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Hypocalciuric Hypercalcemia Familial Type I

Features

Familial hypocalciuric hypercalcemia (HHC) is a heritable disorder of mineral homeostasis transmitted as an autosomal dominant trait, and with a high degree of penetrance. It is characterized by lifelong hipercalcemia associated with inappropriately low urinary calcium excretion and a normal or mildly elevated circulating parathyroid hormone (PTH) level. Hypermagnesemia is also characteristic. Affected individuals are usually asymptomatic, but may present chondrocalcinosis and pancreatitis.

Clinical Manifestations

Asymptomatic, mild, intermittent hypercalcemia, with hypermagnesemia may be occasionally found. Many family members can be affected and sometimes diagnosed as primary hyperparathyroidism, which is resistant to parathyroidectomy. Typically calcium renal excretion is reduced. Hypercalcemia begins before age 10 years, and it is not associated with urinary stone or renal damage.

Diagnosis

Mild, intermittent hipercalcemia, with hypermagnesemia, and normal to elevated PTH plasma level are characteristic. Diagnosis is based on a urinary Ca to Creatinine ratio below 0.01 mg/mg, and first-degree family members with benign hipercalcemia.

Genetics

Familial hypocalciuric hypercalcemia is caused by heterozygous loss-of-function mutation in the CASR gene, which encodes the calcium-sensing receptor, on chromosome 3q21. Affected individuals fail to show a hypercalciuric response to hypercalcemia due to an increased calcium concentration level to induce PTH secretion, or increased PTH “set-point”. For the genetic study it will be necessary samples of the index case and the parents.

Treatment

No specific treatment is needed.

Prognosis

Familial hypocalciuric hypercalcemia is a benign disease.

Complications

Hypercalcemia can cause pancreatitis and chondrocalcinosis. Lipomas are frequent too.

Bibliography

  • Aida, K., Koishi, S., Inoue, M., Nakazato, M., Tawata, M., Onaya, T. Familial hypocalciuric hypercalcemia associated with mutation in the human Ca(2+)-sensing receptor gene. J. Clin. Endocr. Metab. 80: 2594-2598, 1995. R.