familial hypocalciuric hypercalcemia

**Pathophysiology** - Inactivating (loss-of-function) mutation of the calcium-sensing receptor (CaSR), a G-protein-coupled receptor (Gq) on parathyroid chief cells and the thick ascending limb (TAL) of the loop of Henle (basolateral membrane) in the kidney. - Inheritance: autosomal dominant, high penetrance. FHH type 1 = CASR (3q21.1), the most common. FHH type 2 = GNA11 (Gα11), type 3 = AP2S1 (adaptor protein 2 sigma subunit, 19q13). - Because the receptor is "set" at a higher threshold, the parathyroid glands sense calcium as falsely low. Result: PTH is not appropriately suppressed despite hypercalcemia. - In the kidney, reduced CaSR signaling in the TAL means more paracellular Ca²⁺ and Mg²⁺ reabsorption, so urinary calcium is low (hypocalciuria). Mg²⁺ is often high-normal or mildly elevated.

**Clinical features** - Usually asymptomatic and found incidentally on labs, often in childhood or in relatives of an affected person. - Mild hypercalcemia, normal-to-mildly elevated PTH, high-normal or mildly elevated serum Mg, and normal or low phosphate. - Usually no kidney stones, bone disease, pancreatitis, or other complications of hypercalcemia. Chondrocalcinosis and pancreatitis are rare reported associations. - Parathyroid glands are normal in size. Subtotal parathyroidectomy does NOT correct the hypercalcemia.

**Diagnosis** - 24-hour urine calcium-to-creatinine clearance ratio: FHH <0.01, and primary hyperparathyroidism (PHPT) usually >0.02. Values of 0.01–0.02 are indeterminate. - Family history of mild hypercalcemia, and onset before age 10 favors FHH. - Genetic testing (CASR, GNA11, AP2S1) confirms the diagnosis. - Rule out thiazide use and vitamin D/calcium supplementation. Thiazides also cause hypocalciuria and hypercalcemia.

**Management** - Typically none. Reassurance and avoiding unnecessary parathyroid surgery. - Cinacalcet (a calcimimetic) is an option for rare symptomatic cases but is usually unnecessary.

**Key associations and complications** - Neonatal severe hyperparathyroidism (NSHPT): when a child inherits two mutated CASR alleles (homozygous or compound heterozygous, often from two FHH parents), it presents with severe hypercalcemia, bone demineralization, failure to thrive, and hypotonia. It requires urgent total parathyroidectomy. - Contrast with autosomal dominant hypocalcemia (ADH), a gain-of-function CASR mutation that causes hypocalcemia with relative hypercalciuria.

**Board-style comparison** - FHH: ↑Ca, ↔/↑PTH, ↓urine Ca (Ca/Cr clearance <0.01), benign. - PHPT: ↑Ca, ↑PTH, ↑urine Ca (↔ to ↑), ↓phosphate, with stones, bones, groans, and psychiatric overtones. - Malignancy (PTHrP): ↑Ca, ↓PTH, ↑urine Ca. - Thiazides: ↑Ca, ↓urine Ca, PTH low-normal/suppressed, resolves after stopping the drug.

**High-yield pearl**: A patient with mild asymptomatic hypercalcemia, inappropriately normal PTH, a family history of hypercalcemia, and low urinary calcium has FHH. The next step is to calculate the calcium/creatinine clearance ratio, not to refer for surgery.