Familial Hypocalciuric Hypercalcaemia

Familial hypocalciuric hypercalcaemia is a lifelong, usually benign, mild hypercalcaemia with low urinary calcium excretion, caused by inactivating variants in genes of the calcium sensing system, and inherited in an autosomal dominant way.

Type 1 (CASR) is the most common, with types 2 (GNA11) and 3 (AP2S1) rare. Prevalence is roughly 1 in 10,000 to 1 in 100,000.

Biallelic CASR variants cause neonatal severe hyperparathyroidism, with life threatening hypercalcaemia, bone disease and failure to thrive.

Pathophysiology.

The calcium sensing receptor sets the calcium level at which the parathyroid gland and kidney respond. Reduced sensing raises the set point: parathyroid hormone is not suppressed until calcium is higher, and the kidney reabsorbs calcium more avidly.

• Almost always asymptomatic, found incidentally. Adjusted calcium is mildly raised (usually under 3.0 mmol/L, 12 mg/dL).
• Family history of mild hypercalcaemia, often with failed parathyroidectomy. Pancreatitis is rare.

Red flags.

• Neonate with hypotonia, poor feeding, fractures or respiratory distress (neonatal severe hyperparathyroidism).
• Calcium over 3.0 mmol/L, which makes another diagnosis more likely.

• Raised albumin adjusted calcium with parathyroid hormone normal or mildly raised, and magnesium high normal or mildly raised.
• Calcium to creatinine clearance ratio, from a 24-hour urine collection and matching serum values: under 0.01 supports familial hypocalciuric hypercalcaemia, over 0.02 supports primary hyperparathyroidism, and 0.01 to 0.02 is indeterminate. Correct vitamin D deficiency first because it lowers the ratio.
• Genetic testing (CASR, GNA11, AP2S1) confirms the diagnosis and enables family testing. Calcium measurements in relatives support it.

Differential diagnosis.

• Primary hyperparathyroidism (clearance ratio over 0.02).
• Lithium or thiazide use, vitamin D deficiency with low urinary calcium, and kidney disease.
• Autosomal dominant hypocalcaemia is the opposite (activating variants).

• No treatment is needed for adults. Do not perform parathyroidectomy, which does not correct hypercalcaemia.
• Avoid unnecessary investigation and thiazide diuretics.
• Pancreatitis or symptomatic hypercalcaemia in a patient with proven disease: cinacalcet can be tried, starting 30 mg twice daily.
• Neonatal severe hyperparathyroidism: calcium and fluid support, cinacalcet in selected cases (up to 3 mg/kg daily in infants, under specialist care), and urgent parathyroidectomy for refractory disease.

Special groups. Pregnancy: an unaffected foetus of an affected mother may have suppressed parathyroid function and neonatal hypocalcaemia. An affected mother with a biallelic foetus needs specialist planning. Offer genetic counselling to families.

Monitoring. Calcium and parathyroid hormone every 1 to 2 years. Neonates: calcium for the first weeks.

Referral and escalation. Endocrinology and clinical genetics; paediatric endocrinology for any child with severe hypercalcaemia.