Familial benign hypocalciuric hypercalcaemia (FHH) is a lifelong, benign, inherited condition with slightly increased levels of plasma calcium, low urinary calcium excretion, and normal to moderately elevated plasma parathyroid hormone (PTH). In most cases, FHH (type-1) is caused by inactivating mutations in the gene encoding the calcium sensing receptor (CASR) expressed in the parathyroids and the kidneys. The estimated prevalence of FHH is 1 in 78 000 compared with that of primary hyperparathyroidism of 1 in 1000.
At least 234 mutations have been described in the CASR gene and resulting in phenotypes ranging from normocalcemia to pronounced hypercalcemia. Rare cases of FHH have been linked to loci on chromosome 19 (FHH-2 and FHH-3) and antibodies against the CASR.
Homozygous mutations in the CASR gene may result in severe neonatal hyperparathyroidism (SNHPT) which is a life-threatening disorder manifesting with severe hypercalcaemia and elevated PTH immediately after birth. Some cases of SNHPT may be due to a dominant negative effect of some mutations in heterozygous patients.
Most patients with FHH have no symptoms; however, pancreatitis, gall stones and chondrocalcinosis have been described. Data regarding bone mineral density in FHH are conflicting.
The diagnosis of FHH should be suspected in patients with hypercalcemia and low renal calcium excretion, i.e. a calcium/creatinine clearance ratio (Ca/Cr-Cl) below 0.010.02, unsuccessful surgery for presumed primary hyperparathyroidism or familial cases of hypercalcemia.
Subtotal parathyroidectomy does not normalize serum calcium and should be avoided in FHH, while surgery is necessary in NSHPT. Calcimimetics (cinacalcet and NPS R-568) have been used in symptomatic cases of FHH and have been suggested as an option in some cases of NSHPT. Similarly, treatment with pamidronate has been used SNHPT in preparation for parathyroidectomy. Glucocorticoids may control the autoimmune form of FHH.