Characterization of Patients With Idiopathic Hypoparathyroidism, Autosomal Dominant Hypocalcaemia and Pseudohypoparathyroidism

Background:

Hypoparathyroidism (HypoPT) is a group of rare clinical disorders characterized by hypocalcaemia and hyperphosphatemia with inappropriate low levels of parathyroid hormone (PTH). Due to the lack of PTH, the renal production of 1α,25-dihydroxycholecalciferol (1,25(OH)2D) is reduced. Most often, HypoPT is caused by accidental removal of the parathyroid glands during neck surgery (postsurgical hypoPT). However, in rare in-stances HypoPT is caused by autoimmune disorders with immune mediated destruction of the parathyroid glands, or a variety of genetic mutations, including the CATCH-22 (DiGeorge) Syndrome, familial isolated HypoPT or an activating mutation in the gene encoding the calcium-sensing receptor (CaSR), termed autosomal dominant hypocalcaemia (ADH).

The CaSR is not only found in the parathyroid glands, but is also expressed by other tissue including the renal tubules. Low plasma levels of ionised calcium (Ca2+) are registered by the calcium sensing receptors (CaSR) located e.g. in the cell membranes of the parathyroids and in the renal tubules. Low levels of Ca2+ increases the release of PTH from the parathyroids, which normalises plasma Ca2+ and decrease P-phosphate. Lack of PTH decreases the renal synthesis of 1,25-dihydroxycholecalciferol, witch in combination with low PTH decreases bone turnover. Although, large-scale meta-analysis of genome wide association data incorporating 150 candidate genes did not link the CaSR to bone mineral density or osteoporotic fracture risk, no specific data are available on whether BMD in patients with an activating mutation in their CaSR gene (ADH patients) differs from the general population. The largest case series of patients with ADH so far reported included 25 patients and did not report BMD within this group.

Calcium is of importance to many physiological processes, including cardiovascular functioning. The CaSR has been suggested to be of importance in the regulation of blood pressure and a Batter's like phenotype has been reported in patients with ADH. Although the recent study by the investigators' group did not show an increased cardiovascular morbidity in patients with postsurgical hypoPT, no data are available on blood pressure regulation or indices of atherosclerosis in patients with idiopathic hypoPT.

PseudoHypoPT is due to PTH resistance in the target organs, causing hypocalcemia with inappropriate high PTH concentrations. The phenotype in type 1 is known as Albrights's hereditary osteodystrophy, (AOH) (maternal 2 of 8 allele). Pseudo-pseudoHypoPT is characterized by AOH, but without the typical biochemical findings (pater-nal allele). PseudoHypoPT type 2 has typical biochemical changes but no characteristic phenotype. Discrepant results have been reported on effects on bone mineral density (BMD), as some studies has shown a decreased BMD (hyperparathyroid bone disease), whereas other studies have shown that BMD actually may be increased.