ABSTRACT

In primary hypoparathyroidism with hypocalcemia and hyperphosphatemia, deficient parathyroid hormone (PTH) secretion most commonly occurs from surgical excision of, or damage to, the parathyroid glands. The term idiopathic hypoparathyroidism describes isolated cases when a cause is not obvious and there is no family history. However, hypoparathyroidism is also a feature common to a variety of hereditable syndromes that may present de novo. Familial isolated hypoparathyroidism may show autosomal dominant, autosomal recessive, or X-linked inheritance. Genes involved include PTH, SOX3, CASR, GNA11 and GCM2. Parathyroid hypoplasia is a frequent feature of 22q11.2 deletion syndrome with involvement of the TBX1 gene. The Hypoparathyroidism, Nerve Deafness, and Renal Dysplasia syndrome is due to haploinsufficiency of the GATA3 gene. Antibodies against parathyroid tissue are found in isolated hypoparathyroidism or combined with other endocrine deficiencies. Antibodies against the CASR occur in type 1 autoimmune polyglandular syndrome, due to mutations of the AIRE gene, or in acquired hypoparathyroidism. Disorders characterized by end-organ resistance to PTH are described collectively by the term pseudohypoparathyroidism (PHP) and PHP 1a and PHP 1b are caused by maternally-inherited changes at the complex imprinted GNAS locus at 20q13.32 that encodes the Gsα protein. Deleterious mutations of the PTHR1 gene show resistance to PTH and PTHrP and present as Blomstrand lethal chondrodysplasia, Eiken syndrome, endochondromatosis, and primary failure of tooth eruption. Calcium and vitamin D are the standard therapy for management of hypoparathyroidism with hormone replacement [recombinant human PTH(1-84)] therapy recently becoming an option. Calcilytics, PTH analogs and orally-active small molecule PTHR1 agonists may, in the future, join the treatment armamentarium. For complete coverage of this and related areas in Endocrinology, visit our free web-books, www.endotext.org and www.thyroidmanager.org.

PRIMARY HYPOPARATHYROIDISM

Primary hypoparathyroidism is caused by a group of heterogeneous conditions in which hypocalcemia and hyperphosphatemia occur as a result of deficient parathyroid hormone (PTH) secretion (1). This most commonly results from surgical excision of, or damage to, the parathyroid glands. However, autoimmune disease is also a significant factor in acquired cases, and genetic forms of hypoparathyroidism due to decreased PTH secretion are not rare (Table 1).

Table 1. Forms of hypoparathyroidism having a genetic basis

The signs and symptoms of hypoparathyroidism include evidence of latent or overt neuromuscular hyperexcitability due to hypocalcemia (Table 2). The effect may be aggravated by hyperkalemia or hypomagnesemia, but there is wide variation in the severity of symptoms. Patients may complain of circumoral numbness, paresthesias of the distal extremities or muscle cramping which can progress to carpopedal spasm or tetany. Laryngospasm or bronchospasm and seizures may also occur. Other less specific manifestations include fatigue, irritability, and personality disturbance. A comprehensive list of features associated with hypocalcemia can be found in the Endotext chapter, “Hypocalcemia: diagnosis and treatment” by Schafer & Shoback (3).

Severe hypocalcemia may be associated with a prolonged QT_c interval on electrocardiography, which reverses with treatment. More extensive cardiomyopathic changes may be seen. These include chest pain, elevated enzymes (CPK), left ventricular impairment, and T-wave inversion, suggestive of a myocardial infarction (4,5). Patients with chronic hypocalcemia may have calcification of the basal ganglia or more widespread intracranial calcification, detected by skull X-ray or CT scan. Also seen are extrapyramidal neurological symptoms (more often with intracranial calcification), subcapsular cataracts, band keratopathy, and abnormal dentition.

Table 2. Some clinical features of hypocalcemia

Increased neuromuscular irritability may be demonstrated by eliciting a Chvostek or Trousseau sign. A positive Chvostek sign is a prolonged reflex contraction of the facial muscle in response to a digital tap on the cheek just anterior to the ear. As with other hyperreflexias, up to 20% of normal individuals may demonstrate a slight positive reaction. A positive Trousseau sign is carpopedal spasm induced by inflation of a blood pressure cuff covering the upper arm to 20 mm Hg above systolic blood pressure for three minutes. This response reflects the heightened irritability of nerves undergoing pressure ischemia.

In hypoparathyroidism, serum calcium concentrations are decreased and serum phosphate levels are increased. Serum PTH is low or undetectable. (The important exception is PTH resistance, discussed further below.) Usually, serum 1,25-dihydroxyvitamin D (1,25(OH)₂D) is low, but alkaline phosphatase activity is normal. Despite an increase in fractional excretion of calcium, intestinal calcium absorption and bone resorption are both suppressed. The renal filtered load of calcium is decreased, and the 24-h urinary calcium excretion is reduced; nephrogenous cyclic AMP excretion is low and renal tubular reabsorption of phosphate is elevated.

The terms idiopathic or isolated hypoparathyroidism have been traditionally used to describe isolated cases of glandular hypofunction when a cause is not obvious and there is no family history. However, hypoparathyroidism is a feature common to a variety of heritable syndromes that may present de novo. Hypoparathyroidism can occur because of a congenital hypoplasia/aplasia with or without other congenital anomalies such as dysmorphic facies, immunodeficiency, lymphedema, nephropathy, nerve deafness or cardiac malformation. Thus, in patients with hypoparathyroidism of uncertain onset, a careful examination of craniofacial features and assessment of endocrine, cardiac and renal systems should be performed to exclude a syndromic cause. Similarly, autoimmune hypoparathyroidism can occur as an isolated endocrine condition or with other glandular deficiencies in a pluriglandular autoimmune syndrome, requiring attention to multi-organ endocrine dysfunction.

A significant number of patients with idiopathic hypoparathyroidism and hypercalciuria, but no other anomalies may be found to have de novo activating mutations of the CASR gene. Because of the implications for treatment, CASR molecular screening of patients with this presentation is recommended (6,7).

PARATHYROID RESISTANCE SYNDROMES

Pseudohypoparathyroidism

Several clinical disorders characterized by end-organ resistance to PTH have been described collectively by the term pseudohypoparathyroidism (PHP) (134-137). They are associated with hypocalcemia, hyperphosphatemia, and increased circulating PTH. Target tissue unresponsiveness to the hormone manifests as a lack of increased phosphate excretion and, in some cases, cAMP excretion in response to PTH administration (138). The biochemical characteristics of the different forms of PHP are contrasted with those of hypoparathyroidism in Table 3.

Albright Hereditary Osteodystrophy

Fuller Albright first recognized that the likely cause of the hypoparathyroid state in PHP is a constitutive absence of target tissue responsiveness (139). In many patients, the end-organ resistance is accompanied by a specific pattern of physical findings, called Albright hereditary osteodystrophy (AHO; MIM#300800). Typically, patients have short stature, round facies, brachydactyly, obesity, and ectopic soft tissue or dermal ossification(s) (osteoma cutis) (Figure 1). In the calvaria, this may manifest as hyperostosis frontalis interna (134). Intracranial calcification(s), cataracts and band keratopathy, subcutaneous calcifications, and dental hypoplasia are also common but are likely the consequences of longstanding hypoparathyroid hypocalcemia (Table 4, see below Figure 1). The brachydactyly may be asymmetric or not, and may involve one or both hands or feet, but the pattern is quite distinctive (140,141). The shortening tends to involve the first distal phalanx, with a thumbnail (or first toenail) that is wider than it is long. The fourth and fifth metacarpals (or metatarsals) are frequently shortened out of proportion to the others and the second metacarpal is often spared. Radiographic analysis of the hands (pattern profiling) may be helpful in assessment of the brachydactyly (Figure 1) (142).

Figure 1.Features of Albright Hereditary Osteodystrophy (AHO). [A] Young woman with short stature (~ 3rd centile), disproportionate shortening of the limbs, generalized obesity, and round, flattened face. [B] Radiograph of the hand showing the shortened 4th and 5th metacarpals. [C] Fist with the characteristic 'dimples' over the 3rd, 4th, and 5th digits replacing the knuckles formed by the distal head of normally sized metacarpal bones (Archibald sign). [D] Brachydactyly of the hand, with the short 4th and 5th digits, the greatly foreshortened terminal 1st digit, and very short, wide thumbnail (potter's thumb). (Reproduced from Levine, 2000, with permission).

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Table 4. Incidence of signs and symptoms in PHP with AHO a	Percentage
Short stature	80
Obesity	50
Craniofacial
Round face	92
bLenticular opacities	44
Strabismus	10
bDental hypoplasia	51
bBasal ganglia calcification	50
Thickened calvaria	62
Mental deficit	75
Brachydactyly
Brachymetacarpia	68
Brachymetatarsia	43
Brachyphalangia	50
Other connective tissue features
Decreased bone density	15
Ectopic ossification	56
bSubcutaneous calcification	55
a Taken from Drezner and Neelon (1995) b Features common to other forms of chronic hypoparathyroid hypocalcemia

Although affected patients are generally short as adults, their bone age as children may be advanced and growth accelerated (142). Patients with AHO are probably predisposed to hypertension (143), conductive and sensorineural hearing loss (134,144), cord compression due to spinal anomalies (145), and movement disorders due to basal ganglia calcification (146). The features of AHO may be subtle in infancy or early childhood; in a few, there is little to see even in adulthood. The round facies, short neck, and low, flat nasal bridge are often accompanied by central obesity (147). A study showed that the obesity phenotype occurs primarily in those patients who also have multiple hormone resistance, i.e., PHP1a (see below), and according to data from mice, a hypothalamic mechanism, rather than hypothyroidism, is the primary underlying cause (148).

Patients with brachydactyly, mental retardation, and other features closely resembling AHO have been found to carry microdeletions of chromosome 2q37; brachydactyly-mental retardation, BDMR; MIM#600430 (149). Genes important for skeletal and neurological development lie within this region. Haploinsufficiency of HDAC4 (MIM#605314), encoding a histone deacetylase that regulates gene expression during the development of many tissues including the bone, is responsible for the brachydactyly and the mental retardation in those patients (150). Isolated brachydactyly type E (BDE, MIM#113300) has been associated in sporadic cases with mutations in HOX13 (MIM#168470) (151) and mutations in the PTHLH gene (MIM#168470) on 12p11.2 that encodes PTHrP have been implicated. In one family with autosomal BDE a cis-regulatory site downregulates PTHLH in translocation t(8;12)(q13;p11.2) and downregulates its targets ADAMTS-7 and ADAMTS-12 leading to impaired chondrogenic differentiation (152). Affected individuals of one large family with BDE, short stature, and learning difficulties had an ~900 bp microdeletion encompassing PTHLH (153). Additional individuals with BDE and short stature from other different kindreds were found to have PTHLH missense, nonstop, and nonsense mutations (153). Different translocations affecting chromosome 12p have also been identified in two families with BDE, leading to increased abundance of a long noncoding RNA on chromosome 12q, which regulates the expression of PTHLH in cis and of the SOX9 gene located on chromosome 17q in trans (154). BDE is associated with hypertension in some cases, in which the disease is inherited in an autosomal dominant manner (termed HTNB). Missense mutations in PDE3A, a gene encoding a cAMP/cGMP phosphodiesterase, have been recently found in several unrelated families with HTNB. These mutations cause increased cAMP hydrolytic activity and thus lead to diminished cAMP signaling (155). Some patients with AHO-like features have been described, who also showed platelet Gs hypofunction. Those patients were found to have IGF2 hypermethylation and SNURF hypomethylation, as well as imprinting defects within GNAS, the gene encoding the stimulatory G protein alpha-subunit (Gsα; see below) (156).

PHP1a

PHP1a patients, characterized by AHO, PTH resistance, and evidence of target organ resistance to other hormones, are usually found to have a reduction in the activity of the Gsα subunit, which is part of the membrane associated heterotrimeric G-protein complex - transducing signals between G-protein coupled receptors and adenylate cyclase (157-159). Adenylyl cyclase catalyzes the synthesis of the second messenger cAMP, and therefore, PHP-1a patients tend to have a deficiency in cAMP generation, particularly in certain tissues. As explained above, this deficiency is clearly evident when measuring cAMP excretion in response to PTH administration.

The GNAS gene (MIM#168470) encoding the Gsα protein maps to 20q13.2-13.3 and has at least 4 alternative transcriptional start sites (Figure 2) and an antisense transcript, GNAS-AS1 (160). The three upstream exons and the preceding promoter regions are genetically imprinted, i.e., methylated in an allele specific manner. The promoter of the Gsα transcript, which uses exon 1, is unmethylated. Unlike the other alternative GNAS products, Gsα expression is biallelic except in a small set of tissues, where Gsα is derived predominantly from the maternal allele (161-164). This tissue-specific monoallelic Gsα expression affects penetrance of the PHP phenotype. The maternal transmission of the hormone resistance in PHP1a (165) can be explained by silencing of the paternal Gsα allele, which would otherwise allow expression of 50% of Gsα protein (166). Thus, full expression of a coding GNAS mutation, which occurs in maternally transmitted cases, leads to AHO plus hormone resistance (PHP1a), whereas a paternally transmitted mutation causes AHO alone (pseudopseudohypoparathyroidism; PPHP). Despite clinical evidence supporting imprinting in portions of the kidney tubule, it has been difficult to confirm this experimentally in humans (167). The imprinting of GNAS is complex and involves multiple differentially methylated regions (DMR) (160). Moreover, it is tissue-specific and may vary with developmental stage (168,169), although key imprinting of the 1A (also referred to as A/B) DMR is thought to be a primary event that occurs during gametogenesis and is maintained thereafter (170). Ablation of the Gsα ortholog in mice (Gnas) has confirmed that maternal, but not paternal, transmission of the deleted allele results in PTH resistance. The homozygous deletion of Gnas is embryonic lethal (161). Comparison of Gsα expression in mice with maternally vs paternally disrupted Gsα expression also demonstrated that Gsα expression is predominantly maternal in the renal cortex, but not in renal medulla (161). PTH resistance is delayed until after infancy in most PHP1a patients, and exon 1A imprinting may not be evident in the fetus (167). Indeed, a study using mice demonstrated that the silencing of the paternal Gsα allele develops postnatally (171).

Figure 2

Simplified view of the GNAS region and its transcripts. The normal allele-specific methylation and expression patterns of the four alternate first exons of GNAS which splice onto exon 2 to produce transcripts encoding NESP55, XLαs, a transcript of unknown function (1A; also known as A/B), and Gsα (which uses exon 1). NESP55 and XLαs promoters are oppositely imprinted: NESP55 is expressed from the maternal allele and its promoter region is methylated on the paternal allele, whereas XLαs is expressed from the paternal allele and its promoter is methylated on the maternal allele. Gsα is paternally silenced in some tissues e.g., renal proximal tubule cells, indicated by the dashed arrow. NESP55 protein is unrelated to Gsα, and its entire coding region is located within its first exon. In contrast, XLαs and Gsα proteins have identical COOH-terminal domains (encoded by exons 2-13), while their unique NH2-terminal domains are encoded within their respective first exons. Exon 1A does not have a translational start site, but is transcriptionally active. Loss of exon 1A imprinting (methylation) is associated with decreased Gsα expression in renal proximal tubules and some other hormone-responsive tissues, and is the typical cause of PHP1b. (figure from Liu et al., 2000, with permission).

A variety of inactivating mutations in the portion of the GNAS gene encoding Gsα have been identified in PHP1a patients (141,172-176). The spectrum includes missense mutations, point mutations impairing efficient and accurate splicing, and small insertion/deletion mutations. The 4bp deletion in exon 7 (DGACT 188/190) has been observed in multiple unrelated cases, suggesting that this may be a hot spot (136,176). Several other mutations have also been observed in more than one kindred, indicating that additional susceptibility regions may exist. The identification of de novo germline mosaicism (177) is consistent with the view that most sporadic cases harbor new mutations, but the separation of such sporadic cases from familial ones, in which there is suppression of phenotype due to imprinting, may be difficult without detailed molecular studies.

PHP1a cases have been described in which no mutations of the GNAS gene have been found by nucleotide sequence analysis of exons encoding Gsα. This may be because the mutation is in a regulatory region of the gene not yet examined, or it may be that a large deletion prevents amplification of the mutant allele for subsequent analyses. In cases without identified GNAS coding mutations, an assessment of Gsα bioactivity in erythrocytes is helpful in ruling out regulatory region mutations or large deletions. A 35 kb deletion spanning exons 1 through 5 has been identified by using comparative genome hybridization in a patient with PHP1a in whom coding mutations had been ruled out but a marked reduction of erythrocyte Gsα activity demonstrated (178,179). Typically, PHP1a is associated with multiple hormone resistance, including thyroid stimulating hormone (TSH) and gonadotropins, causing hypothyroidism and gonadal failure, respectively. Because the hypothyroidism may express before hypocalcemia is observed (136), early surveillance of thyroid function is warranted. However, thyroid replacement from birth does not appear to prevent the mental deficit typical of PHP1a. In women, the hypogonadism is partial (180) so that oral contraceptives may help regulate the menstrual cycle. Estrogen can antagonize bone resorption leading to an exacerbation of hypocalcemia (181), but placental 1,25-dihydroxyvitamin D synthesis likely obviates this effect altogether in pregnancy so women are frequently normocalcemic at that time (182). Abnormalities of the somatotropin axis have also been reported, with documentation of subnormal growth hormone release following stimulation by L-arginine or growth hormone releasing hormone (183,184). The effect of growth hormone replacement has been investigated in a small group of pre-pubertal PHP1a patients (185). This study concluded that the treatment is potentially effective but has to be initiated as early as possible.

The tissue-specific silencing of the paternal Gsα allele also plays a key role in the development of the additional hormone resistance phenotypes, as monoallelic Gsα expression has been demonstrated in the thyroid, the ovaries, and the pituitary (162-164,186). Studies have revealed that obesity also develops primarily in patients who inherit the inactivating Gsα mutations from their mothers (187). Gsα is not imprinted in the white adipose tissue (188), but the investigations of mice in which Gsα is ablated conditionally in the brain showed that Gsα is also monoallelic in certain parts of the hypothalamus (189), thus explaining the imprinted mode of inheritance of the obesity phenotype. Likewise, it has been noted that cognitive impairment, a typical AHO feature, also develops primarily after maternal inheritance of the inactivating Gsα mutation (190).

PHP1b

PHP1b is typically not associated with AHO or a generalized reduction in Gsα expression (135). PHP1b patients show a defect in renal PTH signaling, but an apparently normal response to PTH in bone. Affected individuals are therefore functionally hypoparathyroid but show normal skeletal architecture and development. Due to unimpaired PTH responsiveness in bone, however, signs of hyperparathyroid bone disease (osteitis fibrosa cystica) are occasionally observed, complicating the picture (191,192). Biochemical abnormalities suggestive of thyroid stimulating hormone resistance are also seen in some patients (186), and abnormalities of renal uric acid handling have been documented (193,194). In fact, sometimes, PHP1b cases can present first with hypothyroidism (195,196). A recent study also demonstrated short stature and growth hormone deficiency in monozygotic twins with PHP1b (197). However, clinically significant hormone resistance is restricted to PTH in most cases. Because the hormone resistance is mostly limited to PTH, it was thought at one time that these findings could be explained by a defect in the type-1 parathyroid hormone receptor (PTHR1, MIM#168468), but sequencing in PHP1b patients found no mutations in protein-coding exons or gene promoter regions of the gene (198-200), and studies of PHP1b families show no linkage to PTHR1 (201,202).

Most cases of PHP1b are sporadic, but a familial form of PHP1b with an apparent autosomal dominant mode of inheritance also exists (AD-PHP1b). In four AD-PHP1b kindreds, linkage to chromosome 20q13.3 was established, the same region which includes the GNAS locus (201). In these families, the pattern of transmission suggested paternal imprinting, and inheritance is therefore the same as for PHP1a. A further 13 PHP1b subjects were studied, some of whom had bone responsiveness to PTH (166). All lacked methylation of the alternate exon 1A, an epigenetic defect that is postulated to inhibit expression of the functional exon 1-containing Gsα transcript in renal tissues only (Figure 2). Thus, the loss of methylation of the maternal exon 1A allele leads to the silencing of the maternal as well as paternal Gsα allele, causing PTH resistance specifically in renal proximal tubule cells. Genetic analysis indicated that mutations in a regulatory region some distance from the GNAS coding exons were likely to account for the unique imprinting defect(s) associated with PHP1b (203). A search for the mutation revealed the presence of a 3 kb microdeletion that segregated with the disease in 12 kindreds with AD-PHP1b and also occurred in 4 sporadic cases (204). The deletion, flanked by direct repeats, removes 3 exons of the STX16 gene, which encodes syntaxin-16. Two other private deletions within STX16 have been identified in AD-PHP1b kindreds. One removes exons 2 to 4 (205) and the other exons 2 to 8 (206). In all these cases, maternal, but not paternal, inheritance of the STX16 deletion led to PTH resistance. Because STX16 is apparently not imprinted (205), loss of one copy of this gene is not predicted to underlie the PHP1b pathogenesis. Instead, these deletions presumably disrupt a cis-acting element that controls imprinting at GNAS exon 1A. Interestingly, a study identified a large deletion ablating NESP55 without any overlap with STX16 as the cause of PHP1b in a family in whom affected individuals showed isolated loss of 1A methylation (207). Thus, at least two distinct cis-acting regions appear to be necessary for the methylation imprints at the GNAS 1A region. In two other PHP1b kindreds, nearly identical deletions of the NESP55 DMR including exons 3 and 4 of the antisense transcript segregated with the disease (208). In this instance, however, the 1A DMR was not the only region to lose the differential methylation required to allow maternal expression of Gsα in the kidney. Maternal methylation was also lost in the regions of the XLαs and GNAS-AS1 promoters. Another kindred with these widespread epigenetic defects of GNAS has been described (209). The affected individuals in this kindred carried a maternally inherited deletion that removed antisense exons 3 and 4 with flanking intronic regions but not the NESP55 exon. Additional genomic rearrangements in the chromosomal regions comprising GNAS have also been identified and proposed to underlie the GNAS methylation abnormalities in some AD-PHP-Ib cases (210,211).

Sporadic PHP1b cases also show broad GNAS epigenetic defects that involve 1A. In some of these cases, paternal uniparental disomy of different chromosome 20 segments have been reported as the likely cause of PHP1b in several such cases (212-216). The cause of the epigenetic defects and PTH resistance, however, remains unknown for most cases of sporadic PHP1b. A few cases have deletions within GNAS that are de novo either in the patient or in the unaffected mother’s paternal allele, as reported (217). Additional imprinting defects at other genomic loci have been identified in a few patients with PHP1b (218). Moreover, GNAS methylation defects have been identified in some cases with hypomethylation at multiple maternally methylated imprinted regions (219,220). In fact, some of those cases show both PTH resistance and the clinical features resulting from the methylation changes of the other loci, such as Beckwith-Wiedemann Syndrome (221).

A recent study revealed that, in addition to the exon 1A DMR, methylation at a new GNAS region close to the GNAS-AS1 promoter (termed GNAS-AS2), is lost in patients who carry STX16 deletions (222). Note that this region is also affected in those cases that display broad GNAS methylation changes. The effect of the loss of methylation at GNAS-AS2 has yet to be determined at the level of gene expression, but this finding shows that the different subtypes of PHP-1b are more similar to one another at the molecular level than previously recognized. Based on one report, no clinical differences could be established according to the pattern of GNAS epigenetic defects, although serum PTH levels were significantly higher in females with broad GNAS methylation defects than females with isolated loss of 1A methylation (223). A recent study also found an intrauterine growth advantage for both AD-PHP-1b and sporadic PHP-1b cases, but the results indicate that the sporadic cases are not as markedly growth accelerated as AD-PHP-1b cases at birth (224).

In contradistinction to the classical understanding that AHO features are unique to PHP1a, some studies have identified patients with PTH resistance and AHO features who show GNAS epigenetic defects rather than Gsα coding mutations (225-227). Thus, there may be some overlap between the clinical and molecular features of PHP1a and PHP1b. It is possible that the AHO features observed in patients with GNAS epigenetic defects result from a genetic mechanism that is similar to the mechanism underlying the hormone resistance in PHP1a patients, i.e., due to monoallelic Gsα expression in additional tissues.

A PHP1b family with a novel Gsα mutation, deletion of isoleucine-382 in the carboxyl terminus (leading to uncoupling from the PTHR1 and isolated PTH resistance), shows transmission through 3 generations, consistent with paternal imprinting (228). However, such mutations within Gsα coding exons are rare (166).

PHP1c and PHP2. Patients with PHP1c have multiple hormone resistance but normal Gsα activity. The defect may be in other components of the receptor-adenylate cyclase system, such as the catalytic unit, but some PHP1c cases have been reported to carry Gsα coding mutations (229). These mutations render the Gsα protein unable to mediate cAMP generation in response to receptor activation but do not affect basal adenylate cyclase stimulating activity or the ability to be activated by non-hydrolyzable GTP analogs (230-232). Thus, some forms of PHP1c appear to be an allelic variant of PHP1a. Finally, patients with PHP2 have a normal urinary cAMP response to PTH but an impaired phosphaturic response (233). The defect could be in the cAMP-dependent protein kinase (PKA), one of its substrates or targets, or in a component of the PTH-PKC signaling pathway.

A study (234) has discovered a heterozygous mutation of the gene encoding the regulatory subunit of PKA (PRKAR1A) in three patients with multiple hormone resistance and acrodysostosis, a form of skeletal dysplasia that includes severe brachydactyly type-E and other skeletal findings that resemble AHO. This mutation, p.R368X, which leads to truncation of the COOH-terminal 14 residues, impairs cAMP binding to the regulatory subunit, thereby blocking the activation of PKA (234). In addition to acrodysostosis, patients carrying this mutation display evidence for target organ resistance to PTH, thyrotropin, growth hormone-releasing hormone, and gonadotropins, but these findings are accompanied by elevated basal plasma and urinary cAMP levels and with an apparently normal cAMP response to exogenous PTH administration. In certain other patients with acrodysostosis, but mostly without hormone resistance, it has been shown that the disease is caused by missense mutations in PDE4D, which encodes a cAMP phosphodiesterase (235-236). The type of acrodysostosis caused by PRKAR1A mutations has been termed acrodysostosis-1 (MIM#101800), while the one caused by PDE4D mutations acrodysostosis-2 (MIM#614613).

Other Phenotypes Associated with GNAS Mutations.

In contrast to the PHP phenotype associated with inactivating GNAS mutations, a different form of sporadic bone disease, (polyostotic fibrous dysplasia) results from de novo GNAS mutations that cause constitutive Gsα activity (237,238). A more severe form of this disease (panostotic fibrous dysplasia) with hyperphosphatasia and hyperphosphaturic rickets has also been described (239,240). Patients carrying these activating mutations are mosaic for mutant and wild-type cells, indicating that the mutation is acquired during postzygotic development. These mutations affect the arginine residue at position 201 (exon 8) and, rarely, the glutamine at 227 (exon 9), and inhibit the intrinsic GTP hydrolase activity of Gsα, thereby leading to constitutive activity. Such constitutively activating mutations of GNAS are also found in a variety of endocrine and non-endocrine tumors, such as growth hormone-secreting adenomas (241). A missense mutation in exon 13 (A366S) results in a Gsα protein that is unstable at 37°C, but constitutively active at lower temperatures (242,243). Affected patients have PHP due to PTH resistance and precocious puberty (testotoxicosis) due to hormone-independent constitutive activation of luteinizing hormone receptors at lower ambient temperatures in the testes. Another Gsα mutant carrying Ala-Val-Asp-Thr amino acid repeats in the guanine-binding domain has been described in a patient with neonatal diarrhea and PTH resistance (244). In this instance, the mutant protein is unstable and localized to the cytoplasm rather than plasma membrane, which explains the hormone resistance. On the other hand, this mutation increases the rate of GDP-GTP exchange and, thus, confers overactivity. The increased activity of Gsα seems to be evident during the neonatal period in the gut, where the mutant localizes to the plasma membrane, thus explaining the diarrhea phenotype. Undoubtedly, other patterns of hormone-receptor interaction due to a GNAS mutation await discovery.

Inactivating GNAS mutations have also been identified in patients with congenital osteoma cutis and progressive osseous heteroplasia (POH), suggesting that these connective tissue conditions are another variant in the phenotypic spectrum of GNAS-related disease (245-248). No genotype-phenotype correlation has been revealed regarding these disorders, as the same mutation can be associated with either typical AHO features or severe ossifications that involve deep connective tissues and skeletal muscle (249). Nonetheless, patients with POH inherit the GNAS mutation from their fathers or acquire this mutation de novo on the paternal GNAS allele. This parent-of-origin specific inheritance of POH was established by analyzing 18 unrelated kindreds with this disorder (250). In a single, three generation, kindred, the inheritance of the mutation from males led to POH, while the inheritance of the same mutation from females led to typical AHO. It thus appears likely that alterations in the activity of a paternally expressed GNAS product, such as XLαs, contribute to the pathogenesis of POH. However, POH-like features have also been seen in some patients with maternally inherited GNAS mutations (251). A recent study revealed that the distribution of POH lesions follow dermomyotomes and show a tendency for one-sidedness, suggesting that post-zygotic second hits may contribute to the development of these lesions on top of the inherited heterozygous mutations of GNAS (252).

THE PARATHYROID HORMONE RECEPTOR AND SKELETAL DYSPLASIAS

PTHR1 is a family B G protein-coupled receptor that signals through multiple different G proteins including Gsα (253). It responds to two ligands, PTH and the PTH-related peptide (PTHrP). It would thus be predicted that deleterious mutations might show resistance to PTH, as well as evidence for a defect of PTHrP action. Functional polymorphisms in the PTHR1 are associated with adult height and bone mineral density (254), emphasizing the role that the receptor and its ligands play in endochondral bone formation. Inactivating or loss-of-function mutations in the PTHR1 have been implicated in the molecular pathogenesis of Blomstrand lethal chondrodysplasia (BLC; MIM#215045), and other skeletal dysplasias and dental abnormalities (255). The rare, recessive BLC is characterized by short-limbed dwarfism with craniofacial malformations, hydrops, hypoplastic lungs and aortic coarctation (256-260). The bones show accelerated endochondral ossification and deficient remodeling. The Blomstrand disease has been subdivided into type I, which refers to the severe (classical) form, and type II, which refers to a relatively milder variant, and the difference between severity is attributed to complete or incomplete inactivation of the PTHR1, respectively (261,262). A milder form of recessively inherited skeletal dysplasia, known as Eiken syndrome (MIM#600002), has also been linked to mutations of PTHR1 (263). Dominantly acting PTHR1 mutations have been identified in endochondromas of patients with enchondromatosis (Ollier's disease - MIM#166000), a familial disorder with evidence of autosomal dominance characterized by multiple benign cartilage tumors, and a predisposition to malignant osteocarcinomas (264,265). As many patients with Ollier’s disease do not have PTHR1 mutations, it is likely that the condition is genetically heterogeneous (266). Dominantly inherited symmetrical enchondromatosis is associated with duplication of 12p11.23 to 12p11.22 that includes the PTHLH gene encoding PTHrP suggesting that abnormal PTHR1 signaling may underlie this unusual form of endochondromatosis (267). In addition, some cases of autosomal dominant nonsyndromic primary failure of tooth eruption (PFE) are due to loss-of-function mutations in the PTHR1 that are dominantly acting, leading to haploinsufficiency of the receptor (268-272).

HYPOMAGNESEMIA

In humans, hypomagnesemia leads to a suppression of parathyroid hormone release and some degree of peripheral resistance. Although the exact molecular mechanism underlying the suppression of the parathyroid gland in hypomagnesemia is unknown, it is important to recognize that laboratory testing in cases of hypocalcemia with reduced PTH should include measurement of serum magnesium, particularly in newborns (273). Primary hypomagnesemia with secondary hypocalcemia (HSH) is an autosomal recessive disorder characterized by neuromuscular symptoms in infancy due to extremely low levels of serum magnesium and moderate to severe hypocalcemia. Homozygous mutations in the magnesium transporter gene transient receptor potential cation channel member 6 (TRPM6) cause the disease. HSH, a potentially lethal condition, can be misdiagnosed as primary hypoparathyroidism (274). Long-term prognosis after treatment with high dose of oral magnesium supplementation is good. Hypomagnesemia is also associated with long-term use of proton-pump inhibitors that decrease the luminal pH of the intestine by acting on the enterocyte apical TRPM6/7 channels (275,276).

MANAGEMENT OF HYPOPARATHYROIDISM

Calcium and Vitamin D. The goal of treatment in hypoparathyroid states is to raise the serum calcium sufficiently to alleviate acute symptoms of hypocalcemia and prevent the chronic complications (3,277,278). The calcium concentration required for this purpose is generally the low-normal range. Acute or severe symptomatic hypocalcemia is best treated with intravenous calcium infusion. Initial doses of 2 to 5 millimoles of elemental calcium as the gluconate salt can be given over a 10 to 20 minute period, followed by 2 millimoles elemental calcium per hour as a maintenance dose, to be adjusted according to symptoms and biochemical response. Care must be taken to ensure that the infusion does not extravasate, and ionized or total calcium levels should be monitored frequently on a stat basis. Doses in children 5 to 14 years of age need to be adjusted for body weight, while neonates and infants require age-specific dosing schedules. In adults, intravenous vitamin D therapy is not needed. Hyperphosphatemia, alkalosis and hypomagnesemia should be corrected concomitantly if present. Post-surgical hypocalcemia is now rarely severe and usually transient with appropriate management (279). However, the occasional patient can represent a significant problem, particularly if the indication for surgery is chronic hyperparathyroidism, and the post-operative hypoparathyroid state is permanent (280). The long-term effects of standard therapy, hypercalciuria, nephrolithiasis, nephrocalcinosis, ectopic tissue calcification and mood changes, remain a concern (270,281).

The mainstay of chronic treatment is oral calcium and vitamin D, which should be started as soon as possible to allow reduction and discontinuation of the intravenous calcium. Oral calcium comes in several forms, but calcium carbonate is generally the least expensive. A total of 20 to 80 millimoles elemental calcium daily (2 to 8 g calcium carbonate per day) is generally effective, but should be given in divided doses and adjusted on the basis of gastro-intestinal tolerance, relief of hypocalcemic symptoms, and appropriate biochemical response. Vitamin D is preferably administered as calcitriol (0.25 to 1.0 micrograms per day) but, if cost is a factor, pharmacological doses of cholecalciferol or ergocalciferol or calcidiol may be less expensive and equally efficacious (282). Cholecalciferol and ergocalciferol have the longest duration of action and can result in sustained toxicity. It is therefore appropriate to institute a starting dose of 25,000 IU/day and titrate upwards (to 100,000 IU/daily) with assessment of serum and urinary parameters afterwards with follow-up at 6 and 12 months, even if the patient is relatively asymptomatic. Some authorities recommend the use of active vitamin D (calcitriol or alphacalcidol) where possible providing the rationale that the lack of PTH along with the tendency to hyperphosphatemia impairs the renal conversion of 25-hydroxyvitamin D to active vitamin D (277,278). In any event, serum calcium and 24 hour urinary excretion should be carefully monitored when therapy is started and continued until the patient is stabilized. Hypercalciuria that occurs as treatment is initiated, even prior to the normalization of the serum calcium, may warrant an ongoing assessment of nephrocalcinosis, most sensitively detected by renal ultrasound. Consequently, only a low-normal serum calcium concentration may be attainable, but many patients feel well enough that there is no need to entirely normalize the serum calcium. That way, the risk of renal failure due to chronic hypercalciuria − especially problematic in patients with CASR activating mutations (6,7) − is minimized. Nevertheless, a significant number of patients report problems with easy fatigue and exhaustion, and mood disturbances (e.g., depression, anxiety, hostility, and paranoid ideation) not in keeping with the degree of hypocalcemia, suggesting that there may be non-calcitropic effects of PTH not remedied by maintenance of normocalcemia alone (281). In an epidemiological and health-related quality of life study from Norway, postsurgical hypoparathyroid patients scored worse than those with nonsurgical hypoparathyroidism or pseudohypoparathyroidism (283).

In pseudohypoparathyroidism, monitoring serum PTH levels during treatment is critical with the aim of normalizing or reducing PTH levels as much as possible. This is done to avoid the long-term elevation of circulating PTH, that would likely cause bone resorption. Also, hypercalciuria as a result of the calcitriol and calcium treatment is a lesser concern because PTH actions in the distal tubule are functional, preventing the loss of calcium in the urine. Of note, calcitriol (and not other forms of vitamin D) should be used for the treatment, because the PTH resistance in the proximal tubule does not allow for the efficient synthesis of 1,25(OH)₂D from 25-hydroxyvitamin D (also see comments above).

Hormone replacement therapy.

Hormone replacement has been advocated as a potentially superior form of treatment for decades but only recently have preparations of recombinant human hormone –– teriparatide (PTH 1-34) and full-length parathyroid hormone (PTH 1-84) — become available. In 2015, the U.S. Food and Drug Administration (FDA) approved recombinant human (rh) PTH (1-84) for the management of hypoparathyroidism (284). This provides an additional therapeutic option for the management of those patients who demonstrate poor control with the standard calcium and active vitamin D supplemental therapy. The FDA indication is for subjects with hypoparathyroidism of any etiology, except ADH, but including postsurgical cases. The FDA approved rhPTH(-84) with a “black box” warning because of the history of rat osteosarcoma and PTH use (285), although no evidence for this in primates or in clinical use has been forthcoming (286), but did not limit the duration of use.

The use of PTH in hypoparathyroidism was demonstrated initially with the amino-terminal fragment of PTH, teriparatide [PTH (1–34)] (287). Beneficial control in children and in adults occurred when teriparatide was administered daily with better control when the peptide was administered in twice-daily dosing regimens (287-291). With a pump delivery system by which teriparatide could be administered continuously (292,293), urinary calcium excretion fell and markers of bone turnover normalized. A smaller daily dose was required with pump delivery vs multiple daily dosing regimens. An open-label trial of PTH (1–34) in adult subjects with postsurgical hypoparathyroidism showed improvement in quality of life (294). Beneficial effects on calcium homeostasis have also been demonstrated in specific ADH cases with activating CaSR mutations (295,296).

The full-length PTH (1-84) represents the actual secreted product of the parathyroid gland and its longer biological half-life (than PTH(1-34) makes once-daily dosing feasible (297-299). Studies by several groups have noted a substantial reduction in the requirement for calcium and active vitamin D (300-302); only transient reductions in urinary calcium excretion (299); a tendency for lumbar spine bone mineral density (BMD) to increase and that of the distal one-third radius to fall (301); a rapid increase in bone turnover, assessed by circulating markers and dynamic histomorphometric analyses of bone that achieves a new steady state that is higher than baseline values within 2–3 years (303); and improvements in quality of life in some studies (302,304).

In a placebo-controlled 24-week clinical trial of rhPTH (1-84) in 130 hypoparathyroid patients the primary endpoints of a reduction by 50% in calcium supplements and in active vitamin D along with maintenance of the serum calcium were met in over half of the study subjects (305). There was a greater percentage of subjects in whom active vitamin D could be eliminated entirely while taking no more than 500 mg of oral calcium daily. The drug was titrated from 50 to 100 μg/d, with just over half of the subjects needing the highest dose. The rhPTH(1-84) reduced serum phosphate levels, improved the calcium-phosphate product, and maintained 1,25(OH)₂D and serum calcium levels in the normal range (306). For discussion of selection and management of patients for PTH(1-84) therapy as well as safety issues and research agenda for the future the reader is referred to (277,278).

In the future, analogs of PTH may be useful for the treatment of hypoparathyroidism. To facilitate their study, diphtheria toxin- and GFP-based mouse models of acquired hypoparathyroidism have been developed (307). In each model, a single subcutaneous injection of a long acting PTH analog increased serum calcium levels more effectively and for a longer time than a 10-fold greater dose of PTH(1-34) (307). Also of note is that orally active small-molecule PTHR1 agonists are being developed for the treatment of hypoparathyroidism. Oral administration of one such compound, PCO371, to osteopenic rats provoked a significant increase in bone turnover with some increase in bone mass. In hypocalcemic rats, the compound restored serum calcium levels without increasing urinary calcium, and the effects were stronger and longer-lasting than with PTH injections (308).

Calcilytics.

Calcilytics – small molecule allosteric modulators of the CASR that antagonize the calcium-sensing receptor and promote PTH secretion − are a promising alternative for disorders with intact but hypofunctioning parathyroid glands (309). In clinical studies in patients with ADH1, dosing with PTH(1-34) leads to better control of blood calcium levels (288). However, PTH does not correct the effects of the activated CASR in the kidney, and urinary calcium excretion may not be normalized in contrast to cases of postsurgical hypoparathyroidism (292,296). Thus while FDA approval was given for PTH treatment of hypoparathyroidism, ADH1 was excluded from the indication.

Calcilytics which inhibit the activation of the CASR in the parathyroid and renal tubule that promote not only PTH secretion but also renal calcium reabsorption are therefore of potential interest for the treatment of ADH1. In cell culture experiments studying activating CASR mutants, calcilytics normalize the left-ward shift of the calcium response curve (310,311). The utility of calcilytics was further demonstrated in studies of mice harboring activating Casr mutations. In one study, two knock-in mouse models of ADH1 with activating mutations in the Casr were generated. Daily oral administration of the calcilytic JTT-305/MK-3442 to these mice increased serum PTH and calcium levels, and reduced urinary calcium excretion (310). Intraperitoneal injection of the calcilytic NPS2143 in the nuf mouse model of ADH1, transiently increased circulating PTH and calcium levels without increasing urinary calcium levels (311). In a preliminary clinical study, IV administration of the calcilytic NPSP795 to five patients with ADH1 increased their plasma PTH levels and decreased their fractional urinary calcium excretion (312). Calcilytics comprise two main classes of compounds; the amino alcohols (e.g., NPS2143, NPSP795, JTT-305/MK-5442) and the quinazolinones (e.g., ATF936 and AXT914) (309). While both classes of compounds corrected the gain-of-function properties of several of the ADH1 CASR mutations tested in vitro, a subset of mutations involving NPS2143 binding sites within the transmembrane domain of the CASR are not fully corrected with NPS2143 but are normalized with the quinazolinone drugs (ATF936 and AXT914) (313-315). Whether this is reflected in mouse model studies and clinical situations remains to be determined.

Cases of hypoparathyroidism presenting as ADH but without CASR mutations have been found to have activating mutations of Gα11 that couples the CASR to signaling pathways (316,317). The syndrome has been designated ADH2. Even though Gα11 is downstream of the CASR the calcilytic NPS2143 has been shown to rectify the altered Ca²⁺ signaling of the overactive mutants in in vitro studies (318). Knock-in mice harboring an ADH2 Gα11 activating mutation faithfully replicate ADH2 (319). Treatment with the calcilytic NPS2143 or a Gα11/q-specific inhibitor, YM-254890 (320), increased circulating PTH and calcium levels in the heterozygous mutant mice (319), Thus, calcilytics, by blocking the renal CASR, are potentially of use to treat ADH1 and ADH2, and Gq/11 inhibitors to treat ADH2 as well as other forms of hypoparathyroidism.

Other therapies.

If the serum calcium attainable with oral calcium and calcitriol is below the normal range and the patient remains symptomatic, then a trial of a thiazide diuretic may be considered, with the aim of reducing the hypercalciuria to raise the serum calcium further. The argument for efficacy seems greatest for responsive forms of autosomal dominant hypocalcemia due to activating CaSR mutations, since the thiazide-sensitive transporter, SLC12A3 (MIM#600968), is a downstream target of and is suppressed by activated CaSR in the kidney. For reasons that are not clear, however, thiazides work well in some patients (321) but not others. It is critical to monitor serum potassium and magnesium levels as thiazide use can lead to renal losses of these cations with resulting hypokalemia and hypomagnesemia. Some authorities suggest thiazides should not be used in APS1 patients with adrenal insufficiency and in ADH1 patients with Bartter syndrome type V (277,278).

As the serum calcium is normalized, elevated serum phosphate concentrations generally decline but phosphate-binding gels such as aluminum hydroxide are occasionally helpful in reducing hyperphosphatemia at the beginning of therapy.

In patients with intracranial calcifications, patients may experience seizures related to chronic neuropathic changes and it may be necessary to add appropriate anti-epileptic medication(s). In all chronically hypocalcemic patients, ocular assessments should be performed periodically.

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