A 32-year-old man presents to the clinic for a routine check-up required by his new employ… — USMLE Step 3

A 32-year-old man presents to the clinic for a routine check-up required by his new employer. He feels well and has no fatigue, abdominal pain, bone pain, or changes in urination. He takes no medications. His family history is significant for his father being diagnosed with a "mild calcium problem" years ago, which never required surgical treatment. Vital signs are within normal limits, and physical examination is unremarkable.

Laboratory studies are obtained:

Test	Result	Reference Range
Serum calcium	$11.2\text{ mg/dL}$	$8.4-10.2\text{ mg/dL}$
Serum albumin	$4.1\text{ g/dL}$	$3.5-5.0\text{ g/dL}$
Serum phosphorus	$2.4\text{ mg/dL}$	$2.5-4.5\text{ mg/dL}$
Intact parathyroid hormone	$72\text{ pg/mL}$	$10-65\text{ pg/mL}$
Serum creatinine	$1.0\text{ mg/dL}$	$0.6-1.2\text{ mg/dL}$
25-hydroxyvitamin D	$34\text{ ng/mL}$	$20-40\text{ ng/mL}$
Spot urine calcium	$4\text{ mg/dL}$	$-$
Spot urine creatinine	$100\text{ mg/dL}$	$-$

Which of the following best explains this patient's laboratory findings?

Decreased sensitivity of calcium-sensing receptors in the parathyroid glands and kidneysAnswer
B
Monoclonal proliferation of parathyroid chief cells forming an adenoma
C
Ectopic secretion of a protein that mimics the action of parathyroid hormone
D
Granuloma-mediated extrarenal conversion of 25-hydroxyvitamin D to its active form
E
Defective mineralization of osteoid leading to a compensatory increase in parathyroid hormone

Answer

The correct underlying mechanism is decreased sensitivity of calcium-sensing receptors in the parathyroid glands and kidneys, characteristic of Familial Hypocalciuric Hypercalcemia.

The correct answer identifies the pathophysiology of Familial Hypocalciuric Hypercalcemia (FHH). The patient presents with asymptomatic hypercalcemia, slightly elevated PTH, and a suggestive family history. To differentiate FHH from primary hyperparathyroidism, the calcium to creatinine clearance ratio (UCCR) is calculated. This patient's UCCR is approximately 0.0035 (less than 0.01), confirming FHH. FHH is caused by an inactivating mutation in the calcium-sensing receptors (CaSR) in the parathyroid glands (requiring higher calcium levels to suppress PTH) and in the kidneys (leading to increased calcium reabsorption and low urine calcium).

Step-by-Step Solution

Analyze the basic metabolic panel and parathyroid hormone results.

The patient has hypercalcemia, hypophosphatemia, and an inappropriately elevated intact PTH level.

This establishes that the hypercalcemia is PTH-dependent, narrowing the differential diagnosis primarily to primary hyperparathyroidism and Familial Hypocalciuric Hypercalcemia (FHH).

Calculate the calcium to creatinine clearance ratio (UCCR) using the spot urine and serum values.

UCCR = \frac{\text{Urine Calcium} \times \text{Serum Creatinine}}{\text{Serum Calcium} \times \text{Urine Creatinine}} = \frac{4 \times 1.0}{11.2 \times 100} = \frac{4}{1120} \approx 0.0035

UCCR is required to distinguish FHH from primary hyperparathyroidism. A UCCR less than 0.01 is diagnostic of FHH, whereas a value greater than 0.02 is seen in primary hyperparathyroidism.

Identify the underlying pathophysiology of the diagnosed condition.

The patient has FHH, an autosomal dominant disorder caused by an inactivating mutation in the calcium-sensing receptor (CaSR) gene.

This mutation requires higher serum calcium levels to suppress PTH secretion and simultaneously causes increased renal tubular reabsorption of calcium, leading to hypocalciuria.

Key Concept

Familial Hypocalciuric Hypercalcemia (FHH) is differentiated from primary hyperparathyroidism by calculating the calcium to creatinine clearance ratio (UCCR). A UCCR < 0.01 in the setting of PTH-dependent hypercalcemia indicates FHH, caused by an inactivating mutation of the calcium-sensing receptor.

Estimated Time:1m 30s

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