Familial hypocalciuric hypercalcemia
Familial hypocalciuric hypercalcemia is an autosomal dominant, lifelong, asymptomatic hypercalcemia caused by an inactivating mutation of the calcium-sensing receptor, which raises the parathyroid hormone and renal calcium reabsorption set point. The clinching test is a 24-hour urine calcium-creatinine clearance ratio below 0.01, and management is reassurance and family screening, since parathyroidectomy does not correct the calcium and is not indicated.
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What this article covers
- Overview
A benign, inherited set-point disorder, not a parathyroid disease: familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant condition caused by an inactivating mutation of the…
- Epidemiology
Rare relative to primary hyperparathyroidism: primary hyperparathyroidism remains the most common cause of hypercalcemia overall, with FHH recognized as an uncommon inherited mimic.
- Risk factors
A family history of hypercalcemia: autosomal dominant inheritance means an affected parent has an expected transmission pattern to roughly half of offspring.
- Pathophysiology
The calcium-sensing receptor is the shared sensor for two organs: normally, the CaSR on the parathyroid chief cell and on the renal tubule detects the serum calcium concentration and adjusts PTH…
- Clinical features
Asymptomatic hypercalcemia is the defining presentation: most patients have no symptoms attributable to the elevated calcium and are identified incidentally or through family screening.
- Differential diagnosis
Primary hyperparathyroidism: hypercalcemia with elevated or inappropriately normal PTH, but distinguished from FHH by a high-normal or high 24-hour urine calcium, unlike the low urine calcium in FHH.
- Diagnosis
The diagnostic basis to establish is a low calcium-creatinine clearance ratio on a 24-hour urine collection, specifically a ratio below 0.01, obtained in a patient with hypercalcemia and a normal or…
- Management
First, once the calcium-creatinine clearance ratio confirms FHH, provide reassurance and stop any hypercalcemia workup directed at primary hyperparathyroidism, since no treatment is required for the hypercalcemia itself.
- Complications
None attributable to the hypercalcemia in typical FHH: patients do not develop the kidney stones, bone disease, or other sequelae that accompany chronic hypercalcemia from primary…
- Prognosis
Excellent and lifelong benign course: hypercalcemia remains mild and stable through life without progression to the complications of unregulated PTH excess.
- Prevention
Cascade screening of first-degree relatives with a serum calcium is the key preventive step once one family member is confirmed, since it avoids unnecessary hypercalcemia workups and inappropriate parathyroidectomy in relatives.
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Related articles
- Primary hyperparathyroidism
Primary hyperparathyroidism is autonomous PTH oversecretion, most often from a solitary parathyroid adenoma, producing hypercalcemia with an elevated or inappropriately normal PTH and low or low-normal phosphorus. Most patients are asymptomatic and identified on routine labs; parathyroidectomy is curative and is first-line for symptomatic disease or when specific biochemical, skeletal, or renal criteria are met, while observation with annual monitoring suffices for mild, asymptomatic disease.
- Hypercalcemia
Hypercalcemia is an elevated serum calcium concentration, most often caused by primary hyperparathyroidism in ambulatory patients or malignancy in hospitalized patients. Mild disease requires only treatment of the underlying cause, while severe or symptomatic hypercalcemia is treated with aggressive IV isotonic fluids, followed by an IV bisphosphonate or denosumab for sustained control and subcutaneous calcitonin as a rapid but short-lived bridge.
- Multiple endocrine neoplasia type 1
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant tumor-suppressor syndrome causing parathyroid, pancreatic, and pituitary tumors, the '3 Ps.' First-line treatment is organ-specific: parathyroidectomy for hyperparathyroidism, dopamine agonists for prolactinoma, and surgical resection or acid suppression for pancreatic neuroendocrine tumors.
- Hypocalcemia
Hypocalcemia is a low serum calcium concentration, most often from insufficient parathyroid hormone action (postsurgical or autoimmune hypoparathyroidism, hypomagnesemia, or PTH resistance) or from vitamin D deficiency and chronic kidney disease. Severe or symptomatic disease requires urgent intravenous calcium, while chronic disease is managed with oral calcium, vitamin D repletion, and calcitriol when PTH is absent or the kidney cannot activate vitamin D.