Schwannomatosis is one form of a genetic disorder

Genetic disorder

A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....

 called neurofibromatosis

Neurofibromatosis

Neurofibromatosis is a genetically-inherited disorder in which the nerve tissue grows tumors that may be benign or may cause serious damage by compressing nerves and other tissues...

 (NF) that has only recently been recognized. Originally described in Japanese

Japanese people

The are an ethnic group originating in the Japanese archipelago and are the predominant ethnic group of Japan. Worldwide, approximately 130 million people are of Japanese descent; of these, approximately 127 million are residents of Japan. People of Japanese ancestry who live in other countries...

 patients, 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.

Schwannomas

Schwannomas

Schwannomas

A schwannoma is a benign nerve sheath tumor composed of Schwann cells, which normally produce the insulating myelin sheath covering peripheral nerves....

 are mostly benign tumors that commonly occur in individuals with NF2 and schwannomatosis. 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.

Symptoms

Many of the symptoms of schwannomatosis overlap with NF2.

• Schwannomas occur instead of the neurofibroma
  Neurofibroma
  A neurofibroma is a benign nerve sheath tumor in the peripheral nervous system. Usually found in individuals with neurofibromatosis type I , an autosomal dominant genetically-inherited disease, they can result in a range of symptoms from physical disfiguration and pain to cognitive disability...
  
  s that are hallmarks of neurofibromatosis Type 1 (NF1).
• Multiple schwannomas manifest throughout the body or in isolated regions.
• The schwannomas develop on cranial, spinal and peripheral nerves.
• Chronic pain, and sometimes numbness, tingling and weakness.
• About 1/3 of patients have segmental schwannomatosis, which means that the schwannomas are limited to a single part of the body, such as an arm, a leg or the spine.
• There are several cases where people with schwannomatosis have developed a vestibular schwannoma (acoustic neuroma
  Acoustic neuroma
  A vestibular schwannoma, often called an acoustic neuroma, is a benign primary intracranial tumor of the myelin-forming cells of the vestibulocochlear nerve . The term "vestibular schwannoma" involves the vestibular portion of the 8th cranial nerve and arises from Schwann cells, which are...
  
  ). An acoustic neurinoma is a schwannoma on the vestibular nerve in the brain. This nerve is involved in hearing and patients with vestibular schwannomas experience hearing loss. However, bilateral vestibular schwannomas (vestibular schwannomas on both sides of the brain) do not occur in schwannomatosis. Juvenile vestibular tumors do not occur either.
• Patients with schwannomatosis do not have learning disabilities related to the disease.
• Symptoms are sometimes brought on by hormonal changes such as puberty and pregnancy.

Diagnostic criteria

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

Post-natally, the criteria are:

• Two or more nonintradermal (cutaneous) schwannomas
• No evidence of vestibular tumor
• No known NF-2 mutation

or

• One pathologically confirmed nonvestibular schwannoma plus a first degree relative who meets the above criteria.

Cause

The candidate schwannomatosis gene, named SMARCB1

SMARCB1

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 is a protein that in humans is encoded by the SMARCB1 gene.-Interactions:...

, is a tumor suppressor gene

Tumor suppressor gene

A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...

 that regulates cell cycle, growth and differentiation. An inactivating germline mutation

Germline mutation

A germline mutation is any detectable and heritable variation in the lineage of germ cells. Mutations in these cells are transmitted to offspring, while, on the other hand, those in somatic cells are not. A germline mutation gives rise to a constitutional mutation in the offspring, that is, a...

 in exon

Exon

An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...

 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

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

Point mutation

A point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. Often the term point mutation also includes insertions or deletions of a single base pair...

 or frameshift

Frameshift mutation

A frameshift mutation is a genetic mutation caused by indels of a number of nucleotides that is not evenly divisible by three from a DNA sequence...

. 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.

Treatment

• Schwannomatosis patients represent 2.4% to 5% of patients undergoing surgical resection of their schwannomas.
• In isolated regions of the body schwannomas are small and difficult to locate. Intraoperative sonography offers invaluable assistance in such cases by localizing small schwannomas and decreasing operative time and extent of the surgical incision.
• If feasible, the schwannomas can be surgically removed. Any tumor-associated pain usually subsides after tumor removal. Damaged nerves and scar tissue can be a result of surgery and pain can be an ongoing problem.
• Sometimes, a tumor will reappear at the same site after surgery.
• If surgery is unfeasible, then pain management will have to be used. Schwannomatosis can sometimes cause severe, untreatable pain over time.
• Other than surgery and/or pain management, there are no other medical treatments available. There are no drugs available to treat Schwannomatosis.
• Gamma knife radiosurgery can be performed on head tumors to help stop growth of a tumor, although there is no guarantee that it will work. The University of Pittsburgh published their experience with over 829 cases and reported 97% of patients had long term tumor control (defined as requiring no further treatment) with Gamma knife radiosurgery.
• Recently, many advances are being made in the treatment of schwannomas. Of interest is CyberKnife
  Cyberknife
  The CyberKnife is a frameless robotic radiosurgery system used for treating benign tumors, malignant tumors and other medical conditions. The system was invented by John R. Adler, a Stanford University Professor of Neurosurgery and Radiation Oncology, and Peter and Russell Schonberg of Schonberg...
  
  , manufactured by Accuray. Success rates, although limited in data, appear to be in the low to mid ninety percent range.
• As most schwannomas are benign, many doctors will take the “watch and wait” approach and leave the tumors alone until they start causing harmful side effects. Schwannomatosis patients have multiple tumors and the risks of having so many surgeries outweigh the benefits.

External links

• Tumornators A group of Fundraisers leading the way with the Children's Tumor Foundation for Schwannomatosis research.
• www.ctf.org The Children's Tumor Foundation "Solve the NF Puzzle"