Non-NF2-related schwannomatosis
As the actual name implies (a previous underused name was NF3), schwannomatosis (ORPHA:93921) is characterized by the development of multiple noncancerous (benign) tumours called schwannomas, which are tumours of the tissue that covers nerves, usually on peripheral nerves and spinal nerves. After exclusion of NF2-related schwannomatosis, other forms affect around 1 in 70,000 people at some point in their lifetime. Up to one third of patients show segmental schwannomatosis, confined to one limb or few adjacent spinal segments. Cranial nerve involvement is uncommon, most commonly on the trigeminal nerve. Meningiomas (a type of benign brain tumour) and unilateral vestibular schwannoma (a tumour from the balance branch of the acoustic nerve supplying the inner ear) can occur, with a substantial overlap with NF2 and a misdiagnosis of at least 9% of cases.
The absence of bilateral vestibular schwannomas (schwannomas affecting both hearing nerves) is the clue for the differential diagnosis from NF2-related schwannomatosis. Symptom onset is typically after the age of 30. The distinctive hallmark is neuropathic pain, usually disproportionate to the size of the tumours. The intensity and frequency of pain varies significantly among individuals. Pain can be intractable, disabling and resulting in a diminished quality of life.
Pathogenic variants in SMARCB1, LZTR1 and possibly the DGCR8 genes can cause non NF2-related schwannomatosis. The proteins produced from these genes are thought to act as tumour suppressors, which normally keep cells from growing and dividing too rapidly or in an uncontrolled way. Mutations in these genes may help cells grow and divide without control or order to form a tumour. All three genes are located on chromosome 22q, near the NF2 gene. Meningiomas although uncommon can occur in SMARCB1-related schwannomatosis, whereas unilateral vestibular schwannoma may occur with LZTR1-related schwannomatosis. Current genetic testing does not reveal a mutation in all affected individuals, and there may be additional genes responsible for the disorder in some people yet to be discovered. Although analysis of at least two separate schwannomas is required to rule out mosaic NF2.
The genetics of schwannomatosis is complex and remains incompletely understood. Studies suggest that 15 to 25 percent of cases of schwannomatosis run in families. These familial cases have an autosomal dominant pattern of inheritance, which means a mutation in one copy of the SMARCB1, LZTR1 or DGCR8 genes in each cell greatly increases the risk of developing schwannomas. However, some people who have an altered gene never develop tumours, which is a situation known as reduced penetrance. This is a particular issue in LZTR1 where germline loss-of-function variants are found in around 1 in 270 people but <1% of these will develop schwannomatosis. New alterations occurring in sperm or eggs can end up in every cell of the child and represent approximately 30% for LZTR1-related schwannomatosis and 10% for SMARCB1-related schwannomatosis. Familial occurrence is inexplicably uncommon.
The general rule is observation, with 1-3 yearly imaging of intracranial and spinal tumours, as they can potentially cause spinal cord compression. Surgery is indicated for schwannomas associated with uncontrolled localized pain or neurologic deficits. It is important that surgery be performed in conjunction with ongoing pharmacologic pain management, as pain relief following tumour resection is not ensured. Overwhelming pain remains the primary clinical problem and need a comprehensive, multimodal approach to pain management, guided by a pain management specialist. Referral to mental health professionals is needed for anxiety and/or depression. Meningioma treatment is the same as for sporadic meningioma. Malignancy remains a theoretical risk especially in individuals with a SMARCB1 pathogenic variant.
GeneReviews® - LZTR1- and SMARCB1-Related schwannomatosis
Orphanet: Schwannomatosis
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Written by ERN GENTURIS |
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Schwannomatosis guideline - ERN GENTURIS clinical practice guidelines for the diagnosis, treatment, management and surveillance of people with schwannomatosis. |
Thematic Group 1: Schwannomatosis and neurofibromatosis Non-NF2-related schwannomatosis
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* ERN GENTURIS uses AGREE II as a tool for the endorsement of guidelines. The quality of the guideline is evaluated through assessing the rigor and transparency of the guideline development process. The content of the guideline is not evaluated, although selection of the guideline for endorsement includes expert opinion on the usefulness of the content of the guideline.
ERN GENTURIS webinars - Thematic group 1: Neurofibromatosis
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A list of healthcare providers with expertise inThematic Group 1: schwannomatosis and neurofibromatosis can be found here.
A non-exhaustive list of patient associations for genetic tumour risk syndromes in EU member states can be found here.