Pediatrics

Question 1

Angelman Syndrome

Answer 1

Maternal imprinting
Clinical: happy, excitable demaner with frequent laughing
-developmental delay
-microcephaly
-seizures (usually myoclonic)
-hyperactive (hand flapping, waving)
-ASD (autism)

Question 2

Pradi Willy Syndrome

Answer 2

Paternal imprinting
Clinical: hypotonia, hyperphagia and obesity (+++appetitie)
-compulsive behaviour
-hypogonadism
-short-stature 
-seizures (focal more common)

Question 3

Rett syndrome

Answer 3

X-linked (fatal in males)–> MECP2 mutation

• normal development upto 18 months, then rapid regression
• stereotypic movements–> hand wringing, repetitive blows to face
• inconsolable crying
• mircocephaly
• language regression
• gait ataxia

MAIN CRITERIA:

1. ) loss of acquired hand skill
2. ) loss of acquired SPOKEN language
3. ) Gait abnormalities: impaired of absence ability
4. ) Stererotypic hand movements; hand wringing, clapping/tapping, mouthing and washing/rubbing automatisms,

EXCLUSION CRITERIA:

1. ) grossly abnormal psychomotor development in first 6 months
2. ) secondary cause (i.e. structural, metabolic, etc)

Question 4

Fragile X

Answer 4

X-linked; females may have milder symptoms
-CGG repeats >200 in fragile X gene; decreased levels of fragile X mental retardation protein
-clinical: post-puberty most obvious
-long face with prominent brow and jaw
-large ears, macroorchidism, hyperextensible skin and joints
-Neurological: intellectual disability, epilepsy, autism
**if presenting in adult life (>50), following clinical features: intention tremor, ataxia, parkinsonism, cognitive decline (dementia, decline in executive dysfunction), neuropathy, psychiatric features (anxiety, depression)
Adult females may have primary ovarian insufficiency (early menopause)
Imaging: T2/FLAIR middle cerebellar peduncles

-check for: SCOLIOSIS, GERD, sinusitis, otitis media, early childhood–> focus on dislocations, hypotonia, hernias

Question 5

Ataxia Telangiectasia

Answer 5

AR
Normal early development until gait and truncal ataxia become apparent 
Clinical:
1.) progressive ataxia
-polyneuropathy
2.) choreoathetosis
3.) oculcutaneous telangiectatsia
4.) infections
5.) malignancies (leukemia/lymphoma)
6.) increased sensitivity to ionized radiation 
7.) premature aging

1. ) MRI: cerebellar atrophy
2. ) decreased serum Ig levels
3. ) elevated alpha feto-protein

Question 6

Von Hippel-Lindau disease

Answer 6

AD
-hemangioblastoma of cerebellum, kidneys, retina, spinal cord
-median age 20-25 y 
Clinical features:
1.) angiomatosis
2.) hemangioblastomas (cerebellum and brainstem)
3.) pheochromocytoma
4.) renal cell carcinoma 
5.) pancreatic cysts
6.) cafe-au lait macules

Management: surveillance!!

HARP pneumonic: hemangioblastoma, angiomatosis, renal cell carcinoma, pheochromocytoma

Question 7

Sturge-Weber Syndrome

Answer 7

Somatic Mosaic mutation
Clinical:
1.) facial portwine cutaneous in distribution of trigeminal nerve (V1 and V2)
2.) ipsilateral glaucoma
3.) seizures
4.) ipsilateral leptomeningeal vascular lesions–> leads to cortical calcification

Management: symptomatic; hemispherectomy to control seizures when medical therapy fails; monitor for galucoma!!

Question 8

Aicardi Syndrome

Answer 8

X-linked dominant disorder; lethal in affected male

• IS
• agenesis of the corpus callosum
• chorioretinopathy
• vertrebral anolomalies
• severe mental retardation
• EEG: asymmetric hypsarrthymia

Question 9

Chiari I Malformation

Answer 9

-downward herniation of cerebellar tonsils through foramen magnum >5mm

Question 10

Friedreich Ataxia

Answer 10

AR

• trineucleotide expansion >66 GAA
  1. ) face: hearing loss, optic atrophy, nystagmus, dysarthria
  2. ) heart: cardiomyopathy, dysrhythmia
  3. ) endo: diabetes
  4. ) MSK: scoliosis, pes cavus (high arch), talipes equinovarus
  5. ) limb and head tremor

***ataxia, pyramidal signs, sensorimotor neuropathy, optic atrophy

Management:

1. ) atrophy of spinal cord and medulla
2. ) NCS: axonal neuropathy

Question 11

Neurulation

Answer 11

3rd-4th week of gestation
Issues:

1. )failure of rostral fusion=anencephaly, encephelocele
2. )failure of caudal fusion=myelomeningocele (issues with ambulation, hydrocephalus, motor/sensory dysfunction depending on the level, spinchter function)

Myelomeningocele+displacement of cerebellar tonsils=Arnold-chiari malformation

Question 12

Prosencephalic development

Answer 12

Begins 5th-6th week of gestation and continues…
Forebrain takes shape–>
3 stages: 1.) formation 2.) cleavage 3.) midline development
1.) Anomalies of formation stage are not viable and are rare

2.) rostral end expands and creates forebrain and prosencephalon–> after formation of prosencephalon, midline structure indents and cleaves into telencephalon
Issues: Holoprosencephaly (absence of hemipsheric seperation) ; thalamus and hypothalmus do not seperate properly; face–> cyclopia to single central incisor SHH gene (sonic hedgehog gene)

3. )agenesis of corpus callosum and septooptic dysplasia
   - Septooptic dysplasia–>optic nerve hypoplasia, pituitary dysfunction, absence of septum pellucidum

Question 13

Neuronal Proliferation

Answer 13

Disorders of 1.) decreased proliferation 2.) disordered proliferation 3.) abnormal differentiation/maturation

1. ) microcephaly: primary
   - primary: genetic (decreased proliferation), destructive process (i.e. intrauterine infections, HIE)
2. ) Hemimegalencephaly: unilateral enlargement of one hemisphere; a/w TSC, hypomelanosis of Ito, linear nevus sebaceous syndrome
3. ) Cortical dysplasia or cortical hamartoma in TSC

Question 14

Stages of brain development

Answer 14

1. ) neurulation
2. ) prosencepahlic development
3. ) neuronal proliferation
4. )Neuronal migration
5. ) Postmigrational cortical organization

Question 15

Neuronal Migration

Answer 15

3-5 month of gestation–> neurons and glia migrate to cerebral cortex

• Heterotopia: ectopic neurons outside cortex
• Lissencephaly: paucity of normal gyri/sulci; “smooth brain”
• -> can get infantile spasms
• -> spastic quadriparesis
• -> intellectual disability
• -> epilepsy
• -> de novo mutation

1. ) classic lissencepahly: agyria or pachygyria
2. ) cobblestone: overmigration of neurons beyond disrupted basal membrane and pial surface (overlying subarachnoid tissue); associated with congenital muscular dystrophies

Question 16

Postmigrational cortical organization

Answer 16

impairment of cortical organization after migration
1.) polymicrogyria: intrauterine CMV or genetic (focal but symmetric lesions such as bilateral perislyvian polymicrogyria or any other region)

2. ) Schizencephaly: slit or clefts in the cerebral hemisphere
3. ) post migrational microcephaly

Question 17

Pompe’s disease

Answer 17

• AR
• ->mutation in GAA gene
• GAA deficiency (acid alpha-glucosidase)
• accumulation of glycogen within the lysosome in tissues

1. )infantile form
   - cardiomyopathy
   - generalized hypotonia
   - respiratory distress
   - feeding difficulties
   - TONGUE enlargement
2. ) juvenile and adult form
   - progressive myopathy→ limb-girdle distribution, particularly hip flexors
   - delayed gross-motor development
   - early involvement of diaphragm
   - camptocormia (severe anterior flexion of the spine)

3.) GI: dysphagia, GERD, diarrhea, constipation

Work-up

• Increase CK
• Increase LDH
• Increase AST
• GAA enzyme measured in WBC

Treatment:
-enzyme replacement therapy with alglucosidase alfa

Question 18

Niemann-Pick Disease

Answer 18

• AR
• storage of lipids
• 3 types

1. ) NPD-A
   - Ashkenazai jews
   - hepatosplenomegaly
   - feeding difficulties
   - loss of early motor skills

PNS: hypotonia, absent reflexes, peripheral neuropathy
Lungs: respiratory failure, interstitial lung disease, respiratory infections
Eye: MACULAR CHERRY RED SPOT

2. ) NPD-B
   - pan-ethnic
   - less severe than A

Neurological signs: cerebellar involvement, nystagmus, extrapyramidal involvement, intellectual disability, peripheral neuropathy
Other: short stature, hyperlipidemia

MRI: cerebellar and supratentorial atrophy

3. )NPD-C
   - liver, spleen, lung
   - Neurological: clumsiness, gait problems→ ataxia, slow cognitive deterioration, vertical supranuclear opthalmoplegia, seizures, progressive dystonia, dysarthria and dysphagia, hearing loss

Diagnosis of NPD-A and NPD-B and NPD-C

NPD-A

• hepatosplenomegaly
• interstitial lung disease
• macular cherry red spot
• developmental delay

NPD-B

• Hepatosplenomegaly
• thrombocytopenia
• interstitial lung disease
• hyperlipidemia

NPD-C

• newborns: ascites, abnormal LFTs
• childhood: hepatosplenomegaly, vertical supranuclear gaze palsy, ataxia, dystonia, seizures
• gelastic cataplexy
• adults: dementia, depression bipolar, schizophrenia

Treatment:
-Miglustat (decreases lipid storage)

Question 19

Tay-Sachs disease

Answer 19

• AR
• HEXA mutation
• Lipid storage disease

1.) infantile form: startle reaction to sound, developmental regression, paralysis, dementia, blindness

2. ) Juvenile:
   - Psychiatric presentation
   - Proximal muscle weakness
   - Cerebellar: clumsiness, incoordination, ataxia, dysarthria, tremor, abnormal saccades

3.)Adult: progressive dystonia, spinocerebellar degeneration, motor neuron disease with muscle weakness and fasciculations, and/or psychosis

Other: Macular Cherry-Red spot

MRI: cerebellar atrophy
Labs: Elevated CPK, foamy leukocytes, deficient enzyme activity in leukocytes
Biopsy: liver/rectal accumulation of globosides and GM2 gangliosides
EMG: fasciculations
Dx: absent hexasaminidase A enzymatic activity in serum, genetic testing