Neurofibromatosis Type II

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: NF2 (HGNC:7773)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 06/20/2014
• Curation Status: Released - Under Revision (1.2.0)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
NF2	N/A ()	101000	Assertion Pending

Actionability Assertion Rationale

• This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Vestibular schwannoma / MRI/Screening	2	3B	2B	3	10BB

Severity of Outcome

Prevalence of the Genetic Condition

In the past, the estimated prevalence of neurofibromatosis 2 (NF2) was estimated at 1:210,000. However, a recent 2010 study estimated a higher prevalence of 1:60,000.

Clinical Features (Signs / symptoms)

NF2 is characterized by the development of nervous system tumors (schwannomas and meningiomas), ocular abnormalities, and skin tumors. Bilateral vestibular schwannomas occur in 95% of adult patients; vestibular schwannoma growth rates are extremely variable, both between patients and over time in the same patient. Schwannomas typically affect both vestibular nerves, leading to hearing loss and deafness, tinnitus, dizziness and imbalance.While the tumors caused by NF2 are not malignant, their anatomical location and multiplicity lead to great morbidity and early mortality.

Natural History (Important subgroups & survival / recovery)

Average age of onset in individuals with NF2 is 18 to 24 years (range birth to 70 years). Nearly all affected individuals develop bilateral vestibular schwannomas by age 30. The average age of death is 36 years; actuarial survival from correct diagnosis is 15 years. NF2 has no racial or ethnic predilections.Childhood-onset NF2 typically presents with non-8th nerve tumors and non-vestibular symptoms, while adult-onset NF2 typically presents with vestibular symptoms. Age at diagnosis, presence of intracranial meningiomas, type of treatment center and type of NF2 mutation are informative predictors of the risk of mortality. Age at diagnosis is, by far, the strongest single predictor.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Unknown

Prevalence of NF2 mutations was not identified.

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

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

Tier 4

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

Expressivity

Vestibular schwannoma growth rates are extremely variable, both between patients and over time in the same patient. Growth rates are highly variable even among multiple NF2 patients of similar ages in the same family.

Tier 3

Intervention Effectiveness

Patient Management

At diagnosis, the following evaluations are recommended: head MRI, hearing evaluation including BAER, ophthalmologic evaluation, cutaneous evaluation, and a genetics consultation.

Tier 4

NF2 patients should be managed in specialty centers. NF2 patients who are managed at specialty centers have a significantly lower risk of mortality than those who are treated at non-specialty centers (relative risk 0.34, 95% CI 0.12-0.98).

Tier 2

Hearing preservation and augmentation are important in the management of individuals with NF2; all affected individual and their families should be referred to an audiologist.

Tier 2

A cervical spine scan should be performed before cranial surgery to prevent complications from manipulation under anesthesia. Lumbosacral imaging should be performed before regional analgesia is given.

Tier 3

Surveillance

MRI screening every 2 years for patients less than 20 and every 3 years for older patients should be sufficient for at-risk patients without tumors. The initial MRI scan could be at 10-12 years of age, or earlier in severely affected families. In 10% of cases, individuals with NF2 become symptomatic before 10 years of age. Once tumors are present, MRI screening should be at least annual until the individual growth rate is established. Annual audiological tests, including auditory brainstem response, may be useful. A full annual neurological examination is a wise precaution, with a spinal MRI every 2-3 years unless no tumors are present on the initial scan.

Tier 2

Nature of Intervention

Nature of Intervention

Management of NF2 requires a variety of non-invasive screening tests.

Context: Adult

Chance to Escape Clinical Detection

Regular screening (MRI, neurological, audiology) is recommended beginning at diagnosis, or earlier for family members. These screenings are above and beyond general population recommendations.

Context: Adult

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			NF2			101000

References List

Baser ME, R Evans DG, Gutmann DH. (2003) Neurofibromatosis 2. Current opinion in neurology. 16(1):27-33.

Evans DG, Baser ME, O'Reilly B, Rowe J, Gleeson M, Saeed S, King A, Huson SM, Kerr R, Thomas N, Irving R, MacFarlane R, Ferner R, McLeod R, Moffat D, Ramsden R. (2005) Management of the patient and family with neurofibromatosis 2: a consensus conference statement. British journal of neurosurgery. 19(1):5-12.

Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D. (1997) The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA. 278(1):51-7.

Neurofibromatosis 2. Gene Reviews (2011) URL: http://www.ncbi.nlm.nih.gov/books/NBK1201/

Neurofibromatosis type 2. Orphanet (2009) URL: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=637