Invitae Schwannomatosis Test

• schwannomatosis

Schwannomatosis is a rare form of neurofibromatosis that results in multiple schwannomas (a benign myelin sheath tumor derived from Schwann cells). Schwannomas arise primarily along the peripheral nerves but they can also appear along intracranial nerves and/or the spinal nerve root. Schwannomatosis is distinguished from neurofibromatosis type 2 (NF2) in that there are no concomitant bilateral vestibular schwannomas—a diagnostic criterion of NF2.

Affected schwannomatosis patients generally present in the second or third decade of life with chronic, severe pain (although pain intensity varies between individuals) and neurologic dysfunction if the schwannoma is pressing on a nerve or nearby tissue. Overall, symptomatology is widely variable and is dependent upon where schwannomas are located. Additional symptoms can include tingling, weakness due to nerve or spinal cord compression, difficulty with urination or bowel dysfunction, facial weakness, headaches, vision changes, and lumps or swollen areas where tumors form under the skin. Malignant transformation rarely occurs. Some patients may also develop meningiomas (generally benign tumors of meningeal tissue). Up to one third of schwannomatosis patients present with a segmental or mosaic form, in which schwannomas are localized to one limb or five or fewer spinal segmental segments. Life expectancy is normal, but there can be significant morbidity depending upon the location of the schwannomas.

Pathogenic variants in SMARCB1 are identified in approximately 60% of individuals with hereditary schwannomatosis. Mutations are more frequently identified in individuals with familial schwannomatosis than those without family history.

Single schwannomas occur frequently in the general population and these cases are generally sporadic. The inheritance of multiple schwannomas (schwannomatosis) is not well understood and only about 15%-25% of those cases are considered hereditary. Hereditary forms exhibit autosomal dominant inheritance, highly variable expressivity, and incomplete penetrance.

Schwannomatosis exhibits highly variable expressivity and incomplete penetrance.

The exact incidence of inherited schwannomatosis is not definitively known, but it may be as common as neurofibromatosis type 2, which affects approximately 1 in 40,000 births. There is no known predilection for race or gender.

Testing for schwannomatosis may be indicated in an individual with a family history of multiple schwannomas in a first-degree relative or for diagnostic confirmation in a proband. Current diagnostic criteria for schwannomatosis, published in the American Journal of Medical Genetics Part A, are as follows:

• Plotkin, SR, et al. Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria. Am. J. Med. Genet. A. 2013; 161A(3):405-16.

Clinical diagnosis:

• The individual has two or more non-intradermal schwannomas, one with pathological confirmation, including no bilateral vestibular schwannoma by high-quality MRI (detailed study of internal auditory canal with slices no more than 3 mm thick); Some mosaic NF2 patients will be included in this diagnosis at a young age and some schwannomatosis patients have been reported to have unilateral vestibular schwannomas or multiple meningiomas.
• The individual has one pathologically confirmed schwannoma or intracranial meningioma and an affected first-degree relative.
• Consider schwannomatosis as a possible diagnosis if there are two or more non-intradermal tumors but none has been pathologically proven to be a schwannoma. The occurrence of chronic pain in association with the tumor(s) increases the likelihood of schwannomatosis.

For management guidelines please refer to:

• Plotkin, SR, et al. Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria. Am. J. Med. Genet. A. 2013; 161A(3):405-16.