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Neurofibromatosis, type 2(NF2)

MedGen UID:
18014
Concept ID:
C0027832
Neoplastic Process
Synonyms: Acoustic neurinoma bilateral; Acoustic schwannomas bilateral; Bilateral acoustic neurofibromatosis; Neurofibromatosis central type; Neurofibromatosis type II; NF 2; NF2
SNOMED CT: BANF - Bilateral acoustic neurofibromatosis (92503002); Neurofibromatosis type 2 (92503002); Bilateral acoustic neurofibromatosis (92503002); Familial vestibular schwannoma (92503002); NF2 (92503002); Neurofibromatosis, central type (92503002); Familial acoustic neuroma (92503002)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): NF2 (22q12.2)
 
Monarch Initiative: MONDO:0007039
OMIM®: 101000
Orphanet: ORPHA637

Disease characteristics

Excerpted from the GeneReview: Neurofibromatosis 2
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. [from GeneReviews]
Authors:
D Gareth Evans   view full author information

Additional descriptions

From OMIM
The central or type II form of neurofibromatosis (NF2) is an autosomal dominant multiple neoplasia syndrome characterized by tumors of the eighth cranial nerve (usually bilateral), meningiomas of the brain, and schwannomas of the dorsal roots of the spinal cord. The incidence of neurofibromatosis type II is 1 in 25,000 live births (Asthagiri et al., 2009). NF2 has few of the hallmarks of the peripheral or type I form of neurofibromatosis (NF1; 162200), also known as von Recklinghausen disease. Asthagiri et al. (2009) provided a detailed review of neurofibromatosis type II.  http://www.omim.org/entry/101000
From MedlinePlus Genetics
Neurofibromatosis type 2 is a disorder characterized by the growth of noncancerous tumors in the nervous system. The most common tumors associated with neurofibromatosis type 2 are called vestibular schwannomas or acoustic neuromas. These growths develop along the nerve that carries information from the inner ear to the brain (the auditory nerve). Tumors that occur on other nerves are also commonly found with this condition.\n\nThe signs and symptoms of neurofibromatosis type 2 usually appear during adolescence or in a person's early twenties, although they can begin at any age. The most frequent early symptoms of vestibular schwannomas are hearing loss, ringing in the ears (tinnitus), and problems with balance. In most cases, these tumors occur in both ears by age 30. If tumors develop elsewhere in the nervous system, signs and symptoms vary according to their location. Complications of tumor growth can include changes in vision, numbness or weakness in the arms or legs, and fluid buildup in the brain. Some people with neurofibromatosis type 2 also develop clouding of the lens (cataracts) in one or both eyes, often beginning in childhood.  https://medlineplus.gov/genetics/condition/neurofibromatosis-type-2

Clinical features

From HPO
Astrocytoma
MedGen UID:
438
Concept ID:
C0004114
Neoplastic Process
Astrocytoma is a neoplasm of the central nervous system derived from astrocytes. Astrocytes are a type of glial cell, and thus astrocytoma is a subtype of glioma.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Ependymoma
MedGen UID:
41825
Concept ID:
C0014474
Neoplastic Process
Ependymomas are rare glial tumors of the brain and spinal cord (Yokota et al., 2003).
Headache
MedGen UID:
9149
Concept ID:
C0018681
Sign or Symptom
Cephalgia, or pain sensed in various parts of the head, not confined to the area of distribution of any nerve.
Meningioma
MedGen UID:
7532
Concept ID:
C0025286
Neoplastic Process
The presence of a meningioma, i.e., a benign tumor originating from the dura mater or arachnoid mater.
Peripheral neuropathy
MedGen UID:
18386
Concept ID:
C0031117
Disease or Syndrome
A disorder affecting the peripheral nervous system. It manifests with pain, tingling, numbness, and muscle weakness. It may be the result of physical injury, toxic substances, viral diseases, diabetes, renal failure, cancer, and drugs.
Seizures
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Tinnitus
MedGen UID:
52760
Concept ID:
C0040264
Disease or Syndrome
Tinnitus is an auditory perception that can be described as the experience of sound, in the ear or in the head, in the absence of external acoustic stimulation.
Vertigo
MedGen UID:
53006
Concept ID:
C0042571
Sign or Symptom
An abnormal sensation of spinning while the body is actually stationary.
Cafe-au-lait spot
MedGen UID:
113157
Concept ID:
C0221263
Finding
A light brown, sharply demarcated skin patch. It is a manifestation of neurofibromatosis type 1 and McCune-Albright syndrome.
Cortical cataract
MedGen UID:
82868
Concept ID:
C0271160
Acquired Abnormality
A cataract which affects the layer of the lens surrounding the nucleus, i.e., the lens cortex. It is identified by its unique wedge or spoke appearance.
Epiretinal membrane
MedGen UID:
87388
Concept ID:
C0339543
Acquired Abnormality
A membrane on the vitreal surface of the retina resulting from the proliferation of one or more of three retinal elements: (1) fibrous astrocytes; (2) fibrocytes; and (3) retinal pigment epithelial cells. Localized epiretinal membranes may occur at the posterior pole of the eye without clinical signs or may cause marked loss of vision as a result of covering, distorting, or detaching the fovea centralis. Epiretinal membranes may cause vascular leakage and secondary retinal edema. In younger individuals some membranes appear to be developmental in origin and occur in otherwise normal eyes. The majority occur in association with retinal holes, ocular concussions, retinal inflammation, or after ocular surgery. (Newell, Ophthalmology: Principles and Concepts, 7th ed, p291)
Bilateral vestibular Schwannoma
MedGen UID:
209678
Concept ID:
C1136042
Neoplastic Process
A bilateral vestibular Schwannoma (acoustic neurinoma).
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
Partial or complete loss of the ability to detect or understand sounds resulting from damage to the outer, middle, or inner ear structures. Causes include exposure to loud noise, ear infections, injuries to the ear, genetic, and congenital disorders.
Juvenile posterior subcapsular lenticular opacities
MedGen UID:
354976
Concept ID:
C1863408
Finding
Retinal hamartoma
MedGen UID:
354977
Concept ID:
C1863411
Neoplastic Process
A hamartoma (a benign, focal malformation consisting of a disorganized mixture of cells and tissues) of the retina.
Unilateral vestibular Schwannoma
MedGen UID:
350232
Concept ID:
C1863653
Finding
A unilateral vestibular Schwannoma (acoustic neurinoma).
Occasional neurofibromas
MedGen UID:
816804
Concept ID:
C3810474
Finding
Neurofibromas present in a smaller number than usually seen in neurofibromatosis type 1.
Peripheral Schwannoma
MedGen UID:
869845
Concept ID:
C4024276
Neoplastic Process
The presence of a peripheral schwannoma.
Lisch nodules
MedGen UID:
395461
Concept ID:
C1860334
Finding
The presence of pigmented, oval and dome-shaped raised hamartomatous nevi of the iris..
The following clinical feature is unrelated to Neurofibromatosis, type 2

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Neurofibromatosis, type 2 in Orphanet.

Professional guidelines

PubMed

ACMG Board of Directors.
Genet Med 2015 Jan;17(1):68-9. Epub 2014 Nov 13 doi: 10.1038/gim.2014.151. PMID: 25356965
Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire AL, Nussbaum RL, O'Daniel JM, Ormond KE, Rehm HL, Watson MS, Williams MS, Biesecker LG; American College of Medical Genetics and Genomics.
Genet Med 2013 Jul;15(7):565-74. Epub 2013 Jun 20 doi: 10.1038/gim.2013.73. PMID: 23788249Free PMC Article

External

Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.

ACMG SF v3.0, 2021

Recent clinical studies

Etiology

Noonan KY, Rock J, Barnard Z, Lekovic GP, Brackmann DE, Wilkinson EP
Otolaryngol Head Neck Surg 2021 Aug;165(2):339-343. Epub 2020 Dec 15 doi: 10.1177/0194599820977420. PMID: 33317418
Ontario Health (Quality) .
Ont Health Technol Assess Ser 2020;20(4):1-85. Epub 2020 Mar 6 PMID: 32190165Free PMC Article
Glass C, Sholl LM, Landgraf JR, Chirieac L, Roggli VL
Am J Surg Pathol 2020 Feb;44(2):288-292. doi: 10.1097/PAS.0000000000001359. PMID: 31567203
Gaudioso C, Listernick R, Fisher MJ, Campen CJ, Paz A, Gutmann DH
Neurology 2019 Sep 3;93(10):e964-e967. Epub 2019 Jul 30 doi: 10.1212/WNL.0000000000008065. PMID: 31363058
Hexter A, Jones A, Joe H, Heap L, Smith MJ, Wallace AJ, Halliday D, Parry A, Taylor A, Raymond L, Shaw A, Afridi S, Obholzer R, Axon P, King AT; English Specialist NF2 Research Group., Friedman JM, Evans DG
J Med Genet 2015 Oct;52(10):699-705. Epub 2015 Aug 14 doi: 10.1136/jmedgenet-2015-103290. PMID: 26275417

Diagnosis

Noonan KY, Rock J, Barnard Z, Lekovic GP, Brackmann DE, Wilkinson EP
Otolaryngol Head Neck Surg 2021 Aug;165(2):339-343. Epub 2020 Dec 15 doi: 10.1177/0194599820977420. PMID: 33317418
Glass C, Sholl LM, Landgraf JR, Chirieac L, Roggli VL
Am J Surg Pathol 2020 Feb;44(2):288-292. doi: 10.1097/PAS.0000000000001359. PMID: 31567203
Gaudioso C, Listernick R, Fisher MJ, Campen CJ, Paz A, Gutmann DH
Neurology 2019 Sep 3;93(10):e964-e967. Epub 2019 Jul 30 doi: 10.1212/WNL.0000000000008065. PMID: 31363058
Ferner RE, Bakker A, Elgersma Y, Evans DGR, Giovannini M, Legius E, Lloyd A, Messiaen LM, Plotkin S, Reilly KM, Schindeler A, Smith MJ, Ullrich NJ, Widemann B, Sherman LS
Am J Med Genet A 2019 Jun;179(6):1098-1106. Epub 2019 Mar 25 doi: 10.1002/ajmg.a.61112. PMID: 30908866Free PMC Article
Hexter A, Jones A, Joe H, Heap L, Smith MJ, Wallace AJ, Halliday D, Parry A, Taylor A, Raymond L, Shaw A, Afridi S, Obholzer R, Axon P, King AT; English Specialist NF2 Research Group., Friedman JM, Evans DG
J Med Genet 2015 Oct;52(10):699-705. Epub 2015 Aug 14 doi: 10.1136/jmedgenet-2015-103290. PMID: 26275417

Therapy

Ontario Health (Quality) .
Ont Health Technol Assess Ser 2020;20(4):1-85. Epub 2020 Mar 6 PMID: 32190165Free PMC Article
Greenberg J, Carter S, Lester E, Funes CJ, Macklin EA, Plotkin S, Vranceanu AM
J Neurooncol 2019 Dec;145(3):561-569. Epub 2019 Nov 1 doi: 10.1007/s11060-019-03326-5. PMID: 31677033
Funes CJ, Mace RA, Macklin EA, Plotkin SR, Jordan JT, Vranceanu AM
J Neurooncol 2019 Jul;143(3):505-513. Epub 2019 May 2 doi: 10.1007/s11060-019-03182-3. PMID: 31049826
Linder C, Smith MJ, Bulman M, Wallace A, Freemont AJ, Mangham DC, Evans DGR
Fam Cancer 2019 Jan;18(1):97-100. doi: 10.1007/s10689-018-0084-4. PMID: 29761250
Jayanetti V, Klistorner AI, Graham SL, Dexter M, Flaherty MP, Jones K, Billson FA, Wilson M, North K, Grigg JR, Fraser CL
J Clin Neurosci 2018 Apr;50:262-267. Epub 2018 Feb 3 doi: 10.1016/j.jocn.2018.01.012. PMID: 29398196

Prognosis

Glass C, Sholl LM, Landgraf JR, Chirieac L, Roggli VL
Am J Surg Pathol 2020 Feb;44(2):288-292. doi: 10.1097/PAS.0000000000001359. PMID: 31567203
Ferner RE, Bakker A, Elgersma Y, Evans DGR, Giovannini M, Legius E, Lloyd A, Messiaen LM, Plotkin S, Reilly KM, Schindeler A, Smith MJ, Ullrich NJ, Widemann B, Sherman LS
Am J Med Genet A 2019 Jun;179(6):1098-1106. Epub 2019 Mar 25 doi: 10.1002/ajmg.a.61112. PMID: 30908866Free PMC Article
Evans DG, King AT, Bowers NL, Tobi S, Wallace AJ, Perry M, Anup R, Lloyd SKL, Rutherford SA, Hammerbeck-Ward C, Pathmanaban ON, Stapleton E, Freeman SR, Kellett M, Halliday D, Parry A, Gair JJ, Axon P, Laitt R, Thomas O, Afridi S, Ferner RE, Harkness EF, Smith MJ; English Specialist NF2 Research Group.
Genet Med 2019 Jul;21(7):1525-1533. Epub 2018 Dec 7 doi: 10.1038/s41436-018-0384-y. PMID: 30523344
Tripathi M, Satapathy A, Chauhan RB, Batish A, Gupta SK
World Neurosurg 2018 Sep;117:74-79. Epub 2018 Jun 12 doi: 10.1016/j.wneu.2018.05.245. PMID: 29902600
Hexter A, Jones A, Joe H, Heap L, Smith MJ, Wallace AJ, Halliday D, Parry A, Taylor A, Raymond L, Shaw A, Afridi S, Obholzer R, Axon P, King AT; English Specialist NF2 Research Group., Friedman JM, Evans DG
J Med Genet 2015 Oct;52(10):699-705. Epub 2015 Aug 14 doi: 10.1136/jmedgenet-2015-103290. PMID: 26275417

Clinical prediction guides

Noonan KY, Rock J, Barnard Z, Lekovic GP, Brackmann DE, Wilkinson EP
Otolaryngol Head Neck Surg 2021 Aug;165(2):339-343. Epub 2020 Dec 15 doi: 10.1177/0194599820977420. PMID: 33317418
Evans DG, King AT, Bowers NL, Tobi S, Wallace AJ, Perry M, Anup R, Lloyd SKL, Rutherford SA, Hammerbeck-Ward C, Pathmanaban ON, Stapleton E, Freeman SR, Kellett M, Halliday D, Parry A, Gair JJ, Axon P, Laitt R, Thomas O, Afridi S, Ferner RE, Harkness EF, Smith MJ; English Specialist NF2 Research Group.
Genet Med 2019 Jul;21(7):1525-1533. Epub 2018 Dec 7 doi: 10.1038/s41436-018-0384-y. PMID: 30523344
Tripathi M, Satapathy A, Chauhan RB, Batish A, Gupta SK
World Neurosurg 2018 Sep;117:74-79. Epub 2018 Jun 12 doi: 10.1016/j.wneu.2018.05.245. PMID: 29902600
Best SR, Ahn J, Langmead S, Dhillon V, Hillel AT, Akst LM, Blakeley JO
Otolaryngol Head Neck Surg 2018 Mar;158(3):505-510. Epub 2017 Nov 21 doi: 10.1177/0194599817741839. PMID: 29160153
Hexter A, Jones A, Joe H, Heap L, Smith MJ, Wallace AJ, Halliday D, Parry A, Taylor A, Raymond L, Shaw A, Afridi S, Obholzer R, Axon P, King AT; English Specialist NF2 Research Group., Friedman JM, Evans DG
J Med Genet 2015 Oct;52(10):699-705. Epub 2015 Aug 14 doi: 10.1136/jmedgenet-2015-103290. PMID: 26275417

Recent systematic reviews

Shi J, Lu D, Gu R, Sun H, Yu L, Pan R, Zhang Y
Am J Otolaryngol 2021 Nov-Dec;42(6):103148. Epub 2021 Jun 26 doi: 10.1016/j.amjoto.2021.103148. PMID: 34214711
Snyder MH, Ampie L, DiDomenico JD, Asthagiri AR
J Clin Neurosci 2021 Apr;86:79-84. Epub 2021 Feb 1 doi: 10.1016/j.jocn.2021.01.010. PMID: 33775351
Borsetto D, Hammond-Kenny A, Tysome JR, Axon PR, Donnelly NP, Vijendren A, Phillips V, Bance ML
Cochlear Implants Int 2020 Jan;21(1):9-17. Epub 2019 Sep 8 doi: 10.1080/14670100.2019.1662161. PMID: 31496442
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
Vranceanu AM, Merker VL, Park E, Plotkin SR
J Neurooncol 2013 Sep;114(3):257-62. Epub 2013 Jul 2 doi: 10.1007/s11060-013-1195-2. PMID: 23817811

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