Schwannomatoses

Scwhannomatoses : NF2, SMARCB1, LZTR1 and the others are genetic syndromes predisposing individuals to develop multiple schwannomas, as well as meningiomas and ependymomas, primarily in the context of NF2-related schwannomatosis (1). They are rare diseases, with prevalence varying significantly depending on the causative genetic mutation. The most recent epidemiological data report a prevalence of 1 in 61,332 individuals for NF2-related schwannomatosis, 1 in 527,000 for LZTR1-related schwannomatosis, and 1 in 1.1 million for SMARCB1-related schwannomatosis (2).

Unlike patients with Neurofibromatosis type 1 (NF1), patients with schwannomatoses often experience a diagnostic delay of several years after the onset of initial symptoms. This delay is explained by the rarity of familial forms, where at least one parent is affected, which account for only 23% of NF2-related schwannomatosis cases and 15% of non-NF2-related schwannomatoses. Sporadic forms, in which neither parent is affected, are much more common. Additionally, mosaic forms (50% of sporadic cases), where the phenotype is less severe and more variable, contribute to diagnostic challenges (3). Even within the two clinical forms (familial and sporadic), there exists a subgroup of patients with segmental schwannomatosis, where only a single limb is affected.

Schwannomatoses are linked to mutually exclusive germline mutations in three tumor suppressor genes: NF2, SMARCB1 (4), and LZTR1 (5), all located on chromosome 22. NF2-related schwannomatosis is, as the name suggests, exclusively linked to the NF2 gene. Among non-NF2-related schwannomatoses, SMARCB1 mutations are found in 40–45% of familial cases and 8–10% of sporadic cases, while LZTR1 mutations are present in 30–35% of familial cases and 25–30% of sporadic cases. A significant proportion of familial and sporadic schwannomatoses unrelated to NF2 currently lack an identified genetic cause (6).

In NF2-related schwannomatosis, biallelic loss of the NF2 gene is both necessary and sufficient to initiate tumor formation. In non-NF2-related schwannomatoses, the formation of each schwannoma follows a more complex three-step tumorigenesis mechanism: an initial germline mutation in a tumor suppressor gene (SMARCB1 or LZTR1), followed by somatic inactivation of the second allele on chromosome 22 through loss of heterozygosity (LOH), and finally, a somatic mutation in the NF2 gene, leading to biallelic inactivation of both NF2 and the other schwannomatosis-associated gene.

Patients with schwannomatoses are typically diagnosed between the ages of 18 and 24 for NF2-related schwannomatosis and later, between 20 and 40 years, for non-NF2-related schwannomatoses. NF2-related schwannomatosis most commonly presents with sensorineural hearing loss or, in childhood cases (<16 years), with vision loss (7). Patients exhibit bilateral vestibular schwannomas, intracranial meningiomas in 50% of cases, intramedullary ependymomas, spinal tumors (meningiomas and schwannomas), and peripheral schwannomas. In addition to tumors, patients may develop axonal neuropathies resembling pseudo-Charcot-Marie-Tooth disease, causing significant motor deficits (8).  

In non-NF2-related schwannomatoses, the primary symptoms at diagnosis include pain (46%), palpation of a mass (27%), or both (11%). Sensory-motor deficits are rarely present at the initial assessment. Patients predominantly present with peripheral nerve schwannomas (89%) and spinal schwannomas (74%). Cranial nerve schwannomas are rare (8%); unilateral vestibular schwannomas are found in 15% of LZTR1-related schwannomatosis cases, while trigeminal schwannomas occur in other cases. Unilateral vestibular schwannomas, though uncommon, can be observed in patients with schwannomatoses. Intracranial meningiomas are also rare (5%), appearing exclusively in SMARCB1-related schwannomatoses, predominantly along the falx (9).

Initial imaging evaluation includes a brain MRI with fine slices centered on the internal auditory canals, a whole-spine MRI, and additional MRIs targeting painful regions based on each patient's presentation. If feasible, whole-body imaging (MRI or PET-MRI) (10) is recommended at the initial evaluation. Subsequent MRI follow-ups are conducted annually or biennially, depending on tumor burden. The radiological appearance of schwannomas in schwannomatosis patients is similar to that of sporadic schwannomas, except for multinodular forms, resulting from the fusion of multiple contiguous schwannomas along a single peripheral nerve, which are notably present in vestibular schwannomas (11). High-resolution MRI neurography can also reveal multiple intrafascicular microlesions along peripheral nerves (12). These microlesions are present throughout the limbs in segmental schwannomatosis, where macroscopic schwannomas and pain are confined to a single limb. There is no definitive link between these microlesions and patient-reported pain. Furthermore, electrophysiological studies are typically normal in schwannomatosis patients (13).

Schwannomatosis patients receive care in specialized "rare disease" centers that integrate clinical management with genetic counseling. Clinically, management in NF2-related schwannomatosis focuses on preserving neurosensory functions, whereas in non-NF2-related schwannomatoses, the priority is pain management. Unlike NF1, malignant transformation is exceedingly rare in schwannomatoses, usually associated with prior radiation therapy (14), and therefore, cancer prevention is not a primary concern.

In NF2-related schwannomatosis, preserving hearing is a key therapeutic goal, achieved through a combination of surgery (vestibular schwannoma resection, internal auditory canal decompression), radiosurgery, and chemotherapy (Avastin, Everolimus, Brigatinib) (15–17). When hearing loss occurs, restoration options include cochlear or brainstem implants. Other neurological functions, such as motor control, sensation, vision, and speech, may be impaired, necessitating tumor-specific surgical intervention (intracranial or spinal meningioma, intramedullary ependymoma, or spinal schwannoma).

In non-NF2-related schwannomatoses, pain management, affecting 68% of patients, is the primary focus. Pain presents as episodic attacks, sometimes with a continuous baseline pain, and may or may not be associated with an underlying schwannoma (9). Initial treatment is medical, though refractory pain is common; 27% of patients report using more than six pain medications (9). Surgery is reserved for rapidly growing tumors or those explicitly causing symptoms. Peripheral schwannoma surgery in schwannomatosis patients yields slightly lower pain relief rates than in sporadic cases (85%). Additionally, post-operative deficits occur more frequently (33%), particularly in patients with multi-segmental disease or undergoing resection of multiple tumors in a single procedure (18). To date, the effects of radiotherapy and chemotherapy in treating non-NF2-related schwannomatoses remain limited.

The natural history of the disease includes the emergence of new meningiomas and schwannomas over time (18). It remains unclear whether this is due to incomplete initial assessment—since whole-body MRI is not routinely performed—or actual tumor progression. Malignant transformation of peripheral schwannomas has been reported in schwannomatoses (18), primarily in SMARCB1-related forms and very rarely in NF2-related schwannomatosis, though its true prevalence remains uncertain due to diagnostic revisions in reference pathology series (9).

Michel Kalamarides
Referral centre for neurofibromatosis type 2 and schwannomatosis
AP-HP - Pitié-Salpêtrière Hospital - 75013 - Paris - France

Matthieu Peyre
Sorbonne University – Neurosurgery department
AP-HP – Pitié-Salpêtrière Hospital – 75013 – Paris – France

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