✅ Model Answer:
• Diagnosis: Idiopathic infantile hypercalcemia (CYP24A1 mutation) – impaired 1,25-(OH)₂D degradation. Features: hypercalcemia, suppressed PTH, normal 25-OH D, elevated 1,25-(OH)₂D, hypercalciuria.
• Any other test: CYP24A1 gene sequencing; 24-hour urine calcium; renal ultrasound for nephrocalcinosis; exclude granulomatous disease (sarcoid, TB) with chest X-ray, ACE levels, and ophthalmology exam.
• What to do next: Low calcium and low vitamin D diet; IV fluids for hydration; pamidronate 1 mg/kg IV if severe hypercalcemia.
• Follow-up plan: Monitor calcium, phosphorus, 1,25-(OH)₂D, urine calcium; avoid vitamin D supplements; renal ultrasound annually; genetic counseling. May improve with age.

✅ Model Answer:
• Gene: CYP24A1 (encodes 24-hydroxylase) located on chromosome 20q13.2.
• Function: CYP24A1 is the key enzyme that degrades 1,25-dihydroxyvitamin D (1,25-(OH)₂D) into inactive metabolites.
• Mutation: Loss-of-function mutations in CYP24A1 → impaired 1,25-(OH)₂D breakdown → accumulation of active vitamin D.
• Inheritance: Autosomal recessive.
• Pathophysiology: Elevated 1,25-(OH)₂D → increased intestinal calcium absorption → hypercalcemia, suppressed PTH, hypercalciuria, nephrocalcinosis.
• Other associated mutations: SLC34A1 (sodium-phosphate cotransporter) – less common.

✅ Model Answer:
• Classic presentation (infants/toddlers):
- Hypercalcemia: Often discovered incidentally or during workup for failure to thrive.
- Hypercalciuria: Recurrent urinary tract infections, hematuria, nephrolithiasis.
- Nephrocalcinosis: Renal calcification (seen on ultrasound).
- Failure to thrive: Poor weight gain, vomiting, constipation.
- Dehydration, polyuria, polydipsia.
- Muscle hypotonia.
- Irritability, lethargy.
• Severe hypercalcemia: Can cause seizures, arrhythmias, or coma.
• Presentation: Usually diagnosed in infancy or early childhood (2-6 months of age).
• No dysmorphic features (unlike Williams syndrome).

✅ Model Answer:
• Biochemical tests:
- Serum calcium: Elevated.
- Ionized calcium: Elevated.
- Serum phosphorus: Normal (or low-normal).
- PTH: Low or suppressed (due to feedback inhibition).
- 25-OH vitamin D: Normal (excludes vitamin D toxicity).
- 1,25-(OH)₂ vitamin D: Elevated (pathognomonic).
- 24-hour urine calcium: Elevated (>4 mg/kg/day).
- Urine calcium/creatinine ratio: Elevated.
• Imaging:
- Renal ultrasound: For nephrocalcinosis or nephrolithiasis.
• Genetic testing:
- CYP24A1 gene sequencing: Confirmatory.
• Exclude other causes:
- Granulomatous disease: Chest X-ray, ACE levels, ophthalmology exam.
- Vitamin D toxicity: History, 25-OH D level.
- Williams syndrome: FISH/microarray for 7q11.23.

✅ Model Answer:
• Dietary management:
- Low calcium diet: Avoid dairy products, calcium-fortified foods.
- Low vitamin D diet: Avoid vitamin D-fortified foods and supplements.
- High fluid intake: To promote calciuresis.
• Medical therapy:
- IV hydration: Normal saline for severe hypercalcemia.
- Loop diuretics: Furosemide (if hydration adequate).
- Bisphosphonates: Pamidronate 1 mg/kg IV (for severe or symptomatic hypercalcemia).
- Corticosteroids: Prednisone (reduces intestinal calcium absorption – less effective in this condition).
• Ketoconazole: May reduce 1,25-(OH)₂D production (rarely used in children).
• Avoid: Vitamin D supplements, thiazide diuretics (increase calcium).

✅ Model Answer:
• Renal complications:
- Nephrocalcinosis: Calcium deposition in renal tubules → can lead to chronic kidney disease.
- Nephrolithiasis: Kidney stones → obstruction, pain, infection.
- Chronic kidney disease: In severe, long-standing cases.
- Polyuria, polydipsia.
• Metabolic:
- Hypercalcemic crisis: Ca >14 mg/dL → dehydration, confusion, seizures, arrhythmias.
- Soft tissue calcification.
• Gastrointestinal:
- Vomiting, constipation, failure to thrive.
• Neurologic:
- Irritability, lethargy, seizures.

✅ Model Answer:
• Prognosis:
- Variable: Depends on severity of hypercalcemia and response to treatment.
- Improved with early diagnosis: Dietary restriction can prevent complications.
- May improve with age: Some children show spontaneous improvement over time.
- Nephrocalcinosis: May be irreversible if established.
- Risk of chronic kidney disease: If nephrocalcinosis is severe.
• Long-term follow-up:
- Monitor calcium, phosphorus, 1,25-(OH)₂D: Every 3-6 months.
- Urine calcium/creatinine: To monitor for hypercalciuria.
- Renal ultrasound: Annually to monitor nephrocalcinosis.
- Blood pressure monitoring.
- Avoid: Vitamin D and calcium supplements.
- Genetic counseling: Autosomal recessive (25% recurrence risk).

✅ Model Answer:
• CYP24A1 (24-hydroxylase): A mitochondrial enzyme that initiates the degradation of 1,25-dihydroxyvitamin D (1,25-(OH)₂D) and 25-hydroxyvitamin D (25-OH D).
• Normal function:
- Hydroxylates 1,25-(OH)₂D at the C-24 position → forms 1,24,25-(OH)₃D → biologically inactive metabolites.
- Regulates 1,25-(OH)₂D levels to prevent hypercalcemia.
• In CYP24A1 deficiency:
- Impaired 1,25-(OH)₂D degradation → accumulation of active vitamin D.
- Results in increased intestinal calcium absorption → hypercalcemia, suppressed PTH, hypercalciuria.
• Clinical significance:
- Idiopathic infantile hypercalcemia: CYP24A1 mutations cause this condition.
- Diagnosis: Elevated 1,25-(OH)₂D with normal 25-OH D is a hallmark.
- Treatment: Low calcium/vitamin D diet and avoiding vitamin D supplements.