Congenital Hyperparathyroidism/Primary Hyperparathyroidism.

Primary hyperparathyroidism is a rare condition caused by parathyroid hyperplasia and occurs by sporadic or autosomal recessive inheritance. Clinical presentation includes symptoms listed previously but also hypophosphatemia, hypercalciuria, and hyperphosphaturia. Bone demineralization and even osteitis fibrosa and fractures can occur. A renal ultrasound may reveal nephrocalcinosis.

Parathyroid tumors are a rare event in neonates, with adenomas being the most common. Parathyroid tumors occur either isolated or as part of a tumor syndrome (e.g., the multiple endocrine neoplasias [MENs] or hyperparathyroidism with jaw tumors). Parathyroid tumors can be due to heterozygous somatic mutations (gain-of-function mutation) resulting in overexpression of oncogenes, such as RET (causing MEN2) or PRAD1 (parathyroid adenoma 1) or recessive mutations in tumor-suppressor genes (loss-of-function mutation). MEN type 1 is caused by autosomal dominant mutations in the MEN1 gene (a tumor suppressor gene which encodes Menin) and is characterized by parathyroid, pancreatic, or pituitary tumors. MEN type 2 (MEN2) is due to activating, heterozygous mutations in the proto-oncogene RET1. These mutations typically result in hyperparathryroidism due to a parathyroid adenoma, medullary carcinoma of the thyroid, and pheochromocytoma. Parathyroid carcinoma and tumors of the mandible occur in a rare genetic syndrome called hyperparathyroidism–jaw tumor syndrome, which is caused by mutations in the gene HRPT2 (which encodes the tumor suppressor parafibromin).

The diagnosis of primary hyperparathyroidism is made by the detection of elevated PTH or inappropriately normal PTH levels given higher circulating Ca ²⁺ levels, 1,25 Vitamin D concentrations are elevated or normal, serum phosphate levels are low-normal or low, and alkaline phosphatase can be elevated due to bone disease. A spot urine Ca ²⁺ to creatinine ratio (normally <1 in infants) and a 24-hour urine collection enable the diagnosis of hypercalciuria. A renal ultrasound may detect nephrocalcinosis, and an x-ray of the wrist may demonstrate bone involvement. The treatment of choice is total parathyroidectomy with partial autotransplantation. Preoperatively, hyperparathyroid adenomas are detected by technetium 99m sestamibi scan. Following parathyroidectomy the influx of Ca ²⁺ into the healing bone may aggravate the duration of hypocalcemia, a phenomenon called “hungry bone syndrome.” In very low birth weight infants and newborns the removal of the parathyroid glands may be complicated by the small size of the parathyroid glands. Adjunct medical treatment in such cases is possible with the Ca ²⁺ -sensing receptor (CaSR) mimetic Cinacalcet, which may provide intermittent relief until surgery is an option.

Familial Hypocalciuric Hypercalcemia/Neonatal Severe Hyperparathyroidism.

Characteristics of familial hypocalciuric hypercalcemia (FHH) are mild hypercalcemia, inappropriately normal or mildly elevated PTH, and hypocalciuria. Genetically, three different forms of FHH (FHH1-3) were identified by genetic linkage. For FHH1 and FHH2, there are usually no signs of hypercalcemia and no nephrocalcinosis, and PTH levels remain normal; there may be mild hypermagnesemia, but overall patients remain asymptomatic. Rarely, pancreatitis and chondrocalcinosis may occur. For FHH1, inactivating mutations in the CaSR gene have been described that are inherited in an autosomal dominant fashion. To maintain Ca ²⁺ homeostasis within the body, a sensing mechanism for Ca ²⁺ is required. This function is provided by CaSR, which is a seven transmembrane–spanning G protein–coupled receptor (GPCR). The gene encoding the CaSR is most highly expressed in organs involved in Ca ²⁺ homeostasis, such as the parathyroid glands, C cells of the thyroid gland, bone, and kidneys. CaSR recognizes surprisingly minor perturbations in extracellular Ca ²⁺ concentration and reacts by adjusting PTH secretion. Stimulation of CaSR by Ca ²⁺ binding reduces PTH secretion via G protein–coupled signaling via Gα _q/11 , Gα _i , Gα _12/13 , and Gα _qs and other pathways such as MAPK. In FHH1 the altered CaSR on the parathyroid gland does not respond appropriately to increasing serum Ca ²⁺ concentrations so that higher serum Ca ²⁺ concentrations are required to suppress PTH. This results in a shift of the set point for PTH release to the right. The CaSR mutation can also impair renal Ca ²⁺ excretion, thereby contributing to the hypocalciuria. In the kidney, activation of CaSR increases Ca ²⁺ excretion, acidifies urinary pH, and impairs urinary concentration in an attempt to reduce the risk of nephrocalcinosis and nephrolithiasis. In addition, in an attempt to maintain solubility of urinary Ca ²⁺ salts and to prevent tubular Ca ²⁺ precipitation, CaSR activation at the apical membrane of the collecting duct enhances acid secretion by stimulation of H ⁺ -ATPase and inhibits water absorption by interference with vasopressin-induced aquaporin-2 (AQP2) insertion in the apical membrane. Chronic hypercalcemia results in diabetes insipidus by AQP2 downregulation via the CaSR.

In the context of hypophosphatemia, hypocalciuria helps to distinguish FHH versus hyperparathyroidsim (which causes hypercalciuria). Approximately 65% of FHH patients have CaSR mutations. The opposite pathophysiology can be seen with autosomal dominant hypocalcemia (see later). Gain-of-function mutations of the CaSR, which induce a higher sensitivity to extracellular Ca ²⁺ , can also result in Bartter syndrome. As these mutations imitate elevated extracellular Ca ²⁺ concentrations, PTH secretion is suppressed and impairs renal Ca ²⁺ and Mg ²⁺ absorption.

Over the following years, FHH was found to be a genetically heterogeneous condition. Loss-of-function mutations in Gα ₁₁ , which encodes a protein involved in the signaling cascade of the CaSR, were found in FHH2 patients. Because Gα ₁₁ is part of the CaSR signaling cascade, it was a candidate gene for FHH2. In vitro experiments confirmed that loss-of-function mutations in the encoding gene GNA11 decreased the sensitivity of the CaSR to extracellular Ca ²⁺ and resulted in a rightward shift in the concentration-response curve, with significantly higher half-maximal effective concentration (EC50) values. Interestingly, gain-of-function mutations in the genes encoding Gα ₁₁ result in the opposite phenotype of autosomal dominant hypocalcemia (see later).

In FHH3, clinical characteristics can be different with elevated PTH levels, hypophosphatemia, and osteomalacia. FHH3 is caused by dominant mutations in the adaptor protein-2 sigma subunit (AP2σ1, encoded by the AP2S1 gene), which results in loss of function of the encoded protein, which is important as a component of clathrin-coated vesicles. AP2S1 mutations decrease the sensitivity of CaSR-expressing cells to extracellular Ca ²⁺ and impair CaSR endocytosis by reducing the affinity for the dileucine motif. Mutations were identified in 20% of FHH patients without CASR mutations. Overall the disease severity in FHH is relatively mild, and some patients remain asymptomatic. Sporadic CaSR mutations are also possible. FHH patients are usually treated with thiazides or calcimimetics. Parathyroidectomy is contraindicated.

A more pronounced phenotype than FHH is associated with neonatal severe hyperparathyroidism (NSHPT), which is due to homozygous or compound heterozygous, inactivating mutations in the CaSR gene. Symptoms include severe hypercalcemia, markedly elevated PTH levels, failure to thrive, polyuria, hypotonia, and hypophosphatemia. Infants with NSHPT often have pronounced bone disease. NSHPT patients are treated with rehydration, bisphosphonates, and calcimimetics. Patients who are not responding to medical treatment may benefit from parathyroidectomy.

Congenital Hypoparathyroidism.

Familial isolated hypoparathyroidism can be inherited as an autosomal recessive, dominant, or X-linked trait or it may occur sporadically. Mutations occur in genes regulating parathyroid gland development or in the PTH gene (in the PTH precursor preproPTH). Patients present with hypocalcemia, hyperphosphatemia, inappropriately low PTH, and low 1,25 Vitamin D concentrations. Due to the lack of renal PTH action, tubular absorption of Ca ²⁺ is diminished, resulting in hypercalciuria and a higher risk for nephrocalcinosis and chronic kidney disease (CKD). Interestingly, CASR gene mutations have also been found to result in hypoparathyroidism in addition to causing autosomal dominant hypocalcemia (see later).

Hypoparathyroidism, Deafness, and Renal Anomalies Syndrome.

Hypoparathyroidism, deafness, and renal anomalies (HDR) syndrome is characterized by congenital hypoparathyroidism, bilateral sensorineural deafness, and renal dysplasia/cysts. HDR patients present with hypocalcemia and low to undetectable PTH concentrations. HDR syndrome is caused by heterozygous mutations in the transcription factor GATA3 on chromosome 10p14. GATA3 expression during human and murine development (e.g., in otic vesicle, parathyroid glands, kidneys) is consistent with the HDR phenotype.

DiGeorge Syndrome.

Hypoparathyroidism can be part of DiGeorge syndrome, which is characterized by branchial cleft abnormalities including hypoplasia of pharyngeal arches, parathyroid glands, thymus, cardiac and craniofacial defects. This syndrome is due to chromosomal deletions of 22q11.2, which includes approximately 30 genes. One of these genes is the TBX1 gene, and mice lacking Tbx1 and humans with TBX1 point mutations develop DiGeorge syndrome. TBX1 encodes a transcription factor of the T-box family and is crucial in organogenesis. Another form of DiGeorge syndrome is due to a deletion of 10p. Approximately 17% of DiGeorge patients have no detectable chromosomal abnormality. In approximately 50% to 60% of DiGeorge patients, hypocalcemia is diagnosed. Transient hypocalcemia at birth can be seen due to abrupt discontinuation of maternal Ca ²⁺ supply and the delivery stress. Patients are treated with vitamin D and Ca ²⁺ to keep serum Ca ²⁺ concentrations in the low normal to avoid nephrocalcinosis and nephrolithiasis.

GCMB Mutations.

Isolated parathyroid gland agenesis was published due to heterozygous (dominant negative) or recessive (loss-of-function) mutations in the glial cell missing B ( GCMB or GCM2 ) gene, which encodes for a parathyroid specific transcription factor and contributes to regulation of PTH gene expression.

Autoimmune Polyendocrine Syndrome.

Another syndrome that includes hypoparathyroidism is autoimmune polyendocrine syndrome type 1 (APS1), which is caused by autosomal recessive mutations in the autoimmune regulator gene (AIRE). APS1 is characterized by multiple endocrine gland insufficiencies (e.g., hypoparathyroidism, adrenal insufficiency, hypogonadism, DM, hypothyroidism) and chronic mucocutaneous candidiasis in childhood. This gene encodes a nuclear transcription factor which eliminates self-reactive T cells in the thymus. As a consequence the immune system fails to establish immunologic tolerance.

Mitochondrial Disorders Associated With Hypoparathyrodism.

Three mitochondrial disorders are associated with hypoparathyroidism, including Kearns-Sayre syndrome (KSS), mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS), and mitochondrial trifunctional protein deficiency syndrome.

Other Syndromes (e.g., Kenney-Caffey and Blomstrand Disease).

In approximately 50% of patients with Kenney-Caffey syndrome (KCS), hypoparathyroidism has been described. Genetic heterogeneity with mutations in the genes encoding tubulin-specific chaperone (TBCE) and family with sequence similarity 111A (FAM111A) were described.

Another rare, autosomal recessive cause for hypocalcemia is Blomstrand chondrodysplasia. This condition is characterized by accelerated bone maturation, advanced chondrocyte differentiation, hyperdensity of the skeleton, accelerated ossification, and early lethality. The causes for this disease are mutations of the PTH receptor impairing its binding of PTH, function, or expression.

Treatment for these conditions include Ca ²⁺ and 1,25 Vitamin D supplements, which may be complicated by developing hypercalciuria and nephrocalcinosis. Thiazide diuretics may be able to improve hypercalciuria. Recombinant PTH (1–84) and (1–34) have been successfully used to improve successfully Ca ²⁺ homeostasis. An orally active small molecule PTHR1 agonist called PCO371 was discovered as potential therapeutic option.

Autosomal Dominant (Hypercalciuric) Hypocalcemia.

In autosomal dominant hypocalcemia type 1, approximately 50% of patients remain asymptomatic or have mild hypocalcemia. Hypocalcemia may be present in the neonatal period. The other 50% can develop seizures, paresthesia, and carpopedal spasms. Although overall rare, this condition may be responsible for up to a third of patients with idiopathic hypoparathyroidism. Approximately 10% have hypercalciuria with nephrocalcinosis and kidney stones. Patients with autosomal dominant hypocalcemia often present with hypomagnesemia and hypermagnesuria. Approximately one-third of patients have ectopic and basal ganglia calcifications. PTH concentration may be normal or inappropriately low. As a cause for autosomal dominant hypocalcemia type 1, gain-of-function mutations in the CaSR were identified resulting in higher serum Ca ²⁺ threshold for PTH release (see Fig. 20.3A ). This imitates higher extracellular calcium concentrations, and as a result PTH secretion is suppressed and renal Ca ²⁺ and Mg ²⁺ absorption is impaired. Some patients may present with hypokalemia and alkalosis, symptoms consistent with Bartter syndrome, which is thought to be due to the CaSR effect on sodium absorption in the TAL. The Bartter syndrome phenotype is thought to be due to impaired NKCC2 and ROMK function induced by an inhibitable adenyl cyclase, thus reducing Na ⁺ , K ⁺ , and Cl ⁻ reabsorption in the TAL (see Fig. 20.3A ).

In a cohort of autosomal dominant hypocalcemia patients without hypercalciuria, heterozygous gain-of-function mutations of GNA11 were identified, also resulting in an increased sensitivity of CaSR-expressing cells to extracellular Ca ²⁺ , thereby causing a leftward shift in the concentration-response curves. GNA11 encodes a G protein that connects CaSR sensing with the Ca ²⁺ /IP3/PKC signaling pathway in the parathyroid gland. Differentiation between autosomal dominant hypocalcemia and hypoparathyroidism is important because treatment of autosomal dominant hypocalcemia patients with calcium and vitamin D may aggravate hypercalciuria and may worsen nephrocalcinosis.