How to diagnose Familial Hypocalciuric Hypercalcemia (FHH)?

Diagnosis of Familial Hypocalciuric Hypercalcemia (FHH)

The diagnosis of Familial Hypocalciuric Hypercalcemia requires measurement of the calcium/creatinine clearance ratio from a 24-hour urine collection, with a ratio ≤0.020 being diagnostic, followed by genetic testing for mutations in the CASR gene for confirmation. 1

Clinical Presentation and Laboratory Findings

FHH is characterized by:

• Mild to moderate PTH-dependent hypercalcemia (typically asymptomatic)
• Normal to reduced urinary calcium excretion despite hypercalcemia
• Calcium/creatinine clearance ratio <0.01 (key diagnostic feature)
• Unsuppressed or mildly elevated parathyroid hormone (PTH) levels
• Normal renal function
• Mild hypermagnesemia may be present
• Normal phenotype with absence of hypercalcemic symptoms 1, 2

Diagnostic Algorithm

1. Initial Laboratory Evaluation:

   • Serum calcium (total and ionized)
   • Serum phosphate
   • Serum PTH
   • Serum magnesium
   • Serum creatinine
   • 24-hour urine collection for calcium and creatinine

2. Calculate Calcium/Creatinine Clearance Ratio:

   • Formula: (Urine calcium × Serum creatinine) / (Serum calcium × Urine creatinine)
   • Ratio ≤0.020 is highly suggestive of FHH 1

3. Genetic Testing:

   • Perform genetic testing for mutations in:
     • CASR gene (FHH type 1, most common)
     • GNA11 gene (FHH type 2, rare)
     • AP2S1 gene (FHH type 3) 3

4. Family Screening:

   • Test first-degree relatives for hypercalcemia
   • Document pattern of inheritance (typically autosomal dominant) 2

Differential Diagnosis

The main differential diagnosis is primary hyperparathyroidism (PHPT). Key distinguishing features:

Feature	FHH	PHPT
Calcium/creatinine clearance ratio	≤0.020	>0.020
Urinary calcium excretion	Low/normal	Elevated
PTH levels	Normal to mildly elevated	Elevated
Family history	Often positive	Usually negative
Symptoms	Usually asymptomatic	Often symptomatic
Response to parathyroidectomy	No resolution of hypercalcemia	Resolution of hypercalcemia

Other conditions to consider in differential diagnosis:

• Hypercalcemia of malignancy
• Thiazide diuretic use
• Tertiary hyperparathyroidism 1, 2

Important Clinical Considerations

• FHH can occasionally coexist with parathyroid adenoma, complicating the diagnosis 4
• Even without a family history, hypocalciuric hypercalcemia should be considered before proceeding with neck surgery in patients with hypercalcemia 5
• FHH is a benign condition that typically does not require treatment 1
• Parathyroidectomy is not indicated for FHH and will not normalize calcium levels 2
• Genetic testing is crucial for definitive diagnosis, but a negative test does not rule out FHH if clinical presentation strongly suggests the condition 3

Pitfalls to Avoid

• Misdiagnosing FHH as primary hyperparathyroidism, leading to unnecessary parathyroidectomy
• Failing to calculate calcium/creatinine clearance ratio in patients with hypercalcemia
• Not considering FHH in asymptomatic patients with hypercalcemia
• Overlooking the need for genetic testing in patients with calcium/creatinine clearance ratio ≤0.020
• Not screening family members after diagnosis of index case
• Failing to consider FHH in patients without family history of hypercalcemia 1, 5

By following this diagnostic approach, clinicians can accurately diagnose FHH and avoid unnecessary interventions for this benign condition.