A 6-day-old infant who was born via uncomplicated vaginal delivery at 39 weeks of gestation is brought to the family physician for poor feeding. The mother received adequate prenatal care throughout the pregnancy, and has no medical conditions. On physical exam, the infant's temperature is 36.5°C (97.7°F), blood pressure is 70/45 mmHg, pulse is 170/min, and respirations are 40/min. The infant has dry mucous membranes, capillary refill of 4 seconds, and a depressed anterior fontanelle. No abdominal masses are noted. Genital exam shows enlargement of the clitoris with fusion of the labioscrotal folds. Serum chemistry is remarkable for hyponatremia and hyperkalemia. The infant's karyotype is 46,XX. Which of the following findings are most likely to be discovered upon further workup?
Q2
A 6-year-old boy is brought to the physician by his mother who is concerned about his early sexual development. He has no history of serious illness and takes no medications. He is at the 99th percentile for height and 70th percentile for weight. His blood pressure is 115/78 mm Hg. Examination shows greasy facial skin and cystic acne on his forehead and back. There is coarse axillary and pubic hair. Serum studies show:
Cortisol (0800 h) 4 μg/dL
Deoxycorticosterone 2.5 ng/dL (N = 3.5–11.5)
Dehydroepiandrosterone sulfate 468 mcg/dL (N = 29–412)
Which of the following is the most likely underlying cause of this patient's symptoms?
Q3
A newborn female is found to have ambiguous genitalia and hypotension. Laboratory workup reveals hyperkalemia, hyperreninemia, and elevated levels of 17-hydroxyprogesterone in the patient's urine. Which of the following enzymes would you expect to be deficient in this patient?
Q4
A 6-day-old newborn girl is brought into the hospital by her mother because of excessive vomiting and poor feeding. The mother did not have antenatal care. Her temperature is 36.8°C (98.2°F), blood pressure is 50/30 mm Hg, and pulse is 150/min. On examination, the infant is dehydrated and demonstrates signs of shock. Her genitalia are ambiguous, with fused labia and an enlarged clitoris. Laboratory results are shown:
Serum sodium (Na) 125 mEq/L
Serum potassium (K) 6 mEq/L
Serum 17-hydroxyprogesterone 100,000 ng/dL (normal level is 1,000–3,000 ng/dL)
Which of the following is the most likely cause of this infant's condition?
Q5
A 5-year-old male visits his pediatrician for a check-up. His height corresponds to the 99th percentile for his age, and pubic hair is present upon physical examination. Serum renin and potassium levels are high, as is 17-hydroxyprogesterone. Which of the following is likely deficient in this patient?
Q6
Steroid hormone synthesis, lipid synthesis, and chemical detoxification are activities of which of the following?
Q7
The human body obtains vitamin D either from diet or from sun exposure. Darker-skinned individuals require more sunlight to create adequate vitamin D stores as the increased melanin in their skin acts like sunscreen; thus, it blocks the necessary UV required for vitamin D synthesis. Therefore, if these individuals spend inadequate time in the light, dietary sources of vitamin D are necessary. Which of the following requires sunlight for its formation?
Q8
A newborn is delivered at term to a 38-year-old woman after an uncomplicated pregnancy and delivery. The newborn's blood pressure is 142/85 mm Hg. Examination shows clitoral enlargement and labioscrotal fusion. Serum studies show a sodium of 151 mg/dL and a potassium of 3.2 mg/dL. Karyotype analysis shows a 46, XX karyotype. The patient is most likely deficient in an enzyme that is normally responsible for which of the following reactions?
Q9
A 7-year-old boy is brought to the pediatrician by his parents due to pubic hair growth and changes in his voice. He has been developing in the 98th percentile for his age. His vaccination is up-to-date. The patient’s blood pressure is within the 60th percentile for his age. Physical examination reveals pubic and armpit hair, and Tanner stage 2 characterized by enlarged scrotum and testes. Laboratory findings are significant for the following:
Hemoglobin 13.1 g/dL
Hematocrit 39.7%
Leukocyte count 8,500/mm3
Neutrophils 65%
Lymphocytes 30%
Monocytes 5%
Mean corpuscular volume 82.2 μm3
Platelet count 20,000/mm3
Urine creatinine clearance 98 mL/min
Serum 17-hydroxyprogesterone 313 ng/dL (normal <110 ng/dL)
Which of the following enzymes is most likely to be defective in this patient?
Q10
An 8-year-old boy is brought to the pediatrician by his mother with nausea, vomiting, and decreased frequency of urination. He has acute lymphoblastic leukemia for which he received the 1st dose of chemotherapy 5 days ago. His leukocyte count was 60,000/mm3 before starting chemotherapy. The vital signs include: pulse 110/min, temperature 37.0°C (98.6°F), and blood pressure 100/70 mm Hg. The physical examination shows bilateral pedal edema. Which of the following serum studies and urinalysis findings will be helpful in confirming the diagnosis of this condition?
Steroid hormone synthesis US Medical PG Practice Questions and MCQs
Question 1: A 6-day-old infant who was born via uncomplicated vaginal delivery at 39 weeks of gestation is brought to the family physician for poor feeding. The mother received adequate prenatal care throughout the pregnancy, and has no medical conditions. On physical exam, the infant's temperature is 36.5°C (97.7°F), blood pressure is 70/45 mmHg, pulse is 170/min, and respirations are 40/min. The infant has dry mucous membranes, capillary refill of 4 seconds, and a depressed anterior fontanelle. No abdominal masses are noted. Genital exam shows enlargement of the clitoris with fusion of the labioscrotal folds. Serum chemistry is remarkable for hyponatremia and hyperkalemia. The infant's karyotype is 46,XX. Which of the following findings are most likely to be discovered upon further workup?
A. Increased aldosterone, decreased cortisol
B. Decreased aldosterone, increased 11-deoxycorticosterone
C. Increased sex hormones, decreased renin activity
D. Increased sex hormones, increased 17-hydroxyprogesterone (Correct Answer)
E. Decreased cortisol, decreased sex hormones
Explanation: ***Increased sex hormones, increased 17-hydroxyprogesterone***
- The combination of **ambiguous genitalia** (clitoral enlargement, labioscrotal fusion) in a 46,XX infant along with signs of **salt-wasting** (hyponatremia, hyperkalemia, dehydration) points to **classic 21-hydroxylase deficiency**.
- In 21-hydroxylase deficiency, the block in cortisol and aldosterone synthesis leads to a buildup of precursors (**17-hydroxyprogesterone**) and shunting towards **androgen production**, causing virilization.
*Increased aldosterone, decreased cortisol*
- **Decreased cortisol** is consistent with congenital adrenal hyperplasia (CAH), but **increased aldosterone** would not be seen in salt-wasting 21-hydroxylase deficiency.
- Salt-wasting forms of CAH, particularly 21-hydroxylase deficiency, result in **decreased aldosterone** due to the enzyme block.
*Decreased aldosterone, increased 11-deoxycorticosterone*
- **Decreased aldosterone** aligns with salt-wasting CAH, but **increased 11-deoxycorticosterone** (DOC) is characteristic of **11β-hydroxylase deficiency**, not 21-hydroxylase deficiency.
- 11β-hydroxylase deficiency leads to **hypertension** due to excess DOC, which is not described in this patient presenting with signs of dehydration and hypotension.
*Increased sex hormones, decreased renin activity*
- **Increased sex hormones** are expected in congenital adrenal hyperplasia due to enzyme deficiencies leading to excessive androgen production.
- However, **decreased renin activity** would occur with conditions causing hyperaldosteronism or mineralocorticoid excess (like 11β-hydroxylase deficiency with high DOC), which contradicts the signs of salt-wasting and likely hypotension in this infant.
*Decreased cortisol, decreased sex hormones*
- While **decreased cortisol** is a hallmark of CAH, **decreased sex hormones** would typically be seen in deficiencies affecting the early steps of steroidogenesis or in primary gonadal failure.
- In 21-hydroxylase deficiency, the blocked pathway upstream of cortisol synthesis diverts precursors towards **increased androgen production**, leading to virilization.
Question 2: A 6-year-old boy is brought to the physician by his mother who is concerned about his early sexual development. He has no history of serious illness and takes no medications. He is at the 99th percentile for height and 70th percentile for weight. His blood pressure is 115/78 mm Hg. Examination shows greasy facial skin and cystic acne on his forehead and back. There is coarse axillary and pubic hair. Serum studies show:
Cortisol (0800 h) 4 μg/dL
Deoxycorticosterone 2.5 ng/dL (N = 3.5–11.5)
Dehydroepiandrosterone sulfate 468 mcg/dL (N = 29–412)
Which of the following is the most likely underlying cause of this patient's symptoms?
A. Deficiency of 21β-hydroxylase (Correct Answer)
B. Idiopathic overproduction of GnRH
C. Constitutive activation of adenylyl cyclase
D. Deficiency of 11β-hydroxylase
E. Deficiency of 17α-hydroxylase
Explanation: ***Deficiency of 21β-hydroxylase***
- The combination of **precocious puberty** (early sexual development, acne, coarse hair), elevated **DHEA-S**, and low **cortisol** with **low-normal DOC** confirms 21β-hydroxylase deficiency, causing **congenital adrenal hyperplasia (CAH)**.
- This enzyme deficiency blocks cortisol and aldosterone synthesis, shunting precursors towards **androgen production**, causing **adrenal androgen excess** and virilization.
- The **low DOC level (2.5 ng/dL, below normal 3.5-11.5)** is the key finding that distinguishes this from 11β-hydroxylase deficiency.
- The mild hypertension may be due to increased androgen-mediated effects or represents an atypical presentation.
*Idiopathic overproduction of GnRH*
- This would cause **central precocious puberty**, characterized by activation of the **hypothalamic-pituitary-gonadal axis** (HPGA).
- While it causes precocious puberty, it would not typically lead to isolated elevation of **adrenal androgens** like DHEA-S with concurrent low cortisol, which points to an adrenal rather than central cause.
- Laboratory findings would show elevated LH, FSH, and gonadal sex steroids rather than adrenal androgens.
*Constitutive activation of adenylyl cyclase*
- This is linked to conditions like **McCune-Albright syndrome**, which can cause peripheral precocious puberty but typically presents with the classic triad: **café-au-lait spots**, **fibrous dysplasia of bone**, and **autonomous endocrine hyperfunction**.
- The hormonal profile reflects the specific endocrine gland involved (often gonadal), not the pattern of **adrenal androgen excess** with low cortisol and low DOC seen here.
*Deficiency of 11β-hydroxylase*
- This is the second most common cause of CAH and also causes adrenal androgen excess leading to virilization and precocious puberty.
- However, 11β-hydroxylase deficiency results in **accumulation of deoxycorticosterone (DOC)**, which causes **hypertension** and **hypokalemia**.
- This patient's **DOC is LOW (2.5 ng/dL, below normal range 3.5-11.5)**, which definitively rules out this diagnosis despite the presence of hypertension.
*Deficiency of 17α-hydroxylase*
- This deficiency impairs synthesis of **cortisol** and **sex steroids**, but increases production of mineralocorticoids (DOC and corticosterone).
- Patients present with **hypertension**, **hypokalemia**, sexual infantilism, and in XY individuals, **female external genitalia** due to lack of androgens.
- This is the opposite of the **virilization and elevated DHEA-S** seen in this patient.
Question 3: A newborn female is found to have ambiguous genitalia and hypotension. Laboratory workup reveals hyperkalemia, hyperreninemia, and elevated levels of 17-hydroxyprogesterone in the patient's urine. Which of the following enzymes would you expect to be deficient in this patient?
A. 11-hydroxylase
B. 3β-hydroxysteroid dehydrogenase
C. 11β-hydroxysteroid dehydrogenase
D. 21-hydroxylase (Correct Answer)
E. 17-hydroxylase
Explanation: ***21-hydroxylase***
- **21-hydroxylase deficiency** is the most common cause of **congenital adrenal hyperplasia (CAH)**, leading to a build-up of **17-hydroxyprogesterone** and its metabolites, which are shunted into androgen pathways.
- The deficiency in cortisol and aldosterone synthesis results in **hyponatremia**, **hyperkalemia**, and **hypotension** (due to salt-wasting) and **ambiguous genitalia** in females due to excess androgens.
*11-hydroxylase*
- **11-hydroxylase deficiency** also causes **CAH** and leads to ambiguous genitalia in females, but it is typically associated with **hypertension** due to the accumulation of 11-deoxycorticosterone, a mineralocorticoid, not hypotension.
- While 17-hydroxyprogesterone might be elevated, the defining feature of this deficiency is elevated levels of **11-deoxycorticosterone** and **11-deoxycortisol**.
*3β-hydroxysteroid dehydrogenase*
- **3β-hydroxysteroid dehydrogenase deficiency** leads to impaired synthesis of all adrenal steroids (glucocorticoids, mineralocorticoids, and androgens), resulting in severe **salt-wasting** and **hypotension**.
- However, females with this deficiency would typically present with **undervirilized** or normal genitalia, rather than ambiguous genitalia, due to reduced androgen synthesis.
*11β-hydroxysteroid dehydrogenase*
- **11β-hydroxysteroid dehydrogenase deficiency** is typically associated with **apparent mineralocorticoid excess syndrome**, leading to **hypertension** and **hypokalemia**, not hyperkalemia or ambiguous genitalia.
- This enzyme is responsible for converting cortisol to cortisone, preventing cortisol from activating mineralocorticoid receptors.
*17-hydroxylase*
- **17-hydroxylase deficiency** impairs the synthesis of sex hormones and cortisol, leading to **hypertension** and **hypokalemia** due to increased mineralocorticoid production (e.g., corticosterone, 11-deoxycorticosterone).
- Females would typically have **normal female external genitalia** but lack pubertal development, and males would present with **undervirilized external genitalia**.
Question 4: A 6-day-old newborn girl is brought into the hospital by her mother because of excessive vomiting and poor feeding. The mother did not have antenatal care. Her temperature is 36.8°C (98.2°F), blood pressure is 50/30 mm Hg, and pulse is 150/min. On examination, the infant is dehydrated and demonstrates signs of shock. Her genitalia are ambiguous, with fused labia and an enlarged clitoris. Laboratory results are shown:
Serum sodium (Na) 125 mEq/L
Serum potassium (K) 6 mEq/L
Serum 17-hydroxyprogesterone 100,000 ng/dL (normal level is 1,000–3,000 ng/dL)
Which of the following is the most likely cause of this infant's condition?
A. Deficiency of 21-hydroxylase (Correct Answer)
B. Deficiency of 11-beta-hydroxylase
C. Deficiency of 5-alpha reductase
D. Deficiency of placental aromatase
E. Deficiency of 17-alpha-hydroxylase
Explanation: ***Deficiency of 21-hydroxylase***
- The combination of **salt-wasting crisis** (hyponatremia, hyperkalemia, hypotension, shock) in a newborn with **ambiguous genitalia** (virilization in a female) and a dramatically elevated **17-hydroxyprogesterone** level is pathognomonic for **21-hydroxylase deficiency**.
- This enzyme defect prevents the synthesis of **cortisol** and **aldosterone**, leading to an accumulation of steroid precursors like 17-hydroxyprogesterone, which are then shunted towards **androgen production**.
*Deficiency of 11-beta-hydroxylase*
- This deficiency causes accumulation of **11-deoxycorticosterone (DOC)**, a mineralocorticoid, leading to **hypertension** and **hypokalemia**, not the salt-wasting crisis seen here.
- While it also causes virilization from increased androgens, the **electrolyte imbalance pattern** is distinct.
*Deficiency of 5-alpha reductase*
- This condition affects **males (XY individuals)**, presenting with **undermasculinized external genitalia** (ambiguous at birth, virilize at puberty).
- It does not cause **adrenal insufficiency** or **salt-wasting symptoms** in either sex.
*Deficiency of placental aromatase*
- This is a rare autosomal recessive disorder where the placenta cannot convert fetal androgens into estrogens, leading to **virilization of the mother** and **female fetus**.
- There are no associated **electrolyte abnormalities** or **adrenal crisis symptoms** as seen in this infant.
*Deficiency of 17-alpha-hydroxylase*
- This deficiency impairs the synthesis of **cortisol** and **sex steroids**, but **mineralocorticoid production (aldosterone and DOC)** is increased.
- Patients typically present with **hypertension**, **hypokalemia**, and **sexual infantilism** (lack of secondary sex characteristics), not virilization or salt-wasting.
Question 5: A 5-year-old male visits his pediatrician for a check-up. His height corresponds to the 99th percentile for his age, and pubic hair is present upon physical examination. Serum renin and potassium levels are high, as is 17-hydroxyprogesterone. Which of the following is likely deficient in this patient?
A. 11ß-hydroxylase
B. 21-hydroxylase (Correct Answer)
C. Aromatase
D. 5a-reductase
E. 17a-hydroxylase
Explanation: ***21-hydroxylase***
- A deficiency in **21-hydroxylase** leads to the accumulation of **17-hydroxyprogesterone**, as conversion to 11-deoxycorticosterone and 11-deoxycortisol is blocked, which aligns with the high levels observed in the patient.
- The shunting of precursors towards **androgen synthesis** due to the block explains the **precocious puberty** (pubic hair, advanced height for age).
- **Mineralocorticoid deficiency** (low aldosterone) causes **salt-wasting** with sodium loss and potassium retention (hyperkalemia), which stimulates compensatory **renin elevation**, explaining the high renin and potassium levels.
*11ß-hydroxylase*
- A deficiency would cause an accumulation of **11-deoxycorticosterone** and **11-deoxycortisol**, not primarily 17-hydroxyprogesterone.
- This deficiency typically presents with **hypertension** and **virilization** due to elevated 11-deoxycorticosterone (has mineralocorticoid activity) and androgens, but mineralocorticoid excess would **suppress renin**, which contradicts the high renin observed.
*Aromatase*
- **Aromatase** is responsible for converting androgens to estrogens. Its deficiency in males would typically result in **tall stature** due to delayed epiphyseal fusion but would not cause precocious puberty or the specific hormonal imbalance seen (high 17-hydroxyprogesterone, high renin/potassium).
- The absence of estrogen conversion would lead to **continued growth** and delayed bone maturation rather than early virilization with adrenal androgen excess.
*5a-reductase*
- **5a-reductase** converts testosterone to the more potent dihydrotestosterone (DHT). A deficiency in males would cause **undervirilization** at birth (ambiguous genitalia) and incomplete masculinization at puberty.
- This scenario contradicts the observed signs of **precocious puberty** and virilization in a 5-year-old male.
*17a-hydroxylase*
- A **17a-hydroxylase deficiency** would block the synthesis of cortisol and sex steroids, leading to increased production of mineralocorticoids like **corticosterone** and **11-deoxycorticosterone**.
- This typically results in **hypertension**, **hypokalemia** (mineralocorticoid excess), and **absent or delayed puberty** (lack of sex steroids), which are contrary to the symptoms presented in this patient (high potassium, precocious puberty).
Question 6: Steroid hormone synthesis, lipid synthesis, and chemical detoxification are activities of which of the following?
A. Peroxisomes
B. Nucleolus
C. Rough Endoplasmic Reticulum
D. Smooth Endoplasmic Reticulum (Correct Answer)
E. Golgi bodies
Explanation: ***Smooth Endoplasmic Reticulum***
- The **smooth endoplasmic reticulum (SER)** is rich in enzymes that catalyze the synthesis of **lipids**, including steroid hormones, and is crucial for the detoxification of drugs and poisons, particularly in liver cells.
- Its tubular structure, devoid of ribosomes, differentiates its functions from the rough ER, focusing on metabolic processes like **calcium ion storage** and carbohydrate metabolism.
*Peroxisomes*
- Peroxisomes are primarily involved in the breakdown of **fatty acids** and amino acids, producing hydrogen peroxide as a byproduct.
- They also play a role in detoxification but are not the primary site for steroid hormone or general lipid synthesis.
*Nucleolus*
- The **nucleolus** is a dense structure within the nucleus responsible for synthesizing **ribosomal RNA (rRNA)** and assembling ribosomes.
- It has no direct role in steroid hormone synthesis, lipid metabolism, or chemical detoxification.
*Rough Endoplasmic Reticulum*
- The **rough endoplasmic reticulum (RER)** is studded with **ribosomes** and is primarily involved in the synthesis and modification of **proteins** destined for secretion or insertion into membranes.
- While it's part of the endomembrane system, it does not directly perform lipid synthesis or chemical detoxification as its main functions.
*Golgi bodies*
- **Golgi bodies (or Golgi apparatus)** are responsible for modifying, sorting, and packaging **proteins and lipids** synthesized in the ER into vesicles for secretion or delivery to other organelles.
- They do not perform the initial synthesis of steroid hormones or lipids, nor are they the primary site for chemical detoxification.
Question 7: The human body obtains vitamin D either from diet or from sun exposure. Darker-skinned individuals require more sunlight to create adequate vitamin D stores as the increased melanin in their skin acts like sunscreen; thus, it blocks the necessary UV required for vitamin D synthesis. Therefore, if these individuals spend inadequate time in the light, dietary sources of vitamin D are necessary. Which of the following requires sunlight for its formation?
A. 1,25-dihydroxyvitamin D
B. 25-hydroxyvitamin D
C. 7-dehydrocholesterol
D. Cholecalciferol (D3) (Correct Answer)
E. Ergocalciferol (D2)
Explanation: ***Cholecalciferol (D3)***
- **Cholecalciferol** (vitamin D3) is synthesized in the skin when **7-dehydrocholesterol** is exposed to **ultraviolet B (UVB) radiation** from sunlight.
- This is the initial step in the body's natural production of vitamin D, which then undergoes further hydroxylation in the liver and kidneys to become its active form.
*1,25-dihydroxyvitamin D*
- This is the **active form of vitamin D**, also known as **calcitriol**, produced in the **kidneys** from 25-hydroxyvitamin D via 1-alpha-hydroxylase.
- Its formation requires prior synthesis of cholecalciferol and subsequent hydroxylation, but it does not directly require sunlight.
*25-hydroxyvitamin D*
- This compound, also known as **calcidiol**, is formed in the **liver** from cholecalciferol (or ergocalciferol) through **25-hydroxylation**.
- While its precursor, cholecalciferol, is sunlight-dependent, 25-hydroxyvitamin D itself is not directly formed by sunlight.
*7-dehydrocholesterol*
- **7-dehydrocholesterol** is a **precursor molecule** found in the skin that is converted to cholecalciferol upon exposure to sunlight.
- It is not "formed" by sunlight; rather, it's the substrate upon which sunlight acts.
*Ergocalciferol (D2)*
- **Ergocalciferol** (vitamin D2) is primarily obtained from **plant-based sources** and fortified foods.
- It is not synthesized in the human skin through exposure to sunlight.
Question 8: A newborn is delivered at term to a 38-year-old woman after an uncomplicated pregnancy and delivery. The newborn's blood pressure is 142/85 mm Hg. Examination shows clitoral enlargement and labioscrotal fusion. Serum studies show a sodium of 151 mg/dL and a potassium of 3.2 mg/dL. Karyotype analysis shows a 46, XX karyotype. The patient is most likely deficient in an enzyme that is normally responsible for which of the following reactions?
A. 11-deoxycorticosterone to corticosterone (Correct Answer)
B. Progesterone to 17-hydroxyprogesterone
C. Testosterone to dihydrotestosterone
D. Progesterone to 11-deoxycorticosterone
E. Androstenedione to estrone
Explanation: ***11-deoxycorticosterone to corticosterone***
- This reaction is catalyzed by **11β-hydroxylase**. Deficiency of this enzyme (second most common cause of congenital adrenal hyperplasia) leads to the clinical triad seen in this patient:
1. **Virilization** in XX individuals (clitoral enlargement, labioscrotal fusion) due to shunting of steroid precursors toward **androgen synthesis**
2. **Hypertension** due to accumulation of **11-deoxycorticosterone (DOC)**, which has potent mineralocorticoid activity
3. **Hypokalemia and hypernatremia** resulting from the mineralocorticoid excess caused by accumulated DOC
- The 46,XX karyotype with ambiguous genitalia confirms this is a disorder of **androgen excess** affecting a genetic female
- 11β-hydroxylase deficiency accounts for approximately 5-8% of CAH cases
*Progesterone to 11-deoxycorticosterone*
- This reaction is catalyzed by **21-hydroxylase** (most common cause of CAH, ~90-95% of cases)
- However, 21-hydroxylase deficiency typically presents with **salt-wasting** (hypotension, hyponatremia, hyperkalemia) in 75% of cases, or simple virilizing form with normal blood pressure and electrolytes in 25% of cases
- The **hypertension with hypokalemia and hypernatremia** in this case is NOT consistent with 21-hydroxylase deficiency, which causes **decreased** mineralocorticoid production
- While virilization occurs in 21-hydroxylase deficiency, the cardiovascular and electrolyte findings rule this out
*Progesterone to 17-hydroxyprogesterone*
- This reaction is catalyzed by **17α-hydroxylase**
- Deficiency leads to **decreased androgens and estrogens**, causing **undervirilization** in XY individuals and absent secondary sexual characteristics
- Would cause hypertension due to mineralocorticoid excess, but **cannot explain the virilization** seen in this XX patient
- The clinical picture of masculinization directly contradicts 17α-hydroxylase deficiency
*Androstenedione to estrone*
- This reaction is catalyzed by **aromatase**
- Aromatase deficiency causes accumulation of androgens and deficiency of estrogens
- While this could explain virilization, it **does not cause hypertension** or the electrolyte abnormalities (hypernatremia, hypokalemia) seen in this patient
- Aromatase deficiency would present with virilization but normal blood pressure
*Testosterone to dihydrotestosterone*
- This conversion is mediated by **5α-reductase**
- Deficiency causes **undervirilization** in XY individuals with ambiguous genitalia at birth
- **Would not cause virilization** in an XX individual, as this enzyme affects androgen potency rather than androgen production
- Does not explain the hypertension or electrolyte abnormalities
- 5α-reductase deficiency presents in genetic males (46,XY), not genetic females (46,XX)
Question 9: A 7-year-old boy is brought to the pediatrician by his parents due to pubic hair growth and changes in his voice. He has been developing in the 98th percentile for his age. His vaccination is up-to-date. The patient’s blood pressure is within the 60th percentile for his age. Physical examination reveals pubic and armpit hair, and Tanner stage 2 characterized by enlarged scrotum and testes. Laboratory findings are significant for the following:
Hemoglobin 13.1 g/dL
Hematocrit 39.7%
Leukocyte count 8,500/mm3
Neutrophils 65%
Lymphocytes 30%
Monocytes 5%
Mean corpuscular volume 82.2 μm3
Platelet count 20,000/mm3
Urine creatinine clearance 98 mL/min
Serum 17-hydroxyprogesterone 313 ng/dL (normal <110 ng/dL)
Which of the following enzymes is most likely to be defective in this patient?
A. Aromatase
B. 21-hydroxylase (Correct Answer)
C. 11ß-hydroxylase
D. 17-α-hydroxylase
E. 5-α-reductase
Explanation: ***21-hydroxylase***
- The elevated 17-hydroxyprogesterone level is a hallmark of **21-hydroxylase deficiency**, the most common cause of **congenital adrenal hyperplasia (CAH)**.
- Deficiency in this enzyme leads to the shunting of steroid precursors towards **androgen production**, causing premature pubic hair, voice changes, and accelerated growth in males, as seen in this patient.
*Aromatase*
- **Aromatase** converts androgens to estrogens; a deficiency would lead to masculinization in females and tall stature with delayed epiphyseal closure in males due to lack of estrogen for bone maturation.
- This enzyme deficiency would not lead to elevated 17-hydroxyprogesterone.
*11ß-hydroxylase*
- **11ß-hydroxylase deficiency** also causes CAH and leads to androgen excess but is characterized by an accumulation of **11-deoxycorticosterone** and **11-deoxycortisol**, which have mineralocorticoid activity, leading to **hypertension**.
- This patient has normal blood pressure and an elevated 17-hydroxyprogesterone, not 11-deoxycorticosterone or 11-deoxycortisol.
*17-α-hydroxylase*
- **17-α-hydroxylase deficiency** impairs the production of cortisol and sex steroids, leading to an accumulation of **mineralocorticoids** (like corticosterone and deoxycorticosterone), causing **hypertension** and **hypokalemia**.
- This condition would result in **decreased androgen production** and **delayed puberty**, which is contrary to the clinical presentation of this patient.
*5-α-reductase*
- **5-α-reductase** converts testosterone to the more potent dihydrotestosterone (DHT), which is crucial for external male virilization.
- A deficiency in this enzyme would lead to **undervirilization of external genitalia** in 46, XY individuals, typically not premature puberty with significant androgenic effects.
Question 10: An 8-year-old boy is brought to the pediatrician by his mother with nausea, vomiting, and decreased frequency of urination. He has acute lymphoblastic leukemia for which he received the 1st dose of chemotherapy 5 days ago. His leukocyte count was 60,000/mm3 before starting chemotherapy. The vital signs include: pulse 110/min, temperature 37.0°C (98.6°F), and blood pressure 100/70 mm Hg. The physical examination shows bilateral pedal edema. Which of the following serum studies and urinalysis findings will be helpful in confirming the diagnosis of this condition?
A. Hyperuricemia, hyperkalemia, hyperphosphatemia, and urinary monoclonal spike
B. Hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, urine supernatant pink, and positive for heme
C. Hyperkalemia, hyperphosphatemia, hypocalcemia, and extremely elevated creatine kinase (MM)
D. Hyperuricemia, hyperkalemia, hyperphosphatemia, lactic acidosis, and oxalate crystals
E. Hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and urate crystals in the urine (Correct Answer)
Explanation: ***Hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and urate crystals in the urine***
- This patient's presentation following chemotherapy, particularly with a high pre-treatment leukocyte count, is highly suggestive of **tumor lysis syndrome (TLS)**. TLS is characterized by rapid tumor cell breakdown, releasing intracellular contents into the bloodstream.
- The **four cardinal laboratory findings** of TLS are **hyperuricemia** (from nucleic acid breakdown), **hyperkalemia** (from intracellular potassium release), **hyperphosphatemia** (from intracellular phosphate release), and **hypocalcemia** (secondary to calcium-phosphate precipitation). The presence of **urate crystals in the urine** confirms the renal effects of uric acid overload, leading to acute kidney injury.
*Hyperuricemia, hyperkalemia, hyperphosphatemia, and urinary monoclonal spike*
- While **hyperuricemia, hyperkalemia, and hyperphosphatemia** are consistent with tumor lysis syndrome, a **urinary monoclonal spike** is typically associated with multiple myeloma or other plasma cell dyscrasias, not tumor lysis syndrome.
- The patient's history of acute lymphoblastic leukemia and recent chemotherapy points away from a monoclonal gammopathy.
- This option is also missing the key finding of **hypocalcemia**.
*Hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, urine supernatant pink, and positive for heme*
- **Hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia** are indeed the four cardinal metabolic abnormalities of TLS. However, a **pink urine supernatant and positive heme** indicate **hemoglobinuria** or **myoglobinuria**, pointing towards hemolysis or rhabdomyolysis, respectively.
- While TLS can lead to acute kidney injury, these specific urinalysis findings are not typical for TLS. The expected urinary finding would be **urate crystals**, not heme pigments.
*Hyperkalemia, hyperphosphatemia, hypocalcemia, and extremely elevated creatine kinase (MM)*
- **Hyperkalemia, hyperphosphatemia, and hypocalcemia** are consistent with TLS. However, **extremely elevated creatine kinase (MM)** is a hallmark of **rhabdomyolysis**, a condition involving breakdown of skeletal muscle.
- This option is also missing **hyperuricemia**, which is a cardinal feature of TLS.
- There is no clinical indication for rhabdomyolysis in this patient's presentation.
*Hyperuricemia, hyperkalemia, hyperphosphatemia, lactic acidosis, and oxalate crystals*
- While **hyperuricemia, hyperkalemia, and hyperphosphatemia** are characteristic of TLS, this option is missing **hypocalcemia**, one of the four cardinal metabolic abnormalities.
- Additionally, the presence of **oxalate crystals** in the urine is typically associated with **ethylene glycol poisoning** or primary hyperoxaluria, not tumor lysis syndrome. **Urate crystals**, not oxalate crystals, are expected due to the rapid breakdown of purines in TLS.
- **Lactic acidosis** can occur in severe TLS but is not a defining laboratory criterion.
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