Genetic and Metabolic Disorders — MCQs

Q: A 4-year-old boy presents to his pediatrician for severe developmental delay. On exam he is noted to have macroorchidism, hypertelorism, large protruding ears, a large jaw, and a long thin face. Suspicious of what the diagnosis may be, the pediatrician orders a PCR and DNA sequencing. The results reveal an expansion of 250 repeats of CGG. What is the diagnosis of the boy?

Fragile X syndrome. ***Fragile X syndrome*** - The combination of **developmental delay**, characteristic physical features (**macroorchidism, large protruding ears, long thin face, large jaw**), and a **CGG repeat expansion** (250 repeats) is pathognomonic for Fragile X syndrome. - This is an **X-linked disorder** caused by an expansion of CGG trinucleotide repeats in the *FMR1* gene, leading to reduced or absent fragile X mental retardation protein (FMRP). *Huntington's disease* - Characterized by **chorea**, psychiatric symptoms, and cognitive decline, typically manifesting in adulthood, not early childhood developmental delay. - Caused by a **CAG trinucleotide repeat expansion** in the *HTT* gene, not CGG. *Spinal and bulbar muscular atrophy* - This is an **X-linked recessive** neurodegenerative disorder leading to muscle weakness and atrophy, which usually presents in adulthood. - It is caused by a **CAG repeat expansion** in the androgen receptor gene. *Myotonic dystrophy type 1* - Presents with progressive **muscle wasting and weakness**, myotonia, cataracts, and cardiac conduction defects, typically later in childhood or adulthood. - Caused by a **CTG trinucleotide repeat expansion** in the *DMPK* gene. *Friedreich ataxia* - Characterized by progressive **ataxia**, dysarthria, and loss of vibration/proprioception, usually beginning in childhood or adolescence. - Caused by a **GAA trinucleotide repeat expansion** in the *FXN* gene.

Q: An 8-month-old boy is brought to the physician for the evaluation of shortening of his arms and legs. The parents report that they have also noticed that their son's head is progressively enlarging. The patient was born at term via vaginal delivery. There is no personal or family history of serious illness. His immunizations are up-to-date. He is at the 3rd percentile for height, 25th percentile for weight, and 95th percentile for head circumference. Examination shows macrocephaly and prominent brow bones. The extremities are short and plump. Muscle strength is 3/5 in all muscle groups. Deep tendon reflexes are 4+ bilaterally. An x-ray of the lateral skull shows midfacial hypoplasia and frontal prominence. X-rays of the spine show abnormally narrow interpedicular distance. Which of the following is the most appropriate next step in management?

CT scan of the head. The patient's features, including **shortening of arms and legs**, **progressively enlarging head with macrocephaly**, **prominent brow bones**, **midfacial hypoplasia**, and **frontal prominence**, are classical signs of **achondroplasia**. In patients with achondroplasia, **hydrocephalus** due to impaired cerebrospinal fluid outflow at the foramen magnum is a common and serious complication, making a CT scan of the head the most appropriate next step to assess for this [1]. The patient presents with significant and progressive clinical signs such as **abnormal growth parameters**, **macrocephaly**, and **neurological symptoms** (hyperreflexia, muscle weakness), which warrant further investigation to identify anomalies of skull configuration [1].

Q: Ectopia lentis in a child is seen in which of the following diseases?

Homocystinuria. ***Homocystinuria*** - Ectopia lentis (lens dislocation) is a characteristic feature of **homocystinuria**, often presenting at a young age. - The dislocation in homocystinuria is typically **inferomedial (inferonasally)** due to weakened zonular fibers. - Homocystinuria is an **inborn error of methionine metabolism** with elevated homocysteine levels. *Marfan syndrome* - While **Marfan syndrome** is the most common cause of ectopia lentis, the lens typically dislocates **superiorly and temporally**. - Marfan syndrome is a connective tissue disorder but is not primarily a metabolic disorder like homocystinuria. - Both conditions can present with ectopia lentis, but the direction of dislocation and associated features differ. *Sarcoidosis* - Ocular manifestations of sarcoidosis usually include **uveitis**, **conjunctivitis**, and **retinal vasculitis**, but not typically ectopia lentis. - Sarcoidosis is a multisystem granulomatous disease and is rare in young children presenting with ectopia lentis. *Wilson disease* - **Kayser-Fleischer rings**, which are deposits of copper in the cornea, are pathognomonic for Wilson disease. - Ocular involvement in Wilson disease does not typically involve ectopia lentis. *Alkaptonuria* - This condition is characterized by the accumulation of **homogentisic acid**, leading to **ochronosis** (black pigmentation) in cartilaginous tissues and urine that turns black on standing. - Ocular manifestations can include scleral pigmentation, but ectopia lentis is not a feature of alkaptonuria.

Q: Which of the following is the least common cause of ambiguous genitalia in a female child

Fetal placental aromatase deficiency. ***Fetal placental aromatase deficiency*** - This condition is exceedingly rare and is considered one of the **least common genetic causes** of ambiguous genitalia in a female. - Deficiency of **aromatase** in the placenta prevents the conversion of androgens to estrogens, leading to **masculinization of a female fetus**, but this pathway is only a minor contributor to fetal androgenization. *WNT-4 gene mutation* - **WNT-4** is crucial for **female sexual differentiation** and acts as an anti-testis factor. - Mutations can lead to **Müllerian aplasia** and variable degrees of virilization in genetic females, making it a recognized, though not the most common, cause of ambiguous genitalia. *Congenital adrenal hyperplasia* - This is the **most common cause** of ambiguous genitalia in a female, primarily due to **21-hydroxylase deficiency**. - Excess adrenal androgens lead to **virilization** of the external genitalia in genetic females. *Maternal androgen exposure* - Virilization can occur from **maternal sources** such as androgen-secreting tumors, exogenous androgen use, or aromatase inhibitors during pregnancy. - This is an **uncommon but recognized cause**, more frequent than aromatase deficiency but far less common than CAH. *Fetal placental steroid sulfatase deficiency* - This deficiency typically results in **low maternal estrogen levels** and can cause **placental insufficiency** and abnormalities in labor, but it does **not directly cause ambiguous genitalia** in a female fetus. - While it affects steroid metabolism, it does not lead to the accumulation of androgens necessary for virilization of female external genitalia.

Q: All are features of Osteogenesis imperfecta except-

Cataract. ***Cataract*** - **Cataracts** are not typically associated with **osteogenesis imperfecta (OI)**. Ocular manifestations in OI predominantly involve the sclera. - While other connective tissue disorders might feature cataracts, they are not a characteristic diagnostic or common finding in OI. *Multiple fractures* - **Multiple fractures** with minimal or no trauma are a hallmark of **osteogenesis imperfecta**, due to defective **type I collagen** synthesis. - The severity and frequency of these fractures vary depending on the specific type of OI. *Blue sclera* - **Blue sclera** is a classic feature of **osteogenesis imperfecta**, caused by the underlying choroidal veins showing through a thinned, translucent sclera due to defective **collagen**. - This is a key diagnostic clue, often present from birth or early childhood. *Hearing loss* - **Hearing loss** is common in **osteogenesis imperfecta**, particularly the **conductive type**, but can also be sensorineural or mixed. - It results from **ossicular chain abnormalities**, otosclerosis, or fragility of the middle ear bones, all related to the collagen defect. *Dentinogenesis imperfecta* - **Dentinogenesis imperfecta** is a characteristic dental manifestation of **osteogenesis imperfecta**, seen in approximately 50% of cases. - It involves defective dentin formation leading to discolored (gray, blue, or brown), translucent teeth that are prone to wear and fracture due to the same collagen defect affecting bones.

Q: A 10-year-old male child presented with complaints of severe progressive weakness of bilateral lower limbs, imbalance in walking, and slurred speech for the past 3 years, with recent development of visual disturbance, behavioral symptoms, and rapid progression of motor weakness. MRI was performed at the time of presentation. What is the diagnosis?

X-linked adrenoleukodystrophy. ***X-linked adrenoleukodystrophy*** - This condition presents in males, typically between ages 4 and 10 years, with progressive neurological deterioration including **motor weakness**, **ataxia**, **visual disturbances**, and **behavioral changes**, consistent with the patient's symptoms. - The disease involves demyelination in the central nervous system due to the accumulation of **very long-chain fatty acids (VLCFAs)** and is inherited in an **X-linked recessive pattern**. *Alexander's disease* - This typically presents in infancy or early childhood with **megalencephaly**, developmental delay, and seizures, which are not described in this patient. - MRI often shows characteristic frontal white matter changes and **periventricular rim enhancement**. *Krabbe's disease* - This is an autosomal recessive disorder that usually presents in infants, with irritability, feeding difficulties, and rapid neurodegeneration, leading to **severe developmental regression**. - It involves the accumulation of **galactocerebroside** in neural tissues due to **beta-galactocerebrosidase deficiency**. *Metachromatic leukodystrophy* - This is an autosomal recessive lysosomal storage disorder that can present in late infancy, juvenile, or adult forms with progressive **demyelination** and neurological deficits. - While it causes **motor weakness** and cognitive decline, it often involves **peripheral neuropathy** and is characterized by the accumulation of **sulfatides**, not VLCFAs. *Canavan disease* - This is an autosomal recessive disorder caused by **aspartoacylase deficiency** leading to accumulation of **N-acetylaspartic acid (NAA)**. - Typically presents in early infancy (3-6 months) with **hypotonia**, **macrocephaly**, and **severe developmental delay**, earlier than the presentation in this case. - MRI shows diffuse white matter changes with characteristic involvement of subcortical U-fibers.

Q: X-linked disease leading to intellectual disability is -

Fragile-X syndrome. ***Fragile-X syndrome*** - This is the most common inherited cause of **intellectual disability** and is inherited in an **X-linked dominant pattern**. - It is caused by an expansion of a **CGG trinucleotide repeat** in the *FMR1* gene on the X chromosome. *Down syndrome* - This is a **chromosomal disorder** (trisomy 21), not X-linked. - It is the most common **genetic cause** of intellectual disability overall, resulting from an extra copy of chromosome 21. *Tuberous sclerosis* - This is an **autosomal dominant** disorder, not X-linked. - It involves the growth of **benign tumors** in various organs, including the brain, skin, kidneys, and heart. *Phenylketonuria* - This is an **autosomal recessive** metabolic disorder, not X-linked. - It results from a deficiency of the enzyme **phenylalanine hydroxylase**, leading to a buildup of phenylalanine. *Myotonic dystrophy* - This is an **autosomal dominant** disorder, not X-linked. - It is characterized by progressive **muscle wasting** and **myotonia** (delayed muscle relaxation).

Q: A male child with Fanconi syndrome with nephrocalcinosis has a variant of dent disease. All are true except :

Similar presentation in father. ***Similar presentation in father*** - Dent disease is an **X-linked recessive disorder** primarily affecting males due to mutations in the *CLCN5* or *OCRL1* genes. - While the father carries the Y chromosome and does not have the gene mutation, the mother is an asymptomatic carrier, passing the disease-causing allele to her sons. - **The father cannot present with the same X-linked condition** as he passes only his Y chromosome to male offspring. *Proteinuria* - **Low molecular weight proteinuria** is a hallmark of Dent disease and Fanconi syndrome, resulting from impaired reabsorption in the proximal tubules. - This is a direct consequence of the tubular dysfunction characteristic of these conditions. *Rickets* - **Rickets** can develop due to the renal phosphate wasting (hypophosphatemia) and vitamin D abnormalities (impaired activation) seen in Dent disease and Fanconi syndrome. - These bone manifestations are common complications of chronic kidney tubule dysfunction in children. *Hypercalciuria* - **Hypercalciuria** is a primary feature of Dent disease, leading to nephrocalcinosis and nephrolithiasis. - This excessive urinary calcium excretion contributes to the formation of kidney stones and calcification of renal tissue. *Progressive chronic kidney disease* - **Progressive CKD** is a recognized long-term complication of Dent disease, with many patients developing end-stage renal disease (ESRD) by adulthood. - The chronic tubular dysfunction and recurrent nephrolithiasis contribute to progressive nephron loss over time.

Q: A 10-year-old child presents with fever since 24 hours. History reveals 3 episodes of chest infection and passage of bulky, foul smelling stools. The most probable diagnosis is?

Cystic fibrosis. ***Cystic fibrosis*** - This genetic disorder causes defective **chloride transport**, leading to thick secretions in various organs, including the lungs and pancreas. - Recurrent **chest infections** are due to thick mucus trapping bacteria in the airways, and **bulky, foul-smelling stools** result from pancreatic insufficiency and malabsorption. *Crigler-Najjar syndrome* - This is a rare **genetic disorder** affecting bilirubin metabolism, leading to severe unconjugated hyperbilirubinemia. - Its primary presentation is **jaundice** and potential neurologic complications (**kernicterus**), not recurrent respiratory infections or steatorrhea. *Maple syrup urine disease* - This is an **autosomal recessive metabolic disorder** affecting the metabolism of branched-chain amino acids (leucine, isoleucine, valine). - It presents with characteristic **sweet-smelling urine** and severe neurological dysfunction, not primarily respiratory or gastrointestinal symptoms. *Bilirubin conjugation defect* - This is a broad term that can encompass several conditions like Crigler-Najjar syndrome or Gilbert's syndrome, all primarily presenting with **jaundice** due to impaired bilirubin processing. - It does not explain the recurrent chest infections or malabsorptive stools described in the child. *Shwachman-Diamond syndrome* - This is a rare **autosomal recessive disorder** featuring bone marrow dysfunction, pancreatic insufficiency, and skeletal abnormalities. - While it can cause malabsorption and increased infection risk due to **neutropenia**, the pattern of recurrent chest infections with steatorrhea is more classic for cystic fibrosis, which has a higher prevalence.

Q: All of the following are seen in Fragile X syndrome except:

Female preponderance. ***Female preponderance*** - **Fragile X syndrome** primarily affects males more severely due to it being an **X-linked dominant inheritance pattern** with variable expression and penetrance. - While females can be carriers or mildly affected, the full syndrome with significant intellectual disability and physical features is much more common in males. *Autism* - **Autistic-like behaviors** and **autism spectrum disorder** are frequently observed in individuals with Fragile X syndrome. - This is a common **neurodevelopmental comorbidity** associated with the genetic mutation. *Cardiac murmurs* - **Mitral valve prolapse (MVP)** is a common cardiac anomaly found in individuals with Fragile X syndrome, which can present as a **cardiac murmur**. - This is one of the associated physical features of the syndrome, likely due to connective tissue abnormalities. *Mental retardation* - **Intellectual disability**, ranging from mild to severe, is a **hallmark feature** of Fragile X syndrome. - It is the **most common inherited cause of intellectual disability**. *Macro-orchidism* - **Post-pubertal macroorchidism** (enlarged testicles) is seen in approximately **80% of adult males** with Fragile X syndrome. - This is one of the characteristic **physical features** associated with the condition.

A 4-year-old boy presents to his pediatrician for severe developmental delay. On exam he is noted to have macroorchidism, hypertelorism, large protruding ears, a large jaw, and a long thin face. Suspicious of what the diagnosis may be, the pediatrician orders a PCR and DNA sequencing. The results reveal an expansion of 250 repeats of CGG. What is the diagnosis of the boy?

An 8-month-old boy is brought to the physician for the evaluation of shortening of his arms and legs. The parents report that they have also noticed that their son's head is progressively enlarging. The patient was born at term via vaginal delivery. There is no personal or family history of serious illness. His immunizations are up-to-date. He is at the 3rd percentile for height, 25th percentile for weight, and 95th percentile for head circumference. Examination shows macrocephaly and prominent brow bones. The extremities are short and plump. Muscle strength is 3/5 in all muscle groups. Deep tendon reflexes are 4+ bilaterally. An x-ray of the lateral skull shows midfacial hypoplasia and frontal prominence. X-rays of the spine show abnormally narrow interpedicular distance. Which of the following is the most appropriate next step in management?

Ectopia lentis in a child is seen in which of the following diseases?

Which of the following is the least common cause of ambiguous genitalia in a female child

All are features of Osteogenesis imperfecta except-

A 10-year-old male child presented with complaints of severe progressive weakness of bilateral lower limbs, imbalance in walking, and slurred speech for the past 3 years, with recent development of visual disturbance, behavioral symptoms, and rapid progression of motor weakness. MRI was performed at the time of presentation. What is the diagnosis?

X-linked disease leading to intellectual disability is -

A male child with Fanconi syndrome with nephrocalcinosis has a variant of dent disease. All are true except :

A 10-year-old child presents with fever since 24 hours. History reveals 3 episodes of chest infection and passage of bulky, foul smelling stools. The most probable diagnosis is?

Q10

All of the following are seen in Fragile X syndrome except:

Genetic and Metabolic Disorders US Medical PG Practice Questions and MCQs

Question 1: A 4-year-old boy presents to his pediatrician for severe developmental delay. On exam he is noted to have macroorchidism, hypertelorism, large protruding ears, a large jaw, and a long thin face. Suspicious of what the diagnosis may be, the pediatrician orders a PCR and DNA sequencing. The results reveal an expansion of 250 repeats of CGG. What is the diagnosis of the boy?

A. Huntington's disease
B. Spinal and bulbar muscular atrophy
C. Myotonic dystrophy type 1
D. Fragile X syndrome (Correct Answer)
E. Friedreich ataxia

Explanation: ***Fragile X syndrome*** - The combination of **developmental delay**, characteristic physical features (**macroorchidism, large protruding ears, long thin face, large jaw**), and a **CGG repeat expansion** (250 repeats) is pathognomonic for Fragile X syndrome. - This is an **X-linked disorder** caused by an expansion of CGG trinucleotide repeats in the *FMR1* gene, leading to reduced or absent fragile X mental retardation protein (FMRP). *Huntington's disease* - Characterized by **chorea**, psychiatric symptoms, and cognitive decline, typically manifesting in adulthood, not early childhood developmental delay. - Caused by a **CAG trinucleotide repeat expansion** in the *HTT* gene, not CGG. *Spinal and bulbar muscular atrophy* - This is an **X-linked recessive** neurodegenerative disorder leading to muscle weakness and atrophy, which usually presents in adulthood. - It is caused by a **CAG repeat expansion** in the androgen receptor gene. *Myotonic dystrophy type 1* - Presents with progressive **muscle wasting and weakness**, myotonia, cataracts, and cardiac conduction defects, typically later in childhood or adulthood. - Caused by a **CTG trinucleotide repeat expansion** in the *DMPK* gene. *Friedreich ataxia* - Characterized by progressive **ataxia**, dysarthria, and loss of vibration/proprioception, usually beginning in childhood or adolescence. - Caused by a **GAA trinucleotide repeat expansion** in the *FXN* gene.

Question 2: An 8-month-old boy is brought to the physician for the evaluation of shortening of his arms and legs. The parents report that they have also noticed that their son's head is progressively enlarging. The patient was born at term via vaginal delivery. There is no personal or family history of serious illness. His immunizations are up-to-date. He is at the 3rd percentile for height, 25th percentile for weight, and 95th percentile for head circumference. Examination shows macrocephaly and prominent brow bones. The extremities are short and plump. Muscle strength is 3/5 in all muscle groups. Deep tendon reflexes are 4+ bilaterally. An x-ray of the lateral skull shows midfacial hypoplasia and frontal prominence. X-rays of the spine show abnormally narrow interpedicular distance. Which of the following is the most appropriate next step in management?

A. Reassurance
B. CT scan of the head (Correct Answer)
C. Growth hormone therapy
D. MRI of cervical spine
E. Bisphosphonate therapy

Explanation: The patient's features, including **shortening of arms and legs**, **progressively enlarging head with macrocephaly**, **prominent brow bones**, **midfacial hypoplasia**, and **frontal prominence**, are classical signs of **achondroplasia**. In patients with achondroplasia, **hydrocephalus** due to impaired cerebrospinal fluid outflow at the foramen magnum is a common and serious complication, making a CT scan of the head the most appropriate next step to assess for this [1]. The patient presents with significant and progressive clinical signs such as **abnormal growth parameters**, **macrocephaly**, and **neurological symptoms** (hyperreflexia, muscle weakness), which warrant further investigation to identify anomalies of skull configuration [1].

Question 3: Ectopia lentis in a child is seen in which of the following diseases?

A. Sarcoidosis
B. Wilson disease
C. Homocystinuria (Correct Answer)
D. Alkaptonuria
E. Marfan syndrome

Explanation: ***Homocystinuria*** - Ectopia lentis (lens dislocation) is a characteristic feature of **homocystinuria**, often presenting at a young age. - The dislocation in homocystinuria is typically **inferomedial (inferonasally)** due to weakened zonular fibers. - Homocystinuria is an **inborn error of methionine metabolism** with elevated homocysteine levels. *Marfan syndrome* - While **Marfan syndrome** is the most common cause of ectopia lentis, the lens typically dislocates **superiorly and temporally**. - Marfan syndrome is a connective tissue disorder but is not primarily a metabolic disorder like homocystinuria. - Both conditions can present with ectopia lentis, but the direction of dislocation and associated features differ. *Sarcoidosis* - Ocular manifestations of sarcoidosis usually include **uveitis**, **conjunctivitis**, and **retinal vasculitis**, but not typically ectopia lentis. - Sarcoidosis is a multisystem granulomatous disease and is rare in young children presenting with ectopia lentis. *Wilson disease* - **Kayser-Fleischer rings**, which are deposits of copper in the cornea, are pathognomonic for Wilson disease. - Ocular involvement in Wilson disease does not typically involve ectopia lentis. *Alkaptonuria* - This condition is characterized by the accumulation of **homogentisic acid**, leading to **ochronosis** (black pigmentation) in cartilaginous tissues and urine that turns black on standing. - Ocular manifestations can include scleral pigmentation, but ectopia lentis is not a feature of alkaptonuria.

Question 4: Which of the following is the least common cause of ambiguous genitalia in a female child

A. WNT-4 gene mutation
B. Congenital adrenal hyperplasia
C. Fetal placental aromatase deficiency (Correct Answer)
D. Fetal placental steroid sulfatase deficiency
E. Maternal androgen exposure

Explanation: ***Fetal placental aromatase deficiency*** - This condition is exceedingly rare and is considered one of the **least common genetic causes** of ambiguous genitalia in a female. - Deficiency of **aromatase** in the placenta prevents the conversion of androgens to estrogens, leading to **masculinization of a female fetus**, but this pathway is only a minor contributor to fetal androgenization. *WNT-4 gene mutation* - **WNT-4** is crucial for **female sexual differentiation** and acts as an anti-testis factor. - Mutations can lead to **Müllerian aplasia** and variable degrees of virilization in genetic females, making it a recognized, though not the most common, cause of ambiguous genitalia. *Congenital adrenal hyperplasia* - This is the **most common cause** of ambiguous genitalia in a female, primarily due to **21-hydroxylase deficiency**. - Excess adrenal androgens lead to **virilization** of the external genitalia in genetic females. *Maternal androgen exposure* - Virilization can occur from **maternal sources** such as androgen-secreting tumors, exogenous androgen use, or aromatase inhibitors during pregnancy. - This is an **uncommon but recognized cause**, more frequent than aromatase deficiency but far less common than CAH. *Fetal placental steroid sulfatase deficiency* - This deficiency typically results in **low maternal estrogen levels** and can cause **placental insufficiency** and abnormalities in labor, but it does **not directly cause ambiguous genitalia** in a female fetus. - While it affects steroid metabolism, it does not lead to the accumulation of androgens necessary for virilization of female external genitalia.

Question 5: All are features of Osteogenesis imperfecta except-

A. Multiple fractures
B. Blue sclera
C. Hearing loss
D. Cataract (Correct Answer)
E. Dentinogenesis imperfecta

Explanation: ***Cataract*** - **Cataracts** are not typically associated with **osteogenesis imperfecta (OI)**. Ocular manifestations in OI predominantly involve the sclera. - While other connective tissue disorders might feature cataracts, they are not a characteristic diagnostic or common finding in OI. *Multiple fractures* - **Multiple fractures** with minimal or no trauma are a hallmark of **osteogenesis imperfecta**, due to defective **type I collagen** synthesis. - The severity and frequency of these fractures vary depending on the specific type of OI. *Blue sclera* - **Blue sclera** is a classic feature of **osteogenesis imperfecta**, caused by the underlying choroidal veins showing through a thinned, translucent sclera due to defective **collagen**. - This is a key diagnostic clue, often present from birth or early childhood. *Hearing loss* - **Hearing loss** is common in **osteogenesis imperfecta**, particularly the **conductive type**, but can also be sensorineural or mixed. - It results from **ossicular chain abnormalities**, otosclerosis, or fragility of the middle ear bones, all related to the collagen defect. *Dentinogenesis imperfecta* - **Dentinogenesis imperfecta** is a characteristic dental manifestation of **osteogenesis imperfecta**, seen in approximately 50% of cases. - It involves defective dentin formation leading to discolored (gray, blue, or brown), translucent teeth that are prone to wear and fracture due to the same collagen defect affecting bones.

Question 6: A 10-year-old male child presented with complaints of severe progressive weakness of bilateral lower limbs, imbalance in walking, and slurred speech for the past 3 years, with recent development of visual disturbance, behavioral symptoms, and rapid progression of motor weakness. MRI was performed at the time of presentation. What is the diagnosis?

A. X-linked adrenoleukodystrophy (Correct Answer)
B. Alexander's disease
C. Krabbe's disease
D. Metachromatic leukodystrophy
E. Canavan disease

Explanation: ***X-linked adrenoleukodystrophy*** - This condition presents in males, typically between ages 4 and 10 years, with progressive neurological deterioration including **motor weakness**, **ataxia**, **visual disturbances**, and **behavioral changes**, consistent with the patient's symptoms. - The disease involves demyelination in the central nervous system due to the accumulation of **very long-chain fatty acids (VLCFAs)** and is inherited in an **X-linked recessive pattern**. *Alexander's disease* - This typically presents in infancy or early childhood with **megalencephaly**, developmental delay, and seizures, which are not described in this patient. - MRI often shows characteristic frontal white matter changes and **periventricular rim enhancement**. *Krabbe's disease* - This is an autosomal recessive disorder that usually presents in infants, with irritability, feeding difficulties, and rapid neurodegeneration, leading to **severe developmental regression**. - It involves the accumulation of **galactocerebroside** in neural tissues due to **beta-galactocerebrosidase deficiency**. *Metachromatic leukodystrophy* - This is an autosomal recessive lysosomal storage disorder that can present in late infancy, juvenile, or adult forms with progressive **demyelination** and neurological deficits. - While it causes **motor weakness** and cognitive decline, it often involves **peripheral neuropathy** and is characterized by the accumulation of **sulfatides**, not VLCFAs. *Canavan disease* - This is an autosomal recessive disorder caused by **aspartoacylase deficiency** leading to accumulation of **N-acetylaspartic acid (NAA)**. - Typically presents in early infancy (3-6 months) with **hypotonia**, **macrocephaly**, and **severe developmental delay**, earlier than the presentation in this case. - MRI shows diffuse white matter changes with characteristic involvement of subcortical U-fibers.

Question 7: X-linked disease leading to intellectual disability is -

A. Tuberous sclerosis
B. Phenylketonuria
C. Myotonic dystrophy
D. Fragile-X syndrome (Correct Answer)
E. Down syndrome

Explanation: ***Fragile-X syndrome*** - This is the most common inherited cause of **intellectual disability** and is inherited in an **X-linked dominant pattern**. - It is caused by an expansion of a **CGG trinucleotide repeat** in the *FMR1* gene on the X chromosome. *Down syndrome* - This is a **chromosomal disorder** (trisomy 21), not X-linked. - It is the most common **genetic cause** of intellectual disability overall, resulting from an extra copy of chromosome 21. *Tuberous sclerosis* - This is an **autosomal dominant** disorder, not X-linked. - It involves the growth of **benign tumors** in various organs, including the brain, skin, kidneys, and heart. *Phenylketonuria* - This is an **autosomal recessive** metabolic disorder, not X-linked. - It results from a deficiency of the enzyme **phenylalanine hydroxylase**, leading to a buildup of phenylalanine. *Myotonic dystrophy* - This is an **autosomal dominant** disorder, not X-linked. - It is characterized by progressive **muscle wasting** and **myotonia** (delayed muscle relaxation).

Question 8: A male child with Fanconi syndrome with nephrocalcinosis has a variant of dent disease. All are true except :

A. Proteinuria
B. Rickets
C. Hypercalciuria
D. Similar presentation in father (Correct Answer)
E. Progressive chronic kidney disease

Explanation: ***Similar presentation in father*** - Dent disease is an **X-linked recessive disorder** primarily affecting males due to mutations in the *CLCN5* or *OCRL1* genes. - While the father carries the Y chromosome and does not have the gene mutation, the mother is an asymptomatic carrier, passing the disease-causing allele to her sons. - **The father cannot present with the same X-linked condition** as he passes only his Y chromosome to male offspring. *Proteinuria* - **Low molecular weight proteinuria** is a hallmark of Dent disease and Fanconi syndrome, resulting from impaired reabsorption in the proximal tubules. - This is a direct consequence of the tubular dysfunction characteristic of these conditions. *Rickets* - **Rickets** can develop due to the renal phosphate wasting (hypophosphatemia) and vitamin D abnormalities (impaired activation) seen in Dent disease and Fanconi syndrome. - These bone manifestations are common complications of chronic kidney tubule dysfunction in children. *Hypercalciuria* - **Hypercalciuria** is a primary feature of Dent disease, leading to nephrocalcinosis and nephrolithiasis. - This excessive urinary calcium excretion contributes to the formation of kidney stones and calcification of renal tissue. *Progressive chronic kidney disease* - **Progressive CKD** is a recognized long-term complication of Dent disease, with many patients developing end-stage renal disease (ESRD) by adulthood. - The chronic tubular dysfunction and recurrent nephrolithiasis contribute to progressive nephron loss over time.

Question 9: A 10-year-old child presents with fever since 24 hours. History reveals 3 episodes of chest infection and passage of bulky, foul smelling stools. The most probable diagnosis is?

A. Cystic fibrosis (Correct Answer)
B. Crigler-Najjar syndrome
C. Maple syrup urine disease
D. Bilirubin conjugation defect
E. Shwachman-Diamond syndrome

Explanation: ***Cystic fibrosis*** - This genetic disorder causes defective **chloride transport**, leading to thick secretions in various organs, including the lungs and pancreas. - Recurrent **chest infections** are due to thick mucus trapping bacteria in the airways, and **bulky, foul-smelling stools** result from pancreatic insufficiency and malabsorption. *Crigler-Najjar syndrome* - This is a rare **genetic disorder** affecting bilirubin metabolism, leading to severe unconjugated hyperbilirubinemia. - Its primary presentation is **jaundice** and potential neurologic complications (**kernicterus**), not recurrent respiratory infections or steatorrhea. *Maple syrup urine disease* - This is an **autosomal recessive metabolic disorder** affecting the metabolism of branched-chain amino acids (leucine, isoleucine, valine). - It presents with characteristic **sweet-smelling urine** and severe neurological dysfunction, not primarily respiratory or gastrointestinal symptoms. *Bilirubin conjugation defect* - This is a broad term that can encompass several conditions like Crigler-Najjar syndrome or Gilbert's syndrome, all primarily presenting with **jaundice** due to impaired bilirubin processing. - It does not explain the recurrent chest infections or malabsorptive stools described in the child. *Shwachman-Diamond syndrome* - This is a rare **autosomal recessive disorder** featuring bone marrow dysfunction, pancreatic insufficiency, and skeletal abnormalities. - While it can cause malabsorption and increased infection risk due to **neutropenia**, the pattern of recurrent chest infections with steatorrhea is more classic for cystic fibrosis, which has a higher prevalence.

Question 10: All of the following are seen in Fragile X syndrome except:

A. Autism
B. Female preponderance (Correct Answer)
C. Cardiac murmurs
D. Mental retardation
E. Macro-orchidism

Explanation: ***Female preponderance*** - **Fragile X syndrome** primarily affects males more severely due to it being an **X-linked dominant inheritance pattern** with variable expression and penetrance. - While females can be carriers or mildly affected, the full syndrome with significant intellectual disability and physical features is much more common in males. *Autism* - **Autistic-like behaviors** and **autism spectrum disorder** are frequently observed in individuals with Fragile X syndrome. - This is a common **neurodevelopmental comorbidity** associated with the genetic mutation. *Cardiac murmurs* - **Mitral valve prolapse (MVP)** is a common cardiac anomaly found in individuals with Fragile X syndrome, which can present as a **cardiac murmur**. - This is one of the associated physical features of the syndrome, likely due to connective tissue abnormalities. *Mental retardation* - **Intellectual disability**, ranging from mild to severe, is a **hallmark feature** of Fragile X syndrome. - It is the **most common inherited cause of intellectual disability**. *Macro-orchidism* - **Post-pubertal macroorchidism** (enlarged testicles) is seen in approximately **80% of adult males** with Fragile X syndrome. - This is one of the characteristic **physical features** associated with the condition.

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Chromosomal Disorders

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Genetic Counseling

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Genetic Testing in Pediatrics

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Inborn Errors of Metabolism

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Lysosomal Storage Diseases

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Mitochondrial Disorders

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Multifactorial Inheritance Disorders

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Newborn Screening

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Single Gene Disorders

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