A 7-day-old girl in a NICU in Lucknow, born to first-cousin parents, has poor feeding, vomiting, alternating hypertonia and lethargy, and her nappies have a sweet, burnt-sugar smell. Urine gives a positive 2,4-dinitrophenylhydrazine test, and plasma alloisoleucine is raised. Deficiency of which enzyme complex is most likely?

Branched-chain alpha-ketoacid dehydrogenase

Alpha-ketoglutarate dehydrogenase

A 12-day-old baby in Bhopal, registered as a girl, is brought to casualty with vomiting, poor feeding and lethargy. She has an enlarged clitoris and fused, rugose labioscrotal folds, with no palpable gonads. BP is 60/30 mmHg; serum sodium is 124 mmol/L, potassium 7.2 mmol/L and glucose 40 mg/dL. What is the next best step?

IV saline, dextrose and hydrocortisone after a blood sample

IV calcium and insulin-dextrose for the potassium only

Await serum 17-hydroxyprogesterone before any treatment

Pelvic ultrasound and karyotype before giving fluids

A newborn with Down syndrome in Chennai has a total leucocyte count of 62,000/µL with many blasts on the smear, a large liver and a normal haemoglobin. The blasts show megakaryoblastic features, and testing finds a GATA1 mutation in them. What is the most likely course?

Spontaneous resolution, with later leukaemia risk

Persistent blasts needing a marrow transplant

Evolution into chronic myeloid leukaemia

Progression to acute lymphoblastic leukaemia

Genetic and metabolic disorders in children

27 NEET-PG practice questions on Genetic and metabolic disorders in children, part of Paediatrics. The first 25 are below; the first 5 with answers and explanations (tap Show answer after you have chosen), the rest in Learn with a free account.

Question 1 · Medium
A 4-year-old boy in Jaipur has coarse facial features, a hoarse voice, stiff joints, hepatosplenomegaly and pebbly skin lesions over the scapulae. His corneas are clear. His maternal uncle had a similar illness. Urine shows excess dermatan and heparan sulphate. Which enzyme is deficient?
1. ABeta-glucocerebrosidase
2. BIduronate-2-sulphatase
3. CHexosaminidase A
4. DAlpha-L-iduronidase
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Answer: B · Iduronate-2-sulphatase
Coarse features, organomegaly, joint stiffness and urinary dermatan and heparan sulphate indicate a mucopolysaccharidosis. Clear corneas, pebbly skin over the scapulae and X-linked inheritance through the maternal uncle identify Hunter syndrome (MPS II), due to iduronate-2-sulphatase deficiency. Hurler syndrome (MPS I), from alpha-L-iduronidase deficiency, is autosomal recessive and causes corneal clouding. Enzyme replacement therapy is available for both.
- A: Glucocerebrosidase deficiency is Gaucher disease, without mucopolysaccharides in the urine.
- C: Hexosaminidase A deficiency is Tay-Sachs disease, with a cherry-red spot and no organomegaly.
- D: Alpha-L-iduronidase deficiency is Hurler syndrome, with corneal clouding and recessive inheritance.
Question 2 · Medium
A 7-day-old girl in a NICU in Lucknow, born to first-cousin parents, has poor feeding, vomiting, alternating hypertonia and lethargy, and her nappies have a sweet, burnt-sugar smell. Urine gives a positive 2,4-dinitrophenylhydrazine test, and plasma alloisoleucine is raised. Deficiency of which enzyme complex is most likely?
1. APropionyl-CoA carboxylase
2. BAlpha-ketoglutarate dehydrogenase
3. CBranched-chain alpha-ketoacid dehydrogenase
4. DPyruvate dehydrogenase complex
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Answer: C · Branched-chain alpha-ketoacid dehydrogenase
A burnt-sugar or maple-syrup odour with encephalopathy in the first week, a positive DNPH test for alpha-keto acids and raised alloisoleucine (which is diagnostic) indicate maple syrup urine disease. It is due to deficiency of the branched-chain alpha-ketoacid dehydrogenase complex, so leucine, isoleucine and valine and their keto acids accumulate, leucine being the most neurotoxic. Acute treatment removes leucine by dialysis and stops catabolism with high calories; long-term treatment is a diet low in branched-chain amino acids. Some cases respond partly to thiamine.
- A: Propionyl-CoA carboxylase deficiency causes propionic acidaemia with metabolic acidosis and ketosis.
- B: Alpha-ketoglutarate dehydrogenase deficiency is very rare and does not raise branched-chain amino acids.
- D: PDH deficiency causes lactic acidosis without a burnt-sugar odour or alloisoleucine.
Question 3 · Hard
A 12-day-old baby in Bhopal, registered as a girl, is brought to casualty with vomiting, poor feeding and lethargy. She has an enlarged clitoris and fused, rugose labioscrotal folds, with no palpable gonads. BP is 60/30 mmHg; serum sodium is 124 mmol/L, potassium 7.2 mmol/L and glucose 40 mg/dL. What is the next best step?
1. AIV saline, dextrose and hydrocortisone after a blood sample
2. BIV calcium and insulin-dextrose for the potassium only
3. CAwait serum 17-hydroxyprogesterone before any treatment
4. DPelvic ultrasound and karyotype before giving fluids
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Answer: A · IV saline, dextrose and hydrocortisone after a blood sample
A virilised girl with salt-losing crisis (hyponatraemia, hyperkalaemia, hypoglycaemia, shock) in the second week of life has congenital adrenal hyperplasia from 21-hydroxylase deficiency until proved otherwise. Lack of cortisol and aldosterone causes the crisis, and shunting of precursors into androgens causes the virilisation. Blood is drawn for 17-hydroxyprogesterone, electrolytes and cortisol, and treatment with IV normal saline, dextrose and stress-dose hydrocortisone starts at once without waiting for results; fludrocortisone is added later. Gender assignment and counselling come after stabilisation, with karyotype and ultrasound.
- B: Treating the potassium alone misses the cortisol and volume deficit; hydrocortisone and saline correct it.
- C: Waiting for 17-OHP risks death from adrenal crisis.
- D: Ultrasound and karyotype matter for sex assignment but must not delay resuscitation.
Question 4 · Medium
A newborn with Down syndrome in Chennai has a total leucocyte count of 62,000/µL with many blasts on the smear, a large liver and a normal haemoglobin. The blasts show megakaryoblastic features, and testing finds a GATA1 mutation in them. What is the most likely course?
1. APersistent blasts needing a marrow transplant
2. BEvolution into chronic myeloid leukaemia
3. CProgression to acute lymphoblastic leukaemia
4. DSpontaneous resolution, with later leukaemia risk
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Answer: D · Spontaneous resolution, with later leukaemia risk
This is transient abnormal myelopoiesis, seen in some newborns with Down syndrome: a clone of megakaryoblasts carrying a GATA1 mutation appears in the fetal liver and blood. In most babies it resolves on its own within the first months, needing only supportive care unless there is liver failure or hydrops. A proportion later develop acute megakaryoblastic leukaemia in early childhood, so these children need regular blood counts. Children with Down syndrome also have an increased risk of acute lymphoblastic leukaemia, but that is not the outcome of this disorder.
- A: Most cases resolve without transplant.
- B: CML is not linked with transient abnormal myelopoiesis.
- C: ALL risk is raised in Down syndrome but is not the evolution of this GATA1 clone.
Question 5 · Hard
A healthy 24-year-old woman in Chandigarh, whose younger brother has phenylketonuria, plans to marry a man from the general population with no family history. The carrier frequency of PKU in that population is taken as 1 in 50. What is the risk that their first child will have PKU?
1. A1 in 400
2. B1 in 200
3. C1 in 75
4. D1 in 300
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Answer: D · 1 in 300
PKU is autosomal recessive, so both her parents are carriers. Since she is unaffected, she is one of three unaffected outcomes (one non-carrier and two carriers), so her chance of being a carrier is 2/3. The partner's carrier risk is 1/50, and two carriers have a 1/4 chance of an affected child: 2/3 x 1/50 x 1/4 = 2/600 = 1 in 300. Carrier testing for both, by mutation analysis of the PAH gene once the brother's mutation is known, would replace these estimates with certainty.
- A: 1 in 400 uses a carrier chance of 1/2 instead of 2/3.
- B: 1 in 200 assumes she is certainly a carrier (1 x 1/50 x 1/4).
- C: 1 in 75 leaves out the 1/4 chance for two carriers.
Question 6 · Medium
A 3-day-old boy in a NICU in Hyderabad becomes lethargic and stops feeding after 2 days of normal breastfeeding. Blood ammonia is 520 µmol/L, arterial pH 7.48 with low PaCO2, glucose and anion gap are normal, plasma citrulline is low and urinary orotic acid is markedly raised. Deficiency of which enzyme is most likely?
1. AOrnithine transcarbamylase
2. BCarbamoyl phosphate synthetase I
3. CArgininosuccinate lyase
4. DArgininosuccinate synthetase
Answer and explanation in LearnFree account
Question 7 · Medium
A 34-year-old woman in Kochi has a second-trimester quadruple marker test at 16 weeks. Her report is flagged as high risk for Down syndrome in the fetus. Which pattern of results is most likely on her report?
1. AHigh AFP, high estriol, low hCG, low inhibin A
2. BLow AFP, low estriol, low hCG, normal inhibin A
3. CHigh AFP, normal estriol, normal hCG, normal inhibin A
4. DLow AFP, low estriol, high hCG, high inhibin A
Answer and explanation in LearnFree account
Question 8 · Easy
A 9-month-old boy from a consanguineous family in Haryana has developmental delay, fair hair and skin lighter than his parents', eczema and a musty odour to his urine. What is the most likely enzyme deficiency?
1. ACystathionine beta-synthase
2. BTyrosinase
3. CHomogentisate oxidase
4. DPhenylalanine hydroxylase
Answer and explanation in LearnFree account
Question 9 · Medium
A day-old baby with features of Down syndrome in a district hospital NICU has bilious vomiting after every feed. The abdomen is not distended below the epigastrium. A plain X-ray shows two large air bubbles in the upper abdomen with no gas further down. What is the most likely diagnosis?
1. AHirschsprung disease
2. BHypertrophic pyloric stenosis
3. CMidgut volvulus with malrotation
4. DDuodenal atresia
Answer and explanation in LearnFree account
Question 10 · Medium
A 7-year-old boy in Thrissur has intellectual disability, hyperactivity, poor eye contact, a long face, large prominent ears and hyperextensible finger joints. His mother's brother has similar learning problems. Which test is most appropriate to confirm the diagnosis?
1. ADNA testing for CGG repeats in FMR1
2. BFISH for a deletion at 15q11-q13
3. CChromosomal microarray for 22q11
4. DStandard G-banded karyotype
Answer and explanation in LearnFree account
Question 11 · Medium
A 36-year-old mother in Delhi has just been told by the obstetrician that her newborn son has features suggesting Down syndrome; the father is on his way to the hospital. She asks the paediatrician on the postnatal ward what is wrong with her baby. What is the best way to break this news?
1. AWait for the karyotype result before saying anything at all
2. BTell her on the open ward round so the team can answer questions
3. CTell the father alone first, and let him decide what to tell her
4. DTell both parents together soon, in private, with the baby present
Answer and explanation in LearnFree account
Question 12 · Medium
A newborn in the postnatal ward in Pune has features of Down syndrome. The paediatrician discusses four statements with the residents: 1. Most cases are due to an unbalanced Robertsonian translocation. 2. Atrioventricular septal defect is the characteristic heart lesion. 3. The recurrence risk is the same whatever the karyotype. 4. Thyroid function should be checked at birth and then periodically. Which statements are correct?
1. A1, 2 and 4 only
2. B1 and 3 only
3. C2 and 4 only
4. D2, 3 and 4 only
Answer and explanation in LearnFree account
Question 13 · Easy
A 39-year-old woman in Delhi delivers a baby girl with upslanting palpebral fissures, a flat nasal bridge, a single palmar crease, a wide gap between the first and second toes and marked hypotonia. Karyotype shows 47,XX,+21. What is the most common mechanism behind this karyotype?
1. AMitotic non-disjunction after fertilisation
2. BMaternal non-disjunction in meiosis I
3. CRobertsonian translocation in a parent
4. DPaternal non-disjunction in meiosis II
Answer and explanation in LearnFree account
Question 14 · Medium
A heel-prick sample taken at 48 hours in a district hospital shows a TSH of 64 mIU/L (screening cut-off 20 mIU/L) in a term baby who looks well and is feeding normally. What should be done next?
1. ARepeat the heel-prick screen at 2 weeks
2. BStart levothyroxine only if goitre or symptoms appear
3. CThyroid ultrasound and scan before any treatment
4. DSerum TSH and free T4, then levothyroxine at once
Answer and explanation in LearnFree account
Question 15 · Hard
A karyotype report on a mother reads 45,XX,der(14;21)(q10;q10). It was done because her first child, a girl with Down syndrome, has the karyotype 46,XX,der(14;21)(q10;q10),+21. The mother is healthy and of normal appearance, and the father's karyotype is 46,XY. She is now 10 weeks pregnant again and comes to the genetic clinic of a medical college in Chennai with her husband after a long bus journey from their village near Vellore, asking how likely it is that this baby will also have Down syndrome. Which figure best describes the observed risk of Down syndrome in a liveborn child?
1. A100%
2. BAbout 1%
3. CAbout 50%
4. DAbout 10-15%
Answer and explanation in LearnFree account
Question 16 · Medium
Fasting hypoglycaemia (blood glucose 32 mg/dL after a 4-hour gap between feeds), lactic acidosis, high uric acid and high triglycerides are found in an infant of 6 months with a doll-like face, a protuberant abdomen and a liver 8 cm below the costal margin. The spleen is not enlarged and serum CK is normal. Glucagon given during hypoglycaemia does not raise the glucose. Which enzyme is most likely deficient?
1. AGlucose-6-phosphatase
2. BMuscle glycogen phosphorylase
3. CDebranching enzyme
4. DAcid alpha-glucosidase
Answer and explanation in LearnFree account
Question 17 · Medium
Neck pain, a clumsy gait and new urinary incontinence have developed over 2 weeks in a boy of 12 years with Down syndrome who recently began gymnastics at a special school. He has brisk reflexes and extensor plantars in both legs. His thyroid tests last month were normal. What is the most likely diagnosis?
1. AHypothyroid myopathy
2. BAtlantoaxial instability
3. CCervical disc prolapse
4. DMoyamoya disease with stroke
Answer and explanation in LearnFree account
Question 18 · Easy
In a newborn with trisomy 21, consider: 1. Atrioventricular septal defect is the most characteristic heart defect. 2. Thyroid function should be checked at birth and then periodically. 3. The risk of acute leukaemia is raised. 4. Hirschsprung disease is more common than in other babies. Which are correct?
1. A1 and 3 only
2. B1, 2 and 3 only
3. C1, 2, 3 and 4
4. D2 and 4 only
Answer and explanation in LearnFree account
Question 19 · Easy
On day 6 of life, a breastfed baby girl in the postnatal ward has vomiting, poor feeding, jaundice and hepatomegaly; her blood culture grows Escherichia coli. Urine is positive for reducing substances but negative on a glucose oxidase strip. Besides antibiotics, what is the most important step now?
1. AStop breast milk and start a lactose-free soy formula
2. BGive a low-protein diet with sodium benzoate
3. CContinue breastfeeding and start intensive phototherapy
4. DStart a low-phenylalanine formula
Answer and explanation in LearnFree account
Question 20 · Hard
After 18 hours of vomiting and poor intake with gastroenteritis, a previously well boy of 15 months becomes lethargic and has a seizure. Blood glucose is 30 mg/dL; urine dipstick shows only trace ketones. Ammonia is mildly raised (90 µmol/L, normal below 50) and ALT is mildly elevated. His elder brother died suddenly at 2 years after a similar illness, and the death was labelled Reye syndrome. He recovers with IV 10% dextrose. Before discharge, the team wants to confirm the likely group of disorders. Which test is most useful?
1. ALiver biopsy for glycogen
2. BPlasma acylcarnitine profile
3. CUrine reducing substances
4. DSerum lactate to pyruvate ratio
Answer and explanation in LearnFree account
Question 21 · Medium
Downward and inward dislocation of both lenses is found by the ophthalmologist in a tall, thin boy of 10 years with long fingers, mild intellectual disability and a past deep vein thrombosis of the leg. His echocardiogram shows no aortic root dilatation. Which test will best confirm the likely diagnosis?
1. APlasma total homocysteine
2. BPlasma ammonia
3. CFBN1 gene sequencing
4. DUrine organic acids
Answer and explanation in LearnFree account
Question 22 · Medium
A girl with classical phenylketonuria was treated from the second week of life and was doing well in school. Her blood phenylalanine levels at each annual visit are shown, and by 12 years she has poor concentration. She says she stopped taking the special formula 'because it tastes awful'. What is the best next step?
Figure: MedExams
1. AAdd thyroxine to the present diet
2. BRestart the phenylalanine-restricted diet
3. CStart an antiepileptic drug
4. DStop dietary treatment, as the brain has matured
Answer and explanation in LearnFree account
Question 23 · Medium
A family has a progressive neurological illness with lactic acidosis, hypotonia and symmetrical lesions in the basal ganglia. The pedigree is shown. Which pattern of inheritance is the most likely?
Figure: MedExams
1. AAutosomal recessive
2. BAutosomal dominant with reduced penetrance
3. CMitochondrial inheritance
4. DX-linked dominant
Answer and explanation in LearnFree account
Question 24 · Hard
A 4-month-old boy has infantile spasms. His mother, who has had seizures since childhood and a few pale skin patches, has the facial skin shown, and the father is healthy. Genetic testing confirms a pathogenic variant in the TSC2 gene in the boy and the mother. What is the chance that a further child of this couple will inherit the same variant?
Figure: Photo: M. Sand, D. Sand, C. Thrandorf, V. Paech, P. Altmeyer, F. G. Bechara, CC BY 2.0, via Wikimedia Commons
1. A1 in 2
2. B1 in 4
3. CAlmost nil
4. DNearly 100%
Answer and explanation in LearnFree account
Question 25 · Medium
In the pedigree shown, the two brothers have Duchenne muscular dystrophy, with a high serum CK and a deletion in the dystrophin gene. Their mother is clinically normal, and there is no other affected relative. Their unaffected sister (arrow) plans a pregnancy with a healthy husband who has no family history. Ignoring a new mutation, what is the chance that her first son will be affected?
Figure: MedExams
1. AAlmost nil
2. B1 in 8
3. C1 in 2
4. D1 in 4
Answer and explanation in LearnFree account

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Genetic and metabolic disorders in children

A 4-year-old boy in Jaipur has coarse facial features, a hoarse voice, stiff joints, hepatosplenomegaly and pebbly skin lesions over the scapulae. His corneas are clear. His maternal uncle had a similar illness. Urine shows excess dermatan and heparan sulphate. Which enzyme is deficient?

A newborn with Down syndrome in Chennai has a total leucocyte count of 62,000/µL with many blasts on the smear, a large liver and a normal haemoglobin. The blasts show megakaryoblastic features, and testing finds a GATA1 mutation in them. What is the most likely course?

A healthy 24-year-old woman in Chandigarh, whose younger brother has phenylketonuria, plans to marry a man from the general population with no family history. The carrier frequency of PKU in that population is taken as 1 in 50. What is the risk that their first child will have PKU?

A 34-year-old woman in Kochi has a second-trimester quadruple marker test at 16 weeks. Her report is flagged as high risk for Down syndrome in the fetus. Which pattern of results is most likely on her report?

A 9-month-old boy from a consanguineous family in Haryana has developmental delay, fair hair and skin lighter than his parents', eczema and a musty odour to his urine. What is the most likely enzyme deficiency?

A day-old baby with features of Down syndrome in a district hospital NICU has bilious vomiting after every feed. The abdomen is not distended below the epigastrium. A plain X-ray shows two large air bubbles in the upper abdomen with no gas further down. What is the most likely diagnosis?

A 7-year-old boy in Thrissur has intellectual disability, hyperactivity, poor eye contact, a long face, large prominent ears and hyperextensible finger joints. His mother's brother has similar learning problems. Which test is most appropriate to confirm the diagnosis?

A 36-year-old mother in Delhi has just been told by the obstetrician that her newborn son has features suggesting Down syndrome; the father is on his way to the hospital. She asks the paediatrician on the postnatal ward what is wrong with her baby. What is the best way to break this news?

A 39-year-old woman in Delhi delivers a baby girl with upslanting palpebral fissures, a flat nasal bridge, a single palmar crease, a wide gap between the first and second toes and marked hypotonia. Karyotype shows 47,XX,+21. What is the most common mechanism behind this karyotype?

A heel-prick sample taken at 48 hours in a district hospital shows a TSH of 64 mIU/L (screening cut-off 20 mIU/L) in a term baby who looks well and is feeding normally. What should be done next?

On day 6 of life, a breastfed baby girl in the postnatal ward has vomiting, poor feeding, jaundice and hepatomegaly; her blood culture grows Escherichia coli. Urine is positive for reducing substances but negative on a glucose oxidase strip. Besides antibiotics, what is the most important step now?

A family has a progressive neurological illness with lactic acidosis, hypotonia and symmetrical lesions in the basal ganglia. The pedigree is shown. Which pattern of inheritance is the most likely?