A 29-year-old female was referred for post-thyroidectomy tetany. She had undergone surgery for a benign multinodular goiter, without evidence of malignancy at pathology review. The morning after surgery, her serum total calcium was decreased at 5.8 mg/dL (normal, 8.9–10.1), serum phosphorus mildly increased at 4.8 mg/dL (normal, 2.5–4.5), and serum creatinine normal at 0.9 mg/dL (normal, 0.8–1.3). Her serum 25-hydroxyvitamin D was normal at 38 ng/mL (optimal, 20–50 ng/mL). Her serum parathyroid hormone was undetectable at <6 pg/mL (normal, 15–65). Her serum magnesium was normal at 1.9 mg/dL (normal, 1.7–2.3 mg/dL). These findings indicate that postsurgical hypoparathyroidism was the cause of her hypocalcemia and hyperphosphatemia. Unfortunately about 75 % of adults diagnosed with acquired hypoparathyroidism are postsurgical, with surgery sometimes being done for benign causes such as goiter or primary hyperparathyroidism, but more often for thyroid or other head or neck cancers.

Most patients with postsurgical hypoparathyroidism have transient hypoparathyroidism. Experience of the surgeon performing surgery generally predicts the incidence of postsurgical hypoparathyroidism. Immediate postoperative PTH levels may be useful in predicting which patients will develop permanent hypocalcemia due to postsurgical hypoparathyroidism [9].

Nonsurgical hypoparathyroidism may be due to deficiency or excess of serum magnesium [10, 11]. Hypomagnesemia usually causes hypoparathyroidism when serum magnesium is less than 1.0 mg/dL. Up to 11 % of hospitalized patients may have hypomagnesemia, while up to 9 % may have hypermagnesemia [12]. Hypomagnesemia may be due to gastrointestinal losses associated with vomiting related to excessive alcohol intake, chronic diarrhea, steatorrhea, malabsorption, or intestinal resection; renal tubular losses due to medications such as furosemide, aminoglycosides, cisplatin, cyclosporin, amphotericin B, pentamidine, tacrolimus, or proton pump inhibitors [13]; or rare genetic disorders such as Gitelman syndrome. Hypomagnesemia occurs frequently in critically ill patients, which contributes to the hypocalcemia frequently seen in intensive care unit patients. Hypermagnesemia may occur in the setting of late-stage chronic kidney disease in patients treated with magnesium antacids, enemas, or infusions, or acute renal failure associated with rhabdomyolysis or tumor lysis syndrome [14].

A 48-year-old male was referred for possible hypoparathyroidism. His serum calcium was decreased at 6.7 mg/dL (normal, 8.9–10.1 mg/dL), with serum phosphorus increased at 5.5 mg/dL (normal, 2.5–4.5 mg/dL), and serum creatinine normal at 1.3 mg/dL (normal, 0.8–1.3 mg/dL). His serum 25-hydroxyvitamin D was normal at 45 ng/mL (optimal, 20–50 ng/mL). His serum PTH was decreased at 8 pg/mL (normal, 15–65 pg/mL). His serum magnesium was very low at 0.8 mg/dL (normal, 1.7–2.3 mg/dL). These findings indicate that significant magnesium deficiency was the primary cause of his hypoparathyroidism leading to hypocalcemia and hyperphosphatemia. Further evaluation demonstrated renal tubular magnesium wasting due to previous use of outdated aminoglycoside antibiotics.

Primary intestinal hypomagnesemia results from a rare inherited disorder causing magnesium malabsorption leading to hypomagnesemia in early infancy. This condition is thought to primarily occur due to deficient intestinal magnesium absorption, but there may also be defects in renal magnesium reabsorption. Patients usually present with neurological symptoms, including tetany, muscle spasms, and seizures due to both hypomagnesemia and hypocalcemia associated with hypoparathyroidism. Lifelong high oral intake of magnesium supplements decreases symptoms and restores serum calcium levels to normal. Mutations in the TRMP6 gene on chromosome 9 have been identified to cause this disorder [15, 16]. The TRMP6 protein is a member of the transient receptor membrane potential channel family that complexes to TRPM7, a calcium- and magnesium-permeable cation channel.

Other acquired causes of hypoparathyroidism are much rarer. Infiltration and destruction of the parathyroid glands by iron overload may occur in hemochromatosis, or thalassemia requiring multiple blood transfusions [17]. Copper overload occurring due to Wilson’s disease may also result in hypoparathyroidism [18].

Hypoparathyroidism may result from metastases to the parathyroid glands in extremely rare circumstances [19]. External beam radiation therapy to the neck for treatment of malignant disease in this region, or radioactive iodine therapy for Graves’ disease, may also rarely result in destruction of the parathyroid glands [20].

Inherited causes of hypoparathyroidism include autosomal dominant hypocalcemia (ADH), a condition in which there is a gain-of-function mutation in the CaSR [21]. This type of mutation changes the threshold of PTH secretion by parathyroid cells in response to circulating ionized calcium, leading to low or inappropriately normal PTH secretion despite hypocalcemia. Most of the mutations reported to date affect the extracellular amino-terminal or transmembrane domains of the receptor. The mutant receptors may show both increased receptor sensitivity to calcium and increased maximal signal transduction capacity.

Since this activating mutation is also expressed in the CaSR on proximal renal tubular cells in the thick ascending limb of Henle, absolute or relatively increased 24-h urinary calcium excretion is a hallmark of the disorder. Most patients with ADH are asymptomatic and have mild hypocalcemia with significant hypercalciuria, but occasional patients may present with moderate or severe hypocalcemia. This form of CaSR-mediated hypoparathyroidism may cause increased risk of nephrocalcinosis compared to other forms of hypoparathyroidism. In one series, almost half of the patients evaluated had nephrocalcinosis associated with hypercalciuria [22]. Calcium supplementation must therefore be monitored carefully in this condition.

Occasional reports have described patients with CaSR gain-of-function mutations associated with a Bartter-like syndrome, suggesting that the CaSR may also play a role in sodium chloride regulation [23]. These patients present with hypocalcemia, hypercalciuria, and nephrocalcinosis, associated with hypokalemic alkalosis, renal salt wasting that may cause hypotension, hyperreninemic hyperaldosteronism, and increased urinary prostaglandin excretion. Extensive burns may lead to upregulation of the CaSR, with lower than normal serum calcium suppressing PTH secretion, resulting in hypocalcemia and hypoparathyroidism.

Autoimmune hypoparathyroidism is thought to be the second most common form of acquired hypoparathyroidism. Isolated autoimmune destruction of the parathyroid glands may occur, resulting in idiopathic hypoparathyroidism, or autoimmune destruction may occur in association with other autoimmune conditions as part of autosomal recessive autoimmune polyglandular endocrinopathy candidiasis ectodermal dystrophy (APECED) syndrome [24]. This syndrome is caused by mutations in the autoimmune regulator gene AIRE, which results in abnormal thymic expression of tissue antigens, generation of autoreactive T cells, ultimate loss of central tolerance to specific self-antigens, and the development of multiple autoimmune disorders [25]. Antibodies against the CaSR have been identified in some individuals with both idiopathic hypoparathyroidism or APECED syndrome [26, 27], but it is not yet clear if these antibodies are causative or simply markers of disease [28]. Idiopathic autoimmune hypoparathyroidism most often occurs in the teens or the young adulthood, but may occur at any age. APECED usually presents in childhood, and is characterized by chronic mucocutaneous candidiasis in addition to variable expression of endocrine and other autoimmune diseases. Variation in the clinical phenotype of individuals with identical mutations in the AIRE gene is incompletely understood, but this suggests that other genetic loci or environmental factors are important in the development of the phenotype.

Hypoparathyroidism may be diagnosed at birth or during childhood due to a variety of genetic mutations causing congenital syndromes, the most widely known being the DiGeorge (velocardiofacial) syndrome [29]. This disorder is caused by abnormal development of neural crest cells in the third and fourth branchial pouches. In 90 % of cases the syndrome is caused by heterozygous chromosomal deletion of the TBX1 gene in the region of chromosome 22q11. Thirty-five genes have been identified in this region, so deletion of other genes, alone or in combination, could also cause this syndrome, but the TBX1 gene is a major determinant of cardiac, thymus, and parathyroid cell phenotypes. A region on chromosome 10p (DiGeorge critical region II) has also been linked to the syndrome. DiGeorge syndrome is associated with distinctive facial abnormalities, cleft lip and/or palate, conotruncal cardiac anomalies, and mild-to-moderate immune deficiency. Hypocalcemia due to hypoparathyroidism has been reported in 17–60 % of affected children [30]. DiGeorge syndrome is estimated to occur in as many as 1:2,000–1:3,000 births, with the incidence rate of new mutations estimated at 1:4,000–1:6,000. Because the clinical phenotype varies, findings may be subtle and therefore overlooked, and mild hypocalcemia may be easily missed. In one study of adults with chromosome 22q11.2 deletion, about half were hypocalcemic, with a median age of presentation of 25 years, and a maximum age of diagnosis of up to 48 years [31]. This disorder may rarely be diagnosed for the first time as late as the mid-60s, with late onset of mild hypocalcemia, and is not infrequently diagnosed in an affected parent in the 20s or 30s after birth of an affected child.

Finally, a variety of other rare genetic or inherited disorders may cause hypocalcemia that is recognized in infancy or childhood. Familial isolated hypoparathyroidism due to autosomal recessive or dominant mutations in the pre–proPTH gene on chromosome 11p15 [32, 33], or parathyroid gland dysgenesis due to mutations in various transcription factors regulating parathyroid gland development such as GCMB (glial cells missing B) [34] or GCM2 (glial cells missing 2) [35], GATA3 [36, 37], or Sry-box 3 (SOX3) [38], is thought to be very rare. Autosomal dominant hypoparathyroidism associated with deafness and renal anomalies has been linked to mutations in the GATA3 gene on chromosome 10p14-10-pter [36, 37]. Hypoparathyroidism has been very rarely associated with X-linked recessive mutations on Xq26-27, leading to disruption of SOX3 transcription [38]. The syndrome of autosomal recessive hypoparathyroidism, growth and mental retardation, and dysmorphism due to mutations in the TBCE gene on chromosome 1q42-q43 is another very rare cause of hypoparathyroidism [39]. Hypoparathyroidism with metabolic disturbances and congenital anomalies has been associated with rare maternal mitochondrial gene defects [40, 41].