A 28-year-old man comes to the clinic for a routine wellness examination. He has no physic… — USMLE Step 3

A 28-year-old man comes to the clinic for a routine wellness examination. He has no physical complaints and feels well. His medical history is unremarkable, and he takes no medications. Family history is notable for a father who was told he had "high calcium" but never required surgery. Vital signs are within normal limits. Physical examination reveals no abnormalities.

Laboratory results are as follows:

Test	Result	Reference Range
Serum calcium	$11.1$ mg/dL	$8.4 - 10.2$ mg/dL
Serum albumin	$4.0$ g/dL	$3.5 - 5.0$ g/dL
Serum phosphorus	$2.5$ mg/dL	$2.7 - 4.5$ mg/dL
Intact parathyroid hormone (PTH)	$65$ pg/mL	$15 - 65$ pg/mL
Serum creatinine	$0.9$ mg/dL	$0.6 - 1.2$ mg/dL
24-hour urine calcium	$85$ mg/24h	$100 - 300$ mg/24h
24-hour urine creatinine	$1500$ mg/24h	$1000 - 2000$ mg/24h

Based on the interpretation of these laboratory results, which of the following is the most likely diagnosis?

A
Primary hyperparathyroidism
B
Humoral hypercalcemia of malignancy
C
Tertiary hyperparathyroidism
D
Sarcoidosis
Familial hypocalciuric hypercalcemiaAnswer

Answer

Familial hypocalciuric hypercalcemia

The correct diagnosis is Familial hypocalciuric hypercalcemia (FHH). The initial evaluation of hypercalcemia requires assessing the intact parathyroid hormone (PTH) level. In this patient, the PTH is inappropriately high-normal in the setting of hypercalcemia, indicating a PTH-dependent etiology. The differential diagnosis for PTH-dependent hypercalcemia primarily includes primary hyperparathyroidism and FHH. These are distinguished by evaluating urinary calcium excretion. FHH is an autosomal dominant disorder caused by an inactivating mutation in the calcium-sensing receptor (CaSR) in the parathyroid glands and kidneys. This requires a higher serum calcium concentration to suppress PTH release and results in enhanced renal calcium reabsorption. Consequently, patients exhibit mild hypercalcemia, normal or slightly elevated PTH, and profound hypocalciuria. The most accurate metric for differentiation is the calcium-to-creatinine clearance ratio (CCCR). A CCCR of less than

0.01

(in this patient,

\approx 0.0046

) is highly indicative of FHH, whereas primary hyperparathyroidism typically presents with a CCCR greater than

0.02

Step-by-Step Solution

Analyze the serum calcium and parathyroid hormone levels.

The patient has mild hypercalcemia (

11.1

mg/dL) with an inappropriately high-normal intact PTH (

65

pg/mL).

This establishes a PTH-dependent (or PTH-mediated) process, ruling out PTH-independent causes such as malignancy, vitamin D toxicity, or granulomatous disease.

Calculate the calcium-to-creatinine clearance ratio (CCCR).

Using the formula:

CCCR = (Urine_{Ca} \times Serum_{Cr}) / (Serum_{Ca} \times Urine_{Cr})

CCCR = (85 \times 0.9) / (11.1 \times 1500) = 76.5 / 16650 \approx 0.0046

The CCCR is essential to differentiate primary hyperparathyroidism from familial hypocalciuric hypercalcemia (FHH). A ratio

< 0.01

strongly indicates FHH.

Synthesize laboratory findings with the clinical history.

The low CCCR (

0.0046

), coupled with the family history of asymptomatic hypercalcemia, confirms the diagnosis of FHH.

FHH is caused by an inactivating mutation in the calcium-sensing receptor (CaSR), requiring a higher serum calcium level to suppress PTH and leading to increased renal calcium reabsorption.

Key Concept

Differentiating PTH-dependent causes of hypercalcemia using urinary calcium indices (CCCR).

Estimated Time:1m 30s

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