeding. The medical geneticist is also involved in this and must be able to discuss these issues knowledgeably. The dermatologist and the intensivist must understand the genetic aspects of these conditions. Genetic counseling needs to be provided by all the professionals involved in the care of the patient because the information is overwhelming, confusing, easily forgotten or misunderstood, and bears repeating. Listen to the patients and the parents. Hear their overt questions and respond to their tacit concerns. Be prepared to sideline some discussions and to deal with others based on what the patients or parents are telling you. Ask them what their questions are, what they understand, and what is important to them.