Chromosomal/Genetic Syndromes Flashcards
What disorder is characterized by skin and bone abnormalities resulting from tumors growing along the nerve?
Neurofibromatosis type 1
What characterizes neurofibromatosis type 2?
Bilateral acoustic schwannomas on the 8th cranial nerve, meningiomas, and ependymomas
How is neurofibromatosis type 1 inherited?
- Autosomal dominant genetic disorder
- Gene location: chromosome 17
What are the diagnostic criteria for NF1?
Two or more of the following: 1 )6 or more cafe-au-lait macules 2) 2 or more neurofibromas or 1 plexiform neurofibroma 3) Freckling in the axilla or groin 4) Optic glioma 5) 2 or more Lisch nodules 6) A distinctive bony lesion 7) A first degree relative with NF1
What is the neuropathology of NF1?
- Brain tumors (seen in 15% of people) w/ most present by age 6. Most are optic gliomas (benign)
- T2 hyperintensities (60-70% of those with NF1) in the basal ganglia, cerebellum, thalamus, brainstem, and subcortical white matter
- Macrocephaly/megalencephaly (30-50% of people)
What are the presentation, disease course, and recovery like with NF1?
- Most symptoms worsen over time
- Neurofibromas increase in number during puberty and pregnancy
- But T2H resolve by early adulthood
- Children have delays in development
- There is no recovery; neurocognitive profile remains static
What are the cognitive characteristics of NF1?
- Learning disabilities
- ADHD
- FSIQ ranges from 89-98 (leftward shift)
- Deficits in attention and EF
- Deficits in language, manual dexterity, coordination, and balance
- Verbal and visual mem intact
What are common behavioral characteristics of NF1?
- Internalizing disorders
- Poor impulse control can be associated with ADHD
- Socially awkward
What are the key physical/medical characteristics of tuberous sclerosis complex (TSC)?
- Cortical tubers
- Facial angiofibromas/hypomelanotic macules
- Shagreen pathc
- Subpendymal nodules: hamartomas
- Subpendymal giant cell astrocytoma: slow growing most common brain tumor
- Cardiac rhabdomyoma
- Lymphangiomyomatosis
- Renal angiomyolipoma
- Epilpesy
What are the common cognitive and behavioral characteristics of TSC?
-ID: bimodal distribution (30% have profound ID and 70% normal to superior IQ)
-High rates of LD in those w/ normal IQ
-Deficits in attention and EF
-Only 30% have normal language development
-Deficits in memory recall w/ spared recog
-Autism (40-50% diagnosed with this)
=50% exhibit behavioral problems
How is TSC inherited?
- Variably expressed, autosomally dominant
- From one of 2 genes: TSC1 or TSC2
- Clinical presentation of TSC1 may be milder
What is the morbidity and mortality of TCS?
- 80-90% diagnosed with epilepsy & seizures begin in infancy & typically intractable
- 45% diagnosed with ID
- 40-50% diagnosed with ASD
- 25=50% diagnosed with ADHD (higher prevalence in children with seizures)
- Life expectancy variable
What is the disease course in TSC?
- Variable: those w/ profound ID show little cog progression past the sensorimotor stage
- Infants tend to remain delayed compared to peers over time
- Children w/out early delays fall behind peers during school years
- No intellectual or behavioral regression
What are the major characteristics of Sturge-Weber Syndrome (SWS)?
- Facial capillary malformation or port-wine birthmark (PWB in the region of the ophthalamic division of the trigeminal nerve)
- Vascular malformation of the brain (typically on the same side as the PWB in the occipital and parietal lobes)
- Glaucoma
- Seizures
- Migraines
- Stroke-like episodes: associated with seizures/migraines and present with weakness or sensory disturbance
- 18 fold increase in prevalence of growth hormone deficiency
Is SWS genetic?
It has no known genetic basis and is nonfamilial
What are the cognitive/behavioral characteristics of SWS?
- ID (50-60% diagnosed with ID)
- Varying deficits related to medical complications
What is the neuropathology of SWS?
- Leptomeningeal angioma: capillary-venous vascular malformation of the brain
- PWB increases the risk of brain involvement by 10-20% and is correlated with size
- Cerebral atrophy and cortical calcification: lateralized in the occipital and parietal regions
How many individuals with SWS have unilateral brain involvement?
- 75%
- Of those with bilateral brain involvement, 95% have seizures (contralateral to the PWB)
What group is most susceptible to stroke-like episodes in SWS?
- Toddlers and young children
- These are precipitated by falls typically
Describe the seizures associated with SWS.
- Typically begin in childhood in the first year with unilateral brain invovlement
- Focal motor seizures are most common but complex partial seizures are also common
- Seizures stabilize in older childhood and worsen in adolescence
- AEDs are use and research suggests better cognitive functioning in those who are treated prophylactically
What is associated with better outcome in SWS?
- Later seizure onset (after 9-12 months of age)
- Good seizure control
- Unilateral brain involvement
Are those with SWS at risk for neurologic deterioration?
- Yes, thought to be due to venous occlusions and hypoxia and worsened by seizures
- Early onset dementia can be seen in individuals with SWS in their 50s and 60s
Describe the cognitive and behavioral functioning in those with SWS.
- Difficulty to determine d/t variable course and outcome
- Risk factors for worse outcome: frequent seizures, seizure onset in infancy, diffuse cortical involvement, hx of stroke-like episodes
- 60% of IQ scores in range of ID
- Learning, attention, processing speed, language, visual-perceptual, and sensorimotor problems are reported
- Disrupted behavior disorder is common
- Mood problems such as depression is common
- Substance-related disorders are common in adults
What is are the key physical & medical characteristics of Williams Syndrome?
- Connective tissue abnormalities
- Cardiovascular disease; supravalvar aortic stenosis
- Ocular/visual abnormalities: hyperopia, strabismus
- Ear/auditory abnormalities: chronic otitis media, hypersensitivity to sound
- Kidney/urinary tract abnormalities
- Facial dysmorphology
Describe the facial dysmorphology seen in Williams syndrome.
- “Elfin” appearance
- Broad bow
- Flat nasal bridge
- Short upturned nose
- Wide mouth with full lips
- Starburst iris pattern
What are the cognitive/behavioral characteristics of Williams syndrome?
- ID: average FSIQ is 55
- Better verbal than nonverbal skills
- Impaired visuospatial cognition but intact object and face fecovnition
- Utilize a local/featural rather than global configuration approach
- Impaired dorsal visual stream- poor spatial memory
- Auditory rote mem is a strength
- Reading is better than math
- Hypersociability
- Exhibits conversational sterotypies
- Anxiety/phobias
What is the neuropathology of WIlliams syndrome?
- Reductions of cerebral volume with preservation of cerebellar volume
- Gray matter volume is preserved with reductions in white matter volume
- Narrowing of corpus collosum
- Abnormal cell density in the primary visual cortex
- Reduced sulcal depth in the intraparietal/occipitoparietal sulcus (abnormal dorsal stream function)
- Abnormal neural pathways: increased amygdala activation to threatening scenes and reduced amygdala activation to threatening faces (d/t/ hypersocial and anxious traits)
What is the morbidity and mortality of Williams syndrome?
- Failure to thrive in 70% of infants
- 50-75% develop cardiovascular disease which leads to shortened lifespan
- 50% have strabismus, cataracts, and visual acuity problems
- 85-95% have hypersensitivity to sound
- 65% diagnosed with ADHD
- Majority of IQ in the ID range
What is the typical disease course in Williams Syndrome/
- Motor delays and hypotonia in infancy
- Atypical language developmental schemes
- Delayed expressive language initially but once their vocab develops they use language for social purposes
- Sensorineural hearing loss by age 30
- Adults have diabetes
- Enhances affinity for music, rhythm and timbre are strengths
- No cure
What are the key physical and medical characteristics of 22q11.2 deletion syndrome?
- Cardiac defects: teralogy of Fallot, interrupted aortic arch, ventricular septal defect, vascular ring, tuncus arteriosus
- Hypocalcemia
- Mild conductive hearing loss
- Palatal defects: submucosal cleft palate, velopharyngeal dysfunction
- Facial dysmorphology: long face, long nose, small ears w/ overfold helices, vertically narrow eyes
What are other names for 22q11.2 deletion syndrome?
DiGeorge syndrome, Shprintzen syndrome, or velo-cardio-facial syndrome
Is 22q11.2 deletion syndrome inherited?
10% of cases are inherited from a parent in an autosomally dominant pattern while 90% are due to de novo mutations
What is the neuropathology of 22q11.2 deletion syndrome?
- Decrease in total brain volume with WM more affected than GM & parietal >frontal reduction
- Reduced cerebellar volume
- Hippocampal reduction
- Disorganized axonal traxts
- Cortical thinning: in parieto-occipital and orbitofrontal regions
What is the morbidity and mortality of 22q11.2 deletion syndrome?
- 75-80% have congenital heart defect
- 69% have palatal abnormalities –> speech and feeding difficulties
- 30-40% diagnosed with ADHD
- 30-40% diagnosed w/ anxiety disorders
- 10-30% diagnosed with ASD
- 82-100% have learning difficulties
- 20-30% dx with mood disorders
- 25-30% dx with psychotic disorder
What are the typical cognitive and behavioral characteristics of 22q11.2 deletion syndrome?
- Mild ID to average IQ
- Language skills better than nonverbal (possibly represents a nonverbal learning disorder)
- Strong rote memory, good reading decoding
- Math difficulties, poor attention and EF
- Mood/psych disorders: anxiety, OCD
- Increased risk for schizophrenia (respond less well to antipsychotic meds)
- Deficits in gross motor skills
What is the risk of developing schizophrenia in those with 22q11.2 deletion syndrome?
25x the general population
What is an x-linked, recessive disorder affecting CNS myelin and the andrenal cortex?
Adrenoleukodystrophy (ALD)
What is the biochemical basis for ALD?
Defective oxidation of very-long-chain fatty acids which accumulate in plasma, brain, and adrenal cortex.
What is the disease course of ALD?
Neurodegenerative with death occurring 2-3 years after clinical onset
Describe the genetics behind ALD?
- X-linked recessive
- X-linked disorder so males show greater deficits
- Heterozygous females show mild to moderate myeloneuropathy after age 40
What are the 4 main phenotypes of ALD?
- Cerebral inflammatory: divided into childhood cerebral, adolescent, and adult
- Adrenomyeloneuropathy
- Addison-only
- Asymptomatic
What is the most common phenotype of ALD?
- Childhood cerebral (CCALD): this represents 31-35% of cases
- Age of onset is 3-10 years
- Characterized by progressive behavioral, cognitive, and neurologic decline
What is the age of onset of Adolescent and adult ALD?
- Adolescent: 11-21 years; similar to CCALD but slowed progression
- Adult: 21-35 years: dementia, behavioral disturbance, and focal defects. Similar progression to CCALD
Describe the adrenomyeloneuropathy phenotype of ALD,
- Onset is 28 years on average
- Involves mainly spinal cord and peripheral nerve involvement
- Progressive over decades
Describe the Addison-only phenotype of ALD,
- Onset before 7.5 years
- Primary adrenal insufficiency without neurologic involvement