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MedGen UID:
Concept ID:
Neoplastic Process
Synonyms: Multiple Neurofibroma; Multiple Neurofibromas; Neurofibroma, Multiple; Neurofibromas, Multiple; Neurofibromatoses; Neurofibromatosis Syndrome; Neurofibromatosis Syndromes; Syndrome, Neurofibromatosis; Syndromes, Neurofibromatosis
SNOMED CT: NF - Neurofibromatosis (19133005); Neurofibromatosis (81669005); Multiple neurofibromatosis (81669005); Neurofibromatosis syndrome (19133005); Clinical neurofibromatosis (19133005)
HPO: HP:0001067
Monarch Initiative: MONDO:0021061


A benign peripheral nerve sheath tumor that generally appears as a soft, skin-colored papule or small subcutaneous nodule. Individuals with neurofibromatosis can have numerous neurofibromas. [from HPO]

Conditions with this feature

Neurofibromatosis, type 1
MedGen UID:
Concept ID:
Neoplastic Process
Neurofibromatosis 1 (NF1) is a multisystem disorder characterized by multiple café au lait macules, intertriginous freckling, multiple cutaneous neurofibromas, and learning disability or behavior problems. About half of people with NF1 have plexiform neurofibromas, but most are internal and not suspected clinically. Plexiform neurofibromas can cause pain, neurologic deficits, and abnormalities of involved or adjacent structures. Less common but potentially more serious manifestations include optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, vasculopathy, and gastrointestinal, endocrine, or pulmonary disease.
Gastrointestinal stroma tumor
MedGen UID:
Concept ID:
Neoplastic Process
Gastrointestinal stromal tumors are mesenchymal tumors found in the gastrointestinal tract that originate from the interstitial cells of Cajal, the pacemaker cells that regulate peristalsis in the digestive tract. Approximately 70% of GISTs develop in the stomach, 20% in the small intestine, and less than 10% in the esophagus, colon, and rectum. GISTs are typically more cellular than other gastrointestinal sarcomas. They occur predominantly in patients who are 40 to 70 years old but in rare cases may occur in younger persons (Miettinen et al., 1999, 1999). GISTs are also seen as a feature in several syndromes, e.g., neurofibromatosis-1 (NF1; 162200) and GIST-plus syndrome (175510).
Café-au-lait macules with pulmonary stenosis
MedGen UID:
Concept ID:
Disease or Syndrome
Watson syndrome is an autosomal dominant disorder characterized by pulmonic stenosis, cafe-au-lait spots, decreased intellectual ability (Watson, 1967), and short stature (Partington et al., 1985). Most affected individuals have relative macrocephaly and Lisch nodules and about one-third of those affected have neurofibroma (Allanson et al., 1991).
Neurofibromatosis, familial spinal
MedGen UID:
Concept ID:
Disease or Syndrome
Spinal neurofibromatosis is an autosomal dominant disorder characterized by a high load of spinal tumors. These tumors may be asymptomatic or result in neurologic symptoms, including back pain, difficulty walking, and paresthesias. Spinal NF is considered to be a subtype of neurofibromatosis type I (NF1; 162200), which is an allelic disorder. Patients with spinal NF may or may not have the classic cutaneous cafe-au-lait pigmentary macules or ocular Lisch nodules typically observed in patients with classic NF1. Patients with spinal NF should be followed closely for spinal sequelae (summary by Burkitt Wright et al., 2013).
Legius syndrome
MedGen UID:
Concept ID:
Disease or Syndrome
Legius syndrome is characterized by multiple café au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1 (NF1). Additional clinical manifestations reported commonly include intertriginous freckling, lipomas, macrocephaly, and learning disabilities / attention-deficit/hyperactivity disorder (ADHD) / developmental delays. Current knowledge of the natural history of Legius syndrome is based on the clinical manifestations of fewer than 300 individuals with a molecularly confirmed diagnosis; better delineation of the clinical manifestations and natural history of Legius syndrome will likely occur as more affected individuals are identified.
Neurofibromatosis-Noonan syndrome
MedGen UID:
Concept ID:
Disease or Syndrome
A variant of neurofibromatosis type 1 characterized by the combination of features of neurofibromatosis type 1, such as café-au-lait spots, iris Lisch nodules, axillary and inguinal freckling, optic nerve glioma and multiple neurofibromas; and Noonan syndrome, with features such as short stature, typical facial features, congenital heart defects and unusual pectus deformity.
Chromosome 17q11.2 deletion syndrome, 1.4Mb
MedGen UID:
Concept ID:
Disease or Syndrome
Approximately 5 to 20% of all patients with neurofibromatosis type I (162200) carry a heterozygous deletion of approximately 1.4 Mb involving the NF1 gene and contiguous genes lying in its flanking regions (Riva et al., 2000; Jenne et al., 2001), which is caused by nonallelic homologous recombination of NF1 repeats A and C (Dorschner et al., 2000). The 'NF1 microdeletion syndrome' is often characterized by a more severe phenotype than that observed in the majority of NF1 patients. In particular, patients with NF1 microdeletion often show variable facial dysmorphism, mental retardation, developmental delay, an excessive number of early-onset neurofibromas (Venturin et al., 2004), and an increased risk for malignant peripheral nerve sheath tumors (De Raedt et al., 2003).
Developmental delay, impaired speech, and behavioral abnormalities
MedGen UID:
Concept ID:
Disease or Syndrome
Developmental delay, impaired speech, and behavioral abnormalities (DDISBA) is characterized by global developmental delay apparent from early childhood. Intellectual disability can range from mild to severe. Additional variable features may include dysmorphic facial features, seizures, hypotonia, motor abnormalities such as Tourette syndrome or dystonia, and hearing loss (summary by Cousin et al., 2021).

Professional guidelines


Legius E, Messiaen L, Wolkenstein P, Pancza P, Avery RA, Berman Y, Blakeley J, Babovic-Vuksanovic D, Cunha KS, Ferner R, Fisher MJ, Friedman JM, Gutmann DH, Kehrer-Sawatzki H, Korf BR, Mautner VF, Peltonen S, Rauen KA, Riccardi V, Schorry E, Stemmer-Rachamimov A, Stevenson DA, Tadini G, Ullrich NJ, Viskochil D, Wimmer K, Yohay K; International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC), Huson SM, Evans DG, Plotkin SR
Genet Med 2021 Aug;23(8):1506-1513. Epub 2021 May 19 doi: 10.1038/s41436-021-01170-5. PMID: 34012067Free PMC Article
Goldbrunner R, Weller M, Regis J, Lund-Johansen M, Stavrinou P, Reuss D, Evans DG, Lefranc F, Sallabanda K, Falini A, Axon P, Sterkers O, Fariselli L, Wick W, Tonn JC
Neuro Oncol 2020 Jan 11;22(1):31-45. doi: 10.1093/neuonc/noz153. PMID: 31504802Free PMC Article
Ly KI, Blakeley JO
Med Clin North Am 2019 Nov;103(6):1035-1054. doi: 10.1016/j.mcna.2019.07.004. PMID: 31582003

Recent clinical studies


Jordan JT, Plotkin SR
Hematol Oncol Clin North Am 2022 Feb;36(1):253-267. Epub 2021 Oct 27 doi: 10.1016/j.hoc.2021.08.010. PMID: 34756486
Solares I, Viñal D, Morales-Conejo M, Rodriguez-Salas N, Feliu J
ESMO Open 2021 Aug;6(4):100223. Epub 2021 Aug 10 doi: 10.1016/j.esmoop.2021.100223. PMID: 34388689Free PMC Article
Pediatrics 2019 May;143(5) doi: 10.1542/peds.2019-0660. PMID: 31010905
Cimino PJ, Gutmann DH
Handb Clin Neurol 2018;148:799-811. doi: 10.1016/B978-0-444-64076-5.00051-X. PMID: 29478615
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Hum Mutat 2013 Nov;34(11):1510-8. Epub 2013 Aug 26 doi: 10.1002/humu.22392. PMID: 23913538


Bhatti MT
Ophthalmology 2023 Aug;130(8):862. Epub 2022 Oct 8 doi: 10.1016/j.ophtha.2022.09.001. PMID: 36216646
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Neurol Sci 2020 Oct;41(10):2685-2690. Epub 2020 May 1 doi: 10.1007/s10072-020-04400-x. PMID: 32358705
Hirbe AC, Gutmann DH
Lancet Neurol 2014 Aug;13(8):834-43. doi: 10.1016/S1474-4422(14)70063-8. PMID: 25030515
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J Clin Oncol 2022 Feb 10;40(5):492-516. Epub 2021 Dec 21 doi: 10.1200/JCO.21.02314. PMID: 34932393
Tamura R
Int J Mol Sci 2021 May 29;22(11) doi: 10.3390/ijms22115850. PMID: 34072574Free PMC Article
Cui XW, Ren JY, Gu YH, Li QF, Wang ZC
Curr Gene Ther 2020;20(2):100-108. doi: 10.2174/1566523220666200806111451. PMID: 32767931
Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, Weiss B, Kim A, Bornhorst M, Shah AC, Martin S, Roderick MC, Pichard DC, Carbonell A, Paul SM, Therrien J, Kapustina O, Heisey K, Clapp DW, Zhang C, Peer CJ, Figg WD, Smith M, Glod J, Blakeley JO, Steinberg SM, Venzon DJ, Doyle LA, Widemann BC
N Engl J Med 2020 Apr 9;382(15):1430-1442. Epub 2020 Mar 18 doi: 10.1056/NEJMoa1912735. PMID: 32187457Free PMC Article
Hirbe AC, Gutmann DH
Lancet Neurol 2014 Aug;13(8):834-43. doi: 10.1016/S1474-4422(14)70063-8. PMID: 25030515


Pikis S, Mantziaris G, Dumot C, Xu Z, Sheehan J
Neurosurg Clin N Am 2023 Jul;34(3):455-462. Epub 2023 Apr 7 doi: 10.1016/j.nec.2023.02.010. PMID: 37210134
Phillips D, Auguste KI, Gupta N
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Dang JD, Cohen PR
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Clinical prediction guides

Purdenko TI, Delva MY, Ostrovskaya LI, Tarianyk KA, Sylenko HY, Pushko OO, Purdenko SV
Wiad Lek 2022;75(5 pt 2):1408-1414. doi: 10.36740/WLek202205231. PMID: 35758466
Bettegowda C, Upadhayaya M, Evans DG, Kim A, Mathios D, Hanemann CO; REiNS International Collaboration
Neurology 2021 Aug 17;97(7 Suppl 1):S91-S98. Epub 2021 Jul 6 doi: 10.1212/WNL.0000000000012436. PMID: 34230207Free PMC Article
Eoli M, Saletti V, Finocchiaro G
Curr Opin Oncol 2019 Nov;31(6):554-561. doi: 10.1097/CCO.0000000000000576. PMID: 31436563
Halliday D, Parry A, Evans DG
Curr Opin Oncol 2019 Nov;31(6):562-567. doi: 10.1097/CCO.0000000000000579. PMID: 31425178
Miettinen MM, Antonescu CR, Fletcher CDM, Kim A, Lazar AJ, Quezado MM, Reilly KM, Stemmer-Rachamimov A, Stewart DR, Viskochil D, Widemann B, Perry A
Hum Pathol 2017 Sep;67:1-10. Epub 2017 May 24 doi: 10.1016/j.humpath.2017.05.010. PMID: 28551330Free PMC Article

Recent systematic reviews

Acar S, Nieblas-Bedolla E, Armstrong AE, Hirbe AC
Pediatr Neurol 2022 Sep;134:1-6. Epub 2022 Jun 10 doi: 10.1016/j.pediatrneurol.2022.06.003. PMID: 35759947
Crow AJD, Janssen JM, Marshall C, Moffit A, Brennan L, Kohler CG, Roalf DR, Moberg PJ
Am J Med Genet A 2022 Aug;188(8):2277-2292. Epub 2022 May 12 doi: 10.1002/ajmg.a.62773. PMID: 35546306Free PMC Article
Vogelbaum MA, Brown PD, Messersmith H, Brastianos PK, Burri S, Cahill D, Dunn IF, Gaspar LE, Gatson NTN, Gondi V, Jordan JT, Lassman AB, Maues J, Mohile N, Redjal N, Stevens G, Sulman E, van den Bent M, Wallace HJ, Weinberg JS, Zadeh G, Schiff D
J Clin Oncol 2022 Feb 10;40(5):492-516. Epub 2021 Dec 21 doi: 10.1200/JCO.21.02314. PMID: 34932393
Bargiela D, Verkerk MM, Wee I, Welman K, Ng E, Choong AMTL
Eur J Radiol 2018 Mar;100:66-75. Epub 2017 Dec 23 doi: 10.1016/j.ejrad.2017.12.014. PMID: 29496081
Lloyd SKW, King AT, Rutherford SA, Hammerbeck-Ward CL, Freeman SRM, Mawman DJ, O'Driscoll M, Evans DG
Clin Otolaryngol 2017 Dec;42(6):1329-1337. Epub 2017 Apr 26 doi: 10.1111/coa.12882. PMID: 28371358

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