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Familial hypocalciuric hypercalcaemia 

Familial hypocalciuric hypercalcaemia
Familial hypocalciuric hypercalcaemia

Edward M. Brown

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date: 21 May 2022

Familial hypocalciuric hypercalcaemia (FHH) is a generally asymptomatic form of mild to moderate, parathyroid hormone (PTH)-dependent hypercalcaemia, which was initially confused with the more common hypercalcaemic disorder, primary hyperparathyroidism (PHPT) (1–3). Subsequent studies showed that FHH differs from PHPT in several important respects, although distinguishing between these two conditions can still be difficult on a clinical basis alone (4). Urinary calcium excretion is lower in the former than in the latter, and in FHH, unlike PHPT, hypercalcaemia recurs rapidly following surgical treatment with anything less than total parathyroidectomy. Indeed, given FHH’s generally benign natural history, surgery is usually ill advised (3).

The phenotype of FHH implicated some abnormality in the sensing and/or handling of calcium by parathyroid and kidney (3, 5). For more than two decades after its initial description, however, the genetic defect in FHH was unknown. In 1992, the major genetic locus for this condition was identified on the long arm of chromosome 3 (6). The following year saw the cloning of a G protein-coupled extracellular calcium (Ca2+o)-sensing receptor (CaSR) mediating direct regulation of PTH secretion by Ca2+o (7). The CaSR’s function and its location of its gene on the same region chromosome 3 in humans made it an obvious candidate gene for FHH. Shortly thereafter, heterozygous inactivating mutations in the CaSR were identified in several FHH families (8). Moreover, patients with a related condition, neonatal severe hyperparathyroidism (NSHPT), also turned out to harbour inactivating CaSR mutations in the homozygous, compound heterozygous, and in a milder disorder, neonatal hyperparathyroidism (NHPT), in the heterozygous state (8). This chapter reviews the clinical and biochemical features of FHH, its genetics, pathophysiology, and pathogenesis, and its relationship to NSHPT.

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