Molecular Genetics and Syndromes Flashcards
Which of the following is the most common neoplasm of the central nervous system associated with neurofibromatosis type 1?
(a) Neurofibroma
(b) Optic pathway glioma
(c) Optic nerve sheath meningioma
(d) Sphenoid wing meningioma
b
Optic Pathway Glioma
The most common central nervous system tumor seen in patients with NF1. WHO grade 1 pilocytic astrocytoma, histologically.
The second most common tumor in the CNS in such patients is a brain stem glioma.
NF1
The most common genetically inherited neurological disorder
1 in 3000 to 4000 live births
NF1 tumor suppressor gene (chromosome 17q11.2)
Encodes neurofibromin (a cytoplasmic protein) which is a negative regula- tor of the RAS-MAP kinase pathway involved in cell proliferation. Autosomal dominant
50% of patients may present with de novo mutations Lifetime cancer risk—59.6%
The initial treatment of optic pathway glioma presenting with precocious puberty in a patient with neurofibromatosis type 1 is
(a) Surgical decompression
(b) Radiotherapy
(c) Chemotherapy
(d) Hormone therapy
d
* Clinical indications for treatment in OPG:
(a) Progressive visual decline
(b) Severe exophthalmos
(c) Precocious puberty not responding to hormonal therapy (d) Radiographic progression
* Clinical indication for surgery in OPG: Visual loss, hydrocephalus
* Treatment of OPG: Chemotherapy (regimen including carboplatin with vin-
cristine), everolimus
* Five-year survival—90% following chemotherapy
The unidentified bright objects seen in the MRI scan of the craniospinal neuroaxis
of occasional patients with neurofibromatosis are structurally
(a) Neurofibromas
(b) Schwannomas
(c) Hamartomas
(d) Intramyelin edema
d
UBOs are derived from
* altered microstructural compartmentalization
* increase in intracellular water
* intramyelinic edema
Which of the following is not a major criterion for the diagnosis of tuberous sclerosis?
(a) Shagreen patch
(b) Fibrous cephalic plaque
(c) Retinal hamartoma
(d) “Confetti” skin lesions
d
Diagnostic Criteria for TSC:
Dermatologic and dentistry
Major criteria:
Hypomelanotic macules (≥3, at least 5 mm diameter) Angiofibromas (≥3) or fibrous cephalic plaque
Ungual fibromas (≥2) Shagreen patch
Minor criteria:
“Confetti” skin lesions Dental enamel pits (≥3) Intraoral fibromas (≥2)
Ophthalmologic
Major criterion:
Retinal hamartoma
Minor criterion:
Retinal achromic patch
Brain structure, tubers, and tumors
Major criteria:
Cortical dysplasia Subependymal nodules SEGA
Cardiology and pulmonary
Major criteria:
Cardiac rhabdomyoma LAM
Nephrology
Major criterion:
Angiomyolipomas (≥2) Minor criterion:
Multiple renal cysts
Other (endocrine, GI)
Minor criterion: Nonrenal hamartomas
Extra-nervous System Manifestations
Cutaneous angiofibromas, subungual fibromas, cardiac rhabdomyomas, intestinal polyps, visceral cysts, pulmonary lymphangioleiomyomatosis, and renal angiomyolipomas.
Central Nervous System Manifestations
Cortical hamartomas called tubers, subcortical glioneuronal hamartomas, subependymal nodules, and retinal and subependymal giant cell astrocytomas (SEGAs).
Which of the following drugs has been approved by the US FDA for the treat- ment of progressive and inoperable plexiform neurofibromas in symptomatic children?
(a) Trametinib (b) Cabozantinib (c) Nilotinib
(d) Selumetinib
d
* Selumetinib—oral selective inhibitor of mitogen-activated protein kinase (MEK or MAPK/ERK kinase) 1 and 2.
* Indications: Symptomatic children ≥2 years with inoperable and progres- sive plexiform neurofibromas.
Which of the following genetic mutations have been identified as a major deter- mining pathomechanism in Sturge Weber syndrome?
(a) GNAQ
(b) GNAT-1
(c) PIK3CA
(d) ERCC2
a. GNAQ (9q21)
Which of the following modalities has shown promise in the treatment of pres- ymptomatic patients with Sturge-Weber syndrome?
(a) Antiplatelet medications
(b) Anticonvulsants
(c) Antiplatelet medications and anticonvulsants (d) Observation alone
c
75% of children with brain involvement due to SWS develop seizures in the first year of life.
Early onset of seizures → poor neurological outcome. Treatment to be started at an early age
Which of the following is not a major criterion in the diagnosis of Gorlin syndrome?
(a) Odontogenic keratocysts of the jaw
(b) Palmar/plantar hyperkeratosis
(c) Bilamellar calcification of the falx cerebri
(d) Ovarian or cardiac fibroma
d
Gorlin-Glotz Syndrome Major criteria:
* Basal cell carcinoma <20 years of age
* Odontogenic keratocysts of the jaws—histologically proven
* ≥3 Palmar or plantar pits
* Bilamellar calcification of the falx cerebri
* First-degree relative with the same syndrome
Minor criteria:
* Macrocephaly
* Cleft lip or palate
* Hand/feet/rib/vertebral anomalies
* Ovarian fibroma
* Medulloblastoma
2 major +1 minor OR 1 major +3 minor criteria are necessary to establish a diagnosis.
Curaçao clinical criteria are used in the diagnosis of which neurocutaneous syndrome?
(a) Hereditary hemorrhagic telangiectasia
(b) Gorlin syndrome
(c) Tuberous sclerosis
(d) Sturge Weber syndrome
a
Curaçao Diagnostic Criteria for HHT (Osler-Weber-Rendu Syndrome)
* Spontaneous and recurrent epistaxis
* Multiple telangiectases— lips, oral cavity, fingers, nose
* Visceral vascular lesions—gastrointestinal telangiectasia; pulmonary, cere-
bral, hepatic, spinal AVMs
* Family history—first-degree relative with HHT
Three or more criteria to be present for the diagnosis.
What is the most common presenting symptom in HHT?
(a) Bleeding port-wine stain
(b) Epistaxis
(c) Hemoptysis
(d) Melena
b
Epistaxis is the most common symptom that brings a patient with HHT to medical attention.
Infantile spasms in tuberous sclerosis can be effectively treated with which of the following medicines?
(a) Lamotrigine
(b) Levetiracetam
(c) Vigabatrin
(d) Topiramate
c
Oral ganaxolone—phase III evaluation in the treatment of tuberous sclerosis complex-related epilepsy.
The genetic cause of Gorlin syndrome is a mutation in the gene located in which of the following chromosomes?
(a) 9p (b) 9q (c) 14p (d) 14q
b
Which of the following tumor syndromes is less likely to have an association with medulloblastoma formation?
(a) Gorlin syndrome
(b) Ataxia-telangiectasia (c) Li-Fraumeni syndrome (d) Cowden syndrome
d
The syndromes usually associated with medulloblastoma are
* Gorlin syndrome (nevoid basal cell carcinoma)
* Li Fraumeni syndrome
* Turcot syndrome
* Rubinsten-Taybi syndrome
* Nijmegen breakage syndrome (NBS1 gene—chromosome 8q21)
* Neurofibromatosis
* Ataxia-telangiectasia
The NF-1 mutation is located on locus 17q.11.2 which encodes neurofibromin. What is the normal function of this protein?
(a) Inhibition of the mTOR pathway (b) Activation of the mTOR pathway (c) Accelerates the inactivation of Ras (d) Accelerates the activation of Ras
c
* The most common tumor-predisposing disease in humans—NF1
* NF1 gene—17q11.2 locus
* Neurofibromin—Tumor suppressor protein
* Neurofibromin = GTPase-activating protein of Ras (Ras-GAP) → increases
the intrinsic GTPase activity of Ras → promotes the hydrolysis of the active form of Ras (GTP-bound Ras) to an inactive form of Ras (GDP-bound Ras) → downregulates the Ras signaling pathway
Which is the most common intramedullary spinal cord tumor associated with NF-2?
(a) Astrocytoma
(b) Schwannoma
(c) Ependymoma
(d) Ganglioglioma
c
NF2:
* Autosomal dominant
* 1 in 33,000 to 40,000 live births
* *
* * *
1.
NF2 tumor suppressor gene (chromosome 22q12)
Encodes merlin (Moesin-ezrin-radixin-like protein) or schwannomin (a cytoplasmic protein) which is an enzyme involved in linking membrane- associated proteins to the actin cytoskeleton
Acts through Ras/Rac/PAK cell proliferation pathway
Complete penetrance—50% of patients will harbor de novo mutations Clinical Criteria:
Bilateral VIII nerve masses seen with appropriate imaging (CT or MRI) OR First-degree relative with NF-2
AND
Either: Unilateral VIII nerve mass, OR
2.
Two of the following:
(i) Neurofibroma (ii) Meningioma
(iii) Glioma
(iv) Schwannoma
(v) Juvenile posterior subcapsular lenticular opacity
* Dermal tumors are typically schwannomas.
* Bilateral VS (WHO grade I) are pathognomonic for NF2.
* Collision tumors are composed of both meningioma and schwannoma.
* Initial evaluation of a patient with confirmed or suspected NF2:
– Comprehensive history and physical examination
– Audiometry including pure tone threshold and word recognition
– MRI of the brain with axial and coronal fine cuts through the auditory
canal (3-mm slice thickness)
– MRI of the cervical spine to evaluate for spinal ependymoma.
– A baseline ophthalmologic examination to assess for posterior subcapsu-
lar cataracts (the juvenile form being pathognomonic for NF2) Surveillance:
* Neuroimaging of suspicious lesions and audiometry every 6 months
* Patients with VS—annual neuroimaging with fine cuts through the internal
auditory canal and audiometry. Goals of treatment:
* Preservation of function—hearing
* Maximizing quality of life.
Causes of hearing loss:
* Vestibular nerve compression
* Cochlear aperture obstruction
* Intralabyrinthine protein accumulation
* Primary hair cell dysfunction
Bilateral VS arise from the superior and inferior vestibular branches of the eighth cranial nerve.
There is no consensus on the management of VS Less than 3 cm—Surgery vs SRS.
Indications for Surgery:
1. Tumor >3 cm
2. Brainstem compression or hydrocephalus
3. Patients not interested in SRS
Drug shown to be effective in the management of NF2-associated VS—Bev- acizumab.
Surgery for NF2 meningiomas—Rapid tumor growth or symptomatic neuro- logical decline.
Spinal ependymomas have an indolent course and are typically observed.
