FLORENCE, ITALY — A decade of remarkable progress in molecular genetics has brought new clarity to the diagnosis of skin diseases. DNA-based testing is providing important information to clinicians and offering families predictions about potentially lethal disorders in blastomere-stage embryos, even before implantation takes place.
“We can now recognize close to 300 different genes that harbor mutations in a manner that explains the clinical manifestations of these [dermatologic] conditions,” announced Jouni Uitto, M.D., professor and chair of dermatology and cutaneous biology at Jefferson Medical College in Philadelphia, at the 13th Congress of the European Academy of Dermatology and Venereology.
Putting genetic advances in perspective, Dr. Uitto noted that even a dozen years ago, inherited skin diseases mystified many community dermatologists and even confounded experts.
“Many of these conditions are evident at birth or shortly thereafter in the neonatal period, but the skin manifestations can be highly variable,” he said. Some resolve early or involve mainly cosmetic manifestations, whereas others are multisystemic and severe, even fatal.
“Genodermatoses have been and continue to be a diagnostic challenge for practitioners. Many of these are relatively rare conditions, so that practitioners are not familiar with [their] salient clinical features. Their classification schemes are very puzzling, riddled with eponyms that are not very informative at all.”
The completion of the Human Genome Project and concentrated effort by the dermatologic and genetic research communities have begun to change all that, offering clear insight into the differences and similarities of subtypes of disorders. This provides the opportunity for solid diagnoses in infancy, pregnancy, and prepregnancy.
To illustrate his point, Dr. Uitto reviewed 8 years of discoveries from his university's epidermolysis bullosa (EB) molecular diagnostics laboratory, which serves as a global diagnostic center and centralized mutation database for the blistering disease.
In 908 families, 783 distinct mutations have been identified on 10 different genes now associated with EB.
Genetic clues have led to a methodical classification of four distinct forms of EB, clarifying 30 subtypes historically identified by uninformative eponyms related to whichever physician first described them, Dr. Uitto said.
Improved diagnosis and classification provides better direction to physicians in terms of management and prognosis, and to families in terms of genetic risks to future children.
“This information certainly has profound consequences for genetic counseling,” he said.
DNA-based genetic tests have been sought out by 181 sets of parents, including 88 seeking information about the genetic status of a pregnancy at risk for junctional EB, which is usually lethal in the first year of life.
These tests can be conducted on embryos prior to implantation after in vitro fertilization, or can be conducted early in pregnancy.
Some families choose to terminate an affected pregnancy, if, for example, they have already lost a child to EB. Other families, however, want the information from this kind of genetic testing to help them plan a safe delivery in an appropriate medical setting with available access to a high-level neonatal intensive care unit.
At the Philadelphia program, the correct genetic phenotypic prediction was made in 155 of 181 pregnancies. In eight pregnancies, which occurred in the early years of the program when mutation detection was in its infancy, the result was inconclusive. The outcome is pending in 18 pregnancies.
The future of prenatal genetic diagnosis is even brighter than its recent past, according to Dr. Uitto.
Promising research is exploring genetic analysis of free fetal DNA within maternal blood samples as early as the seventh week of pregnancy.
Noninvasive diagnoses from maternal blood have already been successfully made in pregnancies at risk for a variety of inherited diseases such as β-thalassemia, sickle cell anemia, and lamellar ichthyosis, he said.
KEVIN FOLEY, RESEARCH