- Familial hypocalciuric hypercalcemia (FHH):
- Also known as benign familial hypercalcemia hypocalciuria:
- Is an autosomal dominant disorder with nearly 100% penetrance:
- Characterized by:
- Lifelong asymptomatic hypercalcemia
- Low urinary calcium excretion
- Inappropriately normal or mildly elevated PTH levels
- Characterized by:
- Is an autosomal dominant disorder with nearly 100% penetrance:
- Also known as benign familial hypercalcemia hypocalciuria:
- Genetics and Pathophysiology
- FHH results from heterozygous loss-of-function mutations affecting the:
- Calcium-sensing receptor (CaSR) signaling pathway
- Three genetic subtypes exist:
- FHH1:
- Most common – 65% to 70% of cases:
- Inactivating mutations in CASR gene:
- Encoding the calcium-sensing receptor
- FHH2 (rarest):
- Mutations in GNA11 gene:
- Encoding the Gα11 protein subunit
- Mutations in GNA11 gene:
- FHH3:
- Mutations in AP2S1 gene:
- Affecting receptor endocytosis
- Mutations in AP2S1 gene:
- FHH1:
- These mutations cause reduced sensitivity of parathyroid cells and renal tubular cells:
- To extracellular calcium:
- Resulting in a rightward shift in the set point for PTH suppression and increased renal calcium reabsorption (hypocalciuria)
- To extracellular calcium:
- FHH results from heterozygous loss-of-function mutations affecting the:
- Clinical Features
- FHH is typically benign and asymptomatic:
- With hypercalcemia often detected incidentally
- Most patients require no intervention
- Onset occurs in the first week of life:
- With lifelong persistence
- Rarely, adults may develop pancreatitis or chondrocalcinosis
- FHH3:
- May present with a more pronounced phenotype than FHH1 or FHH2
- FHH is typically benign and asymptomatic:
- Laboratory Findings
- The characteristic biochemical profile includes:
- Elevated serum calcium (mild to moderate)
- Low urinary calcium excretion:
- Fractional excretion of calcium typically < 0.01
- Normal or low-normal serum phosphate
- The characteristic biochemical profile includes:
- Distinguishing FHH from Primary Hyperparathyroidism:
- Differentiating FHH from primary hyperparathyroidism (PHPT):
- Is critical because FHH does not require surgery:
- Whereas PHPT is often treated surgically
- However, significant biochemical overlap exists between these conditions
- Is critical because FHH does not require surgery:
- Key distinguishing features:
- Important caveats:
- Up to 20% of FHH patients have fractional excretion of calcium > 0.01, and there is considerable overlap in all biochemical parameters
- The 24-hour urine calcium excretion has 96% sensitivity for PHPT but only 29% specificity for FHH:
- While the calcium/creatinine clearance ratio has 47% sensitivity for PHPT but 93% specificity for FHH
- Important caveats:
- Differentiating FHH from primary hyperparathyroidism (PHPT):
- Genetic Testing:
- Genetic testing for CASR, GNA11, and AP2S1 mutations is appropriate in:
- Young patients with hypercalcemia
- Patients with family history of hypercalcemia
- Fractional excretion of calcium < 0.02
- Fail parathyroidectomy
- Multigland disease
- Genetic testing for CASR, GNA11, and AP2S1 mutations is appropriate in:
- Management:
- FHH is a benign condition that does not require surgery
- Parathyroidectomy is contraindicated as hypercalcemia persists after subtotal parathyroidectomy and total parathyroidectomy causes permanent hypoparathyroidism
- For symptomatic cases (particularly FHH3):
- The calcimimetic cinacalcet has been used successfully to lower calcium levels and alleviate symptoms
- References
Familial Hypocalciuric Hypercalcemia as an Atypical Form of Primary Hyperparathyroidism. Marx SJ. Journal of Bone and Mineral Research : The Official Journal of the American Society for Bone and Mineral Research. 2018;33(1):27-31. doi:10.1002/jbmr.3339.
Familial Hypocalciuric Hypercalcemia and Related Disorders. Lee JY, Shoback DM. Best Practice & Research. Clinical Endocrinology & Metabolism. 2018;32(5):609-619. doi:10.1016/j.beem.2018.05.004.
Mutations Affecting G-Protein Subunit α11 in Hypercalcemia and Hypocalcemia. Nesbit MA, Hannan FM, Howles SA, et al. The New England Journal of Medicine. 2013;368(26):2476-2486. doi:10.1056/NEJMoa1300253.
Familial Hypocalciuric Hypercalcemia in an Infant: Diagnosis and Management Quandaries. Goldsweig B, Turk Yilmaz RS, Ravindranath Waikar A, Brownstein C, Carpenter TO. Journal of Bone and Mineral Research : The Official Journal of the American Society for Bone and Mineral Research. 2024;39(10):1406-1411. doi:10.1093/jbmr/zjae137.
Hyperparathyroid and Hypoparathyroid Disorders. Marx SJ. The New England Journal of Medicine. 2000;343(25):1863-75. doi:10.1056/NEJM200012213432508.
Hypercalcemia: A Review. Walker MD, Shane E. JAMA. 2022;328(16):1624-1636. doi:10.1001/jama.2022.18331.
Familial Hypocalciuric Hypercalcemia Types 1 and 3 and Primary Hyperparathyroidism: Similarities and Differences. Vargas-Poussou R, Mansour-Hendili L, Baron S, et al. The Journal of Clinical Endocrinology and Metabolism. 2016;101(5):2185-95. doi:10.1210/jc.2015-3442.
Urinary Calcium Indices in Primary Hyperparathyroidism (PHPT) and Familial Hypocalciuric Hypercalcaemia (FHH): Which Test Performs Best?. Arshad MF, McAllister J, Merchant A, et al. Postgraduate Medical Journal. 2021;97(1151):577-582. doi:10.1136/postgradmedj-2020-137718.
Cinacalcet for Symptomatic Hypercalcemia Caused by AP2S1 Mutations. Howles SA, Hannan FM, Babinsky VN, et al. The New England Journal of Medicine. 2016;374(14):1396-1398. doi:10.1056/NEJMc1511646.
Rodrigo Arrangoiz MS, MD, FACS, FSSO 