Natural History Study of Patients With Neurofibromatosis Type 2

Objective

With this prospective natural history study on neurofibromatosis type 2 (NF2) study, we hope
to understand the factors leading to tumor progression and neurological disease burden in
NF2.

Study Population

The study is currently suspended at 169 participants. If re-opened, 100 new participants will
be enrolled. A total of 269 participants, ages 8-75, with a clinical or genetic diagnosis of
NF2 will participate in this study.

Design

Study participants will be evaluated with a thorough physical and neurologic examination upon
enrollment. This initial outpatient evaluation will include magnetic resonance imaging with
contrast of brain and spine and blood collection for research use. Participants with
measurable hearing will have audiology assessment performed during the initial visit.
Participants with untreated vestibular schwannomas will have vestibular assessment performed
during the initial visit. Genetic studies performed outside will be acceptable as
confirmation of NF2 in enrolled patients. If needed to confirm NF2 with genetic studies, or
for research purpose, whole genome/whole exome sequencing may be performed on blood or tissue
obtained from subjects enrolled in this study.

Participants who report speech and swallowing dysfunction will be evaluated by a speech
language pathologist.

Subjects will be followed as outpatients for up to ten years, during which clinical, and
radiologic evaluation will be performed annually. Auditory testing will be performed annually
for participants with measurable hearing. Participants with initially untreated vestibular
schwannomas will be followed annually with vestibular testing. Speech and swallowing
reassessments will be performed if worsening of speech or swallowing is reported. Blood will
be collected at each visit for blood biomarker testing

Outcome measures

We hope to understand the biologic basis for speech and swallowing dysfunction in patients
with NF2. We will study and report the strength of association of MRI findings, clinical
assessments cranial nerve deficits and speech/swallowing dysfunction. We hope to

identify imaging biomarkers of hearing loss in NF2. We will attempt to discover the mode of
peripheral neuropathy in patients with NF2. Lastly, we will attempt to discover previously
unknown serum biomarkers associated with high tumor burden in NF2.

Summary of findings to date

This ongoing natural history study has resulted in significant improvements in the
understanding how NF2 affects patients. We found that central nervous system tumors in NF2
demonstrate a stepwise growth pattern. We also found that these tumors are made of many
different populations of tumor cells. These finding emphasize the need for long term follow
up of patients with NF2 to evaluate disease progression. Patients with NF2 have symptoms that
significantly affect their lives such as hearing loss and speech/swallowing dysfunction. This
natural history study has helped us understand how these symptoms arise even when the tumors
are very small or quiescent. These findings will help clinicians find better ways to prevent
hearing loss and to counsel patients about speech and swallowing problems.

Re-opening study to new enrollment

Enrollment was stopped at 169 subjects in November 2013. Significant revisions were made to
the protocol and the study was subsequently re-opened to new enrollment in 2019. At the time
of study re-opening, all previously enrolled subjects had already met

the 5 year protocol timepoint. Therefore, the changes to the protocol required procedures and
length of monitoring did not affect these previously enrolled individuals. The up to 10-year
monitoring program and study procedures referenced in the current protocol document apply
only to new enrollees (subjects enrolled after the study reopened in 2019).

- INCLUSION CRITERIA:

To be eligible for entry into the study, candidates must meet all the following criteria:

- Have the diagnosis of NF2 by established clinical criteria or genetic testing.

- Be between the age of 8 and 75.

- Have the capacity to undergo serial MRI scanning of the CNS without IV sedation.

- Able to give informed consent, or have a parent able to provide informed consent if a
child.

EXCLUSION CRITERIA:

Candidates will be excluded if they:

- Have a clinically unstable condition that precludes serial clinical and imaging
evaluation (i.e. Class 3 congestive heart failure, severe chronic renal insufficiency,
severe chronic obstructive pulmonary disease).

- Cannot have an MRI scan due to an allergy or relative contraindication to MRI contrast
agents.

- Have prior surgery or implant that involves metal clips or wires, which might be
expected to cause tissue damage or produce image artifacts such as pacemakers,
stimulators, pumps, aneurysm clips, metallic prostheses, and artificial heart valves.

- ABIs or cochlear implants are not approved by the NIH Radiology department for safe
use on NIH scanners..

- Have severe chronic renal insufficiency (glomerular filtration rate less than 30
mL/min/1.73 m2), hepatorenal syndrome or post-liver transplantation.

- Are pregnant at time of intake visit (women of childbearing age will be tested with a
urine pregnancy test).