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Neurofibromatosis

MedGen UID:
58149
Concept ID:
C0162678
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

Definition

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:
18013
Concept ID:
C0027831
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.
Neurofibromatosis, type 2
MedGen UID:
18014
Concept ID:
C0027832
Neoplastic Process
Neurofibromatosis 2 (NF2) is characterized by bilateral vestibular schwannomas with associated symptoms of tinnitus, hearing loss, and balance dysfunction. The average age of onset is 18 to 24 years. Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. Affected individuals may also develop schwannomas of other cranial and peripheral nerves, meningiomas, ependymomas, and, very rarely, astrocytomas. Because NF2 is considered an adult-onset disease, it may be underrecognized in children, in whom skin tumors and ocular findings (retinal hamartoma, thickened optic nerves, cortical wedge cataracts, third cranial nerve palsy) may be the first manifestations. Mononeuropathy that occurs in childhood is an increasingly recognized finding; it frequently presents as a persistent facial palsy or hand/foot drop.
Gastrointestinal stromal tumor
MedGen UID:
116049
Concept ID:
C0238198
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:
107817
Concept ID:
C0553586
Disease or Syndrome
Watson syndrome (WTSN) 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:
320296
Concept ID:
C1834235
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:
370709
Concept ID:
C1969623
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:
419089
Concept ID:
C2931482
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:
1726802
Concept ID:
C5401456
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:
1794167
Concept ID:
C5561957
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).
Basal cell nevus syndrome 2
MedGen UID:
1841087
Concept ID:
C5830451
Neoplastic Process
The basal cell nevus syndrome (BCNS), also known as Gorlin syndrome, is characterized by numerous basal cell cancers and epidermal cysts of the skin, calcified dural folds, keratocysts of the jaws, palmar and plantar pits, ovarian fibromas, medulloblastomas, lymphomesenteric cysts, fetal rhabdomyomas, and various stigmata of maldevelopment (e.g., rib and vertebral abnormalities, cleft lip or cleft palate, and cortical defects of bones) (summary by Koch et al., 2002). For a discussion of genetic heterogeneity of BCNS, see BCNS1 (109400).

Professional guidelines

PubMed

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
Miller DT, Freedenberg D, Schorry E, Ullrich NJ, Viskochil D, Korf BR; COUNCIL ON GENETICS; AMERICAN COLLEGE OF MEDICAL GENETICS AND GENOMICS
Pediatrics 2019 May;143(5) doi: 10.1542/peds.2019-0660. PMID: 31010905

Recent clinical studies

Etiology

Saleh M, Dib A, Beaini S, Saad C, Faraj S, El Joueid Y, Kotob Y, Saoudi L, Emmanuel N
Neurol Sci 2023 Jun;44(6):1931-1947. Epub 2023 Feb 24 doi: 10.1007/s10072-023-06680-5. PMID: 36826455
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
Miller DT, Freedenberg D, Schorry E, Ullrich NJ, Viskochil D, Korf BR; COUNCIL ON GENETICS; AMERICAN COLLEGE OF MEDICAL GENETICS AND GENOMICS
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
Sabbagh A, Pasmant E, Imbard A, Luscan A, Soares M, Blanché H, Laurendeau I, Ferkal S, Vidaud M, Pinson S, Bellanné-Chantelot C, Vidaud D, Parfait B, Wolkenstein P
Hum Mutat 2013 Nov;34(11):1510-8. Epub 2013 Aug 26 doi: 10.1002/humu.22392. PMID: 23913538

Diagnosis

Saleh M, Dib A, Beaini S, Saad C, Faraj S, El Joueid Y, Kotob Y, Saoudi L, Emmanuel N
Neurol Sci 2023 Jun;44(6):1931-1947. Epub 2023 Feb 24 doi: 10.1007/s10072-023-06680-5. PMID: 36826455
Bhatti MT
Ophthalmology 2023 Aug;130(8):862. Epub 2022 Oct 8 doi: 10.1016/j.ophtha.2022.09.001. PMID: 36216646
Ly KI, Blakeley JO
Med Clin North Am 2019 Nov;103(6):1035-1054. doi: 10.1016/j.mcna.2019.07.004. PMID: 31582003
Hirbe AC, Gutmann DH
Lancet Neurol 2014 Aug;13(8):834-43. doi: 10.1016/S1474-4422(14)70063-8. PMID: 25030515
Adigun CG, Stein J
Dermatol Online J 2011 Oct 15;17(10):25. PMID: 22031651

Therapy

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
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

Prognosis

Lee TJ, Chopra M, Kim RH, Parkin PC, Barnett-Tapia C
Orphanet J Rare Dis 2023 Sep 14;18(1):292. doi: 10.1186/s13023-023-02911-2. PMID: 37710322Free PMC Article
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
Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, Upadhyaya M, Towers R, Gleeson M, Steiger C, Kirby A
J Med Genet 2007 Feb;44(2):81-8. Epub 2006 Nov 14 doi: 10.1136/jmg.2006.045906. PMID: 17105749Free PMC Article
Miettinen M, Lasota J
Arch Pathol Lab Med 2006 Oct;130(10):1466-78. doi: 10.5858/2006-130-1466-GSTROM. PMID: 17090188
Frank-Stromborg M
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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
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
Legius E, Descheemaeker MJ, Fryns JP, Van den Berghe H
Genet Couns 1994;5(3):225-41. PMID: 7811422

Recent systematic reviews

Lee TJ, Chopra M, Kim RH, Parkin PC, Barnett-Tapia C
Orphanet J Rare Dis 2023 Sep 14;18(1):292. doi: 10.1186/s13023-023-02911-2. PMID: 37710322Free PMC Article
Charoenngam N, Wattanachayakul P, Jaroenlapnopparat A, Ungprasert P, Chenbhanich J
Calcif Tissue Int 2023 Aug;113(2):166-174. Epub 2023 May 23 doi: 10.1007/s00223-023-01094-z. PMID: 37221347
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

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