Importance and necessity of extended molecular diagnostic – Confirmation of the clinical diagnosis of neurofibromatosis type 1

Introduction: Neurofibromatosis type 1 (NF1) is one of the most common neurocutaneus disorders. NF1 is caused by defects in the NF1 gene, coding for the neurofibromin protein which acts as a tumor suppressor. The inheritance of NF1 is autosomal dominant. Patients with NF1 present with a wide range of symptoms like café-au-lait spots, freckling, neurofibroma, iris Lisch nodules, optic nerve glioma, bone lesions or an affected first degree relatives, in the first years of life. Patients: We present a German family (clinical affected family members in three generations) with NF1. The index case was diagnosed with NF1 in early childhood and now presents with freckling, isolated café-au-lait spots and about 700 neurofibroma. He has had surgery for a symptomatic optic nerve glioma and a neurofibroma previously. No relevant movement disorders or learning difficulties in childhood were reported. His mother showed café-au-lait spots and neurofibroma and his daughter already presents with café-au-lait spots and a neurofibroma at the age of 3. Previous molecular genetic testing of father and daughter revealed no mutation in the NF1 gene by sequence analysis of PCR products of all coding exons, including corresponding exon-intron boundaries, and excluded a NF1 µ deletion. Methods and Results: Genetic testing by Multiplex Ligation-Dependent Probe Amplification (MLPA, SALSA P081-B2, P082-B2 probemixes, MRC-Holland) indicated the presence of a heterozygous deletion of at least 6.5kb in size which encompasses exons 4 and 5 within the NF1 gene, for father and daughter. Conclusion: Our findings suggest that the diagnostics of the NF1 gene necessitates screening for deletions and duplications of one or more exons (e.g. by MLPA) if no mutation is found by sequence analysis. In addition, genetic counselling is very important for NF1 patients due to the autosomal dominant heredity of the disease and with regard to family planning and a desire for children.