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CASR-Related Disorders of Calcium Homeostasis

Gene: CASR

Protein: calcium-sensing receptor

Clinical Characteristics

Familial Hypocalciuric Hypercalcemia Type I (FHH)

• Caused by inactivating mutations:
  • Heterozygous mutation
  • Mutation causes mild to moderate impairment of CASR function
• Mild to moderate hypercalcemia with relative hypocalciuria
• Normal serum parathyroid (PTH) levels
• May have hypermagnesemia and urine calcium/creatinine clearance ratio below 0.01
• Typically asymptomatic
• Individuals with moderate disease may have:
  • Chondrocalcinosis
  • Gallstones
  • Kidney stones
  • Pancreatitis
  • Fatigue and weakness
  • Polydipsia/polyuria

Neonatal Severe Hyperparathyroidism (NSHPT)

• Caused by inactivating mutations:
  • Compound heterozygous or homozygous mutations
  • Heterozygous mutations with a dominant negative effect (rare)
• Presents within first six months of life
• Severe symptomatic hypercalcemia with relative hypocalciuria
• Multiglandular parathyroid hyperplasia
• Bone demineralization resulting in rib cage deformities, rachitic changes and multiple fractures
• Failure to thrive, hypotonia, lethargy
• Severe neurodevelopmental defects if left untreated 

Autosomal Dominant Hypocalcemia (ADH)/Familial Isolated Hypoparathyroidism (FIH)

• Caused by activating mutations (gain of function)
• Wide clinical spectrum
• May present with neonatal or childhood seizures secondary to fever and infection
• Hypocalcemia and hypercalciuria
• Normal to mildly elevated phosphate levels
• Low to normal parathyroid levels
• Increased risk for renal complications such as nephrocalcinosis, kidney stones or impaired renal function

Bartter Syndrome, Type V

• Caused by more severe activating mutations (gain of function)
• Hypocalcemia and hypercalciuria
• Renal salt wasting
• Hypokalemic metabolic alkalosis
• Elevated renin and aldosterone levels with low blood pressure

Inheritance Pattern

• Autosomal dominant for FHH, ADH, FIH, Bartter syndrome Type V
• Autosomal recessive for NSHPT
• Rarely autosomal dominant for NSHPT