Chapter 9 – Hypoparathyroidism and Pseudohypoparathyroidism
Updated August 2011
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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 uncommon (Table 1).
Table 1. Forms of hypoparathyroidism having a genetic basis |
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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.
Severe hypocalcemia may be associated with a prolonged Q-Tc 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 [2,3]. 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. Clinical features of hypocalcemia |
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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 Ellsworth-Howard test has been used in the past to distinguish parathyroid resistance from glandular hypofunction. In patients with pseudohypoparathyroidism (see Table 3), parenteral administration of biologically active PTH fails to provoke an increase in plasma and urinary cyclic AMP and inorganic phosphate [4]. However, better biochemical profiling has led to a decline in the use of the test and it is rarely performed now. Decreased parathyroid gland reserve can be detected by an ethylenediaminetetraacetate (EDTA) infusion study [5], but this test is no longer in clinical use.
The term "idiopathic hypoparathyroidism" has 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, molecular screening of patients with this condition is usually recommended [6].
Familial Isolated Hypoparathyroidism
Familial isolated hypoparathyroidism (FIH) may show autosomal dominant, autosomal recessive, or X-linked inheritance.
In a few instances of autosomal dominant disease, a mutation in the PTH gene (MIM# 168450 [7] - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM) has been found. In one family, a missense mutation (c18R) in the signal sequence of the preproPTH precursor has been identified [8] and the mutant shown to be defective in vitro in processing preproPTH to proPTH, although as patients had one normal gene copy the autosomal dominant mode of inheritance remained unexplained. Further studies in transfected cells showed that the mutant was trapped in the endoplasmic reticulum promoting ER stress and apoptosis [9]. In a family with autosomal recessive hypoparathyroidism, a different, homozygous, signal sequence mutation (S23P) segregates with affected status [10]. This mutation may prevent proper cleavage of the signal peptide during processing of the nascent protein. In another family with autosomal recessive hypoparathyroidism, a donor splice site mutation at the exon 2/intron 2 junction of the PTH gene was identified [11]. The mutation leads to exon skipping and loss of exon 2 containing the initiation codon and signal sequence of preproPTH mRNA. In two multigeneration families with X-linked recessive hypoparathyroidism exhibiting neonatal onset of hypocalcemia and parathyroid agenesis, the trait was mapped to a 906-kb region on distal Xq27 that contains three genes including SOX3 but no intragenic mutations were found (MIM# 307700) [12]. An interstitial deletion-insertion involving chromosomes 2p25.3 and Xq27.1, was found downstream of the SOX3 gene that may be involved in the embryonic development of the parathyroid gland [13].
Gain-of-function mutations in the calcium-sensing receptor (CASR) gene (MIM#601199) have been identified in several families clinically diagnosed with autosomal dominant hypocalcemia (ADH) (MIM# 601198), autosomal dominant hypoparathyroidism (MIM# 241400), and hypocalcemic hypercalciuria (MIM#146200) [14,15]. In the parathyroid gland, the activated CASR suppresses PTH secretion and in the kidney, it induces hypercalciuria which may contribute to the hypocalcemia. In many cases of ADH, the family history is positive, but de novo mutations are quite common [16,17]. Mosaicism for de novo mutation in an otherwise healthy parent has been described [18], and may explain some cases of apparently recessive disease. More importantly, there are implications for counseling parents about risks of recurrence.
More than seventy activating mutations (almost all missense) have been identified and appear almost equally divided between the amino-terminal third of the extracellular domain (ECD) and the transmembrane domain (TMD) (Figure 1). Of special interest is the cluster of ECD mutations (A116T to C131W) which cause an increase in receptor sensitivity to extracellular calcium, suggesting that this region is critical for receptor activation. This cluster overlaps the two cysteine residues –cys-129 and cys-131– involved in the interface of the mature protein dimer [19]. Further details can be found in the locus-specific database –http://data.mch.mcgill.ca/casrdb/ [20].
 |
Figure 1. Locations of CASR gene activating mutations found in patients with ADH. The schema outlines the relationship between CASR gene exons (II to VII) and the portions of the protein that they encode. Exons II to VI and the beginning of exon VII encode the ECD of ~610 amino acids, exon VII encodes the TMD of ~250 amino acids including membrane-spanning helices TM1-TM7 (indicated by the shaded boxes), ECL1 to ECL3, ICL1 to ICL3, and the ICD of ~200 amino acids. Recurrent mutations are highlighted. (Abbreviations: ECD, extracellular domain; TMD, transmembrane domain; TM, membrane-spanning helix; ECL, extracellular loop; ICL, intracellular loop; ICD, intracellular domain). |
Recessively inherited FIH may occur with mutations of the glial cell missing-2 gene (GCM2; MIM#603716). The GCM2 gene localizes to chromosome 6p24.2 and encodes a transcription factor. It is expressed in the PTH-secreting cells of the developing parathyroid glands and is critical for their development in terrestrial vertebrates [21,22,23]. A patient with neonatal hypoparathyroidism was found to be homozygous for a partial deletion acquired from both parents [24], and a pair of siblings with homozygous mutations has been reported [25]. Additional studies have identified inactivating GCM2 mutations in cases with autosomal recessive FIH (26,27). On the other hand, heterozygous mutations that cause dominant-negative GCM2 mutants have recently been identified in patients with autosomal dominant hypoparathyroidism [26,28,29]. Nevertheless, it appears that the prevalence of genetic defects affecting GCM2 function is not high in FIH, as a recent study investigating 20 unrelated cases with this disorder (10 familial and 10 sporadic) failed to identify any GCM2 mutations segregating with the disease and/or leading to loss of function [30].
Hypoparathyroidism with Multiple Malformations
Hypoparathyroidism due to parathyroid hypoplasia is a frequent feature of 22q11.2 microdeletions, the common cause of DiGeorge syndrome (MIM#188400) [31,32]. This syndrome complex arises from a failure of the third and fourth pharyngeal pouches to develop, leading to agenesis or hypoplasia of the parathyroid glands, thymus, and the anterior heart field. Patients with DiGeorge syndrome may typically present with neonatal hypocalcemic seizures due to hypoparathyroidism, severe infections due to thymic hypoplasia, and conotruncal heart defects [33]. Because a microdeletion is involved, the identification of novel developmental genes in the 22q11 region has been keenly pursued. Mouse models with Tbx1 transcription factor haploinsufficiency were used to establish the essential contribution of this factor to conotruncal development [34], and to place it in developmental context during organogenesis [35,36]. It is likely, however, that full expression of DiGeorge syndrome involves loss of other contiguous genes [37]. Thus, 22q11 deletions are responsible for a wider spectrum of clinical conditions that includes isolated congenital heart disease and velocardiofacial (VCF) syndrome [32,38]. Associated craniofacial abnormalities include cleft palate, pharyngeal insufficiency and mildly dysmorphic facies. In the VCF syndrome, anatomical anomalies of the pharynx are prominent and hypernasal speech due to abnormal pharyngeal musculature with or without cleft palate is typical. In most patients, some degree of intellectual deficit is present and there is strong predisposition to psychiatric illness (schizophrenia or bipolar disorder) in adolescents and adults [39,40]. Further information, both clinical and educational, can be found at web sites devoted to this condition (e.g., http://www.vcfsef.org/ and http://www.22q.org/).
The 22q11.2 defect is one of the most common of microdeletions (1 in 3000 to 1 in 6000 livebirths), and it may go clinically unrecognized in its milder or incomplete forms. Most cases are the result of sporadic new mutations, but familial patterns are evident in up to 10%. Although many cases of DiGeorge syndrome occur de novo, autosomal dominant inheritance is not unknown. In utero influences may be important determinants of the clinical picture, since there are at least three reported instances of monozygotic twins with discordant phenotypes [41,42,43]. Phenocopies occur with diabetic embryopathy, fetal alcohol syndrome, and retinoid embryopathy. In rare instances, it has been shown that a phenotypically normal parent can transmit a microdeletion to an offspring. Such parents have been found to carry a duplication of the 22q11 on the second chromosome, and the combination of duplication and deletion alleles in a parent generates a balanced state that has been termed “gene dosage compensation” [44,45].
Although the hypoparathyroidism affects about half of all carriers it is usually not severe, and frequently treatment following neonatal hypocalcemia can be tapered or stopped in older children. However, the hypoparathyroidism may also remain asymptomatic until adolescence or emerge at times of stress, such as corrective cardiac surgery or severe infection, suggesting that continued surveillance of parathyroid gland reserve is important. [46,47,48].
Currently, diagnosis of 22q11.2 microdeletion requires specific cytogenetic studies -- usually with locus-specific fluorescence in-situ hybridization (FISH) testing or PCR-based techniques. These tests reliably pick up many of the larger common deletions that involve regions of low-copy number repeats (LCRs). However, array-based analyses suggest that the 15 to 30% of microdeletions that are atypical are being missed [32], and it seems likely that microarray methods will eventually become the preferred diagnostic approach. Because the clinical picture is so variable and the prevalence so high, testing for 22q11.2 microdeletion should be considered in the workup for any new hypoparathyroid case for which another cause is not found.
Clinicians will also want to be aware that a small but significant minority (~10%) of patients will have associated autoimmune disease, driven in part, perhaps, by the thymus-based defect in T cell function [32,49]. Among the more common (non-endocrine) conditions are arthritis, celiac disease and autoimmune hematologic disease, particularly idiopathic thrombocytopenic purpura. Autoimmune thyroid disease, with either hypo- or hyperparathyroid states, has been reported [49,50]. It has been suggested that the later-onset hypoparathyroid disease may be partly autoimmune in origin, not developmental. A survey of 59 Norwegian patients showed discordance of adult onset disease with neonatal hypoparathyroidism, but a significant correlation with parathyroid autoantibodies and the presence of autoimmune disease [49].
The clinical features of this condition also occur with other cytogenetic abnormalities, notably chromosome 10p haploinsufficiency [51,52]. Hypoparathyroidism is part of the Barakat or HDR (Hypoparathyroidism, nerve Deafness, and Renal dysplasia) syndrome (MIM#146255) [53,54]. Deletions of two non-overlapping regions of chromosome 10p contribute to a DiGeorge-like phenotype (the DiGeorge critical region II on 10p13-14 [55]) and the HDR syndrome (10p14-10pter [56,57]). The latter is due to haploinsufficiency of the GATA3 gene (MIM#131320), which encodes a dual zinc finger transcription factor [58] that is essential for normal embryonic development of the parathyroids, auditory system, and kidney. Since the original description several additional GATA3 loss-of-function mutations have been described in HDR patients [e.g., 59,60,61]. Heterozygous Gata3-deficient mice develop parathyroid abnormalities as revealed by challenge with a diet low in calcium and vitamin D that are due to dysregulation of the parathyroid-specific transcription factor, Gcm2. Gata3-/- embryos at E12.5 lack Gcm2 expression and have gross defects in the fourth pharyngeal pouches, including absent parathyroid/thymus primordia [62]. GATA3 transactivates the GCM2 promoter and with GCM2 forms part of a transcriptional cascade essential for the differentiation and survival of parathyroid progenitor cells.
In another congenital disorder, Kenny-Caffey syndrome, hypoparathyroidism is found variably associated with the typical picture of growth retardation, osteosclerosis, cortical thickening of the long bones, and delayed closure of the anterior fontanel [63,64]. Both dominant and recessive modes of inheritance have been observed (MIM#127000 and MIM#244460, respectively).
The Sanjad -Sakati syndrome (MIM# 241410) is a similar recessive condition characterized by congenital hypoparathyroidism, seizures, growth and developmental retardation and characteristic dysmorphic features, including deep set eyes, depressed nasal bridge with beaked nose, long philtrum, thin upper lip, micrognatia and large, floppy ear lobes. Radiographs showed medullary stenosis reminiscent of Kenny-Caffey syndrome [65]. Linkage studies localized recessive Kenny-Caffey and Sanjad-Sakati syndromes to 1q42-43, and causative mutations in the tubulin chaperone E, TBCE, gene were identified in this Hypoparathyroidism, Retardation and Dysmorphism (HRD) syndrome [66,67]. This highlighted the role of TBCE that binds microtubules and proteasomes and protects against misfolded stress [68] in parathyroid development [69].
Hypoparathyroidism due to Metabolic Disease
Hypoparathyroidism is also a variable component of the neuromyopathies caused by mitochondrial gene defects. Among these are the Kearns-Sayre syndrome (ophthalmoplegia, retinal degeneration, and cardiac-conduction defects) (MIM# 530000), the Pearson marrow pancreas syndrome (lactic acidosis, neutropenia, sideroblastic anemia, and pancreatic exocrine dysfunction) [70] (MIM#557000) and mitochondrial encephalomyopathy (MIM#540000). The molecular defects range from large deletions and duplications of the mitochondrial genomes in a large number of tissues [71,72] to single base-pair mutations in one of the transfer RNA genes found only in a restricted range of cell types (MIM#590050). The role of these mitochondrial mutations in the pathogenesis of hypoparathyroidism remains to be clarified, but hypomagnesemia due to a renal wasting can present with symptoms similar to hypocalcemia and the two may co-exist in these disorders.
Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (MIM#600890) is an inborn error of oxidative fatty acid metabolism that may be accompanied by hypoparathyroidism [73]. Whether the parathyroid disease is directly related to the enzyme deficiency or secondary to the accompanying mitochondrial disease needs further study.
Parathyroid insufficiency and symptoms of hypocalcemia are occasionally seen in inherited metabolic disorders leading to excess storage of iron (thalassemia, Diamond-Blackfan anemia, hemochromatosis) or copper (Wilson disease). In most instances, there is similar dysfunction in other endocrine glands, and the parathyroid disease is usually mild. Nonetheless, recognition of the hypoparathyroid state may help explain otherwise non-specific symptoms and aid in overall management of these multisystem diseases.
Autoimmune Hypoparathyroidism: Acquired and Inherited Disorders
Antibodies directed against parathyroid tissue have been detected in up to 38% of patients with isolated hypoparathyroid disease, and over 40% of patients having hypoparathyroidism combined with other endocrine deficiencies [74]. Subsequently, a survey of a parathyroid expression library led to the identification of one protein selectively associated with the autoimmune process, the NACHT leucine-rich-repeat protein 5 (NALP5) Elevated antibody titres occur in half the patients with autoimmune hypoparathyroidism, with or without other autoimmune disease, but uncommonly in other conditions without hypoparathyroidism. [75]
Antibodies against the extracellular domain of the parathyroid CASR were originally reported in more than half of patients with either type 1 autoimmune polyglandular syndrome (APS-1, also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy or APECED), MIM# 240300, [76] or acquired hypoparathyroidism associated with autoimmune hypothyroidism [77]. This finding was confirmed in a subsequent study of 51 cases of idiopathic hypoparathyroidism, but there was a 13% positive rate in controls [78]. However, larger studies of APS-1 patients failed to reveal a significant preponderance of positives [79,80,81]. Although some have argued that CASR antibody assays are clinically indicated in acquired hypoparathyroidism [82], others have demurred, and it remains to be seen whether the autoantibodies are of primary or secondary importance [74,83]. In contrast, there is now good evidence, noted above, that autoantibodies can be functional activators of CASR and thereby induce hypoparathyroidism. Unfortunately, there is no convincing test for this state, outside of an in vitro demonstration that patient serum activates CASR transfected into HEK cells [84]. In some hypoparathyroid patients, both autoimmune parathyroid destruction and suppression by CASR activation may co-exist [81].
In APS-1, the most common associated manifestations are hypoparathyroidism with mucocutaneous candidiasis and Addison's disease. Additional features include pernicious anemia, chronic active hepatitis, alopecia, keratitis, gonadal failure, thyroid disease, pancreatic insufficiency and diabetes mellitus [76]. The phenotype is highly variable and patients may not express all elements of the basic triad, leading to the suggestion that the criteria used for molecular screening be relaxed [85]. The disease usually presents in infancy with chronic oral thrush, followed by hypoparathyroidism in the first decade, and then adrenocortical failure in the third. Interestingly, there is nearly 100% penetrance of hypoparathyroidism in females, but less than 60% in males, even though the adrenal hypofunction affects both sexes equally [80]. Moreover, patients who develop the adrenal hypofunction first are less likely to be male and may never develop hypoparathyroidism. The responsible gene, called the autoimmune regulator (AIRE), maps to chromosome 21q22 and encodes a transcriptional regulator [86,87,88]. In the absence of AIRE protein, tissue-specific self-antigens are not expressed in the thymus and multiorgan autoimmunity develops, because negative selection of the T cells bearing the autoantigens is disrupted [89]. Many patients with APS-1 can be shown to have autosomal recessive inheritance of the AIRE defect. In families with autosomal recessive mutations of AIRE, obligate heterozygotes may also have common autoimmune disorders but APECED is not seen [90]. A phenocopy leading to acquired APS-1 may occur when the AIRE gene is silenced by thymic neoplasia [91]. APS-1 has been associated with more than 200 mutations of the AIRE gene, and updates can be found in the online mutation database (http://bioinf.uta.fi/AIREbase/).
PARATHYROID RESISTANCE SYNDROMES
Pseudohypoparathyroidism
Several clinical disorders characterized by end-organ resistance to PTH have been described collectively by the term pseudohypoparathyroidism (PHP) [92,93,94,95]. They are associated with hypocalcemia, hyperphosphatemia, and increased circulating PTH. Target tissue unresponsiveness to the hormone manifests as a lack of increased phosphate and, in some cases, cAMP excretion in response to PTH administration [96]. The biochemical characteristics of the different forms of PHP are contrasted with those of hypoparathyroidism in Table 3.
Table 3. Biochemical characteristics of hypoparathyroidism and pseudohypoparathyroidism |
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Defects |
Serum PO4 |
PTH |
25(OH)D |
1,25(OH)2D |
UcAMP* |
UPO4* |
Multiple Endocrine Defects |
Hypoparathyroidism |
↑ |
↓ |
- |
↓ |
- |
- |
Yes/No** |
Pseudohypoparathyroidism |
|||||||
Type 1a |
↑ |
↑ |
- |
↓ |
↓ |
↓ |
Yes |
Type 1b |
↑ |
↑ |
- |
↓ |
↓ |
↓ |
No/Yes# |
Type 1c |
↑ |
↑ |
- |
↓ |
↓ |
↓ |
Yes |
Type 2 |
↑ |
↑ |
- |
↓ |
- |
↓ |
No |
↑, increased; |
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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 [97]. 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 2). In the calvaria, this may manifest as hyperostosis frontalis interna [92]. 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 2). The brachydactyly may be asymmetric or not, and may involve one or both hands or feet, but the pattern is quite distinctive [98,99]. 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 2) [100].
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Figure 2. 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). |
Table 4. Incidence of signs and symptoms in PHP with AHOa |
|
|
Percentage |
Body habitus |
|
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) |
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Although affected patients are generally short as adults, their bone age as children may be advanced and growth accelerated [100]. Patients with AHO are probably predisposed to hypertension [101], conductive and sensorineural hearing loss [92,102], cord compression due to spinal anomalies [103], and movement disorders due to basal ganglia calcification [104]. 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 [105]. A recent study showed that the obesity phenotype occurs primarily in those patients who also have multiple hormone resistance, i.e., PHP1a (see below), but according to data from mice, hypothalamic mechanisms, rather than hypothyroidism, are the primary underlying cause [106].
Patients with brachydactyly, mental retardation, and other features closely resembling AHO have been found to carry microdeletions of chromsome 2q27; brachydactyly-mental retardation, BDMR; MIM#600430 [107]. 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 [108]. Isolated brachydactyly type E (BDE, MIM#113300) has been associated in sporadic cases with mutations in HOX13 (MIM#168470) [109 and recently 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 [110]. Affected individuals of one large family with BDE, short stature and learning difficulties had an ~900 bp microdeletion encompassing PTHLH [111]. Additional individuals with BDE and short stature from other different kindreds were found to have PTHLH missense, nonstop, and nonsense mutations [111].
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 [112,113,114]. 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 3) and an antisense transcript, NESPas [115]. 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 [116,117,118,119]. This tissue-specific monoallelic Gsα expression affects penetrance of the PHP phenotype. The maternal transmission of the hormone resistance in PHP1a [120] can be explained by silencing of the paternal Gsα allele, which would otherwise allow expression of 50% of Gs alpha protein [121]. 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 [122]. The imprinting of GNAS is complex and involves multiple differentially methylated regions (DMR) [115]. Moreover, it is tissue-specific and may vary with developmental stage [123,124], although key imprinting of the 1A DMR is a primary event that occurs during gametogenesis and is maintained thereafter [125]. 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 [116]. 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 [116].
 |
Figure 3. 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 hormonal 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 [99,126,127,128,129,130]. 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 [94,130]. 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 [131] 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 recently 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 [132,133]. 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 [94], 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 [134] so that oral contraceptives may help regulate the menstrual cycle. Estrogen can antagonize bone resorption leading to an exacerbation of hypocalcemia [135], but placental 1,25-dihydroxyvitamin D synthesis likely obviates this effect altogether in pregnancy so women are frequently normocalcemic at that time [136]. 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 [137,138]. The effect of growth hormone replacement has been recently investigated in a small group of pre-pubertal PHP-Ia patients [139]. 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 [117,118,119,140]. Recent studies have revealed that obesity also develops primarily in patients who inherit the inactivating Gsα mutations from their mothers [141]. Gsα is not imprinted in the white adipose tissue [142], 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 [143], thus explaining the imprinted mode of inheritance of the obesity phenotype. Likewise, it has been recently noted that cognitive impairment, a typical AHO feature, also develops primarily after maternal inheritance of the inactivating Gsα mutation [144].
PHP1b
PHP1b is typically not associated with AHO or a generalized reduction in Gsα expression [93]. 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 [145,146]. Biochemical abnormalities suggestive of thyroid stimulating hormone resistance are also seen in some patients [140], and abnormalities of renal uric acid handling have been documented [147,148], although clinically significant hormone resistance is restricted to PTH alone. 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 [149,150,151], and studies of PHP1b families show no linkage to PTHR1 [152,153].
Most cases of PHP1b are sporadic, but a familial form of PHP-Ib with an apparent autosomal dominant mode of inheritance also exists (AD-PHP-Ib). In four AD-PHP1b kindreds, linkage to chromosome 20q13.3 was established, the same region which includes the GNAS locus [152]. 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 [121]. 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 3). 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 [154]. A search for the mutation revealed the presence of a 3kb microdeletion that segregated with the disease in 12 kindreds with AD-PHP1b and also occurred in 4 sporadic cases [155]. The deletion, flanked by direct repeats, removes 3 exons of the STX16 gene, which encodes syntaxin-16. In addition, another deletion within STX16 that removes exons 2 to 4 was later identified in a single kindred with AD-PHP1b [156]. In all these cases, maternal, but not paternal, inheritance of the STX16 deletion led to PTH resistance. Because STX16 is apparently not imprinted [156], 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. 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 [157]. In this instance, however, the 1A DMR was not the only region to lose the differential methylation required to allow maternal expression of Gsαs in the kidney. Maternal methylation was also lost in the regions of the XLαs and NESPas promoters. Another kindred with these widespread epigenetic defects of GNAS has recently been described [158]. 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.
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 [159,160,161,162]. The cause of the epigenetic defects and PTH resistance, however, remains unknown for most cases of sporadic PHP1b. 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 [163].
In contradistinction to the classical understanding that AHO features are unique to PHP1a, some recent studies have identified patients with PTH resistance and AHO features who show GNAS epigenetic defects rather than Gsα coding mutations [164,165,166]. Thus, there may be some overlap between the clinical and molecular features of PHP-Ia and PHP-Ib. 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 [167]. However, such mutations within Gsα coding exons are rare [121].
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 [168]. 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 This mutation results in a Gsα mutant that is unable to mediate cAMP generation in response to receptor activation but can activate adenylyl cyclase basally [169,170,171. Thus, some forms of PHP-Ic appear to be an allelic variant of PHP-Ia. Finally, patients with PHP2 have a normal urinary cAMP response to PTH but an impaired phosphaturic response [172]. 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 recent study [173] has discovered a heterozygous mutation of the gene encoding the regulatory subunit of PKA (PRKAR1A) in three patients with multiple hormone resistance and acrodysostosis (MIM#101800), 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 [173]. 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.
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 [174,175]. A more severe form of this disease (panostotic fibrous dysplasia) with hyperphosphatasia and hyperphosphaturic rickets, has also been described [176,177]. 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 (178). A missense mutation in exon 13 (A366S) results in a Gsα protein that is unstable at 37°C [179], but constitutively active at lower temperatures. Affected patients have PHP due to PTH resistance and precocious puberty (testitoxicosis) 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 recently described in a patient with neonatal diarrhea and PTH resistance [180]. 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 [181,182,183,184]. 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 [185]. 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 [186]. 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.
Differential diagnosis and genetic counseling. Patients with dysmorphic features resembling AHO may require careful endocrinologic work-up to confirm and delineate the form of PHP that is present. Similar studies of family members may also be warranted, since the biochemical and clinical features vary within families. If PHP1a with AHO is established, genetic counselling may aid in understanding the multisystemic nature of the disorder, particularly in relation to the patient's growth and development, and later-onset connective tissue complications. For either PHP1a or PHP1b, extensive counselling may be required to adequately explain the various implications of paternal imprinting for the parent-specific recurrence risks in offspring. Germline mosaicism has been reported [131], which is clearly important in assessing risks for recurrence in future sibs of a singleton family. Given the recently described complexities in the molecular, biochemical, and physical features of PHP1a and PHP1b, molecular testing is critical for achieving a clear diagnosis and validating the inheritance pattern in any given family.
The parathyroid hormone receptor and skeletal dysplasias
PTHR1 is a family B G protein-coupled that signals through multiple different G proteins including Gsα [187]. 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 [188] 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 dysplasia and dental abnormalities [189]. The rare, recessive BLC is characterized by short-limbed dwarfism with craniofacial malformations, hydrops, hypoplastic lungs and aortic coarctation [190,191,192,193,194]. The bones show accelerated endochondral ossification and deficient remodeling. The Blomstrand disease has been recently 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 [195,196]. A milder form of recessively inherited skeletal dysplasia, known as Eiken syndrome (MIM#600002), has also been linked to mutations of PTHR1 [197]. 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 [198,199]. As many patients with Ollier’s disease do not have PTHR1 mutations, it is likely that the condition is genetically heterogeneous [200]. 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 [201]. 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 [202,203].
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 [204].
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 [1]. 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 [205]. 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 [206]. The longterm effects of standard therapy remain a concern [207].
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 [208]. 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. 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] − 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 hypercalcemia, suggesting that there may be non-calcitropic effects of PTH not remedied by maintenance of normocalcemia alone [207].
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.
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 widely available . Preliminary studies on 27 adults suggested that hypercalciuria was less of a problem in hypoparathyroid subjects receiving twice daily subcutaneous injections of PTH 1-34 [209], Similar trials have been reported in hypoparathyroid children, with a reduction in calcitriol requirements [210,211]. Teriparatide administered every other day in hypoparathyroid adults has been shown to reduce calcium and calcitriol requirements over a 24-month period [212], while PTH 1-84 is associated with a reversal in abnormal bone remodeling, without major adverse effects [213]. Although both hormonal agents are well tolerated acutely, longterm exposure of animals to very high doses has been associated with tumor formation [214]. While there is no evidence of increased risk associated with replacement doses, caution has been advised particularly in children. In hypoparathyroidism due to activating CASR mutations, such potential risks need to be balanced against ongoing risks of progressive renal damage associated with excessive hypercalciuria, exacerbated at times by the standard calcium and vitamin D therapy. Although the evidence is limited, it appears that hormone replacement is a safe and beneficial option in some of the affected children [215,216]. However, better criteria for recommending a switch to recombinant human hormone use are needed, along with more data on longterm safety [217].
Calcilytics. Calcilytics − drugs that antagonize the calcium-sensing receptor and promote PTH secretion − are a promising alternative for disorders with intact but hypofunctioning parathyroid glands [218]. When administered to healthy adults, the CASR antagonist, ATF936, causes a dose-dependent rise in serum PTH that constitutes proof of principle [219], but studies have not been reported in hypoparathyroid subjects.
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 suppression by activated CASR in the kidney. For reasons that are not clear, however, thiazides work well in some patients [220] but not others.
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.