How to diagnose neurofibromatosis type 1?

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder characterized by marked phenotypic variability and an incidence of approximately 1 in 3,000 to 5,000 live births. Up to 50% of cases arise from de novo mutations. NF1 primarily affects the skin, nervous system, eyes, and musculoskeletal system, and it is also considered a cancer predisposition syndrome in both childhood and adulthood. Diagnosis is clinical and based on the criteria established by the National Institutes of Health (NIH), updated in 2021. These criteria include: six or more café-au-lait macules, axillary or inguinal freckling, cutaneous or plexiform neurofibromas, Lisch nodules on the iris, optic pathway gliomas, characteristic osseous dysplasias, and a first-degree relative with NF1.

Clinical manifestations emerge at different life stages, with cutaneous signs —such as café-au-lait macules and neurofibromas— being the most frequent and visible. However, neurological, ophthalmological, orthopedic, and oncological complications may occur at any time. In childhood, optic pathway gliomas and bone dysplasias require close surveillance. From an ophthalmologic perspective, Lisch nodules and choroidal abnormalities are relevant findings, particularly in adults.

In adulthood, the risk of several tumors increases, including breast cancer, colorectal cancer, neuroendocrine tumors, and malignant transformation of plexiform neurofibromas into malignant peripheral nerve sheath tumors (MPNST), which represents one of the most severe complications. 

Molecular confirmation can be achieved through genetic testing of the NF1 gene, located on chromosome 17q11.2, especially in cases with atypical manifestations, suspected mosaicism, or for purposes of genetic counseling and prenatal diagnosis. Management requires a multidisciplinary and individualized approach, with regular surveillance to enable early detection and treatment of complications. Although there is no cure, advances in targeted therapies, such as MEK inhibitors, have improved prognosis and quality of life of patients with inoperable plexiform neurofibromas. 

In conclusion, NF1 is a complex multisystem disorder that demands comprehensive clinical care. Early identification, continuous monitoring, and timely interventions are crucial to optimize outcomes and improve the quality of life of affected individuals.