Neurofibromatosis Type II

Actionability Pediatric Summary Report

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

• Gene: NF2 (HGNC:7773)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 03/31/2021
• Curation Status: Released (1.0.2)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
NF2	neurofibromatosis type 2 (0007039)	101000	Strong Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion computed according to the rubric

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity and mortality from NF2-related tumors / Management in specialty centers with multidisciplinary teams for comprehensive care (includes hearing preservation and augmentation, appropriate surveillance, and downstream management)	2	3C	2B	3	10CB

Severity of Outcome

Prevalence of the Genetic Condition

In the past, the estimated prevalence of neurofibromatosis 2 (NF2) was estimated at 1:210,000. More recently, overall diagnostic disease prevalence has been reported between 1:56,000 – 1:60,000 and would be >1:150,000 in children, due to later age at presentation with symptoms.

Clinical Features (Signs / symptoms)

NF2 is characterized by the development of nervous system tumors (schwannomas, multifocal meningiomas, ependymomas, neurofibromas, gliomas, and astrocytomas), ocular abnormalities (retinal hamartoma, thickened optic nerves, cortical wedge cataracts, third cranial nerve palsy), and skin tumors. NF2 is hallmarked by development of bilateral vestibular schwannomas (VSs), which occur in 95% of adult patients, inevitably leading to bilateral profound hearing loss. Schwannomas typically affect both vestibular nerves, leading to hearing loss and deafness, tinnitus, dizziness, and imbalance. A recognized feature of NF2 is a mononeuropathy occurring particularly in childhood, while a progressive polyneuropathy of adulthood is also observed.

While the tumors caused by NF2 are not typically 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). In 10% of cases, individuals with NF2 become symptomatic before 10 years of age. Nearly 50% of individuals present symptomatically by 20 years of age. The average age of death is 36 years; actuarial survival from correct diagnosis is 15 years. Overall, 5-, 10-, and 20-year survival rates after diagnosis of NF2 are 85%, 67%, and 38%, respectively. NF2 has no racial or ethnic predilections.

Childhood-onset NF2 typically presents with non-8th nerve tumors and non-vestibular symptoms. Skin tumors and ocular findings may be the first manifestations. Optic nerve sheath meningiomas can cause visual loss in the first years of life. Retinal hamartomas and epiretinal membranes may be present at a young age. Cataracts and other ocular abnormalities can affect vision in early life, and other tumors (particularly cranial meningiomas) can occur in the first 10 years of life. Childhood onset strabismus and amblyopia have been frequently reported. Pediatric patients may develop mononeuropathy that frequently presents as persistent lower motor neuron facial weakness, seizures, or hand/foot drop, often before the detection of a VS. Some children present with wasting of muscle groups in a lower limb that does not fully recover.

Adult-onset NF2 typically presents with vestibular symptoms, most commonly unilateral hearing loss. Others may present with focal weakness, balance dysfunction, or tinnitus. In adulthood, a progressive polyneuropathy is common in patients with severe disease.

Nearly all affected individuals develop bilateral VSs by age 30, but the growth rate of NF2-associated VSs differs based on the age at presentation. If left untreated, VSs can cause compression of the brain stem and hydrocephalus.

Age at diagnosis, presence of intracranial meningiomas, and type of treatment center are informative predictors of the risk of mortality. Age at diagnosis is, by far, the strongest single predictor. To varying degrees, the age of onset and severity of disease are affected by mosaicism and the nature of the pathogenic variant. Truncating variants are associated with earlier onset, greater number of NF2-associated tumors, and greater disease-related mortality.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

1-2 in 50000

In the United Kingdom, large population-based estimates of birth incidence for NF2 showed that between one in 25,000 to 33,000 people would be born with a pathogenic variant in the NF2 gene.

Tier 3

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

>= 40 %

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

Tier 4

>= 40 %

Bilateral vestibular schwannomas (VSs) occur in 95% of adult patients.

Tier 3

>= 40 %

Auditory abnormalities are present in 90-100% of patients between 10-72 years with NF2, depending on the test used.

Tier 3

5-39 %

Up to 90% of people with NF2 have spinal tumors, but only 30% have symptomatic spinal tumors requiring surgery. Specifically, intramedullary tumors of the spinal cord (astrocytoma and ependymoma) occur in 5-33% of individuals with NF2.

Tier 3

>= 40 %

In cross-sectional studies, approximately half of individuals with NF2 develop cranial meningiomas; however, lifetime risk may approach 80%.

Tier 3

>= 40 %

About 70% of NF2 patients have skin tumors, but only 10% have more than 10 skin tumors.

Tier 3

>= 40 %

In several studies on individuals affected with NF2 of all ages, the frequencies of the following ophthalmologic symptoms were reported:

• Posterior subcapsular cataracts: 27-72%

• Cortical wedge cataracts: 13-41%

• Mixed cataracts: 14-33%

• Retinal hamartomas and epiretinal membranes: 9-22%.

Tier 3

>= 40 %

Recent studies have found that, overall, cataract or retinal changes or both are recorded in 40% to over 70% in the pediatric NF2 series so far reported.

Tier 3

Expressivity

Variable expressivity of NF2 among individuals results in varying size, location, and number of tumors. Vestibular schwannoma growth rates are generally higher in young patients, but 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

Truncating pathogenic variants in exons 2-13 are associated with increased disease severity regarding age of onset and number of tumors. Pathogenic variants in exon 1 and 14/15 cause milder disease.

Tier 3

Intervention Effectiveness

Patient Management

At diagnosis, patients should undergo an MRI scan of the brain and potentially a full spinal MRI. Hearing evaluation including brain stem auditory evoked response (BAER), and ophthalmologic evaluation, should be performed.

Tier 2

A cutaneous evaluation should also be considered.

Tier 4

NF2 patients should be managed in specialty centers with multidisciplinary teams including surgeons of various subspecialties, neurologists, geneticists, ophthalmologists, audiologists, hearing therapists, physiotherapists, and other disciplines; as well as family support coordinators who have experience in NF2. Surgeons should have extensive experience in managing VS and in auditory rehabilitation with both cochlear implantation and the auditory brainstem implant (ABI). 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). An analysis of 1192 patients (771 with known causal variants) from the UK National NF2 registry found the mortality of patients with NF2 diagnosed in more recent decades was substantially lower than that of patients diagnosed earlier, due partly to a shift towards provision of care in specialty centers, which began in 2010 in the UK. In 1990, <30% of patients were managed by specialty centers versus 97% in 2014. Survival curves by era of diagnosis in 485 patients with genetically confirmed NF2 indicated that the survival to age 60 years was 10% if diagnosed prior to 1980, about 68% if diagnosed between 1990-1999, about 82% if diagnosed between 2000-2009 and 100% if diagnosed between 2010-2014.

Tier 2

Minimal interference and maintenance of quality of life are the cornerstones of NF2 management. If a conservative management is reasonably possible, it will generally be preferred for long-term functional preservation. This applies equally to all NF2-associated tumor types. The indication for treatment and the extent of surgical resection is complex and factors must be considered such as: bilateral hearing function; tumor size, extent, location, and growth rate; patient preferences, and comorbidities.

Tier 2

Hearing preservation, augmentation, and/or rehabilitation are important in the management of individuals with NF2; all affected individuals and their families should be referred to an audiologist. Hearing aids may be helpful in the early course of disease. Patients without nerve damage may benefit from a cochlear implant. Teams experienced in the positioning of brainstem implants can offer partial auditory rehabilitation, although results are still behind those achievable for cochlear implants.

Tier 2

A systematic review evaluating hearing outcomes of treatments for VSs in NF2 included 3 studies (5 patients) with small untreated tumors who underwent cochlear implantation. All patients had significant benefit from their device with a mean sentence score in quiet without lip reading of 69.3% at 60 months follow-up.

Tier 1

Surveillance

Because detection of tumors at an early stage is effective in improving the clinical management of NF2, after initial diagnosis, regular evaluations for patients of all ages should include:

• Neurological and physical examination

• MRI scan of the brain and spinal cord

• MRI scans of symptomatic lesions outside the brain if present

• Audiology and BAER evaluations

• Ophthalmologic evaluation (in patients with visual impairment or facial weakness).

Tier 2

Initially, children should be seen relatively frequently (every 3-6 months) until the growth rate and biologic behavior of tumors is determined. Screening typically begins around 10 years of age, but may begin earlier in patients with high-risk genotypes (e.g., truncating pathogenic variants in exons 2-13), or symptomatic diagnoses. Most pediatric patients without severe problems can be followed on a 6- to 24-month basis.

Tier 2

Two case series of 43 and 73 patients (age range 4-69 years) with NF2 reported that full spine MRI detects spinal tumors in up to 90% of patients, but only 30% have symptomatic spinal tumors that require surgery.

Tier 2

In adult patients, imaging of VSs may be more frequent than other NF2-associated tumors due to more variable tumor growth rate. Similar to sporadic VSs, an MRI 6 months after tumor discovery may identify tumors likely to continue growing; otherwise, scans may be obtained annually for 5 years, and scan intervals should be lengthened if no growth is detected.

Tier 1

Spinal MRI may be performed at least annually after tumor growth has stabilized unless no tumors are present on the initial scan.

Tier 2

In general, regular evaluations can be performed less frequently (every 3-5 years) after tumor growth rate has been determined.

Tier 2

Surveillance may be eliminated or reduced in older adult populations if stability is established and the likelihood of lifetime growth declines. In a study of 119 patients with NF2 managed at a single tertiary NF2 reference center, 7 patients diagnosed after age 70 years were followed. Eleven bilateral VSs were present in 4/7 patients, but the majority of older adult NF2 patients that presented with VSs (8/11, 72%) exhibited no significant growth after a mean follow-up period of 8 years, suggesting that older adult patients might be reimaged less frequently than younger patients.

Tier 1

Circumstances to Avoid

Tier 3

Nature of Intervention

Nature of Intervention

Management for NF2 is multi-disciplinary, involving several medical and surgical specialties for adequate monitoring and treatment, and is lifelong. Management of NF2 also requires a variety of non-invasive screening tests including frequent imaging and examination, and patient education. A potential risk of MRI may include the need for sedation, which is particularly relevant in the pediatric setting.

Context: Adult Pediatric

Chance to Escape Clinical Detection

NF2 is rarely confused with other conditions, but pediatric patients may present atypically. Patients with schwannomatosis or multiple meningiomas can cause diagnostic confusion.

Context: Adult Pediatric

Tier 3

Some children may be initially diagnosed as having either NF1 or sporadic benign neuro- fibromas or schwannomas.

Context: Pediatric

Tier 3

Because NF2 is considered an adult-onset disease, it may be underrecognized in children.

Context: Pediatric

Tier 3

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			NF2			101000	0007039

References List

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

DG Evans. Neurofibromatosis 2. (1998) [Updated Aug 18 2011]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1201/

Dunn IF, Bi WL, Mukundan S, Delman BN, Parish J, Atkins T, Asher AL, Olson JJ. (2018) Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Role of Imaging in the Diagnosis and Management of Patients With Vestibular Schwannomas. Neurosurgery. 82(1524-4040):E32-E34.

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.

Evans DGR, Salvador H, Chang VY, Erez A, Voss SD, Druker H, Scott HS, Tabori U. (2017) Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 2 and Related Disorders. Clinical cancer research : an official journal of the American Association for Cancer Research. 23(1557-3265):e54-e61.

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.

Kotecha RS, Pascoe EM, Rushing EJ, Rorke-Adams LB, Zwerdling T, Gao X, Li X, Greene S, Amirjamshidi A, Kim SK, Lima MA, Hung PC, Lakhdar F, Mehta N, Liu Y, Devi BI, Sudhir BJ, Lund-Johansen M, Gjerris F, Cole CH, Gottardo NG. (2011) Meningiomas in children and adolescents: a meta-analysis of individual patient data. The Lancet. Oncology. 12(1474-5488):1229-39.

Lloyd SKW, King AT, Rutherford SA, Hammerbeck-Ward CL, Freeman SRM, Mawman DJ, O'Driscoll M, Evans DG. (2017) Hearing optimisation in neurofibromatosis type 2: A systematic review. Clinical otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery. 42(1749-4486):1329-1337.

Rosahl S, Bohr C, Lell M, Hamm K, Iro H. (2017) Diagnostics and therapy of vestibular schwannomas - an interdisciplinary challenge. GMS current topics in otorhinolaryngology, head and neck surgery. 16(1865-1011):Doc03.

Ruggieri M, Praticò AD, Evans DG. (2015) Diagnosis, Management, and New Therapeutic Options in Childhood Neurofibromatosis Type 2 and Related Forms. Seminars in pediatric neurology. 22(1558-0776):240-58.