A 34-year-old woman comes to the clinic to discuss laboratory results obtained during a ro… — USMLE Step 3

A 34-year-old woman comes to the clinic to discuss laboratory results obtained during a routine employer-mandated health screening. She feels completely well and reports no fatigue, polyuria, abdominal pain, or bone pain. She has no significant past medical history and takes no medications or dietary supplements. Family history is notable for mild, asymptomatic hypercalcemia in her father.

Vital signs and physical examination are within normal limits.

Initial screening labs showed a serum calcium level of $11.3$ mg/dL. Confirmatory laboratory studies are obtained today:

Laboratory Test	Result	Reference Range
Calcium, serum	$11.4$ mg/dL	$8.4 - 10.2$ mg/dL
Albumin, serum	$4.0$ g/dL	$3.5 - 5.0$ g/dL
Phosphorus, serum	$2.3$ mg/dL	$2.5 - 4.5$ mg/dL
Creatinine, serum	$0.8$ mg/dL	$0.6 - 1.1$ mg/dL
25-hydroxyvitamin D	$32$ ng/mL	$20 - 50$ ng/mL
Intact parathyroid hormone (PTH)	$68$ pg/mL	$10 - 65$ pg/mL

A 24-hour urine collection shows a total calcium excretion of $45$ mg/day. The calculated urine calcium-to-creatinine clearance ratio (UCCR) is $0.006$ .

Which of the following is the most likely diagnosis?

Familial hypocalciuric hypercalcemiaAnswer
B
Primary hyperparathyroidism
C
Granulomatous disease-associated hypercalcemia
D
Humoral hypercalcemia of malignancy
E
Secondary hyperparathyroidism

Answer

The most likely diagnosis is Familial hypocalciuric hypercalcemia, evidenced by the combination of hypercalcemia, inappropriately normal intact PTH, and a uniquely low urine calcium-to-creatinine clearance ratio.

The patient's clinical presentation of asymptomatic hypercalcemia, an inappropriately normal intact PTH level, a family history of hypercalcemia, and a calcium-to-creatinine clearance ratio

< 0.01

is classic for Familial hypocalciuric hypercalcemia (FHH). 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 higher serum calcium levels to suppress PTH secretion and causes the kidneys to aggressively reabsorb calcium, leading to profound hypocalciuria.

Step-by-Step Solution

Analyze the serum laboratory profile to determine the mechanism of hypercalcemia.

The patient has hypercalcemia (

11.4

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

68

pg/mL) and low-normal phosphorus. This indicates a PTH-dependent etiology.

Establishing whether hypercalcemia is PTH-dependent (PTH normal or high) or PTH-independent (PTH suppressed) is the critical first step in formulating a differential diagnosis for hypercalcemia.

Differentiate between the causes of PTH-dependent hypercalcemia.

The differential diagnosis narrows down primarily to Primary hyperparathyroidism and Familial hypocalciuric hypercalcemia (FHH).

Both conditions can present with asymptomatic hypercalcemia and normal-to-elevated PTH levels, making them difficult to distinguish on serum blood tests alone.

Evaluate the 24-hour urine indices.

The 24-hour urine calcium is low (

45

mg/day) and the calcium-to-creatinine clearance ratio (UCCR) is

0.006

A UCCR

< 0.01

strongly points toward FHH, which is caused by a defective calcium-sensing receptor leading to increased renal calcium reabsorption. Primary hyperparathyroidism typically has a UCCR

> 0.02

Key Concept

Differentiating primary hyperparathyroidism from familial hypocalciuric hypercalcemia using the urine calcium-to-creatinine clearance ratio.

Estimated Time:1m 30s

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