Invitae Schwannomatosis Panel

• Schwannomatosis
• Rhabdoid Tumor Predisposition SyndromeCoffin-Siris syndrome
• Noonan syndrome

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.

It is difficult to more definitively describe the sensitivity of this test in individuals with schwannomatosis, as a majority of sporadic schwannomatosis cases, as well as individuals with multiple meningiomas, have no known causative mutation.

Single schwannomas occur frequently in the general population and these cases are generally sporadic. The inheritance of schwannomatosis is not well understood and only 15%-25% of such cases are considered hereditary. Hereditary forms due to pathogenic variants in LZTR1, NF2 and SMARCB1 exhibit autosomal dominant inheritance with highly variable expressivity and incomplete penetrance. While most cases of schwannomatosis are inherited from a parent, 10%-30% are the result of a spontaneous de novo mutation (10% for schwannomatosis due to SMARCB1 and 30% for LZTR1). Approximately 25%-30% of simplex NF2 cases are mosaic for an NF2 pathogenic variant.

Schwannomatosis exhibits highly variable expressivity and incomplete penetrance. While penetrance is reduced, the specific lifetime risk of developing schwannomas is currently not established.

The exact incidence of inherited nonsyndromic schwannomatosis is not definitively known, but 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:

• 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 with mosaic NF2 will be included in this diagnosis at a young age and some with schwannomatosis have been reported to have unilateral vestibular schwannomas or multiple meningiomas.
• 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 schwannoma(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.