The NFl gene is a large and complex gene spread over 280Kb of genomic DNA on chromosome l7qll.2, comprising 57 constitutive exons and at minimum 3 alternatively spliced exons.
Mutations in the Nfl gene affect worldwide ~1/3000 individuals and are associated with Neurofibromatosis type 1. Molecular analysis can help with the clinical diagnosis, especially when atypical forms of NFl are present (such as spinal NF, NF-Noonan, Watson syndrome, segmental NF, … ).
Legius syndrome, a recently ras-o-pathy identified, is caused by mutations in the SPREDl gene on chromosome l5q13.2. Individuals with Legius syndrome present mainly with CAL-macules (CALM) and skinfold freckling, indistinguishable in size, shape and number from NFl, however, other typical NF1-
associated features, such as Lisch nodules, neurofibromas, specific bone lesions, optic pathway gliomas and malignant peripheral nerve sheath tumors, are absent.
CALMs are the most common first sign of NFl, and are present in up to 95% of NFl patients by age of 1 year. Multiple CALMs with or without skinfold freckling are usually the only findings in the small child, suspected of having NFl and it may take up to 5 more years before additional clinical features appear and the diagnosis of NFl can be made confidently based solely on clinical grounds. As ~50% of patients with Legius syndrome fulfill NIH diagnostic criteria for NFl, but the tumor complications typically reported in NFl are however absent, a molecular confirmation of NFl versus Legius syndrome is important for counseling and management. In all scenarios considered, SPREDl mutations are rare compared to NFl mutations. Several factors may affect sensitivity and specificity of the NF1/SPRED1 mutational analyses and our experiences with a large cohort of patients will be discussed.