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)
Photo shown of infant with short palpebral fissures, smooth philtrum, short nose and thin upper lip. He presents with irritability. This infant’s condition is due to maternal exposure to: a) cocaine b) heroin c) cigarettes d ) alcohol e) Dilantin
d ) alcohol
Which is a common characteristic in fetal hydantoin syndrome:
a) microcephaly
b) hypoplastic nails
c) intrauterine growth restriction
d) seizures
e) cataracts
b) hypoplastic nails
fetal hydantoin - fetus exposed to hydantoin (phenytoin)
- IUGR
- Facies: flat broad nose, hypertelorism, strabismus, ptosis, large most, malformed ears, webbed neck
- microcephaly
- cleft lip/palate
- stiff tapered fingers, underdeveloped nails
- mild ID
- heart stuff
- increased risk of neuroblastoma
List 4 screening tests you would routinely do for a child with Down’s Syndrome
- ophtho exam for strabismus, cataracts, nystagmus
- hearing test - q6 months until bilateral hearing test possible
- screen for hypothyroidism annually
- screen for celiac (symptoms annually, BW PRN)
- hemoglobin screen annually
Child with trisomy 21. 3 discrete round completely hairless areas on the scalp. No other findings.
a. What is the most likely diagnosis?
b. What will you tell mom is the natural history of this problem
a. alopecia areata
b. ● Spontaneous resolution in 6-12 month
● Recurrence: common
Child with Down syndrome. List three associated hematological disorders
● Neonatal polycythemia ● Neonatal leukemoid reaction ● Transient myeloproliferative disorder ● Anemia (iron deficiency due to poor intake) ● Leukemia (1%)
Family physician calls you about term neonate who weighs 2300 g. Neonate has lymphoedema, low set hair line and wide chest. What test would you send for diagnosis?
Probably Turner as opposed to Noonan because is term and very small. Noonan not usually SGA.
- Karyotype for Turner, RASopathy panel for Noonan
List two investigations that should be done in a neonate with suspected Turner syndrome and their expected findings
AUS - horseshoe kidneys
4 limp BP and echo - aortic valvular disease (bicuspid aortic valve), or coarctation
Scenario of a boy with Fragile X. Mom is a carrier. There is a sister in the family. Mom asks you if you could test the sister to see if she is a carrier. She is currently in grade 5 and doing well. Do you test the daughter?
No! If she is healthy, then the recommendation is to wait until she is an adult and can make her own decisions about what she wants to know. Counsel that she may want investigations before pregnancy if she wants to know about potential risk for her children.
5 Clinical features of turners and 2 cardiac complications
- hearing loss, strabismus, shield chest, widely spaced nipples, increased carrying angle of arms, short stature, ovarian failure, hypothyroidism
- bicuspid aortic valve, coarctation of aorta
List 3 features of Pierre-Robin sequence.
micrognathia retrognathia high arched palate cleft palate glossoptosis (tongue drops back and obstructs because it is relatively large for the oral cavity) Upper airway obstruction
Child with suspected Duchenne muscular dystrophy.
a. What is diagnostic on biopsy (be specific)?
b. What 2 things do you want to know to help with genetic counseling?
a. lack of dystrophin in myofibers, endomysial connective tissue proliferation
b. X-linked recessive condition (2/3 inherited)
- what is the specific genetic defect in the child?
- is mom a carrier of this defect - if yes, 50% chance or having another boy with DMD, if no, was a spontaneous mutation and there is no risk
- is the family planning to have more children?
Child with hemihypertrophy. What condition would you suspect that would require serial follow-up?
Beckwith-Wiedemann
● Cancer risk high until 8 y.o. (~7.5%)
o Need regular surveillance with abdo US + alpha fetoprotein measured every 3 mon. until 8 y.o.
o Then Renal US every 1-2 year as medullary sponge kidney and nephrocalcinosis can happen later
Child with Wilm’s tumor. Which is associated?
a. Down syndrome
b. Prader-Willi syndrome
c. Beckwith-Weideman
d. Angelman’s syndrome
ANSWER: c. Beckwith-Weideman – Wilm’s Tumour, Hepatoblastoma, Neuroblastoma, Adrenocortical carcinoma
a. Down syndrome – acute myeloid leukemias
Cancers are associated with several disease states. Name one cancer associated with each of the following.
- Beckwith Wiedemann
- Down syndrome
- Aniridia
- Beckwith Wiedemann- Wilm’s, Hepatoblastoma, higher risk of neuroblastoma
- Down syndrome – Leukemia (Specifically acute myeloid leukemia)
- Aniridia – Wilm’s Tumour
3d old term infant with absence of abd muscles and undescended testes bilaterally. TFI 90/kg/d. Na 120, K 5, Glu 2.6, normal urea, creatinine 119. U/O 10 cc in last 24 hrs. Kid NPO. Wt 4kg. What is causing this kid’s problems?
Prune belly syndrome - obstructive uropathy
Alpha-1 antitrypsin. Most likely presentation in children?
a. jaundice
b. emphysema
c. bronchiectasis
d. pneumonia
a. jaundice
Boy with MELAS, what do you tell him is his risk of passing it on to his kids?
Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes
- no chance of passing it on to his kids because mitochondrial disorders are all inherited maternally
Child with distress, cannot pass NG through nares. Choanal atresia. List 3 other findings on physical
exam you’d look for?
CHARGE (CHD7 gene mutation)
Coloboma
Heart defects (TOF, AV canal)
Atresia choanae
Retardation of growth (short stature) and motor development
GU abnormalities (micropenis, cryptorchidism, hypoplastic labis in females)
Ear deformities/hearing loss
Mother with DiGeorge syndrome has a child with cleft-palate. What 3 things should you do for investigation/management in the child (3)?
- check calcium (hypocalcemia) and PTH (hypopara)
- echo (TOF, truncus arteriosus)
- renal U/S (renal hypoplasia)
- immunodeficiency W/U: CBC and diff, T and B cell numbers, immunoglobulins
- CXR for absence of thyme silhouette
List 4 features of Rett syndrome.
- loss of previously acquired developmental milestones
- repetitive hand wringing, and loss of purposeful hand movements
- acquired microcephaly
- seizures
- ataxia
- poor weight gain
3 major skeletal diagnostic criteria for Marfans?
- armspan greater than height
- lower segment longer than upper segment
- hindfoot deformity
- pectus carinatum
- positive thumb sign and wrist sign
- scoliosis or thoracolumbar kyphosis
- reduced elbow extension
- protrusio acetabulae
Give a condition that corresponds to coloboma
CHARGE syndrome
Wolf-Hirschorn syndrome
13q deletion syndrome
Give a condition that corresponds to dislocated lens
Marfan’s (superior dislocation)
Homocysteinuria (inferior dislocation)
Give a condition that corresponds to aniridia
WAGR (Wilms tumour, aniridia, GU abnormalities, MR) Miller syndrome (aniridia with Wilm's tumour)
Give a condition that corresponds to glaucoma
Sturge Weber
Trisomy 21
NF1
Mucopolysaccharidoses
List 4 non-infectious risk factors of hearing loss in the newborn period.
- family history of hearing loss
- outer ear malformation/craniofacial malformations
- apgars 0-4 at 1 minute
- NICU stay >2 days
- ototoxic drug use
- hyperbili needing exchange transfusion
- mechanical ventilation
Which of the following is characteristic of Rett syndrome:
a. ataxia
b. seizures
c. head bobbing
d . hand wringing
e. admit and place on a Phenylalanine free diet
d . hand wringing
A 25 year old mother of a child with Down syndrome (47XY (+21)) comes for advice regarding subsequent pregnancies. :
a. no advice can be offered until karyotype of parents is known
b. no antenatal workup needed as recurrence risk is <5%
c. if level 2 ultrasound is abnormal at 16 weeks, then do amniocentesis
d. antenatal karyotyping should be done with all subsequent pregnancies
e. Chromosomes should be offered for any future pregnancy
e. Chromosomes should be offered for any future pregnancy
- the recurrence risk is small but it’s still reasonable to offer prenatal testing if the family wants
(47XY (+21)) - this is your standard T21 karyotype (would be different if there was a translocation in which case the parents would need to be tested and risk of recurrence is much higher)
A 20-year-old mother and 25-year-old husband have just had a child with clinical features of Down syndrome. What is the most likely karyotype:
a) trisomy 21
b) mosaicism
c) translocation 14/21
d) translocation 21/22
a) trisomy 21
95% sporadic non-familial 47+21
3-4% Unbalanced translocation 14/21
1-2% mosaic
Which of the following is done routinely in a 1-week-old infant with trisomy 21:
a) lateral c-spine films
b) abdominal ultrasound
c) ophthalmology consult
d) auditory brainstem response
e) do nothing
d) Auditory brainstem response
AAP Problems in T21 at birth:
- ECHO
- Refer for feeding issues
- Monitor for cataracts (if detected -> optho)
- Duodenal atresia or anorectal atresia/stenosis by Hx+PE
- A/B/D
- Constipation
- GERD
- Stridor/wheeze → pulm
- Heme: CBC
- Congenital Hypothyroidism
In the follow-up of a child with Down syndrome, which would be appropriate:
a) CBC and smear
b) lipid studies
c) thyroid function
d) hepatitis B serology
e) antigliadin antibody
c) thyroid function - TSH on newborn screen, then at 6 & 12 months, then annually
a) CBC and smear - technically do not need a smear, just a CBC between birth and one month, then annually
e) antigliadin Ab- test for celiac - ask about symptoms and do TTG IGA and quantitative IgA of symptomatic
You diagnose a boy as having fragile X by DNA testing. His sister is performing poorly at school, and parents are concerned that she has fragile X. You:
a. order DNA testing on sister to rule out fragile X
b. order cytogenetics on sister to see if she is a carrier
c. order cytogenetics on mother to she if she is a carrier
d. do nothing - females do not get fragile X
a. order DNA testing on sister to rule out fragile X
DNA testing is the same as molecular testing; in fragile X you specifically need DNA PCR to make the diagnosis
cytogenetics is microarray, FISH and karyotype
In a child with Fragile X, all would be present EXCEPT:
a) motor delay
b) speech delay
c) microcephaly
d) large ears
e) autistic-like features
c) microcephaly
They have large heads
Which condition is associated with macroglossia and an umbilical hernia:
a) congenital hyperthyroidism
b) infant of a diabetic mother
c) Beckwith-Wiedemann syndrome
d) Down syndrome
c) Beckwith-Wiedemann syndrome
A 1-month-old child has macroglossia, hemihypertrophy, and an umbilical hernia, consistent with Beckwith-Wiedemann syndrome. You recommend the following:
a) CT head
b) regular abdominal ultrasounds
c) intermittent checks for hypoglycemia
d) measurement of leg-length discrepancy
e) DNA testing for Beckwith-Wiedemann syndrome
b) regular abdominal ultrasounds
Re DNA testing - can make clinical diagnosis if 3 major criteria are present
Monitoring in BWS
- Hypoglycemia in first few days of life
- Screen for dev issues
- Screen for embryonal tumors: AUS q3mos until 4yrs, then renal and adrenal q3mos until 7
- AFP q2-3 mos for first 4 years
+/- Periodic CXR and uniary homovanillic acid and vanilmandelic acid assays to screen for neuroblastoma
Characteristics of Schwachman-Diamond syndrome
a) decreased pancreatic enzyme excretion
b) normal neutrophil count
c) hypocellular bone marrow
d) increased risk of diabetes mellitus
a) decreased pancreatic enzyme excretion
- malabsorption, FTT
- also have neutropenia/myelodysplastic syndrome, bone marrow failure - make cells but cannot push them out, so marrow is not hypocellular
- bone abnormalities (thoracic dystrophy)
Which of the following findings would help to rule out Klinefelter syndrome:
a) normal upper/lower body segment ratio
b) muscular habitus
c) testosterone level 5.0
d) testicular volume of 15 cc
e) behavioural/learning difficulties
d) testicular volume of 15 cc - have small testes (prepubertal even - 4ml)
- all the other options do also go against Klinefelters, but not strongly enough to rule it out
Kleinfelter - 47XXXY (Nelsons)
Behavioural / Psych issues
Tall, Slim - legs longer disproportionate to arms
Body habitus can vary
Small testes - but may only be apparent after puberty
Smaller than average testes
Cryptorchidism more common
Lower BMD
Before 10yrs - normal FSH and LH, response to gonadotropin SH and hCG normal
Mid puberty - gonadotropins elevated and testosterone levels slightly low
Elevated estradiol (high estradiol:testoserone)
Gynecomastia
Sparse facial hair
Picture of child with Down Syndrome. Child noted to be hypotonic. Term, normal Weight. Questions is what test most expediously confirms diagnosis.
a. Chromosome analysis
b. TSH, T4
c. Muscle biopsy
a. Chromosome analysis
FISH or rapid aneuploidy testing would be quickest way get diagnosis (TAT 24-48h); but still need to do a karyotype after to see if there is a translocation
1 week old infant with T21. What should be done prior to discharge home?
a. ABR
b. Ophthalmology consult
c. Abdo U/S
d. Echocardiogram
d. Echocardiogram
should also have ABRs
14 y.o. with T21. What test should be done annually?
a. X-ray of cervical spine
b. TSH
c. Audiology
d. Ophthalmologic exam
b. TSH
c. Audiology - obtain annual ear specific audio evaluation
D. Optho q 3 years
vomiting infant with T21, next step? what are you worried about?
AXR - concern is for duodenal atresia; also consider Hirschsprung, bad GERD
Beckwith-Wiedeman syndrome U/S. A question about how frequently ultrasound should be done.
- AUS q3 months until age 8
- then annually from age 8-mid adolescence for kidney abnormalities, especiallymedullary sponge kidney
Child with Wilm’s tumor. Which is associated?
a. Down syndrome
b. Prader-Willi syndrome
c. Beckwith-Weideman
d. Angelman’s syndrome
c. Beckwith-Weideman
Child with large port wine stain in a distribution of the 1st trigeminal nerve. What do you work him up for? a. optic glioma b. cerebral arteriovenous malformation c. glaucoma d. liver disease
c. glaucoma
Concern is for Sturge Weber
Picture of a baby sucking on a pacifier and looking relatively content. Severe thrombocytopenia. Has a large lesion overlying his left forehead and eyelid (not a port-wine stain). What is the most likely finding on labs?
a. normal INR and PTT
b. elevated fibrinogen
c. schistocytes and RBC fragments on smear
d. neutropenia and anemia
c. schistocytes and RBC fragments on smear
Kasabach-Merritt syndrome (hemangioma with thrombocytopenia)
- fibrinogen is decreased
- can have anemia (MAHA), but not neutropenia
A 3 month old is suspected of having an inborn error of metabolism, and has neurological and cardiac involvement. What can be given before a definitive diagnosis is made to prevent further sequelae:
Carnitine
and glucose
Beckwith-Wiedeman syndrome U/S. A question about how frequently ultrasound should be done.
BW has an increased risk of hepatoblastoma and Wilms tumor
AFP q2-3 months til 4 years old
abdo U/S: q3months until 8 years
Confirmation of DMD
molecular studies
biopsy
EMG
molecular studies
we use molecular genetics for diagnosis; biopsy only necessary if genetics equivocal
4 m.o. male with cardiomegaly, sepsis-like picture and hypoglycemia
1) inborn error of metabolism
2) Sepsis
3) CHD
1) IEM
- Makes you think of glycogen storage disorder like POMPE
Metabolic condition associated with chronic liver disease?
a. MCAD - hypoketotic hypoglycemia in the setting of prolonged fasting/oxidative stress
b. OTC (urea cycle def) = hyperammonemia
c. MSUD - HA, confusion, hallucinations, lethargy, vomiting
d. PKU - brain injury, microcephaly GDD, eczema
Answer: b. OTC (urea cycle def) = hyperammonemia and can rarely have acute liver failure as a complication of severe decompensation.
a. MCAD- hypoketotic hypoglycemia in the setting of prolonged fasting/oxidative stress
c. MSUD - HA, confusion, hallucinations, lethargy, vomiting
d. PKU - brain injury, microcephaly GDD, eczema
Infantile cystinosis. What do you get?
a. cataracts b. end stage renal failure c. nephrocalcinosis
Cystinosis - inherited proximal (type 2) RTA presents as Fanconi syndrome
Infantile - most severe (nephropathic cystinosis) - presents with severe tubular dysfunction and growth failure, if not treated ESRD by first decade
Child with bubbling oral secretions, difficulties passing an NG tube. Also noted to have a hemivertebrae. What do do?
a. echocardiography
b. spine MRI
c. MRI head
a. echocardiography
VACTERL
vertebral anomalies, imperforate anus, CHD, TE fistula, renal anomalies, limb anomalies
Female infant with lymphedema and high arched palate. Also hypertrophic cardiomyopathy. What is your diagnosis:
Turners
Noonan
Russell-Silver Syndrome
Noonan
Similar to Turner but karyotype is normal. Most common CHD is pulmonary stenosis but an also have ASD, HOCM
Turner - coarctation and bicuspid aortic valve
Infant with mild hyperammonemia and metabolic acidosis. Vomiting after feeds
a) methylmalonic acidemia
b) MCAD
c) PKU
a) methylmalonic acidemia
WAGMA and hyper ammonia make you think of organic acidopathies (propionic, methylmalonic, glutamic)
Child with triangular facies and pulmonic stenosis. Also jaundice. Which would be an ophtho finding.
a) glaucoma
b) posterior embroyotoxin
c) cataracts
d) aniridia
b) Posterior embryotoxin
Alagille
- Neonatal jaundice
- mutation of JAG1
- paucity of intrahepatic bile ducts
- Triangular facies
- Posterior embryotoxon, micro cornea, optic disk drusen, shallow anterior chamber
- Peripheral pulmonic stenosis, TOF, PA, VSD, Coarct
- Vertebral - butterfly, fused, spina bifida occulta
- Tubulointerstitial nephropathy
Toddler with café au lait spots, a bump on her leg and vaginal bleeding. No breast development. What do you look for:
a) other endocrinopathies
b) neurofibromas
c) abnormal ECHO
a) other endocrinopathies
McCune Albright (Precocious Puberty with Polyostotic Fibrous Dysplasia and Abnormal Pigmentation)
14 yo old boy who is picked on by his peers. Poor student at school. Ht 97% Wt 70% Wide hips and wide carrying angle. Tanner Stage 1 pubic hair and genitalia. What is the diagnosis:
Marfan
Klinefelters
Noonans
Klinefelter
Classically 47 XXY
- phenotypic male
- Most common hypogonadism and infertility in males
- puberty at normal age but small testes, 50% gynecomastia
- tall stature
- Behavioural problems, problems in language
- Depression, anxiety, substance abuse
Description of infant, 1 or 2 mths. Lack of abdominal muscles. Has bilateral masses on abdo exam. Most likely etiology?
- PCKD ARPCKD
- Multicystic kidney
- Hydronephrosis
- Wilms tumour
- Hydronephrosis - Common association with prune-belly syndrome. Triad of abdominal muscle hypoplasia/partial aplasia, bilateral cryptorchidism (but girls can get it too!), and urinary tract anomalies. Majority have bilateral severe hydronephrosis and renal anomalies. In utero CKD can lead to oligohydramnios, pulmonary hypoplasia and skeletal malformations.
Down syndrome baby, what age to do Neck X-ray
a. 5 years old
b. age 1
c. when clinically indicated
c. when clinically indicated
AAP does not recommend screening X-rays, but instead to review signs and symptoms at primary care visits. For symptomatic children can get neutral position X-ray followed by flexion-extension views if nothign seen. Do not have adequate mineralization until 3 years of age.
Teenager girl with elevated AST, ALT in 300’s conjugated 30, total 40, alpha 1 was 2.5, anti sm ab 1:512 positive, hyperbilirubinemia. Most likely diagnosis:
a. Gilberts
b. Alpha 1 antitrypsin
c. Wilson’s
d. Autoimmune hepatitis
d. Autoimmune hepatitis
Alpha-1 antitrypsin (deficiency is <2)
Elevated anti-smooth muscle antibody (ASMA) seen in type 1 autoimmune hepatitis. Typically more transaminitis than cholestatic picture.
Female baby with hypotonia, head lag, weak facial muscles, deep tendon reflexes 1+, CK 1000, what is diagnosis?
a. Myotonic dystrophy
b. Congenital muscular dystrophy
c. Prader-Willi Syndrome
b. Congenital muscular dystrophy - Almost all are autosomal recessive. Present with markedly elevated CK
a. Myotonic dystrophy - Will have mildly elevated CK, but never in the 1000s.
Most common presentation of Fatty Acid Oxidation defect?
a. Recurrent stroke-like episodes
b. Life threatening coma
b. Life threatening coma
Acute episode of life-threatening coma and hypoglycemia induced by a period of fasting because of defective hepatic ketogenesis
- Will have inappropriately low ketones in an infant with hypoglycemia
A short, obese child is referred to your clinic for behavioural concerns and learning difficulties (vignette describes a child which makes you suspect Prader-Willi syndrome). Which of the following with confirm the diagnosis?
a. Serum ghrelin
b. Morning cortisol
c. Cytogenetic testing
d. Psychoeducational assessment
c. Cytogenetic testing
in PWS will have high ghrelin that do not decline after a meal (continues to stimulate appetite leading to hyperphagia)
DNA methylation analysis: demonstrates abnormal parent-specific imprinting within the Prader-Willi critical region on chromosome 15 —> demonstrates maternal-only imprinting (ie. absence of paternal-only expressed genes)
3 main molecular mechanisms that result in PWS: Paternal deletion (75%), Maternal uniparental disomy (UPD) (25%), Imprinting defect
DNA methylation analysis can detect all 3 above mechanisms and also differentiate PWS from Angelman syndrome in deletion cases → loss of maternal copy = Angelman Syndrome
Which of the following tests is most likely to be abnormal in a young girl with autism?
a. Fragile X testing
b. Karyotype
c. CGH microarray
d. Serum lead levels
c. CGH microarray
Diagnostic yield 0.57 for fragile x testing, and 24% for CMA
A 3 month old is brought to hospital for floppiness. On assessment in the ED, he is found to be hypotonic, hypoglycaemic with a serum glucose of 0.8, with elevated liver enzymes. Serum ketones are negative. Following a dose of intramuscular glucagon, there is no rise in the serum glucose. The most likely cause of this child’s hypoglycemia is:
a. Hyperinsulinism
b. Fatty acid oxidation defect
c. Urea cycle defect
d. Organic academia
b. Fatty acid oxidation defect → hypoglycemia with inappropriately low ketones, elevated LFTs, floppy
a. Hyperinsulinism → responds to glucagon (but is on ddx for hypoketotic hypoglycemia)
Inappropriately low ketonuria:
High insulin state: insulin tumor, infant of DM mother, Beckwith Wiedemann Syndrome
Low insulin state: fatty acid oxidation defects, GSD type I (ketones may be present)
A child has a smooth philtrum, thin upper lip, and developmental delay. His mother mentions that she drank alcohol during the pregnancy until she discovered that she was pregnant, well into the 2nd trimester. What cardiac anomaly is associated with this clinical picture?
a. TOF
b. VSD
c. Coarctation
d. TGA
b. VSD
FAS most commonly a/w cardiac septal defects
4 mo old with vomiting and FTT. pH 7.24, PCO2 30, bicarb 18, K 5.0, Na 138, Cl 108, Phos 2.1, glucose 4. No urine studies.
- Fanconi Syndrome
- RTA (Type 4)
- Mitochondrial disorder
- CF
- RTA (type 4)- hypoaldosteronism is type 4 RTA → metabolic acidosis, elevated K
–
Fanconi would have NAGMA with proteinuria, glycosuria, phosphaturia, aminoaciduria
4 yr old girl, birth length at 50th percentile, currently at 15th percentile, wt 50th percentile. growth velocity 3 cm/yr, with normal physical exam. Bone age 2. What’s the most likely diagnosis?
a. Turner
b. Chondroplasia
c. Celiac
d. GH deficiency
d. GH deficiency
Short + Fat
Mean height velocity for 4yr old is 7cm
What is the inheritance pattern for SMA Type 1
Autosomal recessive
Hemivertibrae - what is the most likely cause?
- IDM
- FAS
- T13
- IDM
common
A baby with hypoglycemia needing GIR >10mg/kg/min
Please list 3 types of hypoglycemia that would have a normal GIR requirement and 3 needed a higher than normal GIR
Normal GIR is ~ 6 mg/kg/min
Normal GIR:
- Transitional hypoglycemia
- IUGR
- IEM (galactosemia, fatty acid oxidation defect, lipolysis disorders)
- Glycogen storage disorder
- Prolonged fasting
- Prematurity
- Panhypopituitarism
- Adrenal insufficiency
- Hypothyroid
HIGH GIR:
- IDM
- Persistent hyperinsulinemic hypoglycemia of infancy
- Beckwith-wiedman
- Hyperthyroidism
- Birth asphyxia
- Erythroblastosis fetalis
- High umbilical catheter
- Exchange transfusion
- Abrupt cessation of IV glucose
- Sepsis
- Cold stress
- WOB
This baby is LGA and has a protruding tongue. What is the physiology of hypoglycemia in this baby.
Hyperinsulinism due to pancreatic islet cell hyperplasia
Child with classic physical features of Marfan’s syndrome.
- How is this condition inherited?
- Name 2 life threatening cardiac conditions Marfan is associated with
- Name two things you would do/follow regularly
- Autosomal Dominant
2. Aortic dissection Aortic rupture Aortic aneurysm Mitral valve insufficiency - pulmonary HTN Arrhythmias
3. Echocardiogram q. yearly Growth Scoliosis Ophthalmology q.yearly PFTs Formal sleep study Routine dental care
Child comes to you, mum concerned as getting recurrent fevers
a. Diagnosis
b. What is the underlying cause
a. Familial Mediterranean Fever
b. Defect in MEFV gene coding for pyrin (which regulates inflammation)
Child with Duchenne Muscular Dystrophy, waking up with HA, you are given his blood gas for an early morning. pH low, HCO3 high, pCO2 high.
a. What is the diagnosis
b. What will you recommend
a. Respiratory insufficiency leading to hypercarbia
b. Bipap
Child 6 months presents with a coma and seizure and glucose 1.6. List 10 laboratory investigations that you would do before treating the hypoglycemia. Do not include glucose. Had to be serum
- insulin
- beta-hydroxybutryate
- blood gas
- lactate
- electrolytes
- ammonia
- serum amino acids
- (urine organic acids)
- c-peptide
- growth hormone
- cortisol
- TSH
- insulin like growth factor bing protein
- acyl-carnitine profile
- free and total carnitines
What genetic disorders are associated with potential for leukemia. List 5
Trisomy 21 Fanconi Anemia Bloom syndrome Li-Fraumeni Schwachman Diamond Diamond Blackfan anemia Wiscott-Aldrich SCID Ataxia Telangiectasia NF-1
Turner syndrome - name 4 future medical problems
Infertility Short stature Hearing loss Recurrent OM Obesity Increased risk of autoimmune conditions (Hypothyroid, Celiac, IBD, JIA) Intellectual disability Behavioural problems Strabismus HTN Complications of CHD - risk of aortic root dilation, dissection, rupture Premature ovarian failure
Family physician calls you about term neonate who weighs 2300 g. Neonate has lymphoedema, low set hair line and wide chest.
a. What test would you send for diagnosis?
b. What result would you expect?
c. List two additional investigations that should be done in this neonate and their expected findings.
a. Karyotype or rapid aneuploidy
b. 45XO
c. Renal US
Echocardiogram
Review newborn screen
Examine hips for hip dysplasia
10 day old baby with failure to thrive, jaundice, hepatomegaly, blood culture positive for E.Coli. What underlying disorder may the child have? What test can you do to confirm this diagnosis (1)?
Galactosemia
Serum GAL screen: Galactose-1 phosphate uridyl transferase
Marfan syndrome – give 3 major complications- non skeletal
Cardiac: MV prolapse, aortic aneurysm/dissection/rupture, arrhythmias
Ocular: dislocation of ocular lense
Pulm: pneumothorax, restrictive lung disease
Skin: stretchmarks
Inguinal hernias
Dural ectasia (widening of dura sac or root sleeves)
Boy is unwell (?gastro, I can’t remember) and has what sounds like vitiligo. His K = 5.4, Na = 125 and BG is low (2.6 or similar). What one diagnosis would be important to consider?
Adrenal insufficiency
Can see vitiligo in polyglandular autoimmune syndrome type 2
Baby is ill and has very high ammonia. Name three things that you would do for immediate management.
NPO IV D10NS + KCl (if peeing) IV Intralipid Consult metabolics for ammonia scavenging drugs Consider dialysis
Boy with MELAS, what do you tell him is his risk of passing it on to his kids?
He will not pass on to his kids
MELAS = Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, Stroke-like episodes
MELAS is a maternally inherited mitochondrial disease based on mitochondrial DNA mutation. Sperm don’t have mitochondria in them so mitochondrial diseases don’t get passed on from males.
