With an incidence of 1 in 3,000–4,000, NF1 (Recklinghausen’s disease) is one of the most common hereditary neurologic diseases associated with benign and malignant tumors of the nervous system. Typical signs are cutaneous and subcutaneous neurofibromas, typically developing during adolescence, café au lait spots (pigmentation anomalies) of the skin, usually manifesting during the first decade of life, freckle-like spots in the arm pits or the groin area and Lisch nodules of the iris. Severe clinical manifestation such as plexiform neurofibromas, optic gliomas, neurofibrosarcomas and bone changes are less common. In 1988, the National Institutes of Health (NIH) established the diagnostic criteria for NF1. NF1 displays full penetrance with a highly variable phenotype. Inheritance is autosomal dominant; 50% of all patients have a positive family anamnesis, while 50% of all diseases occur due to de novo mutations.
NF1 is caused by mutations in the NF1 gene. The gene product neurofibromin functions as tumor suppressor via its GTPase activity through inactivation of GTP-bound RAS. The NF1 gene consists of 57 coding and 3 alternatively spliced exons; 9 pseudogenes have been described. So far, 1,200 different mutations have been identified in the NF1 gene. The mutations are spread nearly over all exons or bordering intron sequences and comprise all types of mutations; while with a proportion of 80%, translational stop mutations are the most frequent ones. With 1 in 10,000 base pairs, the mutation rate in the NF1 gene is one of the highest of all human genes. 5% of all patients have a microdeletion type I (1.4 Mb) or type II (1.2 Mb) in chromosome 17q11.2 between two duplicated regions adjacent to the NF1 gene, which contains the NF1 gene. These deletions can be detected by fluorescence in-situ hybridization (FISH). Affected patients frequently display a severe phenotype with early development of neurofibromas, facial dysmorphia and intellectual disability. Intragenic deletions, which account for approx. 2% of all mutations in the NF1 gene and which may affect one or several exons, can be detected by MLPA (multiplex ligation-dependent probe amplification).
In 95% of all patients who fulfill the diagnostic criteria of the NIH Consensus Development Conference Statement, mutations in the NF1 gene can be detected using a combination of sequence analysis and deletion/duplication diagnostics. Regarding a differential diagnosis, the Legius syndrome is relevant (see respective chapter).
In predictive genetic testing, at-risk, asymptomatic individuals are tested, usually first-degree relatives of affected patients. According to the Genetic Diagnosis Act (GenDG) genetic counseling should be offered along with any genetic diagnostic procedure. In the case of predictive genetic testing, according to the GenDG genetic counseling must be carried out prior to testing as well as after having received the result , unless there exists a written waiver of the at-risk person after having received written information on the content of the counseling. According to the recommendations of medical societies genetic testing should be accompanied by psychotherapeutic counseling prior to, during and after the genetic diagnostic procedure.