NEUROFIBROMATOSIS

Neurofibromatosis is a collective term that encompasses at least three distinct conditions, referred to as NF1, NF2, and schwannomatosis. NF1 and NF2 are inherited as autosomal dominant traits with complete penetrance but variable expression. Schwannomatosis most often occurs sporadically, but familial cases have been seen, inherited in an autosomal dominant manner with incomplete penetrance. Early diagnosis can be important as a prelude to surveillance for treatable complications as well as genetic counseling. All three disorders are diagnosed on the basis of clinical signs and consensus-based diagnostic criteria have been established. Although definitive diagnosis is often possible, clinical diagnosis can be difficult in younger individuals who do not yet manifest sufficient signs to fulfill criteria. This is especially true for NF2 and schwannomatosis, but is also the case for children with NF1. The genes for NF1 and NF2 have been identified and both are amenable to genetic testing. Each disorder is associated with a wide variety of distinct mutations, making it necessary to employ a complementary set of techniques to improve detection rate. The University of Alabama at Birmingham Medical Genomics Laboratory has been offering NF1 testing, with a detection rate of >95% in individuals who fulfill diagnostic criteria. Relatively few genotype-phenotype correlations have been established. Individuals with large deletions tend to have a severe NF1 phenotype, including early onset and large numbers of neurofibromas, developmental delay, and dysmorphic features. Otherwise, specific mutations are not yet known to be predictive of specific outcomes. In NF2, mutations that lead to premature termination of translation tend to be associated with more severe disease as compared with missense mutations. Genetic testing can be useful in patients with NF1 who are too young to fulfill diagnostic criteria, or who present with unusual signs or symptoms. It can also provide a basis for prenatal testing or testing of other family members. In NF2, genetic testing is most useful to determine if individuals at genetic risk of inheriting a mutation need to be followed for complications of the disorder.