Schwannomatosis

Schwannomatosis
Classification and external resources
OMIM 162091

Schwannomatosis is one form of a genetic disorder called neurofibromatosis (NF) that has only recently been recognized. Originally described in Japanese patients,[1] it consists of multiple cutaneous schwannomas, central nervous system tumors, and other neurological complications, excluding hallmark signs of NF. It is a rare disorder, affecting only around 1 in 40,000 individuals.[2]

Schwannomas are mostly benign tumors that commonly occur in individuals with NF2 and schwannomatosis (sometimes called neurofibromatosis type III). Schwann cells are glial cells that myelinate the axons of nerve cells. Myelin is a lipid covering that speeds the conduction of action potentials. When Schwann cells proliferate out of control in an encapsulation it is called a schwannoma. Although schwannomas are benign they become detrimental when the growing tumor compresses the nerve. Schwannomas on sensory nerve axons cause chronic severe pain. Treatment options for schwannomas are to surgically remove them, have radiation, cyberknife or Intracapsular Enucleation. Previous designations for schwannomas include neurinoma and neurilemmoma.[3]

Diagnosis

Prenatal

Schwannomatosis can not presently be diagnosed prenatally or in the embryo, because the gene for it has not yet been positively identified.[4][5]

Postnatal

Ferner et al.[6] give the following diagnostic criteria for Schwannomatosis:

Another set of criteria are:

or

Prognosis

Many of the symptoms of schwannomatosis overlap with NF2.

Treatment

Etiology

The candidate schwannomatosis gene, named SMARCB1, is a tumor suppressor gene that regulates cell cycle, growth and differentiation.[13] An inactivating germline mutation in exon 1 of the tumor suppressor gene SMARCB1 has been reported in patients with schwannomatosis. It is located on chromosome 22 a short distance from the NF2 gene. However, molecular analysis of the NF2 gene in schwannomatosis patients has shown the presence of inactivating mutations in the tumor cells, but no evidence of the germline mutations that are found in NF2 patients.

A mechanism involving both the SMARCB1 and NF2 genes may be responsible for the development of the disease because tumor analysis of schwannomas indicates the presence of inactivating mutations in both the SMARCB1 and NF2 genes. However, there is speculation about the involvement of an unidentified schwannomatosis gene(s) in most cases. This is because one study found no SMARCB1 germinal mutations in patients with familial schwannomatosis. Some schwannomatosis patients do not have SMARCB1 or NF2 mutations. Furthermore, many patients exhibit somatic mosaicism for mutations in the NF2 or SMARCB1 gene, which means that some somatic cells have the mutation and some do not in the same patient. Ultimately, the tumorigenesis of schwannomas is not solely dependent on one gene locus alone. In regards to the SMARCB1 and NF2 genes, it is important to understand constitutional mutations and somatic mutations. Constitutional mutations are the first inactivation events that are often small mutations, such as point mutations and deletion/insertion of single base pairs. Somatic mutations are the second mutations that occur and may also be another small mutation or the loss of the remaining allele of the gene. Schwannomas from one patient share the same constitutional mutations but have distinct somatic mutations. In addition, the constitutional mutation may be present in non-tumor[10]

SMARCB1 is also known as INI1, hSNF5, or BAF47. SMARCB1 is mutated in additional tumors including malignant brain & kidney tumors in children. It seems that heterozygotes for mutations in the SMARCB1 gene have an increased risk to develop a malignant kidney tumor in early childhood but if they survive to adulthood, they may be predisposed to the development of schwannomas. One schwannomatosis patient had a mutation in exon 2 of the SMARCB1 gene. Another patient exhibited a novel germline deletion of the SMARCB1, because most SMARCB1 mutations are point or frameshift. In this patient genetic analysis from different schwannomas indicated inactivation of both the SMARCB1 and NF2 genes. Schwannomatosis is known to be a genetic disorder. However, familial occurrence is inexplicably rare.[14]

See also

References

  1. Ruggieri M, Huson SM (April 1999). "The neurofibromatoses. An overview". Ital J Neurol Sci 20 (2): 89–108. doi:10.1007/s100720050017. PMID 10933430.
  2. Melean G, Sestini R, Ammannati F, Papi L (August 2004). "Genetic insights into familial tumors of the nervous system". Am J Med Genet C Semin Med Genet 129C (1): 74–84. doi:10.1002/ajmg.c.30022. PMID 15264275.
  3. 1 2 Hanemann CO, Evans DG (December 2006). "News on the genetics, epidemiology, medical care and translational research of Schwannomas". J. Neurol. 253 (12): 1533–41. doi:10.1007/s00415-006-0347-0. PMID 17219030.
  4. "Are there any prenatal tests for the neurofibromatoses?"
  5. Schwannomatosis, by Susan Toomey MS, page 4
  6. Ferner, Rosalie E., Susan M. Huson, and D. Gareth R. Evans. Neurofibromatoses in clinical practice. Springer, 2011.
  7. 1 2 Westhout FD, Mathews M, Paré LS, Armstrong WB, Tully P, Linskey ME (June 2007). "Recognizing schwannomatosis and distinguishing it from neurofibromatosis type 1 or 2". J Spinal Disord Tech 20 (4): 329–32. doi:10.1097/BSD.0b013e318033ee0f. PMID 17538359.
  8. MacCollin M, Woodfin W, Kronn D, Short MP (April 1996). "Schwannomatosis: a clinical and pathologic study". Neurology 46 (4): 1072–9. doi:10.1212/wnl.46.4.1072. PMID 8780094.
  9. 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 (June 2005). "Diagnostic criteria for schwannomatosis". Neurology 64 (11): 1838–45. doi:10.1212/01.WNL.0000163982.78900.AD. PMID 15955931.
  10. 1 2 Kluwe, L. (2008). Molecular studies on schwannomatosis. In D. Kaufmann (Ed.), Monographs in Human Genetics (pp. 177-188): Karger.
  11. Senchenkov A, Kriegel A, Staren ED, Allison DC (September 2005). "Use of intraoperative ultrasound in excision of multiple schwannomas of the thigh". J Clin Ultrasound 33 (7): 360–3. doi:10.1002/jcu.20161. PMID 16196005.
  12. Lunsford LD, Niranjan A, Flickinger JC, Maitz A, Kondziolka D (January 2005). "Radiosurgery of vestibular schwannomas: summary of experience in 829 cases". J. Neurosurg. 102 (Suppl): 195–9. doi:10.3171/jns.2005.102.s_supplement.0195. PMID 15662809.
  13. Hulsebos TJ, Plomp AS, Wolterman RA, Robanus-Maandag EC, Baas F, Wesseling P (April 2007). "Germline mutation of INI1/SMARCB1 in familial schwannomatosis". Am. J. Hum. Genet. 80 (4): 805–10. doi:10.1086/513207. PMC 1852715. PMID 17357086.
  14. Sestini R, Bacci C, Provenzano A, Genuardi M, Papi L (February 2008). "Evidence of a four-hit mechanism involving SMARCB1 and NF2 in schwannomatosis-associated schwannomas". Hum. Mutat. 29 (2): 227–31. doi:10.1002/humu.20679. PMID 18072270.
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