Genetics and metabolics

Question 1

Most common chromosome abnormality in first trimester spontaneous miscarriage

Answer 1

• Trisomy

trisomy 16 = most common

Question 2

Trisomy 21 genetic counselling recurrent risk

Answer 2

Recurrence = 1% until age > 40 (then age-related risk is >1%)

95% = “free” T21 aka 47 XY (do not need to check parental genes)

Question 3

22q11 deletion syndrome

Answer 3

Cleft palate
AbN facies
Thymic hypoplasia
Calcium (hypoparathyroidism) 
Heart - conotruncal 
22q11

Question 4

Pierre Robin sequence

• features
• genetic contribution

Answer 4

• cleft palate
• micrognathia
• glossoptosis

50% are genetic #1 = Stickler syndrome (eye findings, cartilage findings) #2 = 22q11

Question 5

Supravalvular aortic stenosis

Answer 5

Williams syndrome

Question 6

William syndrome features

Answer 6

• supravalvular aortic stenosis, HTN
• idiopathic hypercalcemia
• Dev delay
• very friendly
• ADHD, anxiety
• face: broad forehead, long philtrum, full lips

Question 7

Patau (trisomy 13)

Answer 7

• midline cleft,
• cutis aplasia,
• polydactyly

Question 8

Fragile -X

genetics

Answer 8

X-linked

triple repeat disorder
= CGG triclucleotide

Question 9

Angelman syndrome

Answer 9

• Paternal uniparental disomy of chromosome 15

Question 10

Prader-Willi syndrome

Answer 10

• initial failure to thrive
• severe hypotonia
• cryptorchidism
• hyperphagia

Question 11

Prader-Willi genetics

Answer 11

• deletion of paternal copy OR
• uniparental disomy of choromosome 15

(Prader Pas de Father)

Question 12

Beckwith-Wiedemann

Answer 12

• exomphalos
• macroglossia
• giganitsm (hemihypertrophy)

Monitor AFP and U/s (Wilms and hepatoblastoma)

Question 13

Examples or IEM (small molecules)

1. amino acid disorders
2. organic acidemias
3. FAOD
4. CHO disorders

Answer 13

1. UCD, MSUD, PKU
2. propionic acidemia, MMA
3. LCAD, MCAD
4. galactosemia, GSD

Question 14

Examples or IEM: organelles

1. lysosomes
2. peroxisomes
3. mitochondria

Answer 14

1. Tay sachs, Krabbe, MPS, oligosaccharides, Gaucher, Niemann Pick
2. Zellweger, Adrenoleukodystrophy
3. MELAS

Question 15

IEM initial evaluation

Answer 15

Blood: gas, lytes, glucose, CBC, ammonia, lactate
Urine: ketones 
3 acute tests: 
1. plasma amino acids
2. plasma acylcarnitine
3. urine organic acids

Question 16

Acute metabolic disease, initial management

Answer 16

1. aggressive fluid and electrolytes
2. caloric supplementation
3. protein restriction
4. megavitamins
5. hemodialysis/hemofiltration/ PD

Question 17

Respiratory alkalosis with normal electrolytes and anion gap

Answer 17

Think Ammonium!

Question 18

Urea cycle defect

- diagnosis

Answer 18

urine organic acids and plasma amino acids highly suggestive

Dx confirmed by genetics, enzymology

Question 19

UCD features

Answer 19

Infantile: decreased feeding, lethargy, seizures, death, kussmaul breathing
Later: protein avoidance, FTT, recurrent illness, behavioural/psychiatric issues, acute encephalopathic events precipitated by minor illness

Question 20

Diagnosis of digeorge

Answer 20

FISH or chromosome microarray

Question 21

Beckwith-Wiedemann surveillance

Answer 21

-At risk Wilms and hepatoblastoma
u/s every 3 months until age 4 yrs (risk for hepatoblastoma drops after 4 yrs)
then renal ultrasound (and adrenals) every 3 months until 7 yrs
- AFP until 4yrs

Question 22

CHARGE

Answer 22

Coloboma, heart, choanal atresia, retardation of growth and development, GU anomalies

Question 23

DMD genetics

Answer 23

X-linked recessive trait

• Diagnose with PCR for dystrophin gene mutation
• If blood nondiagnostic then muscle biopsy

Question 24

Edwards (Trisomy 18) features

Answer 24

Rocker-bottom feet
cardiac manifestations
clinodactly and overlapping fingers: 
index over 3rd, , 4th over 5th digits
hypoplastic nails
92% mortality in first year

Question 25

Diagnosis of FAOD e.g. MCAD

Answer 25

- acylcarnitine profile (e.g. newborn screen)

Question 26

Confirmed FAS phenotype with or wihtout maternal alcohol exposure

Answer 26

``` Face: - abN facies consistent with FAS or - 2+ of: short palpebral fissures, abN philtrum, thin upper lip CNS: - HC <= 10 %ile at birth or any age or - ID or dev delay or ADHD Growth: - IUGR weight or height <= 10th %ile - postnatal wt or ht <= 10th %ile - postnatal wt for ht <= 10th %ile ```

Question 27

IEM with normal bicarb, pH and ammonia

Answer 27

Think aminoacidopathies e.g. galactosemia or hyperglycinemia

Question 28

Treatment of acute hyperammonemia

Answer 28

1. fluids, electrolytes, glucose (5-15%), lipids (1-2g/kg/d) with minimal amounts of protein (0.25g/kg/d) 2. dose then infusion of: sodium benzoate, sodium phenylacetate, arginine 3. Initiate peritoneal dialysis or hemodialysis Goals: 1. removal of ammonia from body in form other than urea 2. minimize endogenous protein breakdown and favour endogenous protein synthesis by adequate calories and essential amino acids

Question 29

Noonans genetics and features

Answer 29

Autosomal dominant (2/3 de novo) - Features: wide spaced eyes, low set ears, short stature, cryptorchidism, increased NT, renal anomalies, relative fetal macrosomia, - Cardiac: pulmonary stenosis (~50%), 20% hypertrophic cardiomopathy

Question 30

NF type 1 diagnosis

Answer 30

2 of the following 7: 1. CALMS (6+) 2. axillary and inguinal freckling 3. Family history (1st degree relative) 4. Eye hamartomas = lisch nodules (2+) 5. skeletal anomalies e.g. sphenodysphagia or pseudoarthoses 6. plexiform neurofibroma or 2+ neurofibroma 7. Optic tumor (gliomas)

Question 31

NF-1 genetics

Answer 31

``` Autosomal dominant (1/2 are sporadic) ```

Question 32

Trisomy 13 (Patau) - triad - survival

Answer 32

``` Triad: midline cleft, cutis aplasia, polydactyly Other: - ocular hypotelorism, - microcephaly and cerebral malformation - bulbous nose - clinodactyly - congenital heart disease ``` only 5% live >6 mo

Question 33

Prader Willi features

Answer 33

- neonatal hypotonia - slow infant growth - small hands and feet - ID - hypogonadism - hyperphagia leading to severe obesity

Question 34

Rett syndrome - gene - features

Answer 34

``` MeCP2 mutation - normal development until 12 months Regression of language and motor Deceleration of head growth Repetitive hand-wringing movements Autistic behaviours ```

Question 35

Sturge-Weber genetics and features

Answer 35

Sporadic Classic findings: leptomeningeal angiomas, facial capillary malformation, abnormal blood vessels of eye --> glaucoma Other: seizures, hemiparesis, stroke-like episodes, headaches, dev delays

Question 36

Turner syndrome - genetics - findings in newborns

Answer 36

- complete or partial monosomy of X - SGA, webbing neck, protruding ears, lymphedema, Cardiac: bicuspid, also coarct, renal: horseshoe kidney

Question 37

Tuberous sclerosis - Genetics - Diagnosis

Answer 37

AD | 2 major criteria OR 1 major plus 2 minor

Question 38

Tuberous sclerosis surveillance

Answer 38

Brain MRI every 1-3 yrs (to monitor for new SEGA) Renal imaging every 1-3 yr (renal cysts etc. ) Neurodevelopmental testing at grade 1

Question 39

VACTERL (Dx = 3 of component features)

Answer 39

``` Vertebral Anorectal Cardiac Tracheoesophageal Renal Limb ```