A 28-year-old female patient is evaluated at an outpatient clinic to establish primary car… — USMLE Step 3

A 28-year-old female patient is evaluated at an outpatient clinic to establish primary care. She has no specific complaints, exercises regularly, and reports feeling well. She does not take any medications, over-the-counter supplements, or illicit substances. Her family history is notable for a father who was told he had "high blood calcium" years ago but never required surgery. Vital signs are within normal limits. Physical examination reveals a non-palpable thyroid gland and normal deep tendon reflexes.

Laboratory evaluation shows:
Serum calcium: $11.3$ mg/dL (Normal: $8.4-10.2$ mg/dL)
Serum albumin: $4.1$ g/dL (Normal: $3.5-5.0$ g/dL)
Serum phosphorus: $3.0$ mg/dL (Normal: $2.5-4.5$ mg/dL)
Intact parathyroid hormone: $58$ pg/mL (Normal: $15-65$ pg/mL)
24-hour urinary calcium: $42$ mg/24 hr (Normal: $100-300$ mg/24 hr)

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

A
Autonomous monoclonal proliferation of parathyroid chief cells
B
Inhibition of the apical sodium-chloride cotransporter in the distal tubule
Decreased sensitivity of a transmembrane G-protein-coupled receptor to extracellular cationsAnswer
D
Ectopic secretion of a peptide homologous to the amino-terminal sequence of parathyroid hormone
E
Unregulated extrarenal production of 1-alpha-hydroxylase by macrophages

Answer

Decreased sensitivity of a transmembrane G-protein-coupled receptor to extracellular cations

The correct answer accurately describes the pathophysiology of Familial Hypocalciuric Hypercalcemia (FHH). FHH is a benign, autosomal dominant condition caused by a defective Calcium-Sensing Receptor (CaSR) in the parathyroid glands and kidneys. The CaSR is a transmembrane G-protein-coupled receptor. Because the receptor is less sensitive to extracellular calcium cations, higher-than-normal serum calcium levels are required to suppress parathyroid hormone (PTH) release. Simultaneously, the defective receptors in the renal tubules interpret the calcium level as falsely low, leading to maximal calcium reabsorption and thus remarkably low 24-hour urinary calcium. This patient's asymptomatic presentation, mild hypercalcemia, inappropriately normal PTH, profound hypocalciuria, and family history of benign high calcium perfectly match this mechanism.

Step-by-Step Solution

Analyze the patient's clinical and laboratory presentation.

The patient has asymptomatic hypercalcemia with inappropriately high-normal intact PTH (

58

pg/mL) and remarkably low 24-hour urinary calcium (

42

mg).

Establishing the complete laboratory profile is necessary to differentiate the causes of hypercalcemia.

Formulate a differential diagnosis based on the calcium and PTH levels.

Hypercalcemia with unsuppressed PTH narrows the differential to primary hyperparathyroidism, lithium use, and Familial Hypocalciuric Hypercalcemia (FHH).

Most other causes of hypercalcemia (malignancy, vitamin D toxicity, granulomatous disease) would result in a suppressed intact PTH level via normal negative feedback.

Differentiate between primary hyperparathyroidism and FHH.

The severe hypocalciuria (<

100

mg/24 hr) in the absence of thiazide diuretics, combined with a benign family history, strongly points to FHH.

Primary hyperparathyroidism typically presents with hypercalciuria or high-normal urinary calcium due to the increased filtered load of calcium overwhelming renal reabsorption.

Identify the molecular mechanism of FHH.

FHH is caused by an inactivating mutation of the Calcium-Sensing Receptor (CaSR), which is a G-protein-coupled receptor.

The question specifically asks for the underlying molecular mechanism.

Key Concept

Familial Hypocalciuric Hypercalcemia (FHH) is an autosomal dominant disorder caused by inactivating mutations of the Calcium-Sensing Receptor (CaSR), a G-protein-coupled receptor, leading to higher calcium levels needed to suppress PTH and increased renal calcium reabsorption.

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