FaCD Online Syndrome Fact Sheet

Last updated: 29 Jan 2014

Name: Schwannomatosis

Synonym: Congenital Neurilemmomatosis, Segmental Schwannomatosis

Mode of Inheritance: AD

Genes

hSNF5/INI1/SMARCB1, mapped to 22q11.2
LZTR1, mapped to 22q11.21

Tumor features

cutaneous schwannoma
meningioma
schwannoma (neurilemmoma), peripheral nerve

Comment

Schwannomatosis has been defined as the presence of multiple nonvestibular schwannomas in the absence of other signs of neurofibromatosis type 2 (NF2). Sometimes the disorder is lethal[1,2]. It can prresent in a segmental manner[3,4]. It is less frequently familial than NF2 is. In a series of 455 Finnish schwannoma patients[5], 12 (3%) patients had multiple schwannomas in association with NF2. Eleven (2%) of the 455 had multiple schwannomas without NF2 (i.e. schwannomatosis) and of this 11 patients, 2 (0.4% of 455) had familial schannomatosis.

There has been uncertainty as to whether or not schwannomatosis was simply a variant of NF2, caused by NF2 germline mutations. There is now proof that at least part of familial and sporadic schwannomatosis cases are associated with a germline mutation in the INI1/SMARCB1 gene and somatic mutations in the NF2 gene.[7-9]. It has subsequently been demonstrated that germline SMARCB1 mutations can present itself as combined schwannomatosis and meningiomas[10] and as familial meningiomas[11]. Germline mutations in LZTR1 have been identified in 80% of schwannomatosis cases, somatically involving 22q, without germline SMARCB1 mutations[12].

References

[1] Seppala MT, Sainio MA, Haltia MJJ, Kinnunen JJ, Setala KH, Jaaskelainen JE. Multiple schwannomas: schwannomatosis or neurofibromatosis type 2? J Neurosurg 89[1], 36-41. 1998.
[2] Westhout FD, Mathews M, Paré LS, Armstrong WB, Tully P, Linskey ME. Recognizing schwannomatosis and distinguishing it from neurofibromatosis type 1 or 2. Journal of spinal disorders & techniques 2007; 20(4):329-32.
[3] Leverkus M, Kluwe L, Röll EM, Becker G, Bröcker EB, Mautner VF, Hamm H. Multiple unilateral schwannomas: segmental neurofibromatosis type 2 or schwannomatosis?. The British journal of dermatology 2003; 148(4):804-9.
[4] Hasham S, Matteucci P, Stanley PR. Schwannomatosis: multiple schwannomas of the upper limb. Journal of hand surgery (Edinburgh, Scotland) 2006; 31(2):182-4.
[5] Antinheimo J, Sankila R, Carpen O, Pukkala E, Sainio M, Jaaskelainen J. Population-based analysis of sporadic and type 2 neurofibromatosis-associated meningiomas and schwannomas. Neurology 2000; 54(1):71-76.
[6] MacCollin M, Chiocca EA, Evans DG, Friedman JM, Horvitz R, Jaramillo D, Lev M, Mautner VF, Niimura M, Plotkin SR, Sang CN, Stemmer-Rachamimov A, Roach ES. Diagnostic criteria for schwannomatosis. Neurology 2005; 64(11):1838-45.
[7] Hulsebos TJ, Plomp AS, Wolterman RA, Robanus-Maandag EC, Baas F, Wesseling P. Germline mutation of INI1/SMARCB1 in familial schwannomatosis. American journal of human genetics 2007; 80(4):805-10.
[8] Sestini R, Bacci C, Provenzano A, Genuardi M, Papi L. Evidence of a four-hit mechanism involving SMARCB1 and NF2 in schwannomatosis-associated schwannomas. Human mutation 2008; 29(2):227-31.
[9] Hadfield KD, Newman WG, Bowers NL, Wallace A, Bolger CM, Colley A, McCann E, Trump D, Prescott T, Evans G. Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis. Journal of medical genetics 2008; .
[10] Bacci C, Sestini R, Provenzano A, Paganini I, Mancini I, Porfirio B, Vivarelli R, Genuardi M, Papi L.Schwannomatosis associated with multiple meningiomas due to a familial SMARCB1 mutation.Neurogenetics. 2010 Feb;11(1):73-80
[11] Christiaans I, Kenter SB, Brink HC, van Os TA, Baas F, van den Munckhof P, Kidd AM, Hulsebos TJ. Germline SMARCB1 mutation and somatic NF2 mutations in familial multiple meningiomas.J Med Genet. 2011 Feb;48(2):93-7.
[12] Piotrowski A, Xie J, Liu YF, Poplawski AB, Gomes AR, Madanecki P, Fu C, Crowley MR, Crossman DK, Armstrong L, Babovic-Vuksanovic D, Bergner A, Blakeley JO, Blumenthal AL, Daniels MS, Feit H, Gardner K, Hurst S, Kobelka C, Lee C, Nagy R, Rauen KA, Slopis JM, Suwannarat P, Westman JA, Zanko A, Korf BR, Messiaen LM. Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Nat Genet. 2013 Dec 22. doi: 10.1038/ng.2855. [Epub ahead of print]