Genetics and Metabolics - 2019 Updated! Flashcards
What is uniparental disomy? Name a syndrome that it is inherited in this manner?
- when a person gets both chromosomes (or parts of chromosomes) in the pair from the same parents, instead of getting one form each parent
- Prader Willi and Angelman (chromosome 15q11)
PWS: think Trump - small balls, small hands, intellectual disability and obesity from hyperphagia - mom’s part is silenced and the part you’re meant to get from your dad just isn’t there (mom silences (Melania), dad missing (Donald))
You diagnose a child with CF based on an abnormal sweat chloride. The reason for doing DNA testing is:
a. confirm diagnosis
b. rule out whether the parents are carriers
c. to diagnose her cousin who is failing to thrive with CF
d. to give the parents some idea about prognosis
e. so that antenatal testing can be done on subsequent pregnancies
d. to give the parents some idea about prognosis
The sister of a patient with cystic fibrosis is 6 weeks pregnant and wants to know if her unborn child
has cystic fibrosis. What do you suggest:
a) wait until 16 weeks gestation and then perform amniocentesis
b) perform chorionic villus sampling and genetic testing now
c) refer the parents for genetic testing
d) perform a sweat test on the mother
e) you cannot accurately diagnose cystic fibrosis until after the child is born
c) refer the parents for genetic testing
- 50% chance that the sib is a carrier (assuming she would know if she actually had CF, the chance that she’s a carrier is actually 2/3)
- amnio or CVS not recommended unless high risk (mutations in both parents)
Parents of a child with unilateral cleft palate come in for advice regarding next pregnancy. You advise that:
a. There is no recurrence risk
b. 4% recurrence risk
c. 25% of offspring will be affected
b. 4% recurrence risk
Obese parents adopt a 3 month child. What is true regarding the child’s risk of obesity:
a. if biologic parents are thin then child is unlikely to be obese
b. even if biologic parents are thin, the child is likely to be obese
c. obesity is more common in upper socioeconomic groups
d. if child is obese at 1 year then there is a 90% chance of obesity as an adult
a. if biologic parents are thin then child is unlikely to be obese
A child has multiple ash leaf spots, and seizures. The mother is pregnant and wants to know whether or not her unborn child will have the same problems. What do you tell her about the risks to the fetus?
a) 50% if female
b) 50% if male
c) 50% regardless of gender
d) 25% regardless of gender
e) the recurrence risk is minimal
e) the recurrence risk is minimal
TS: AD inheritance but 2/3 sporadic
- if parents are unaffected the risk of another child having TS is low but still higher than the general population because of the chance of germ line mosaicism
Inheritance pattern of ectopic thyroid:
a) autosomal recessive
b) autosomal dominant
c) sporadic
d) X-linked recessive
e) X-linked dominant
c) sporadic
thyroid agencies including ectopic thyroid is usually sporadic, 2% will have family history
You are seeing a pregnant woman during her first. Her father has hemophilia. Regarding the risk of her transmitting the disorder to her own children you tell her:
A. None will have it
b. 50% of her sons will have it and all of her daughters will be carriers
c. 50% of her sons will have it and 50% of her daughters will be carriers
c. 50% of her sons will have it and 50% of her daughters will be carriers
X-linked disorder
Which of the following has AD inheritance?
a. Tuberous Sclerosis
b. Fragile X
c. CF
d. Hereditary Spherocytosis
ANSWER: a. Tuberous Sclerosis, though ⅔ sporadic and
d. Hereditary Spherocytosis - 75% autosomal dominant, 25% autosomal recessive
b. Fragile X - X-linked dominant, FMR1 mutation
c. CF - autosomal recessive
Which has autosomal dominant inheritance?
a. Congenital adrenal hyperplasia
b. PKU
c. Beta-thalassemia
d. Hereditary spherocytosis
ANSWER: d. Hereditary spherocytosis - 75% autosomal dominant, 25% autosomal recessive
a. Congenital adrenal hyperplasia - autosomal recessive
b. PKU - autosomal recessive
c. Beta-thalassemia - usually autosomal recessive; rarely can be AD
Teenager presents with large armspan, suspect Marfans Syndrome. What is the mode of inheritance?
a. Autosomal Dominant
b. Autosomal Recessive
c. X linked
d. Sporadic
a. Autosomal Dominant
FBN1 mutation
25% de novo mutations
Newborn presents with the following lab values pH 7.1; HCO3 decreased, normal sodium/potassium, Elevated lactate, ammonia and neutropenia. Diagnosis:
a) galactosemia
b) MCAD
c) methamelonic acidemia
d) urea cycle defect
c) methylmalonic acidemia
- organic acidemia (metabolic acidosis, high ammonia, neutropenia caused from BM suppression that happens with metabolic acidosis)
- dx: urine organic acids
- issue: unable to metabolize methylmalonic acid which is made in the breakdown of amino acids and some fatty acids
- tx: low protein diet
What broad category of diseases do you think of in an infant with vomiting, lethargy, poor feeding and seizures but who is afebrile and has a normal WBC?
inborn error of metabolism
10 day old baby with failure to thrive, jaundice, hepatomegaly, blood culture positive for E.Coli.
a. What underlying disorder may the child have?
b. What test can you do to confirm this diagnosis ?
a. What underlying disorder may the child have? Galactosemia (see above).
b. What test can you do to confirm this diagnosis ?
● Erythrocyte galactose-1-phosphate uridyltransferase (GALT) activity.
● DNA testing for mutations in GALT gene
- presents 4-7 days of life (after lactose has been introduced in diet - i.e. breast or bottle feeding established)
- also get ketonuria
Child presents with an ammonium level in the 400-range. What 3 things would you do in your management?
- IV rehydration, including dextrose (stop protein catabolism)
- remove ammonia (dialysis or meds - sodium phenyacetate and sodium benzoate, arginine)
- confirm with repeat specimen
- additional testing: serum amino acids, urine organic acids, liver function and transaminases (can have liver failure, lights)
What are 3 symptoms of hyperammonemia?
lethargy, vomiting, cerebral edema, coma - encephalopathy
You are working in an emergency department, and a 5-month-old baby presents with a history of poor intake and occasional vomiting over the past 24 hours. You find that his glucose is 2.8. The remainder of his bloodwork is unremarkable. He has no ketones present on urinalysis. List 2 diagnoses on your differential.
- hyperinsulinemia
- fatty acid oxidation defect (fatty acids have a ketone on the end - with FAO defects, you can’t cut that ketone off so you have high fatty acids, but no ketones)
Hypoketotic hypoglycemia - if your sugar is low, your body should make ketones as an alternate fuel
no ketones = high insulin, fatty acid oxidation defect
3 week old with previous e coli sepsis and persistent jaundice. What is the likely problem?
a. Increased osmotic fragility
b. RBC galactose phosphate uradyl transferase deficiency
c. RBC glu – 1 – phosphate dehydrogenase deficiency
b. RBC galactose phosphate uradyl transferase deficiency
Galactosemia
3-day-old infant with lethargy, vomiting, hypotonia and progressively worsening level of consciousness and coma. There is subtle evidence of intracranial hypertension. He has a respiratory alkalosis. Most likely:
a. encephalitis
b. urea cycle defect
c. maple syrup urine disease
d. phenylketonuria
e. Leigh syndrome
b. urea cycle defect
amino acids–> ammonia and organic acids
ammonia (BAD)–> urea cycle –> urea (pee it out)
Urea Cycle Defects: results in hyperammonimia -> normal at birth, then poor feeding, lethargy -> coma. See hepatomegaly and increased ICP.
Resp alkalosis -> hyperventilation secondary to hyperammonemia -> cerebral edema
MSUD: defect in enzyme that breaks down some amino acids (so you have no ammonia being made)
Leigh disease: subacute necrotizing encephalomyelopathy
You are called because an infant’s PKU screen is positive. Your next step is:
a. order a quantitative urine Phenylalanine level
b. order a quantitative blood Phenylalanine level
c. repeat the screen
d. order a urinary phenylketone level
b. order a quantitative blood Phenylalanine level
Diagnosis should be confirmed with quantitative measurement of plasma phenylalanine concentration. Blood phenylalanine in affected infants may rise to diagnositc levels as early as 4 hours after delivery. Recommended to be collected in first 24-48 hrs after feeding.
Start diet treatment immediately in patients with blood phenylalanine levels >10 mg/dL
Most physicians will advocate for special diet in mild cases
The child of a father with phenylketonuria will have which of the following:
a) no problems
b) developmental delay
c) multiple congenital anomalies
d) microcephaly
e) IUGR
a) no problems
inheritance AR - would expect child to be a carrier, but would only be affected if mother also a carrier
signs PKU: MR, growth retardation, fair skin, eczema
Maternal PKU not treated in pregnancy causes microcephaly, IUGR, MR, congenital heart defects
6 month old with hx of dev delay is brought in to ER and needs resusc. Is now stable. What would you need to help make diagnosis:
a. CT scan
b. Lactate, carnitine, ammonia
c. Serum organic acids
d. Urine amino acids
b. Lactate, carnitine, ammonia
Shock - think organic acidemia
Child with poor feeding, vomiting, lethargy, seizures, afebrile. Ammonia and gas normal. What do you suspect?
amino acidopathy or galactosemia
In a patient with MCAD deficiency what would be the most likely laboratory finding:
a) respiratory alkalosis
b) nonketotic hypoglycemia
c) increased urine/plasma ketone level
d) increased plasma carnitine level
e) normal transaminases
b) nonketotic hypoglycemia
Hallmark finding of MCAD ( a fatty acid oxidation defect) is hypoketotic hypoglycemia.
Normally you make ketones from your metabolism of FA during times of fasting. When you can’t oxidize FA you don’t make ketones.
Abetalipoproteinemia causes all EXCEPT:
a) ataxia
b) hyperlipidemia
c) acanthocytosis
d) retinitis pigmentosa
e) diarrhea and FTT
b) hyperlipidemia
- hereditary inability to synthesize lipoproteins -have very low cholesterol and triglycerides (all the fats get stuck in the gut wall)
- lack of fat soluble vitamins (no vit E - spinocerebellar degeneration, no vit A - night blindness)
14 mos male, FTT, vomiting, met acidosis, pH 7.31, bicarb 14, K 3.5, Na140, Cl 118, urine pH 6.3 a distal RTA b Bartter c organic acidopathy d nutrit. Deprivation
a. distal RTA - hyperchloremic non anion gap metabolic acidosis
- distal RTA - high urine pH
Bartter - alkalosis
organic acidopathy - anion gap
6 month old baby with pallor, hepatosplenomegaly, irritable. Xray shown with very white bones. Diagnosis:
a. osteopetrosis
b. vitamin D deficient rickets
c. osteosarcoma
a. osteopetrosis
Ca, PO4, ALP all normal
Infant (a few weeks old?) with generalized tonic clonic seizure. He looks well and is well grown. Glucose is 1.7. The most important thing to measure is?
a. Urine ketones
b. Lactate/Pyruvate ratio
c. Serum cortisol
a. Urine ketones
Hypoglycaemia, low ketones, low FFA, high insulin in a macrosomic baby - what is the diagnosis?
hyperinsulinemic hypoglycemia of infancy
Hypoglycaemic baby with reducing substances in urine - what is the diagnosis?
Galactosemia
Hypoglycemia, micropenic, cleft palate, cholestatic jaundice - what is the diagnosis?
Hypopituitarism (midline defects)
Hypoglycemia + hepatomegaly. What group of disorders to consider?
Glycogen storage disorders (like G6P deficiency)
Glucose of 1.2, cardiomegaly on chest x-ray. What is the most likely etiology of this presentation?
a. cardiac lesion
b. sepsis
c. inborn error of metabolism
c. inborn error of metabolism
Pompe (type II glycogen storage disease)
- cardiomegaly and macroglossia
- glycogen accumulates in tissues which makes them large and not work well
3 week baby with lethargy, poor feeding, and hepatomegaly. Has a normal lactate, ammonia, pH,CO2.
What is the most likely diagnosis?
a. Maple syrup urine disease
b. Propionic academia
c. Galactosemia
d. Urea cycle defect
c. Galactosemia
Aminoacidopathies (MSUD, PKU, Homocystinuria) and Galactosemia both have normal AG, normal ammonia.
MSUD - present at 3-5 days with poor feeding, opisthotonos, coma
Urea Cycle Defect - high ammonia, NAGMA, respiratory alkalosis
Propionic acidemia = Organic acidemia - High ammonia, WAGMA
What is the most likely presentation of an inborn error of metabolism?
a. encephalopathy preceding focal neuro deficit
b. generalized hyper-reflexia
c. abnormal pupillary reaction
a. encephalopathy preceding focal neuro deficit
(also worded as decreased LOC preceding focal features)
MELAS (mitochrondrial myopathy, encephalopathy, lactic acidosis, stroke-like episode) - mimics stroke with focal neuro defects
A 3 month old is suspected of having an inborn error of metabolism, and has neurological and cardiac
involvement. Which of the following can be given before a definitive diagnosis is made to prevent
further sequelae:
a. Thiamine
b. Carnitine
b. Carnitine - good for organic acidemias, FAO defects, carnitine deficiency; lethargy and cardiomyopathy common presenting features of FAO defects
B12: oragnic acidemia
B6 (pyridoxine): seizures unresponsive to antiepileptics
3 day old with lethargy, decreased level of consciousness and vomiting. On exam he has hyperpnea and respiratory alkalosis. His fontanelle is full and he has signs of mild increase in intracranial pressure. What is his diagnosis?
a. Maple Syrup urine disease
b. Urea cycle defect
c. Encephalitis
b. Urea cycle defect
Liver dysfunction long term complication of:
a. MCAD
b. OTC
c. PKU
d. Maple syrup urine disease
ANSWER: a. MCAD - lipid metabolism defect
b. OTC - urea cycle defect
c. PKU - amino acidemia
d. Maple syrup urine disease - organic acidemia
2½-year-old child is referred with language delay and inferior ectopia lentis. You should
a) molecular studies for Marfan syndrome
b) echocardiogram to rule out aortic root abnormalities
c) fibroblasts/skin biopsy for enzyme
d) quantitative serum amino acids
e) platelet count and coagulation studies for hypercoagulability
d) quantitative serum amino acids
Homocystinuria: IQ down, lens dislocated down
Dx: elevated methionine or homocystine in blood or urine
Tx: high dose vitamin B6
Most likely to be associated with hearing loss:
a) prematurity
b) congenital CMV
c) APGAR of 2 at 1 minute
d) sibling with language delay
e) furosemide given to mother during pregnancy
b) congenital CMV
o TORCH (CMV most common acquired form of congenital hearing loss)
Newborn who has webbed neck, lymphedema at hands and feet, hypertrophic cardiomyopathy (picture given- don’t think they told you if it was a girl or a boy)
a) XO
b) Noonans
c) Williams
b) Noonans
Turners is similar but has left sided heart defects (coarctation)
- note primary hypogonadism - amenorrhea and infertility - not a feature of Noonan’s
Child with facial nevus in V1 distribution. Came to the hospital with focal seizure. What is the suspected diagnosis? What is the CT head finding expected? Name 2 other complications.
- Sturge-Weber
- CT head shows calcifications, MRI could show leptomeningeal angioma
- complications: glaucoma, seizures, hemiparesis, intellectual disability, stroke-like episodes
Picture of rocker bottom feet – what condition do you need to think about? What are 3 other features?
Edward syndrome (trisomy 18)
- prominent occiput
- clenched hands with overlapping fingers
- prominent heels
- small mouth and jaw, short neck
Mother brings her son to see you for assessment of behaviour difficulties. He has been in generally good health. He is large (97, 95, 95%iles) and has prominent ears. He has a broad forehead and hyperextensible joints. Which of the following does he have?
a) fragile X
b) Klinefelters
c) Sotos
a) fragile X
fragile X : - remember large ears and long narrow face and hyperactivity
Kleinfelter - tall + behaviour problems + small testes + hypotonia + LD + metabolic syndrome
Sotos - broad forehead dolichocephalic, spare frontotemporal hair, downslanting palpebral fissure, molar flushing, long chin, LD,, overgrowth
5 mo with white forelock, 1 iris blue 1 brown. What next investigation would you do? What condition is this?
a. Renal ultrasound
b. Hearing test
c. Echo cardiac
d. Cranial ultrasound
b. Hearing test
Waardenburg syndrome - sensorineural hearing loss common, non progressive
Also a/w Hirschsprung
An 8 year old otherwise well child has a hemi-vertebrae noted on CXR. What investigation will you do in the course of your work-up: a. MRI of the head b. MRI of the spine c. Abd U/S d. Echo
c. Abd U/S - VACTERL
or
D. EcHO
VACTERL : vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities.
Previous group :
From genetics review - if it was a newborn would do an echo, but given healthy 8 year old, she probably doesn’t have a serious cardiac lesion; don’t know what’s happening with kidneys though
What are the components of VACTERL association?
vertebral defects anal atresia cardiac defects TEF renal anomalies limb anomalies (missing thumbs, underdeveloped forearms)
Hemivertebra girl. What next imaging
AUS and echo
Child has developmental delay. On exam you note that he is microcephalic, he has small palpebral
fissures, a thin upper lip and a poorly defined philtrum. What is his diagnosis
a. Cornelia De Lange
b. Smith Lemli Opitz
c. Fetal Alcohol Syndrome
c. Fetal Alcohol Syndrome
A child who is described as having a learning disability, has big ears. Mom has an LD as well. What to tell mom to expect:
a. Problems with tics
b. Problems with athetosis
c. Problems with hyperactivity
d. Problems with tremor
e. Problems with nystagmus
c. Problems with hyperactivity
80% of those with Fragile X have ADHD
3 year old girl was normal developmentally for a while but has shown regression in the past year. Now she has microcephaly, and abnormal hand movements
a. Retts
b. Fragile X
c. Autism
d. TORCH infection
e. childhood disintegrative disorder
a. Retts
Child with supravalvular aortic stenosis, prominent lips, developmental delay, and hypercalcemia. This is indicative of: a. DiGeorge b. Williams c. Noonans d. Downs e. Fetal alcohol syndrome
b. Williams
DiGeorge - HYPOcalcemia
Williams - Classic: elfin facines (broad forehead, short nose, long philtre, full lips, wide mouth), Hypercalcemia, GU abn, short
Noonan - AD (male turners)
- webbed neck, low set ears, downstanting palpebral fissures
- cardiac defects * PULM stenosis*, cryptorchidism, normal IQ, short stature, bleeding diatheses
What are the components of DiGeorge syndrome?
- cardiac (TOF)
- abnormal facies (hypertelorism, down slanting palpebral fissures, short philtrum)
- thymic hypoplasia/T cell abnormality
- cleft palate
- hypocalcemia from hypoparathyroidism
- 22q11 deletion
Which feature is typical for achondroplasia?
a. proximal limb shortening
b. distal limb shortening
c. short mid-portion of the bone
d. non-specific shortening
a. proximal limb shortening
Rizomelia
In a patient with Romano-Ward syndrome, what would suggest the diagnosis:
a. presence of cafe-au-lait spots
b. congenital defects
c. sensorineural hearing loss
d. family members have it
d. family members have it
- cardiac syndrome, long QT, family history is key - most cases inherited from an affected parents, few cases are de novo mutations; inheritance is AD with incomplete penetrance
* Long QT plus congenital deafness (SNHL) = Jervell and Lange-Nielson syndromes (autosomal recessive)
Fetal alcohol syndrome
a. 4 facial dysmorphisms
b. 2 clinical features of the syndrome
a. smooth philtrum, thin upper lip, short palpebral fissures, micrognathia, epicanthal folds
b. microcephaly, intellectual disability, small stature, cardiac defects (VSD)
