Genetic and Metabolic Disorders Practice Questions

Q: A 3-year-old presents with recurrent respiratory infections, failure to thrive, and greasy stools. Sweat chloride is 95 mEq/L. Which gene is mutated?

CFTR. ***CFTR*** - The patient's symptoms (recurrent respiratory infections, failure to thrive, greasy stools) combined with a **sweat chloride of 95 mEq/L** are classic for **cystic fibrosis**. - **Cystic fibrosis** is caused by a mutation in the **Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene**, which encodes a chloride channel. *JAK3* - Mutations in **JAK3** are associated with **severe combined immunodeficiency (SCID)**, characterized by profound immune dysfunction. - While recurrent infections occur, the full constellation of symptoms including pulmonary, pancreatic, and elevated sweat chloride points away from JAK3-SCID. *BTK* - The **BTK gene** is associated with **X-linked agammaglobulinemia (Bruton's agammaglobulinemia)**, leading to recurrent bacterial infections due to absent B cells and immunoglobulins. - This condition does not typically cause the lung disease, pancreatic insufficiency, or elevated sweat chloride seen in cystic fibrosis. *FOXP3* - Mutations in **FOXP3** cause **IPEX (Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome**, characterized by severe autoimmune disease, often involving enteropathy, endocrinopathy, and eczema. - While some gastrointestinal issues may be present, it does not typically cause recurrent respiratory infections, the specific type of lung disease, or the characteristic high sweat chloride observed. *ATM* - The **ATM gene** is mutated in **ataxia-telangiectasia**, which presents with progressive cerebellar ataxia, telangiectasias, immunodeficiency, and increased cancer risk. - While patients may have recurrent respiratory infections due to immunodeficiency, they do not present with pancreatic insufficiency, greasy stools, or the pathognomonic elevated sweat chloride test that definitively points to cystic fibrosis.

Q: A 6-year-old presents with developmental delay, musty body odor, and fair skin. Lab tests show high phenylalanine levels. What is the most appropriate management?

Low-phenylalanine diet. ***Low-phenylalanine diet*** - The patient's symptoms (developmental delay, musty body odor, fair skin) and high **phenylalanine levels** are classic for **phenylketonuria (PKU)**. - Management primarily involves a strict **low-phenylalanine diet** to prevent further neurological damage. - This is the **cornerstone of PKU management** and must be initiated as early as possible. *Tetrahydrobiopterin (BH4) supplementation* - While **BH4 (sapropterin)** can be beneficial in some patients with **BH4-responsive PKU** (a subset of PKU cases), it is not first-line management. - BH4 testing is performed after diagnosis, but dietary restriction remains the primary treatment. - Not all PKU patients respond to BH4, and it's used as an adjunct, not a replacement for dietary management. *Avoidance of ascorbic acid* - **Ascorbic acid** (vitamin C) is generally not contraindicated in PKU and does not impact phenylalanine metabolism. - This intervention is not relevant to the management of PKU. *Vitamin D supplementation* - While vitamin D supplementation might be necessary for general health, especially in children with restricted diets, it is not the primary treatment for **phenylketonuria (PKU)**. - It does not directly address the elevated phenylalanine levels. *High-protein diet* - A **high-protein diet** would exacerbate the condition, as proteins are a major source of phenylalanine. - This would lead to even higher phenylalanine levels and worsen the symptoms of PKU.

Q: Which of the following is TRUE about Turner Syndrome?

Webbed neck. ***Webbed neck*** - A **webbed neck** (pterygium colli) is a characteristic physical feature seen in individuals with **Turner Syndrome**, caused by abnormal lymphatic development during fetal life. - This is one of several **dysmorphic features** commonly associated with the 45,X karyotype. *Increased risk of breast cancer* - Individuals with **Turner Syndrome** generally have a **reduced risk of breast cancer** due to hypogonadism and lower estrogen exposure. - Breast development is often incomplete or absent due to **gonadal dysgenesis**. *Normal menstruation* - Individuals with **Turner Syndrome** typically experience **primary amenorrhea** (absence of menstruation) due to **gonadal dysgenesis** and failure of ovarian development. - They lack functioning ovaries and therefore do not produce adequate **sex hormones** for menstrual cycles. *Tall stature* - Individuals with **Turner Syndrome** typically have **short stature** as a defining feature, often requiring growth hormone therapy. - The absence of one X chromosome affects genes involved in **linear bone growth**. *Intellectual disability is universal* - Individuals with **Turner Syndrome** typically have **normal intelligence**, though some may experience specific learning difficulties in visuospatial processing and mathematics. - Unlike some other chromosomal disorders, **intellectual disability is not a typical feature** of Turner Syndrome.

Q: Which diagnostic tool is preferred for metabolic disease screening in children?

Tandem mass spectrometry. ***Tandem mass spectrometry*** - **Tandem mass spectrometry (TMS)** is the preferred method for newborn screening of many **inborn errors of metabolism** because it can simultaneously detect a wide range of metabolites from a single dried blood spot. - This technique rapidly identifies multiple **amino acid disorders**, **fatty acid oxidation disorders**, and **organic acidemias**, allowing for early intervention. *Urinalysis* - While urinalysis can detect some metabolic abnormalities (e.g., **ketones**, **glucose**), it is not a comprehensive screening tool for the broad spectrum of inherited metabolic diseases. - It primarily identifies end-products of metabolism rather than specific enzyme deficiencies or precursor compounds. *Genetic testing* - **Genetic testing** is highly specific for known genetic mutations, but it is typically used for confirmatory diagnosis or targeted screening when a specific condition is suspected, not for broad, universal newborn metabolic screening. - It can be expensive and time-consuming for population-wide screening of hundreds of potential metabolic disorders. *Complete Blood count* - A **complete blood count (CBC)** assesses cellular components of the blood (e.g., **red blood cells**, **white blood cells**, **platelets**) and is useful for detecting hematological disorders. - It does not directly screen for metabolic diseases, although some metabolic disorders can secondarily affect blood cell counts. *Plasma amino acid analysis* - **Plasma amino acid analysis** can detect specific aminoacidopathies (e.g., **phenylketonuria**, **maple syrup urine disease**), but it is limited to amino acid disorders only. - Unlike tandem mass spectrometry, it cannot simultaneously screen for fatty acid oxidation disorders and organic acidemias, making it less comprehensive for broad metabolic screening.

Q: A 6-month-old child presents with jaundice, hepatomegaly, and cataracts. What is the most likely diagnosis?

Galactosemia. ***Galactosemia*** - **Galactosemia** is a genetic disorder affecting galactose metabolism, leading to a build-up of galactose-1-phosphate in tissues. - Symptoms like **jaundice**, **hepatomegaly**, and **cataracts** in an infant are classic presentations, often exacerbated by milk (lactose/galactose) intake. *Fructose intolerance* - **Hereditary fructose intolerance** typically manifests after the introduction of fructose into the diet, causing symptoms like vomiting, hypoglycemia, and liver dysfunction. - While it can cause hepatomegaly and jaundice, **cataracts** are not a typical feature of fructose intolerance. *Hemochromatosis* - **Hemochromatosis** is a disorder of iron overload, usually presenting in adulthood with symptoms such as fatigue, joint pain, liver disease (cirrhosis), and diabetes. - It is rarely diagnosed in infancy and **cataracts** are not a characteristic symptom. *Glycogen storage disease* - **Glycogen storage diseases** involve defects in glycogen synthesis or breakdown, leading to various symptoms depending on the specific enzyme deficiency. - Types affecting the liver often cause **hepatomegaly** and **hypoglycemia**, but **cataracts** are not a common, primary feature in most forms, and jaundice is also less typical than in galactosemia. *Wilson disease* - **Wilson disease** is a copper metabolism disorder that causes liver disease and neuropsychiatric symptoms. - It typically presents later in childhood or adolescence (rarely before age 3), and while it causes hepatomegaly and jaundice, the ocular finding is **Kayser-Fleischer rings**, not cataracts.

Q: A 10-year-old child presents with a history of recurrent fractures, blue sclerae, and early-onset hearing loss. What is the most likely diagnosis?

Osteogenesis imperfecta. ***Osteogenesis imperfecta*** - The classic triad of **recurrent fractures**, **blue sclerae**, and **early-onset hearing loss** is highly indicative of osteogenesis imperfecta. - This condition is caused by a genetic defect in **type I collagen synthesis**, leading to brittle bones. *Ehlers-Danlos syndrome* - Characterized primarily by **joint hypermobility**, skin hyperextensibility, and tissue fragility. - While some types can involve skeletal issues, **recurrent fractures** and **blue sclerae** are not distinguishing features. *Marfan syndrome* - Manifests with tall stature, **arachnodactyly**, lens luxation, and cardiovascular abnormalities like **aortic root dilation**. - **Recurrent fractures** and **blue sclerae** are not typical findings in Marfan syndrome. *Achondroplasia* - This is a form of **short-limbed dwarfism** due to a defect in endochondral ossification, specifically impacting cartilage formation. - Key features include short stature, a large head, and a prominent forehead, but it does not typically present with **blue sclerae** or **recurrent fractures** from fragile bones. *Hypophosphatasia* - A metabolic bone disease with deficiency of alkaline phosphatase leading to defective bone mineralization. - Can present with fractures and skeletal deformities but typically lacks **blue sclerae** and **hearing loss**, which are pathognomonic for osteogenesis imperfecta.

Q: A child presents with recurrent respiratory infections and a sweat chloride test result of 60 mmol/L. What is the most appropriate next step?

Genetic testing for cystic fibrosis. ***Genetic testing for cystic fibrosis*** - A sweat chloride test result of 60 mmol/L is in the **intermediate range** (typically 40-59 mmol/L for infants and 40-60 mmol/L for older children/adults being indeterminate) and, combined with recurrent respiratory infections, strongly suggests **cystic fibrosis (CF)**. - **Genetic testing for CFTR mutations** is the definitive diagnostic step when sweat chloride results are borderline or indicative of CF, confirming the diagnosis and guiding specific treatment strategies. *Repeat the sweat chloride test* - While it might be tempting to repeat a borderline test, the current result of 60 mmol/L, especially with suggestive clinical symptoms, warrants a more definitive diagnostic test immediately. - Repeating the test would delay the diagnosis and would likely yield a similar result, still requiring a confirmatory test. *Start prophylactic antibiotics* - Prophylactic antibiotics are a management strategy for patients with confirmed cystic fibrosis, but initiating them before a definitive diagnosis is premature. - The immediate priority is to confirm the underlying cause of the recurrent infections. *Chest X-ray and pulmonary function tests* - These tests are valuable for assessing the _extent_ of lung damage and _monitoring disease progression_ in a patient with recurrent respiratory infections. - However, they do not establish the underlying diagnosis of cystic fibrosis, which is crucial for appropriate long-term management. *Sputum culture for bacterial pathogens* - While sputum culture is useful for identifying specific pathogens in CF patients and guiding antibiotic therapy, it does not establish the underlying diagnosis. - This would be more appropriate after confirming CF diagnosis to guide targeted antimicrobial treatment for acute exacerbations.

Q: A child presents with multiple bone fractures over the past year with minimal trauma. Which condition should be evaluated as a potential cause?

Osteogenesis imperfecta. ***Osteogenesis imperfecta*** - This condition is characterized by **brittle bones** that fracture easily with **minimal or no trauma**, consistent with the child's presentation. - It is a genetic disorder affecting **collagen formation**, leading to defective bone matrix. *Rickets* - Rickets is a condition caused by a deficiency of **vitamin D, calcium, or phosphate**, leading to **softening and weakening of bones**. - While it can cause bone pain and deformities, **multiple fractures from minimal trauma** are less characteristic compared to osteogenesis imperfecta. *Scurvy* - **Vitamin C deficiency** can cause skeletal abnormalities and bone fragility due to impaired collagen synthesis. - However, scurvy is **extremely rare** in developed countries and typically presents with other signs like **gingival bleeding, petechiae, and poor wound healing**. *Normal childhood activity* - While children are prone to **minor injuries and fractures**, "multiple bone fractures over the past year with minimal trauma" goes beyond what is considered normal. - This pattern strongly suggests an **underlying pathological condition** rather than typical accidents. *Non-accidental trauma* - **Child abuse** can certainly cause multiple fractures, and it should always be considered in cases of unexplained or suspicious injuries. - However, the question specifically asks for a "condition" that should be evaluated as a "potential cause," focusing on **medical diagnoses** rather than external injury mechanisms, making osteogenesis imperfecta a more direct answer in this context.

Q: Which of the following is a key characteristic of Turner syndrome?

Webbed neck. ***Webbed neck*** - A **webbed neck** is a classic physical feature of Turner syndrome, caused by abnormalities in lymphatic development during fetal life. - This condition results from an **X chromosome monosomy** (45,XO) and is associated with various other developmental anomalies. *Tall stature* - Individuals with Turner syndrome typically present with **short stature**, a common and defining feature, rather than tall stature. - This is partly due to the absence of the **SHOX gene** on the missing X chromosome, which is critical for bone growth. *Macrocephaly* - **Macrocephaly** (abnormally large head) is not a characteristic feature of Turner syndrome; head circumference is usually within the normal range. - While some genetic conditions can cause macrocephaly, Turner syndrome primarily affects skeletal and reproductive development. *Gynecomastia* - **Gynecomastia** is the development of breast tissue in males and is not associated with Turner syndrome, which affects females. - Females with Turner syndrome often experience **gonadal dysgenesis**, leading to absent or underdeveloped ovaries and lack of female secondary sexual characteristics. *Normal fertility* - **Infertility** is a hallmark feature of Turner syndrome due to **ovarian dysgenesis** and streak gonads. - Most individuals with Turner syndrome require hormone replacement therapy and assisted reproductive technologies if they wish to conceive.

Question 1

A 3-year-old presents with recurrent respiratory infections, failure to thrive, and greasy stools. Sweat chloride is 95 mEq/L. Which gene is mutated?

Accepted Answer

CFTR

Answer

JAK3

Answer

BTK

Answer

FOXP3

Answer

ATM

Question 2

A 6-year-old presents with developmental delay, musty body odor, and fair skin. Lab tests show high phenylalanine levels. What is the most appropriate management?

Accepted Answer

Low-phenylalanine diet

Answer

Avoidance of ascorbic acid

Answer

Vitamin D supplementation

Answer

High-protein diet

Answer

Tetrahydrobiopterin (BH4) supplementation

Question 3

Which of the following is TRUE about Turner Syndrome?

Accepted Answer

Webbed neck

Answer

Increased risk of breast cancer

Answer

Normal menstruation

Answer

Tall stature

Answer

Intellectual disability is universal

Question 4

Which diagnostic tool is preferred for metabolic disease screening in children?

Accepted Answer

Tandem mass spectrometry

Answer

Urinalysis

Answer

Genetic testing

Answer

Complete Blood count

Answer

Plasma amino acid analysis

Question 5

A 6-month-old child presents with jaundice, hepatomegaly, and cataracts. What is the most likely diagnosis?

Accepted Answer

Galactosemia

Answer

Fructose intolerance

Answer

Hemochromatosis

Answer

Glycogen storage disease

Answer

Wilson disease

Question 6

What are the implications of early newborn screening for homocystinuria on intervention strategies?

Accepted Answer

Early detection enables dietary management and prevents serious complications.

Answer

Outcomes are similar regardless of screening.

Answer

Genetic testing is not necessary if symptoms are absent.

Answer

Screening has minimal impact on long-term outcomes.

Answer

Treatment can be delayed until clinical symptoms appear.

Question 7

A 10-year-old child presents with a history of recurrent fractures, blue sclerae, and early-onset hearing loss. What is the most likely diagnosis?

Accepted Answer

Osteogenesis imperfecta

Answer

Ehlers-Danlos syndrome

Answer

Marfan syndrome

Answer

Achondroplasia

Answer

Hypophosphatasia

Question 8

A child presents with recurrent respiratory infections and a sweat chloride test result of 60 mmol/L. What is the most appropriate next step?

Accepted Answer

Genetic testing for cystic fibrosis

Answer

Repeat the sweat chloride test

Answer

Start prophylactic antibiotics

Answer

Chest X-ray and pulmonary function tests

Answer

Sputum culture for bacterial pathogens

Question 9

A child presents with multiple bone fractures over the past year with minimal trauma. Which condition should be evaluated as a potential cause?

Accepted Answer

Osteogenesis imperfecta

Answer

Rickets

Answer

Normal childhood activity

Answer

Non-accidental trauma

Answer

Scurvy

Question 10

Which of the following is a key characteristic of Turner syndrome?

Accepted Answer

Webbed neck

Answer

Tall stature

Answer

Macrocephaly

Answer

Gynecomastia

Answer

Normal fertility

Genetic and Metabolic Disorders — MCQs

Genetic and Metabolic Disorders — MCQs

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