How to diagnose familial hypocalciuric hypercalcemia (FHH) in a patient with a family history of hypercalcemia?

How to Diagnose Familial Hypocalciuric Hypercalcemia

Diagnose FHH using a two-step approach: first calculate the calcium-to-creatinine clearance ratio (CCCR) from a 24-hour urine collection, then confirm with genetic testing for CASR gene mutations in patients with CCCR ≤0.020. 1

Initial Biochemical Assessment

Measure the following laboratory parameters to establish the biochemical phenotype:

• Serum calcium (typically mild to moderate elevation, usually <12 mg/dL or 3.0 mmol/L) 2, 1
• Serum PTH (normal or mildly elevated, not suppressed despite hypercalcemia) 1, 3
• 24-hour urine calcium and creatinine (hallmark finding is relative hypocalciuria) 1, 4
• Serum creatinine (renal function typically normal) 1
• Serum phosphate (may be low-normal or mildly decreased) 5
• 25-hydroxyvitamin D (typically normal with normal seasonal variations) 1

Calculate Calcium-to-Creatinine Clearance Ratio

The CCCR is the critical discriminating test between FHH and primary hyperparathyroidism (PHPT):

• Calculate CCCR using the formula: (urine calcium × serum creatinine) / (serum calcium × urine creatinine) 1
• CCCR ≤0.010 is highly suggestive of FHH 1
• CCCR ≤0.020 warrants genetic testing (diagnostic sensitivity of 98% when combined with genetic confirmation) 1
• CCCR >0.020 suggests PHPT rather than FHH, though overlap exists in 20-30% of cases 4

Important caveat: Ensure the 24-hour urine collection is complete and accurate, as incomplete collections will falsely lower the CCCR and lead to misdiagnosis 1

Genetic Testing for Confirmation

After identifying a CCCR ≤0.020, proceed with genetic testing:

• Test for CASR gene mutations first (accounts for majority of FHH cases, designated FHH1) 1, 5, 3
• If CASR testing is negative but clinical suspicion remains high, test for GNA11 mutations (FHH2, rarest form) 5
• Consider AP2S1 gene testing (FHH3, may present with more pronounced phenotype including neonatal hyperparathyroidism) 5
• Genetic testing should be performed in a certified laboratory using accredited methods 1

If genetic testing identifies a pathogenic variant, offer cascade testing to first-degree relatives to identify other affected family members 3

Family History Assessment

Obtain a detailed three-generation family history focusing on:

• Asymptomatic hypercalcemia in family members 3
• History of unsuccessful parathyroidectomy for presumed PHPT 1
• Autosomal dominant inheritance pattern (affects both sexes equally) 1, 3
• Consanguinity or both parents affected (raises concern for homozygous FHH/neonatal severe hyperparathyroidism) 5

Key Distinguishing Features from Primary Hyperparathyroidism

FHH differs from PHPT in the following ways:

• Urinary calcium excretion: Low in FHH (<100 mg/24h often), elevated in PHPT (>200 mg/24h typically) 1, 4
• Symptoms: Generally absent in FHH, often present in PHPT 1, 3
• Age of onset: Lifelong/congenital in FHH, typically develops in adulthood in PHPT 1
• Bone mineral density: Normal Z-scores in FHH despite slightly increased bone turnover 1
• Response to parathyroidectomy: No benefit in FHH (calcium remains elevated), curative in PHPT 1, 4

Special Considerations in Neonates and Infants

In newborns presenting with hypercalcemia:

• Consider FHH3 (AP2S1 mutations) if presenting with severe neonatal hyperparathyroidism, fractures, or failure to thrive 5
• Obtain parental calcium levels and genetic testing of both parents 5
• Homozygous or compound heterozygous FHH can present as neonatal severe hyperparathyroidism, a life-threatening condition requiring urgent intervention 5

Common Diagnostic Pitfalls to Avoid

Do not proceed to parathyroidectomy without first excluding FHH - this is the most critical error, as surgery will not correct hypercalcemia in FHH and exposes patients to unnecessary surgical risks 1, 4

Do not rely solely on CCCR - approximately 20-30% of FHH cases have CCCR >0.020, creating overlap with PHPT; genetic testing provides definitive diagnosis 4

Do not assume all hypocalciuric hypercalcemia is benign - homozygous FHH and FHH3 can cause significant morbidity requiring treatment 5

Do not use spot urine calcium-to-creatinine ratios - 24-hour urine collection is essential for accurate CCCR calculation 1

Consider thiazide diuretic use - these medications can mimic FHH by causing hypocalciuria and must be discontinued before testing 1

When FHH Does Not Require Treatment

Most patients with heterozygous FHH require no intervention as it follows a benign course with normal longevity 1, 3, 4

However, consider calcimimetic therapy (cinacalcet) in specific situations:

• Symptomatic hypercalcemia despite FHH diagnosis 2, 4
• Serum calcium >1 mg/dL (0.25 mmol/L) above normal range 2
• Risk of cardiac arrhythmias or QTc prolongation 2
• Neonatal severe hyperparathyroidism or symptomatic FHH3 5