Neurofibromatosis type I

Neurofibromatosis type 1 (NF1) or von Recklinghausen`s disease is one of the most common autosomal dominant diseases and has an incidence of approximately one case per 3000 births. This pathology is characterized by the formation of neurofibromas in the skin.

NF1 is caused by alterations in the NF1 gene that codes for the neurofibromin protein which is thought to have a tumor suppressor function. It is estimated that in 50% of NF1 patients the mutations are spontaneous or sporadic and are not inherited from the parents, while in the other 50% of cases they are germline mutations that are inherited from one parent in an autosomal dominant manner.

Symptoms

The severity and clinical manifestations of NF1 can vary markedly among patients, even among affected members of the same family. It is a disease that can result in the development of multiple nerve and skin tumors, called neurofibromas, which are usually benign. Another characteristic clinical manifestation is the formation of small nodules in the iris known as Lisch nodules.

Other skin changes may also occur, such as abnormal colored spots (pale tan or light brown), which usually appear in the first year of life and increase in number and size during childhood; and freckles in atypical locations (e.g. in the armpits or groin).

Occasionally, tumors may involve the brain or spinal cord nerves. In patients with NF1, the risk of developing gliomas is increased and in women, the predisposition to breast cancer is increased.

Other symptoms include macrocephaly and short stature. Seizures, learning disabilities, speech difficulties, hyperactivity and skeletal malformations such as scoliosis may occasionally occur.

Disease management

Medical follow-up by various specialists should be performed since it is a multisystemic disorder. Neurofibromas are usually monitored. If treatment is required, neurofibromas can be surgically removed. Smaller cutaneous neurofibromas can be treated with laser or electrocautery.

Genes analyzed

NF1

Bibliography

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Ars E, Kruyer H, Morell M, et al . Recurrent mutations in the NF1 gene are common among neurofibromatosis type 1 patients. J Med Genet. 2003 Jun;40(6):e82.

Friedman JM. Neurofibromatosis 1. 1998 Oct 2 [updated 2022 Apr 21]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023.

Koczkowska M, Chen Y, Callens T, et al. Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-848. Am J Hum Genet. 2018 Jan 4;102(1):69-87.

Peduto C, Zanobio M, Nigro V, et al . Neurofibromatosis Type 1: Pediatric Aspects and Review of Genotype-Phenotype Correlations. Cancers (Basel). 2023 Feb 14;15(4):1217.

Rojnueangnit K, Xie J, Gomes A, et al . High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients Carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation. Hum Mutat. 2015 Nov;36(11):1052-63.

Tamura R . Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis. Int J Mol Sci. 2021 May 29;22(11):5850.

Young LC, Goldstein de Salazar R, et al . Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization. Proc Natl Acad Sci U S A. 2023 Jan 31;120(5):e2208960120.