Familial Hypocalciuric Hypercalcemia

Excerpt

Familial hypocalciuric hypercalcemia (FHH) is a genetic condition characterized by mild hypercalcemia, typically found in otherwise healthy and asymptomatic individuals. Hypercalcemia is a common cause for referral and evaluation in medicine commonly encountered in routine serum chemistry. Differential diagnoses of hypercalcemia are usually based on the acuity and severity of presentation and concomitant level of serum parathyroid hormone (PTH). FHH arises from calcium-sensing receptor gene (CASR) mutations, leading to decreased receptor activity in response to serum calcium levels. This results in mild hypercalcemia, hypocalciuria, hypermagnesemia, and hypophosphatemia, with normal or slightly elevated serum PTH levels.

FHH is usually benign and lacks the severe long-term consequences associated with other hypercalcemia syndromes. The condition's hallmark is an altered calcium-sensing mechanism, making the parathyroid glands less sensitive to calcium and requiring a higher serum calcium level to suppress PTH release. Increased calcium and magnesium reabsorption in the kidneys can also result.

Diagnosing FHH can be challenging due to its overlap with primary hyperparathyroidism (PHPT). Diagnostic evaluation usually includes family history, serum chemistry records, and 24-hour urine calcium excretion measurement. A calcium clearance to creatinine clearance ratio (Ca/Cr) of <0.01 is indicative of FHH in most cases. Genetic testing for CASR mutations is recommended in ambiguous cases. While most FHH patients remain asymptomatic, those with symptoms may experience fatigue, weakness, constipation, polyuria, polydipsia, or headaches. FHH typically does not increase fracture risk, although there have been reports of intrauterine bone abnormalities, chondrocalcinosis, and pancreatitis in some patients. Treatment mainly involves patient education and reassurance, with calcimimetic medications like Cinacalcet-HCL or bisphosphonates used in more symptomatic cases despite not being FDA-approved for FHH.