Neurofibromatosis-Noonan syndrome

Neurofibromatosis-Noonan syndrome (NFNS) is a rare genetic condition that combines features of two well-known disorders: neurofibromatosis type 1 (NF1) and Noonan syndrome. Affected individuals typically present with café-au-lait spots, freckling in the axillary and inguinal regions, and neurofibromas characteristic of NF1, alongside Noonan syndrome features such as short stature, distinctive facial features (hypertelorism, down-slanting palpebral fissures, low-set posteriorly rotated ears, and a webbed neck), and congenital heart defects — most commonly pulmonary valve stenosis and hypertrophic cardiomyopathy. The condition affects multiple body systems including the skin, skeletal system, cardiovascular system, and nervous system. Learning difficulties and developmental delays may also be present in some individuals. NFNS is caused by pathogenic variants in the NF1 gene located on chromosome 17q11.2, which encodes neurofibromin, a protein involved in the RAS-MAPK signaling pathway. The overlap between NF1 and Noonan syndrome is explained by the fact that neurofibromin functions as a negative regulator of RAS signaling, and Noonan syndrome is itself a RASopathy. Some patients may also carry variants in other RAS-MAPK pathway genes. The condition is inherited in an autosomal dominant pattern, meaning a single copy of the altered gene is sufficient to cause the disorder, though de novo (new) mutations also occur. There is currently no cure for neurofibromatosis-Noonan syndrome. Management is multidisciplinary and symptom-based, involving regular monitoring for tumor development, cardiac evaluation and treatment of heart defects, orthopedic management for skeletal abnormalities such as scoliosis, and educational support for learning difficulties. MEK inhibitors such as selumetinib, which have been approved for symptomatic inoperable plexiform neurofibromas in NF1, may be considered in appropriate cases. Regular surveillance by a team including geneticists, cardiologists, neurologists, dermatologists, and ophthalmologists is recommended throughout the patient's lifetime.

Common questions about Neurofibromatosis-Noonan syndrome