EURONET-NF: improved diagnostics of the neurofibromatoses

The neurofibromatoses and schwannomatoses (NF-SCHW) comprise three rare disorders with each specific tumor risks (tumor disposition syndromes): neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis. NF2, which is nowadays called NF2-associated schwannomatosis, and the (non-NF2-associated) schwannomatosis show a partly overlapping clinical phenotype and may be differential diagnoses in some patients. Equally, constitutional Mismatch Repair Deficiency (CMMRD), which has an extraordinarily high risk for malignant tumors already in childhood, and Legius syndrome (LGSS), which is not associated with a noticeable tumor risk, are rare alternative diagnoses in patients suspected to have NF1. Hence, these five rare diseases are each associated with a different tumor risks and spectra and, consequently, require different management including adequate tumor surveillance. A definite diagnosis of these clinically in part overlapping disorders is frequently only possible by identification of the genetic disease-causing alteration in the gene mutated in the respective disorder. A genetic diagnosis is in most cases also indispensable for an early diagnosis, since patients develop frequently only during later childhood, adolescence and early adulthood the full clinical picture allowing for an unequivocal clinical diagnosis. Despite the importance of genetic testing, we are daily confronted with complex genetic diagnostic challenges. Currently used techniques can miss the pathogenic, i.e. disease-causing, variant in the relevant gene. In addition, for many variants which are identified it is not clear whether they are disease causing. Therefore, we aim in collaboration with further five NF-SCHW expert centers in different European countries to develop, evaluate and share new sensitive and reliable techniques that can be globally used in the genetic diagnosis of NF-SCHW and related rare diseases. Although we realize not all patients can be finally diagnosed, we expect to improve the genetic diagnosis of the majority of unsolved cases. For a specific subset of negative patients, new potential candidate genes will be searched for. One of our specific aims in Innsbruck will be to evaluate clinical criteria for CMMRD testing in suspected NF1/LGSS children for whom neither of these diagnoses can be genetically confirmed. We expect that the improved genetic diagnostics of NF-SCHW and related disorders by novel, sensitive and reliable assays will open new perspectives for improvement of management, and genetic counseling of patients and their entire families.