What is Familial Hypocalciuric Hypercalcemia (FHH)?

Familial Hypocalciuric Hypercalcemia (FHH)

Familial Hypocalciuric Hypercalcemia (FHH) is an autosomal dominant genetic disorder characterized by mild to moderate hypercalcemia, relative hypocalciuria, and normal to slightly elevated parathyroid hormone (PTH) levels, typically requiring no intervention due to its benign nature.

Definition and Pathophysiology

FHH is caused by mutations that impair the function of the calcium-sensing receptor (CaSR) or related signaling pathways, resulting in:

• Altered calcium homeostasis with elevated set point for calcium
• Reduced sensitivity to extracellular calcium in both parathyroid glands and kidneys
• Inappropriate parathyroid hormone secretion despite hypercalcemia
• Increased renal tubular calcium reabsorption leading to hypocalciuria

Classification

FHH is classified into three subtypes based on the affected gene:

1. FHH1 (most common): Caused by heterozygous inactivating variants in the calcium-sensing receptor gene (CASR) 1
2. FHH2 (rarest form): Due to variants in GNA11, encoding the α-subunit of G11 protein 2
3. FHH3: Results from variants in AP2S1, which may present with more pronounced phenotype than other subtypes 2

Clinical Presentation

Most patients with FHH are asymptomatic and have:

• Mild to moderate hypercalcemia (typically discovered incidentally)
• Normal longevity
• Equal prevalence in men and women
• High penetrance with autosomal dominant inheritance pattern 1

In rare cases, patients may present with:

• Symptoms associated with hypercalcemia
• Incidental bony lesions (as reported in some cases) 3
• In infants: more severe presentations including fractures have been reported 2

Laboratory Findings

Key diagnostic features include:

• Elevated serum calcium (mild to moderate)
• Low urinary calcium excretion (hypocalciuria)
• Normal to slightly elevated PTH levels
• Elevated calcitriol in some cases 3
• Calcium-to-creatinine clearance ratio typically <0.01

Differential Diagnosis

The main differential diagnosis is primary hyperparathyroidism (pHPT), which can be difficult to distinguish from FHH as both conditions present with hypercalcemia 1, 3. Other causes of hypercalcemia should also be considered.

Diagnostic Approach

1. Family history: Presence of hypercalcemia in family members strongly suggests FHH
2. Urinary calcium excretion: Low urinary calcium excretion is characteristic
3. Genetic testing: Confirmation through sequencing of CASR, AP2S1, and GNA11 genes
   • Particularly important when clinical presentation is atypical or overlaps with primary hyperparathyroidism 4

Management

FHH is generally considered a benign condition that typically requires:

• No specific treatment in most cases
• Avoidance of unnecessary parathyroidectomy (which is ineffective for FHH)
• Regular monitoring of calcium levels
• Genetic counseling for affected families 1, 3

In rare cases with more severe phenotypes (particularly FHH3):

• Low-calcium formula and cinacalcet have been reported to improve biochemical profiles in infants 2

Clinical Pitfalls and Caveats

1. Misdiagnosis as primary hyperparathyroidism: Leading to unnecessary parathyroidectomy
2. Overlapping features: Some FHH patients may have parathyroid gland abnormalities that mimic primary hyperparathyroidism 5
3. Variable penetrance: Family members may have different clinical manifestations despite carrying the same mutation 3
4. Novel mutations: Continuously being discovered, requiring comprehensive genetic testing 5

Conclusion

Accurate diagnosis of FHH is crucial to avoid unnecessary surgical or medical interventions. The combination of family history, biochemical profile (hypercalcemia with hypocalciuria), and genetic testing provides the most reliable approach to diagnosis.