Familial Hypocalciuric Hypercalcemia (FHH)

Benign familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant condition characterized by lifelong hypercalcemia, relative hypocalciuria, and inappropriately elevated parathyroid hormone. It is caused by a loss-of-function mutation in the calcium-sensing receptor gene (CASR) leading to a general calcium-hyposensitivity, compensatory hypercalcaemia and hypocalciuria. Benign familial hypocalciuric hypercalcemia is important clinically because it can be difficult to distinguish from primary hyperparathyroidism. Similar to primary hyperparathyroidism (PHPT), FHH is characterized by hypercalcaemia, unsuppressed or elevated plasma parathyroid hormone, and typically normal renal function. The incidence of complications associated with primary hyperparathyroidism, like osteopenia and nephrolithiasis, is not increased in persons with benign familial hypocalciuric hypercalcemia, and the rates are similar to those in the general population. The hallmark is a relatively low urine calcium excretion in contrast to PHPT, in which urine calcium excretion is increased. The vitamin D status as measured by plasma 25-hydroxyvitamin D has been reported to be normal with normal seasonal variations, whereas plasma 1,25-dihydroxyvitamin D has been found slightly increased compared to normal. Bone mineral density Z-scores are normal in spite of a slightly increased bone turnover. Rarely, a severe form of this disease, namely neonatal severe primary hyperparathyroidism is seen in infants with homozygous CASR mutations.

Differential diagnoses include mainly PHPT, but in some cases also hypercalcaemia of malignancy and use of thiazide diuretics.

Familial hypocalciuric hypercalcaemiais a rare, lifelong, benign condition. It is important to separate this condition from other hypercalcaemic states such as hypercalcaemia of malignancy and PHPT.

Benign familial hypocalciuric hypercalcemia is a small but important cause of hypercalcemia, especially in the younger population. It is important to diagnose this condition, not only in the index case but also in family members, because these patients should be advised against surgical intervention. Hypercalcemia persists after subtotal parathyroidectomy. It is a benign condition, and affected patients should be advised against parathyroidectomy.

1) Varghese J, Rich T, Jimenez C. Benign familial hypocalciuric hypercalcemia. Endocr Pract. 2011 Mar-Apr;17 Suppl 1:13-7.
2) Christensen SE, Nissen PH, Vestergaard P, Mosekilde L. Familial hypocalciuric hypercalcaemia: a review. Curr Opin Endocrinol Diabetes Obes. 2011 Dec;18(6):359-70.