A 34-year-old woman comes to the clinic to establish care. She has no acute complaints, fe… — USMLE Step 3

A 34-year-old woman comes to the clinic to establish care. She has no acute complaints, feels well, and exercises regularly. She has no significant past medical history and takes no medications or over-the-counter dietary supplements. She was adopted as an infant and does not know her family medical history.

Vital signs are within normal limits. Physical examination reveals no abnormalities. Routine chemistry panels obtained prior to the visit show the following results:

Laboratory Test	Result	Reference Range
Calcium, serum	11.0 mg/dL	8.4-10.2 mg/dL
Albumin, serum	4.0 g/dL	3.5-5.0 g/dL
Phosphorus, serum	2.5 mg/dL	2.5-4.5 mg/dL
Creatinine, serum	1.0 mg/dL	0.6-1.2 mg/dL
25-Hydroxyvitamin D	35 ng/mL	20-50 ng/mL
Intact parathyroid hormone	62 pg/mL	10-65 pg/mL

Given the serum calcium level, additional laboratory testing is obtained from a spot urine sample:

Laboratory Test	Result	Reference Range
Calcium, spot urine	4.0 mg/dL	Varies
Creatinine, spot urine	100 mg/dL	Varies

Which of the following best describes the underlying mechanism responsible for this patient's laboratory findings?

Inactivating mutation of the calcium-sensing receptorAnswer
B
Autonomous overproduction of parathyroid hormone by a solitary adenoma
C
Ectopic secretion of parathyroid hormone-related peptide
D
Increased macrophage-mediated 1-alpha-hydroxylation of 25-hydroxyvitamin D
E
Increased renal tubular reabsorption of calcium due to a sodium-chloride cotransporter blockade

Answer

Inactivating mutation of the calcium-sensing receptor

The correct answer accurately describes the pathophysiology of familial hypocalciuric hypercalcemia (FHH). This patient presents with hypercalcemia and a high-normal intact parathyroid hormone level. In a healthy individual, hypercalcemia should suppress PTH. An inappropriately normal or elevated PTH indicates a PTH-dependent process. To distinguish between primary hyperparathyroidism and FHH, the calcium-to-creatinine clearance ratio (CCCR) must be calculated. The formula is:

CCCR = \frac{U_{Ca} \times S_{Cr}}{S_{Ca} \times U_{Cr}}

. In this patient, the CCCR is

(4.0 \times 1.0) / (11.0 \times 100) \approx 0.0036

. A CCCR < 0.01 is diagnostic of FHH. This autosomal dominant disorder is caused by an inactivating mutation in the calcium-sensing receptor (CaSR) in the parathyroid glands and kidneys. It requires higher calcium levels to suppress PTH secretion and leads to increased renal tubular reabsorption of calcium, causing the characteristic hypocalciuria.

Step-by-Step Solution

Evaluate the mechanism of hypercalcemia by interpreting the intact parathyroid hormone (PTH) level.

The patient has elevated serum calcium (11.0 mg/dL) but a 'normal' intact PTH (62 pg/mL).

In the setting of hypercalcemia, the parathyroid glands should be physiologically suppressed, leading to low intact PTH levels (< 20 pg/mL). An inappropriately normal or high PTH indicates a PTH-dependent mechanism (e.g., primary hyperparathyroidism or familial hypocalciuric hypercalcemia).

Differentiate between the causes of PTH-dependent hypercalcemia by calculating the calcium-to-creatinine clearance ratio (CCCR).

Calculate CCCR using the formula:

CCCR = \frac{U_{Ca} \times S_{Cr}}{S_{Ca} \times U_{Cr}}

Plugging in the values:

CCCR = \frac{4.0 \times 1.0}{11.0 \times 100} = \frac{4}{1100} \approx 0.0036

A CCCR less than 0.01 strongly suggests familial hypocalciuric hypercalcemia (FHH), while a ratio greater than 0.02 is consistent with primary hyperparathyroidism.

Correlate the diagnostic findings with the underlying pathophysiology.

The laboratory profile is diagnostic for FHH, which is characterized by an inactivating mutation of the calcium-sensing receptor.

Understanding the molecular mechanism confirms the diagnosis and explains both the renal (hypocalciuria) and parathyroid (failure to suppress PTH) laboratory abnormalities.

Key Concept

Familial hypocalciuric hypercalcemia (FHH) presents with PTH-dependent hypercalcemia and a very low calcium-to-creatinine clearance ratio (< 0.01) due to an inactivating mutation of the calcium-sensing receptor.

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