Clinical Guidance

Intrafamilial variability is much lower than interfamilial variability, suggesting a strong effect of the underlying genotype on the resulting phenotype. Large deletions of NF2 have been associated with a milder phenotype ; even if quite large, these deletions are not associated with intellectual disability. The type of NF2 germline pathogenic variant is an important determinant of the number of NF2-associated intracranial meningiomas, spinal tumors, and peripheral nerve tumors .

Source: GeneReviews — "NF2-Related Schwannomatosis"

Penetrance

Penetrance is close to 100%. Virtually all individuals who have a germline pathogenic variant develop the disease in an average lifetime.

Source: GeneReviews — "NF2-Related Schwannomatosis"

Diagnostic Criteria

Updated clinical diagnostic criteria for NF2-related schwannomatosis (NF2) have been published .

Suggestive Findings

NF2 should be suspected in probands with the following clinical, laboratory, and family history findings . Clinical findings in children (two or more of these findings)

• A schwannoma at any location including intradermal

• Skin plaques present at birth or in early childhood (often plexiform schwannoma on histology)

• A meningioma, particularly non-meningothelial (non-arachnoidal) cell in origin

• A cortical wedge cataract

• A retinal hamartoma

• A mononeuropathy, particularly causing a facial nerve palsy, foot or wrist drop, or third nerve palsy

Clinical findings in adults

Source: GeneReviews — "NF2-Related Schwannomatosis"

Differential Diagnosis

Table 3. Genes of Interest in the Differential Diagnosis of NF2-Related Schwannomatosis

Management Guidelines

Clinical practice guidelines for NF2-related schwannomatosis (NF2) have been published . Evaluation and treatment of individuals with NF2 are best undertaken in an NF2 center experienced in managing the multiple complications of the disease . • For NF specialists, see www.ctf.org. • For NF2 service centers in the UK, see www.nfauk.org. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with NF2, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with NF2-Related Schwannomatosis

Source: GeneReviews — "NF2-Related Schwannomatosis"

Clinical Guidance

Radiotherapy for NF2-associated tumors should be avoided in children when malignancy risks are likely to be substantially higher .

Source: GeneReviews — "NF2-Related Schwannomatosis"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "NF2-Related Schwannomatosis"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations in affected individuals and at-risk individuals in whom the known pathogenic variant in the family has been identified or whose genetic status cannot be clarified by molecular genetic testing, the evaluations summarized in are recommended.

Table 5.

Recommended Surveillance for Individuals with NF2-Related Schwannomatosis

System/Concern | Evaluation | Frequency

Neurologic

| Neurologic exam by provider w/experience in NF2 | Annually

Brain MRI | Annually beginning at age 10-12 yrs until 4th decade of life1,2

Hearing

| Hearing eval, incl BAER3 | Annually

Eyes | Complete ophthalmology exam

BAER = brain stem auditory evoked response; NF2 = NF2-related schwannomatosis

1. Annual brain MRI can start at an older age in individuals from families in which the onset of tumors is known to be later .

2. It is not clear if earlier surveillance (e.g., brain MRI before age 10 years) is beneficial, and it is not known at what age surveillance by brain MRI can be safely stopped.

3. May be useful in detecting changes in auditory nerve function before changes can be visualized by brain MRI.

Source: GeneReviews — "NF2-Related Schwannomatosis"