Deletions within two nonoverlapping regions of 10p can lead to a phenotype similar to DiGeorge sequence, namely, the hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome. Unlike patients with the DiGeorge sequence, individuals with HDR do not exhibit cardiac, palatal, or immunologic abnormalities. The HDR disorder is due to haploinsufficiency of the GATA binding protein-3 (GATA3) gene, which is located within a 200-kb critical HDR deletion region on 10p14-10pter and encodes a C-terminal zincfinger protein essential for DNA binding.

The hypoparathyroidism, retardation, dysmorphism (HRD) syndrome, also known as the Sanjad-Sakati (SS) syndrome, is a rare form of autosomal recessive hypoparathyroidism associated with other developmental anomalies. In addition to parathyroid dysgenesis, affected patients have severe growth and mental retardation, microcephaly, microphthalmia, small hands and feet, and abnormal teeth. This disorder is seen almost exclusively in individuals of Arab descent. The Kenny-Caffey syndrome is an allelic disorder that is characterized by hypoparathyroidism, dwarfism, medullary stenosis of the long bones, and eye abnormalities. Both disorders are due to mutations in the tubulin-specific chaperone E (TBCE) gene on chromosome 1q42-43.

Hypoparathyroidism may also occur as an isolated genetic condition. The leading cause of autosomal dominant hypoparathyroidism is an activating mutation of the CASR gene encoding the calcium-sensing receptor. Parathyroid glands are present but secrete little PTH because the activated calcium-sensing receptor behaves as if the extracellular calcium concentration is elevated. Activation of the same receptor in the distal renal tubule decreases calcium reabsorption, so urinary excretion of calcium is inappropriately high. By contrast, autosomal dominant and recessive mutations in the GCM2 gene at 6p23-24 lead to parathyroid gland aplasia or dysplasia and cause severe isolated hypoparathyroidism in neonates.

Transient hypocalcemia and hypoparathyroidism are common in the neonatal period, presumably because of the underactivity and immaturity of the parathyroid glands and/or renal tubules. Despite hypocalcemia, serum PTH levels are low or inappropriately normal. Maternal hypercalcemia (as seen in hyperparathyroidism) may further suppress the fetal parathyroid gland and produce tetany in the neonate. In patients with alcoholism or malabsorption syndromes, hypomagnesemia leads to functional impairment of the parathyroid glands and hypocalcemia. In these patients, magnesium replacement increases serum levels of both parathyroid hormone (PTH) and calcium.

The biochemical hallmarks of hypoparathyroidism are a low serum calcium level and a high serum phosphate level, which result from a lack of PTH. Hypocalcemia occurs because less calcium is absorbed from the gut and resorbed from the skeleton and more calcium is cleared by the kidney. Absorption of calcium from the gut is reduced because synthesis of 1,25-dihydroxyvitamin D, or 1,25(OH)₂D, which enhances absorption, is decreased in the absence of PTH. Because both PTH and 1,25(OH)₂D are critical activators of osteoclastic bone resorption, low levels of both hormones lead to decreased mobilization of calcium from skeletal stores. Because the renal tubular reabsorption of calcium is responsive to PTH, the threshold for calcium excretion is reduced in subjects with hypoparathyroidism, and when the serum calcium level is therapeutically raised to normal, urinary excretion of calcium is inappropriately elevated. However, if the condition is not treated, the serum calcium concentration is usually below the renal threshold and urinary excretion of calcium is therefore low. Hyperphosphatemia in hypoparathyroidism occurs because phosphate reabsorption by the renal tubule increases when PTH levels are low.

Although acute reduction of PTH diminishes bone resorption, when PTH levels are chronically low, the rate of bone formation falls to match the rate of bone resorption. In chronic hypoparathyroidism, the net results are a reduced rate of bone turnover and a normal or slightly increased bone mass.

Most patients with idiopathic hypoparathyroidism exhibit severe hypocalcemia (serum calcium level < 7 mg/dL), but symptoms are mild when hypoparathyroidism has been chronic. On the other hand, patients with postsurgical hypoparathyroidism have variable hypocalcemia but typically have more severe clinical symptoms. Patients with the mildest form may have latent hypoparathyroidism; they can maintain normal serum calcium and phosphate levels, although physiologic or pathologic stresses, such as pregnancy or diarrhea, may cause the onset of hypocalcemia. Patients with postsurgical hypoparathyroidism often manifest moderate-to-severe hypocalcemia that is challenging to manage.

Hypoparathyroidism is treated by a combination of oral calcium supplements and vitamin D analogs; in mild cases, calcium supplementation alone is sufficient. Calcium supplements serve several important roles. First, they ensure a constant daily intake of calcium and thereby reduce day to day fluctuations in dietary calcium due to differences in food consumption. Second, they provide a ready source of gastrointestinal calcium and thereby reduce mobilization of skeletal calcium. And third, oral calcium supplements reduce absorption of dietary (and secreted) phosphorus from the intestine and thereby help maintain a normal serum phosphorus concentration. In most patients, calcium absorption from the intestine is too low, necessitating some form of supplemental vitamin D (in addition to calcium salts) to enhance absorption. Because the activation of vitamin D is impaired in these patients, large amounts of the parent compounds ergocalciferol (vitamin D₂) or cholecalciferol (vitamin D₃) are required (50,000 to 100,000 IU/day). In contrast, 1,25(OH)₂D (calcitriol) and dihydrotachysterol can be used at much lower doses because they do not require PTHdependent activation by the 1α-hydroxylase enzyme in the kidney. Because the renal threshold for calcium is lower in patients with hypoparathyroidism, the total serum calcium concentration should be maintained in the low-to-normal range (8 to 9 mg/dL) to avoid hypercalciuria and nephrolithiasis.