Familial Hypocalciuric Hypercalcemia (FHH)
Definition and Pathophysiology
FHH is a benign, lifelong autosomal dominant condition characterized by mild-to-moderate hypercalcemia, inappropriately normal or elevated PTH levels, and the hallmark feature of relative hypocalciuria (low urinary calcium excretion) despite elevated serum calcium. 1, 2, 3
The disorder results from inactivating mutations affecting the calcium-sensing receptor (CaSR) signaling pathway, causing a generalized calcium hyposensitivity in both the parathyroid glands and kidneys. 2, 3 This means the body's calcium "thermostat" is reset to a higher set point, leading to compensatory hypercalcemia and reduced renal calcium excretion. 3
Genetic Subtypes
FHH has three distinct genetic forms based on the affected gene:
FHH1 (most common): Caused by heterozygous inactivating mutations in the CASR gene encoding the calcium-sensing receptor itself. 1, 2
FHH2 (rarest): Results from variants in GNA11, which encodes the α-subunit of G11, a downstream signaling protein in the CaSR pathway. 1
FHH3: Caused by variants in AP2S1 and may present with a more pronounced phenotype than FHH1 or FHH2. 1
The inheritance pattern is autosomal dominant with high penetrance, affecting both sexes equally. 2
Clinical Presentation
Most patients with FHH are completely asymptomatic with normal phenotype and normal longevity, which is the key distinguishing feature from other hypercalcemic conditions. 2, 3
Key clinical characteristics include:
- Mild-to-moderate hypercalcemia discovered incidentally on routine laboratory testing 2, 3
- Absence of typical hypercalcemic symptoms (fatigue, polyuria, kidney stones, bone pain) 3
- Normal bone mineral density despite slightly increased bone turnover 3
- Normal renal function 3
- Plasma 25-hydroxyvitamin D levels are normal with normal seasonal variations 3
- Plasma 1,25-dihydroxyvitamin D may be slightly increased compared to normal 3
Diagnostic Approach
Step 1: Calculate Calcium-to-Creatinine Clearance Ratio
The diagnostic hallmark is a calcium-to-creatinine clearance ratio (CCCR) ≤0.01 (some sources use ≤0.020) from a 24-hour urine collection, which distinguishes FHH from primary hyperparathyroidism (PHPT) where the ratio is typically >0.02. 3
The formula is: CCCR = (Urine calcium × Serum creatinine) / (Serum calcium × Urine creatinine)
Step 2: Genetic Testing
All patients with CCCR ≤0.020 should undergo genetic testing for mutations in CASR, GNA11, and AP2S1 genes. 3 This two-step diagnostic procedure has a sensitivity of 98%. 3
Step 3: Family Screening
Because FHH is autosomal dominant, obtain a detailed family history and screen first-degree relatives for asymptomatic hypercalcemia. 2 The presence of multiple affected family members strongly supports the diagnosis. 2
Critical Differential Diagnosis
The most important clinical challenge is distinguishing FHH from primary hyperparathyroidism (PHPT) to avoid unnecessary parathyroidectomy. 2, 3, 4
FHH vs. PHPT Comparison:
| Feature | FHH | PHPT |
|---|---|---|
| Urine calcium | Low (hypocalciuria) | Normal to high |
| CCCR | ≤0.01-0.020 | >0.02 |
| Symptoms | Absent | Often present |
| Family history | Positive | Usually negative |
| Age at diagnosis | Any age, often young | Usually >50 years |
| Treatment needed | No | Yes (surgery) |
Other differential diagnoses include hypercalcemia of malignancy and thiazide diuretic use. 3
Common Pitfalls and Caveats
Pitfall 1: Unnecessary Parathyroidectomy
The single most important clinical error is misdiagnosing FHH as PHPT and performing unnecessary parathyroidectomy, which will not normalize calcium levels and subjects patients to surgical risks without benefit. 2, 4
However, rare cases exist where FHH and parathyroid adenoma coexist in the same patient. 5 In these cases, surgery may improve but not normalize hypercalcemia, with calcium returning to FHH-typical levels postoperatively. 5
Pitfall 2: Neonatal Presentations
While FHH is benign in heterozygotes, homozygous or compound heterozygous inheritance can cause neonatal hyperparathyroidism (NHPT) or neonatal severe hyperparathyroidism (NSHPT), which are life-threatening conditions requiring urgent intervention. 1, 4 NSHPT has high morbidity and mortality. 4
Infants may present with severe hypercalcemia, bone demineralization, fractures, and failure to thrive. 1 Treatment may require low-calcium formula, cinacalcet (a calcimimetic that increases CaSR sensitivity), and in severe cases, parathyroidectomy. 1, 4
Pitfall 3: Genetic Counseling
Parents with FHH should receive genetic counseling about the 50% risk of transmission to offspring and the small but serious risk of severe neonatal disease if both parents carry mutations. 4
Management
FHH in heterozygotes requires no treatment—only reassurance and avoidance of unnecessary interventions. 3, 4
Management consists of:
- Confirming the diagnosis with CCCR and genetic testing 3
- Screening family members 2
- Providing genetic counseling 4
- Avoiding parathyroidectomy, calcium-lowering medications, and bisphosphonates 3, 4
- Monitoring for the rare development of concurrent parathyroid adenoma if calcium levels increase significantly 5
For severe neonatal forms (NSHPT), treatment options include low-calcium formula, cinacalcet, and potentially total parathyroidectomy with autotransplantation. 1, 4