FaCD Online Syndrome Fact Sheet

Last updated: 27 Aug 2008

Name: Neurofibromatosis, type 2

Synonym: NF2, Central Neurofibromatosis, Bilateral Acoustic Neurofibromatosis

Mode of Inheritance: AD

Genes

NF2, mapped to 22q12.2

Tumor features

astrocytoma
cutaneous schwannoma
ependymoma
glial microhamartoma
glioma of the brain
meningioma
neurofibroma of the skin
schwannoma (neurilemmoma), cranial nerve
schwannoma (neurilemmoma), peripheral nerve
schwannoma, plexiform
vestibular schwannoma

Tumor features (possible)

mesothelioma, pleural
skin cancer, squamous cell

Non-tumor features

café au lait spots
cataract, congenital
cataract, juvenile
intracranial calcifications, cortical
intracranial calcifications, of choroid plexus
intracranial calcifications, periventricular
meningioangiomatosis
neuropathy
schwannosis

Comment

Typical findings in NF2 [1-3,21] are: vestibular schwannomas, as a rule bilateral and involving frequently the superior vestibular branch of the 8th cranial (the acoustic) nerve), schwannomas of other cranial and peripheral nerves, intracranial meningiomas (18-58% of cases; benign type, malignant meningiomas do not occur more frequently in NF2), meningioangiomatosis[23], optic sheath meningiomas in 4.1-8%, posterior subcapsular lens opacities and cataract (38-81 %)[3;4]. Intracranial astrocytomas have been observed in 1.6-4.1% of cases [3], and ependymomas in 2.5-6% [3]. Cafe-au-lait spots (42-47%) and cutaneous neurofibromas (32-68 %, only 10% more than 10 tumors) may occur, but they are less frequent than in NF1. Spinal tumors (often multiple) have been detected on MR images in 90 % of cases[5;6]. Multiple plexiform schwannomas have been reported in NF2 and may be located in the skin as well as in deeper tissues[7-10,24]. See schwannomatosis for a related condition. Axillary or inguinal freckling and Lisch nodules of the iris, all typical for NF1, are not observed in NF2.

Children with NF2 often first come to medical attention because of ocular, subtle skin, or neurological problems[17,18]. Evans et al. [19] reported that NF2 germ line mutation testing in sporadic unilateral vestibular schwannoma (VS) patients is unlikely to reveal a mutation except <20 years. These authors also reported that constitutional NF2 mutations are the most frequent cause of meningioma in children and in people with a meningioma plus other non-VS features of NF2, and that mosaic NF2 mutations may be the cause of approximately 8% of multiple meningiomas in apparently sporadic adult cases[20].

Jaffe et al.[11] reported a cluster of angiofibromas on the ear of an NF2 patient. Cutaneous squamous cell cancer has been observed in a 23-year-old male with NF2[22]. Mesothelioma is often associated with somatic NF2 mutations. Rare cases of pleural mesothelioma in patients with known or suspected asbestos exposure and a constitutional NF2 mutations have been reported[25,26].

Approximately 50 % of the NF2 cases are caused by a de novo mutation in the NF2 gene[12;13]. Somatic mosaicism may be a more common cause of NF2 than previously suspected [14]. Missense mutations are associated with a milder phenotype[15]

Clinical Criteria[3]:
A or D are considered definite NF2, C or D probable NF2:

• A) bilateral vestibular schwannomas,
• B) a first degree relative with NF2 + either unilateral vestibular schwannoma, or any 2 of: schwannoma, glioma, meningioma, neurofibroma, posterior subcapsular lens opacity
• C) unilateral vestibular schwannoma (<30 yrs) + any 2 of: schwannoma, glioma, meningioma, neurofibroma, posterior subcapsular lens opacity
• D) 2 or more meningiomas + either unilateral vestibular schwannoma, or any 2 of: schwannoma, glioma, neurofibroma, posterior subcapsular lens opacity

Links

Neurofibromatosis, Inc. 23 1 08
The Children's Tumor Foundation 23 1 08
The Neurofibromatosis Association of Australia (NFAA) Inc. 24 1 08
The Neurofibromatosis Association, UK 24 1 08

References

[1] Thomas G, Merel P, Sanson M, Hoang-Xuan K, Zucman J, Desmaze C, Melot T, Aurias A, Delattre O. Neurofibromatosis type 2. Eur J Cancer 1994; 30A:1981-1987.
[2] Pollack IF, Mulvihill JJ. Neurofibromatosis 1 and 2. Brain Pathol 7[2], 823-836. 1997.
[3] Evans DGR, Sainio M, Baser ME. Neurofibromatosis type 2. J Med Genet 37, 897-904. 2000.
[4] Ragge NK, Baser ME, Klein J, Nechiporuk A, Sainz J, Pulst SM, Riccardi VM. Ocular abnormalities in neurofibromatosis 2. Am J Ophthalmol 1995; 120:634-641.
[5] Mautner VF, Tatagiba M, Lindenau M, Funsterer C, Pulst SM, Kluwe L, Zanella FE. Spinal tumors in patients with neurofibromatosis type 2: MR imaging study of frequency, multiplicity, and variety. AJR Am J Roentgenol 1995; 165(4):951-955.
[6] Mautner VF, Lindenau M, Baser ME, Hazim W, Tatagiba M, Haase W, Samii M, Wais R, Pulst SM. The neuroimaging and clinical spectrum of neurofibromatosis 2. Neurosurgery 38[5], 880-885. 1996.
[7] Sheikh S, Gomes M, Montgomery E. Multiple plexiform schwannomas in a patient with neurofibromatosis. J.Thorac.Cardiovasc.Surg. 115[1], 240-242. 1998.
[8] Ishida T, Kuroda M, Motoi T, Oka T, Imamura T, Machinami R. Phenotypic diversity of neurofibromatosis 2: association with plexiform schwannoma. Histopathology 32[3], 264-270. 1998.
[9] Val-Bernal JF, Figols J, Vazquez-Barquero A. Cutaneous plexiform schwannoma associated with neurofibromatosis type 2. Cancer 1995; 76(7):1181-1186.
[10] Reith JD, Goldblum JR. Multiple cutaneous plexiform schwannomas: Report of a case and review of the literature with particular reference to the association with types 1 and 2 neurofibromatosis and schwannomatosis. Arch Pathol Lab Med 120[4], 399-401. 1996.
[11] Jaffe AT, Heymann WR, Schnur RE. Clustered angiofibromas on the ear of a patient with neurofibromatosis type 2. Arch Dermatol 134[6], 760-761. 1998.
[12] Gutmann DH. Molecular insights into neurofibromatosis 2. Neurobiol.Disease. 3[4], 247-261. 1997.
[13] Louis DN, Ramesh V, Gusella JF. Neuropathology and molecular genetics of neurofibromatosis 2 and related tumors. Brain Pathol 1995; 5:163-172.
[14] Evans DGR, Wallace AJ, Wu CL, Trueman L, Ramsden RT, Strachan T. Somatic mosaicism: A common cause of classic disease in tumor- prone syndromes? Lessons from type 2 neurofibromatosis. Am J Hum Genet 63[3], 727-736. 1998.
[15] Demange L, De Moncuit C, Thomas G, Olschwang S. [Phenotype-genotype study in 154 French NF2 mutation carriers]. Revue neurologique 2007; 163(11):1031-8.
[16] Stettner GM, Rostasy KM, Ludwig HC, Merkler D, Fahsold R, Gärtner J. Infratentorial meningioma in an 8-year-old child as first sign of neurofibromatosis type 2. Neuropediatrics 2007; 38(1):29-31.
[17] Ruggieri M, Iannetti P, Polizzi A, La Mantia I, Spalice A, Giliberto O, Platania N, Gabriele AL, Albanese V, Pavone L. Earliest clinical manifestations and natural history of neurofibromatosis type 2 (NF2) in childhood: a study of 24 patients. Neuropediatrics 2005; 36(1):21-34.
[18] Mautner VF, Tatagiba M, Guthoff R, Samii M, Pulst SM. Neurofibromatosis 2 in the pediatric age group. Neurosurgery 1993; 33(1):92-6.
[19] Evans DG, Ramsden RT, Gokhale C, Bowers N, Huson SM, Wallace A. Should NF2 mutation screening be undertaken in patients with an apparently isolated vestibular schwannoma?. Clinical genetics 2007; 71(4):354-8.
[20] Evans DG, Watson C, King A, Wallace AJ, Baser ME. Multiple meningiomas: differential involvement of the NF2 gene in children and adults. Journal of medical genetics 2005; 42(1):45-8.
[21] Ferner RE. Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective. Lancet neurology 2007; 6(4):340-51.
[22] Winer D, Alsaad KO, Bray P, Smith R, Ghazarian D. Early onset cutaneous squamous cell carcinoma associated with neurofibromatosis type 2 (NF2). European journal of dermatology : EJD 2006 Jul-Aug; 16(4):448-9.
[23] Omeis I, Hillard VH, Braun A, Benzil DL, Murali R, Harter DH. Meningioangiomatosis associated with neurofibromatosis: report of 2 cases in a single family and review of the literature. Surgical neurology 2006; 65(6):595-603.
[24] Murray AJ, Hughes TA, Neal JW, Howard E, Evans DG, Harper PS. A case of multiple cutaneous schwannomas; schwannomatosis or neurofibromatosis type 2?. Journal of neurology, neurosurgery, and psychiatry 2006; 77(2):269-71.
[25] Baser ME, Rai H, Wallace AJ, Evans DG. Neurofibromatosis 2 (NF2) and malignant mesothelioma in a man with a constitutional NF2 missense mutation. Familial cancer 2005; 4(4):321-2.
[26] Baser ME, De Rienzo A, Altomare D, Balsara BR, Hedrick NM, Gutmann DH, Pitts LH, Jackler RK, Testa JR. Neurofibromatosis 2 and malignant mesothelioma. Neurology 2002; 59(2):290-1.