Sensory genetics Flashcards
How is the dx of NF2 established
diagnosis of NF2 is established in a proband with bilateral vestibular schwannomas, an identical NF2 pathogenic variant identified in two or more anatomically distinct NF2-related tumors, or a combination of clinical and molecular criteria that fulfill the consensus diagnostic criteria.
What is the recommended tx for NF2
Targeted therapy: The VEGF antibody bevacizumab for rapidly growing vestibular schwannomas; bevacizumab has also shown some clinical benefit in some individuals with ependymoma.
Supportive care: Treatment of vestibular schwannoma is primarily surgical; stereotactic radiosurgery, most commonly with the gamma knife, may be an alternative to surgery. Individuals with vestibular tumors need to be aware of insidious problems with balance and underwater disorientation, which can result in drowning. Cervical spine MRI prior to cranial surgery; lumbosacral MRI prior to regional analgesia. Treatment for hearing loss includes referral to an audiologist, lipreading and sign language instruction, and possibly hearing aids and/or cochlear or brain stem implants. Surgical treatment for infantile cataracts and patching as needed. Management through rehabilitation medicine, physical therapy, and/or occupational therapy should be considered for hand or foot drop due to mono- or polyneuropathy. Surgical removal as needed for cutaneous schwannomas that are causing disfigurement and/or pain.
What is the recommended surveillance for NF2
For affected or at-risk individuals, annual neurologic examination by a provider with experience in NF2; annual brain MRI beginning at approximately age ten to 12 years and continuing until at least the fourth decade of life; annual hearing evaluation, including BAER testing; annual complete ophthalmology examination.
Describe the clinical dx criteria for the dx of NF2
in a proband w ONE of the following:
bilateral vestibular schwannomas
identical NF2 PV in 2 or > anatomically distinct NF2 related tumors (schwannoma, meningioma, and/or ependymoma); if VAF <50%, dx is mosaic NF2
two major criteria
one major and two minor criteria
MAJOR
unilateral vestibular schwannoma
first degree relative other than a sib w NF2
Two or > meningiomas
NF2 PV in an unaffected tissue (blood)
MINOR
ependymoma, schwannoma (two ependymomas or two non-vestibular schwannomas count as two minor criteria)
single meningioma
juvenile subcapsular or cortical cataract, retinal hamartoma, epiretinal membrane in a person <40yo (bilaterally only counts as one minor criterion)
What is the recommended testing for NF2
sequence analysis of NF2 then del dup
CMA uses large dels/dups
a multigene panel
25-50% of individuals have a de novo PV NF2 variant have somatic mosaicism for the variant
molecular genetic testing of tumor tissue may be necessary
when tumor DNA is tested, PVs in both NF2 alleles must be identified; once both NF2 PVs are identified in the tumor, leukocyte DNA can be tested to determine which of the PVs is constitutional and which is somatic
Describe the clinical features associated w NF2
avg age of onset is 18-24yrs
almost all develop bilateral vestibular schwannomas by 30yo; also develop other schwannomas of the cranial and peripheral nerves, meningiomas, ependymomas, and (very rarely) astrocytoma’s
skin findings: intradermal plaque-like tumors that often have excess hair and skin pigmentation
ocular: retinal hamartoma, thickened optic nerves, cortical wedge cataracts that may be congenital and associated w amblyopia, third cranial nerve palsy, epiretinal membranes, retinal tufts on optical coherence tomography
mononeuropathy (facial nerve palsy, foot or wrist drop) w no obvious tumor cause, isolated meningioma or a schwannoma at any site
Describe the vestibular schwannomas seen in NF2
tinnitus, hearing loss, and balance dysfunction
if left untx, cause compression of the brain stem and hydrocephalus
sensory nerves more frequently affected than motor nerves
children/YAs w an apparently isolated vestibular or other cranial nerve schwannoma should be considered at risk for de novo and often mosaic NF2
Describe the spinal tumors seen in NF2
2/3 of individuals w NF2 develop spinal tumors, which are often the most devastating and difficult tumors to manage
typically schwannomas, taking the shape of a dumbbell
astrocytoma and ependymoma in 5-33%
Describe the meningiomas and ocular involvement in NF2
~1/2 will have on, lifetime risk up to 80%
most are intracranial, although spinal meningiomas occur
in the orbit may compress the optic nerve and result in vision loss
at the skull base may cause cranial neuropathy, brain stem compression, and hydrocephalus
ocular: 1/3 have decreased visual acuity in one or both eyes; lens opacities can be seen in children; retinal hamartoma and epiretinal membrane are seen in up to 1/3
Describe the mono and polyneuropathy in NF2
mononeuropathy in children (facial palsy that usually only partially recovers or hand and foot drop)
progressive polyneuropathy in adulthood
renal dz occurs due to bevacizumab use
What is the prognosis for NF2
variable expressivity of NF2 among individuals results in varying size, location, and number of tumors
tumors are not malignant, anatomic location and multiplicity lead to great morbidity and early mortality
avg age of death is 36yo
Describe the histopathology of tumors in NF2
tumors of NF2 are derived from Schwann cells, meningeal cells, and glial cells (ALL BENIGN)
40% of vestibular tumors have a lobular pattern that is uncommon in tumors from individuals without a dx of NF2
schwannomas tend to be more invasive, higher degree of dividing
meningiomas have a higher degree of dividing cells, usually of the fibroblastic variety
Describe the de novo rate for NF2
50% de novo rate
25-50% have a de novo Path NF2 variant have somatic mosaicism for the variant
Should children be tested for NF2
Yes, symptoms/surveillance can start before 18yo
Describe the molecular pathogenesis of NF2
NF2 encodes a large protein containing FERM domains known as merlin; merlin coordinates growth factor receptor signaling and cell adhesion
LOF
using high depth of coverage for sequencing as well as pipelines optimized for the detection of variants w low VAFs is recommended for the detection of mosaic pathogenic NF2 variants
