TSH Elevations as the First Laboratory Evidence for Pseudohypoparathyroidism Type Ib (PHP‐Ib)

Hypocalcemia and hyperphosphatemia because of resistance toward parathyroid hormone (PTH) in the proximal renal tubules are the most prominent abnormalities in patients affected by pseudohypoparathyroidism type Ib (PHP‐Ib). In this rare disorder, which is caused by GNAS methylation changes, resistance can occur toward other hormones, such as thyroid‐stimulating hormone (TSH), that mediate their actions through G protein‐coupled receptors. However, these additional laboratory abnormalities are usually not recognized until PTH‐resistant hypocalcemia becomes clinically apparent. We now describe four pediatric patients, first diagnosed with subclinical or overt hypothyroidism between the ages of 0.2 and 15 years, who developed overt PTH‐resistance 3 to 20 years later. Although anti‐thyroperoxidase (anti‐TPO) antibodies provided a plausible explanation for hypothyroidism in one of these patients, this and two other patients revealed broad epigenetic GNAS abnormalities, which included loss of methylation (LOM) at exons AS, XL, and A/B, and gain of methylation at exon NESP55; ie, findings consistent with PHP‐Ib. LOM at GNAS exon A/B alone led in the fourth patient to the identification of a maternally inherited 3‐kb STX16 deletion, a well‐established cause of autosomal dominant PHP‐Ib. Although GNAS methylation changes were not detected in additional pediatric and adult patients with subclinical hypothyroidism (23 pediatric and 39 adult cases), hypothyroidism can obviously be the initial finding in PHP‐Ib patients. One should therefore consider measuring PTH, along with calcium and phosphate, in patients with unexplained hypothyroidism for extended periods of time to avoid hypocalcemia and associated clinical complications. © 2014 American Society for Bone and Mineral Research © 2014 American Society for Bone and Mineral Research.     

Gsα activity is reduced in erythrocyte membranes of patients with psedohypoparathyroidism due to epigenetic alterations at the GNAS locus

In pseudohypoparathyroidism (PHP), PTH resistance results from impairment of signal transduction of G protein–coupled receptors caused by a deficiency of the Gsα‐cAMP signaling cascade due to diminished Gsα activity in maternally imprinted tissues. In PHP‐Ia, inactivating mutations of the GNAS gene lead to haploinsufficiency in some tissues with biallelic expression, so in addition to PHP, Albright's hereditary osteodystrophy (AHO) is also present. In PHP‐Ib, caused by methylation defects at the GNAS locus, diminished Gsα activity was thought to be limited to maternally imprinted tissues, such as the renal proximal tubule and the thyroid, leading to a lack of AHO. Recently, we demonstrated methylation defects in patients with AHO signs, indicating a connection between epigenetic changes and AHO. Our objective was to determine Gsα activity in erythrocyte membranes in patients with epigenetic defects at the GNAS locus compared to normal controls and patients with inactivating GNAS mutations. Gsα activity and expression, mutation of the GNAS locus, and methylation status were studied in patients with PHP and mild signs of AHO (PHP‐Ia: 12; PHP‐Ib: 17, of which 8 had some features of AHO). Then, we statistically compared the Gsα activity of the different PHP subtypes. Patients with methylation defects at the GNAS locus show a significant decrease in erythrocyte Gsα activity compared to normal controls (PHP‐Ib versus controls, p < .001). This was significantly lower in patients with AHO signs (PHP‐Ib + mild‐AHO versus PHP‐Ib, p < .05). Our research shows that PHP‐Ia and PHP‐Ib classification is not only overlapped genetically, as reported, but also in terms of Gsα activity. Reduced expression of GNAS due to methylation defects could downregulate Gsα activity in other tissues beyond those described and could also be causative of AHO. © 2011 American Society for Bone and Mineral Research     

Analysis of Multiple Families With Single Individuals Affected by Pseudohypoparathyroidism Type Ib (PHP1B) Reveals Only One Novel Maternally Inherited GNAS Deletion

Proximal tubular resistance to parathyroid hormone (PTH) resulting in hypocalcemia and hyperphosphatemia are preeminent abnormalities in pseudohypoparathyroidism type Ib (PHP1B), but resistance toward other hormones as well as variable features of Albright's Hereditary Osteodystrophy (AHO) can occur also. Genomic DNA from PHP1B patients shows epigenetic changes at one or multiple differentially methylated regions (DMRs) within GNAS, the gene encoding Gαs and splice variants thereof. In the autosomal dominant disease variant, these methylation abnormalities are caused by deletions in STX16 or GNAS on the maternal allele. The molecular defect(s) leading to sporadic PHP1B (sporPHP1B) remains in most cases unknown and we therefore analyzed 60 sporPHP1B patients and available family members by microsatellite markers, single nucleotide polymorphisms (SNPs), multiplex ligation‐dependent probe amplification (MLPA), and methylation‐specific MLPA (MS‐MLPA). All investigated cases revealed broad GNAS methylation changes, but no evidence for inheritance of two paternal chromosome 20q alleles. Some patients with partial epigenetic modifications in DNA from peripheral blood cells showed more complete GNAS methylation changes when testing their immortalized lymphoblastoid cells. Analysis of siblings and children of sporPHP1B patients provided no evidence for an abnormal mineral ion regulation and no changes in GNAS methylation. Only one patient revealed, based on MLPA and microsatellite analyses, evidence for an allelic loss, which resulted in the discovery of two adjacent, maternally inherited deletions (37,597 and 1427 bp, respectively) that remove the area between GNAS antisense exons 3 and 5, including exon NESP. Our findings thus emphasize that the region comprising antisense exons 3 and 4 is required for establishing all maternal GNAS methylation imprints. The genetic defect(s) leading in sporPHP1B to epigenetic GNAS changes and thus PTH‐resistance remains unknown, but it seems unlikely that this disease variant is caused by heterozygous inherited or de novo mutations involving GNAS. © 2015 American Society for Bone and Mineral Research.     

Postnatal Establishment of Allelic Gαs Silencing as a Plausible Explanation for Delayed Onset of Parathyroid Hormone Resistance Owing to Heterozygous Gαs Disruption

Pseudohypoparathyroidism type‐Ia (PHP‐Ia), characterized by renal proximal tubular resistance to parathyroid hormone (PTH), results from maternal mutations of GNAS that lead to loss of α‐subunit of the stimulatory G protein (Gαs) activity. Gαs expression is paternally silenced in the renal proximal tubule, and this genomic event is critical for the development of PTH resistance, as patients display impaired hormone action only if the mutation is inherited maternally. The primary clinical finding of PHP‐Ia is hypocalcemia, which can lead to various neuromuscular defects including seizures. PHP‐Ia patients frequently do not present with hypocalcemia until after infancy, but it has remained uncertain whether PTH resistance occurs in a delayed fashion. Analyzing reported cases of PHP‐Ia with documented GNAS mutations and mice heterozygous for disruption of Gnas, we herein determined that the manifestation of PTH resistance caused by the maternal loss of Gαs, ie, hypocalcemia and elevated serum PTH, occurs after early postnatal life. To investigate whether this delay could reflect gradual development of paternal Gαs silencing, we then analyzed renal proximal tubules isolated by laser capture microdissection from mice with either maternal or paternal disruption of Gnas. Our results revealed that, whereas expression of Gαs mRNA in this tissue is predominantly from the maternal Gnas allele at weaning (3 weeks postnatal) and in adulthood, the contributions of the maternal and paternal Gnas alleles to Gαs mRNA expression are equal at postnatal day 3. In contrast, we found that paternal Gαs expression is already markedly repressed in brown adipose tissue at birth. Thus, the mechanisms silencing the paternal Gαs allele in renal proximal tubules are not operational during early postnatal development, and this finding correlates well with the latency of PTH resistance in patients with PHP‐Ia. © 2014 American Society for Bone and Mineral Research.     

Similar frequency of paternal uniparental disomy involving chromosome 20q (patUPD20q) in Japanese and Caucasian patients affected by sporadic pseudohypoparathyroidism type Ib (sporPHP1B)

Pseudohypoparathyroidism type Ib (PHP1B) is caused by proximal tubular resistance to parathyroid hormone that occurs in most cases in the absence of Albright's Hereditary Osteodystrophy (AHO). Familial forms of PHP1B are caused by maternally inherited microdeletions within STX16, the gene encoding syntaxin 16, or within GNAS, a complex genetic locus on chromosome 20q13.3 encoding Gsα and several splice variants thereof. These deletions lead either to a loss-of-methylation affecting GNAS exon A/B alone or to epigenetic changes involving multiple differentially methylated regions (DMRs) within GNAS. Broad GNAS methylation abnormalities are also observed in most sporadic PHP1B (sporPHP1B) cases. However, with the exception of paternal uniparental disomy involving chromosome 20q (patUPD20q), the molecular mechanism leading to this disease variant remains unknown. We now investigated 23 Japanese sporPHP1B cases, who presented with hypocalcemia, hyperphosphatemia, elevated PTH levels, and occasionally with TSH elevations and mild AHO features. Age at diagnosis was 10.6 ± 1.45 years. Calcium, phosphate, and PTH were 6.3 ± 0.23 mg/dL, 7.7 ± 0.33 mg/dL, and 305 ± 34.5 pg/mL, respectively, i.e. laboratory findings that are indistinguishable from those previously observed for Caucasian sporPHP1B cases. All investigated patients showed broad GNAS methylation changes. Eleven individuals were homozygous for SNPs within exon NESP and a pentanucleotide repeat in exon A/B. Two of these patients furthermore revealed homozygosity for numerous microsatellite markers on chromosome 20q raising the possibility of patUPD20q, which was confirmed through the analysis of parental DNA. Based on this and our previous reports, paternal duplication of the chromosomal region comprising the GNAS locus appears to be a fairly common cause of sporPHP1B that is likely to occur with equal frequency in Caucasians and Asians.     

Exclusion of the GNAS locus in PHP‐Ib patients with broad GNAS methylation changes: Evidence for an autosomal recessive form of PHP‐Ib?

Most patients with autosomal dominant pseudohypoparathyroidism type Ib (AD‐PHP‐Ib) carry maternally inherited microdeletions upstream of GNAS that are associated with loss of methylation restricted to GNAS exon A/B. Only few AD‐PHP‐Ib patients carry microdeletions within GNAS that are associated with loss of all maternal methylation imprints. These epigenetic changes are often indistinguishable from those observed in patients affected by an apparently sporadic PHP‐Ib form that has not yet been defined genetically. We have now investigated six female patients affected by PHP‐Ib (four unrelated and two sisters) with complete or almost complete loss of GNAS methylation, whose healthy children (11 in total) showed no epigenetic changes at this locus. Analysis of several microsatellite markers throughout the 20q13 region made it unlikely that PHP‐Ib is caused in these patients by large deletions involving GNAS or by paternal uniparental isodisomy or heterodisomy of chromosome 20 (patUPD20). Microsatellite and single‐nucleotide variation (SNV) data revealed that the two affected sisters share their maternally inherited GNAS alleles with unaffected relatives that lack evidence for abnormal GNAS methylation, thus excluding linkage to this locus. Consistent with these findings, healthy children of two unrelated sporadic PHP‐Ib patients had inherited different maternal GNAS alleles, also arguing against linkage to this locus. Based on our data, it appears plausible that some forms of PHP‐Ib are caused by homozygous or compound heterozygous mutation(s) in an unknown gene involved in establishing or maintaining GNAS methylation. © 2011 American Society for Bone and Mineral Research     

Preferential Maternal Transmission of STX16-GNAS Mutations Responsible for Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B): Another Example of Transmission Ratio Distortion

Preferential transmission of a genetic mutation to the next generation, referred to as transmission ratio distortion (TRD), is well established for several dominant disorders, but underlying mechanisms remain undefined. Recently, TRD was reported for patients affected by pseudohypoparathyroidism type Ia or pseudopseudohypoparathyroidism. To determine whether TRD is observed also for autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP1B), we analyzed kindreds with the frequent 3-kb STX16 deletion or other STX16/GNAS mutations. If inherited from a female, these genetic defects lead to loss-of-methylation at exon A/B alone or at all three differentially methylated regions (DMR), resulting in parathyroid hormone (PTH)-resistant hypocalcemia and hyperphosphatemia and possibly resistance to other hormones. In total, we investigated 212 children born to 80 females who are unaffected carriers of a STX16/GNAS mutation (n = 47) or affected by PHP1B (n = 33). Of these offspring, 134 (63.2%) had inherited the genetic defect (p = .00012). TRD was indistinguishable for mothers with a STX16/GNAS mutation on their paternal (unaffected carriers) or maternal allele (affected). The mechanisms favoring transmission of the mutant allele remain undefined but are likely to include abnormalities in oocyte maturation. Search for mutations in available descendants of males revealed marginally significant evidence for TRD (p = .038), but these analyses are less reliable because many more offspring of males than females with a STX16/GNAS mutation were lost to follow-up (31 of 98 versus 6 of 218). This difference in follow-up is probably related to the fact that inheritance of a mutation from a male does not have clinical implications, whereas inheritance from an affected or unaffected female results in PHP1B. Lastly, affected PHP1B females had fewer descendants than unaffected carriers, but it remains unclear whether abnormal oocyte development or impaired actions of reproductive hormones are responsible. Our findings highlight previously not recognized aspects of AD-PHP1B that are likely to have implications for genetic testing and counseling. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Failure of tooth eruption and brachydactyly in pseudohypoparathyroidism are not related to plasma parathyroid hormone-related protein levels

BackgroundPseudohypoparathyroidism (PHP) is a genetic disorder characterized by resistance to the peripheral action of PTH due to maternally inherited heterozygous inactivating mutations in the coding sequence of G_sα or intronic regions of GNAS leading to aberrant splice variants (PHP1A), or methylation defects at GNAS (PHP1B). Brachydactyly is a clinical feature associated with both PHP1A and PHP1B, although it is more frequent in PHP1A patients. Loss-of-function mutations in PTHLH, the gene coding for parathyroid hormone related protein (PTHrP) were previously described in some patients with brachydactyly. Primary failure of tooth eruption (PFE) is related to some syndromes involving skeletal development, but it is also known as a nonsyndromic autosomal dominant condition. Previous studies showed that familial nonsyndromic PFE is caused by heterozygous mutations in the gene encoding the G protein-coupled receptor (PTH1R) for PTH and PTHrP. Thus, we hypothesized that PTHrP resistance could result in failure of tooth eruption (FTE) and/or brachydactyly in PHP.Subjects and methodsNineteen patients with a molecular diagnosis of PHP underwent dental panoramic radiography (DPR), hand radiography and had their PTHrP levels measured. Patients with alterations at DPR were submitted to clinical dental evaluation.ResultsNine patients had FTE and 7 patients had brachydactyly; 4 patients presented both features and none of them presented high PTHrP levels. Fourteen patients had PTHrP levels within the normal range and only one patient had slightly elevated PTHrP levels. Additionally, three novel GNAS mutations were described.ConclusionWe described the dental abnormalities in a large series of PHP patients that were followed in a single tertiary center. No relationship between plasma PTHrP levels and failure of tooth eruption, dental manifestations of PHP or brachydactyly was found. It is important that doctors pay attention to dental manifestations of the disease in order to refer patients to a proper care with dentists.     

Maternal Transmission Ratio Distortion of GNAS Loss-of-Function Mutations

Pseudohypoparathyroidism type 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are two rare autosomal dominant disorders caused by loss-of-function mutations in the imprinted Guanine Nucleotide Binding Protein, Alpha Stimulating Activity (GNAS) gene, coding G_sα. PHP1A is caused by mutations in the maternal allele and results in Albright's hereditary osteodystrophy (AHO) and hormonal resistance, mainly to the parathormone (PTH), whereas PPHP, with AHO features and no hormonal resistance, is linked to mutations in the paternal allele. This study sought to investigate parental transmission of GNAS mutations. We conducted a retrospective study in a population of 204 families with 361 patients harboring GNAS mutations. To prevent ascertainment bias toward a higher proportion of affected children due to the way in which data were collected, we excluded from transmission analysis all probands in the ascertained sibships. After bias correction, the distribution ratio of the mutated alleles was calculated from the observed genotypes of the offspring of nuclear families and was compared to the expected ratio of 50% according to Mendelian inheritance (one-sample Z-test). Sex ratio, phenotype of the transmitting parent, and transmission depending on the severity of the mutation were also analyzed. Transmission analysis was performed in 114 nuclear families and included 250 descendants. The fertility rates were similar between male and female patients. We showed an excess of transmission from mother to offspring of mutated alleles (59%, p = .022), which was greater when the mutations were severe (61.7%, p = .023). Similarly, an excess of transmission was found when the mother had a PHP1A phenotype (64.7%, p = .036). By contrast, a Mendelian distribution was observed when the mutations were paternally inherited. Higher numbers of females within the carriers, but not in noncarriers, were also observed. The mother-specific transmission ratio distortion (TRD) and the sex-ratio imbalance associated to PHP1A point to a role of G_sα in oocyte biology or embryogenesis, with implications for genetic counseling. © 2019 American Society for Bone and Mineral Research.     

A Homozygous [Cys25]PTH(1‐84) Mutation That Impairs PTH/PTHrP Receptor Activation Defines a Novel Form of Hypoparathyroidism

Hypocalcemia and hyperphosphatemia are encountered in idiopathic hypoparathyroidism (IHP) and pseudohypoparathyroidism type Ib (PHP1B). In contrast to PHP1B, which is caused by resistance toward parathyroid hormone (PTH), the genetic defects leading to IHP impair production of this important regulator of mineral ion homeostasis. So far, only five PTH mutations were shown to cause IHP, each of which is located in the hormone's pre‐pro leader segment and thus impair hormone secretion. In three siblings affected by IHP, we now identified a homozygous arginine‐to‐cysteine mutation at position 25 (R25C) of the mature PTH(1‐84) polypeptide; heterozygous family members are healthy. Depending on the assay used for evaluating these patients, plasma PTH levels were either low or profoundly elevated, thus leading to ambiguities regarding the underlying diagnosis, namely IHP or PHP1B. Consistent with increased PTH levels, recombinant [Cys25]PTH(1‐84) and wild‐type PTH(1‐84) were secreted equally well by transfected COS‐7 cells. However, synthetic [Cys25]PTH(1‐34) was found to have a lower binding affinity for the PTH receptor type‐1 (PTH1R) than PTH(1‐34) and consequently a lower efficiency for stimulating cAMP formation in cells expressing this receptor. Consistent with these in vitro findings, long‐term infusion of [Cys25]PTH(1‐34) resulted only in minimal calcemic and phosphaturic responses, despite readily detectable levels of [Cys25]PTH(1‐34) in plasma. The mineral ion abnormalities observed in the three IHP patients are thus most likely caused by the inherited homozygous missense PTH mutation, which reduces bioactivity of the secreted hormone. Based on these findings, screening for PTH(1‐84) mutations should be considered when clinical and laboratory findings are consistent with PHP1B, but GNAS methylation changes have been excluded. Differentiating between IHP and PHP1B has considerable implications for genetic counseling, therapy, and long‐term outcome because treatment of IHP patients with inappropriately high doses of active vitamin D and calcium can contribute to development of nephrocalcinosis and chronic kidney disease. © 2015 American Society for Bone and Mineral Research.     

Parathyroid hormone signaling via Gαs is selectively inhibited by an NH2‐terminally truncated Gαs: Implications for pseudohypoparathyroidism

Pseudohypoparathyroid patients have resistance predominantly to parathyroid hormone (PTH), and here we have examined the ability of an alternative Gαs‐related protein to inhibit Gαs activity in a hormone‐selective manner. We tested whether the GNAS exon A/B‐derived NH₂‐terminally truncated (Tr) αs protein alters stimulation of adenylate cyclase by the PTH receptor (PTHR1), the thyroid‐stimulating hormone (TSH) receptor (TSHR), the β₂‐adrenergic receptor (β₂AR), or the AVP receptor (V2R). HEK293 cells cotransfected with receptor and full‐length (FL) Gαs ± Tr αs protein expression vectors were stimulated with agonists (PTH [10^?7 to 10^?9 M], TSH [1 to 100 mU], isoproterenol [10^?6 to 10^?8 M], or AVP [10^?6 to 10^?8 M]). Following PTH stimulation, HEK293 cells cotransfected with PTHR1 + FL Gαs + Tr αs had a significantly lower cAMP response than those transfected with only PTHR1 + FL Gαs. Tr αs also exerted an inhibitory effect on the cAMP levels stimulated by TSH via the TSHR but had little or no effect on isoproterenol or AVP acting via β₂AR or V2R, respectively. These differences mimic the spectrum of hormone resistance in pseudohypoparathyroidism type 1a (PHP‐1a) and type 1b (PHP‐1b) patients. In opossum kidney (OK) cells, endogenously expressing the PTHR1 and β₂AR, the exogenous expression of Tr αs at a level similar to endogenous FL Gαs resulted in blunting of the cAMP response to PTH, whereas that to isoproterenol was unaltered. A pseudopseudohypoparathyroid patient with Albright hereditary osteodystrophy harbored a de novo paternally inherited M1I Gαs mutation. Similar maternally inherited mutations at the initiation codon have been identified previously in PHP‐1a patients. The M1I αs mutant (lacking the first 59 amino acids of Gαs) blunted the increase in cAMP levels stimulated via the PTHR1 in both HEK293 and OK cells similar to the Tr αs protein. Thus NH₂‐terminally truncated forms of Gαs may contribute to the pathogenesis of pseudohypoparathyroidism by inhibiting the activity of Gαs itself in a GPCR selective manner. © 2011 American Society for Bone and Mineral Research     

Osteosarcoma in a Patient With Pseudohypoparathyroidism Type 1b Due to Paternal Uniparental Disomy of Chromosome 20q

It is assumed that a persistent high level of parathyroid hormone (PTH) might have a relation with bone malignancy. However, there has been no report of osteosarcoma associated with pseudohypoparathyroidism type 1b (PHP1b), which is accompanied by high PTH. PHP1b is the result of resistance to PTH in certain end‐organ tissues, especially the kidney; the response in bone is unaffected because it normally expresses stimulatory G protein equally from both parental alleles. A 21‐year‐old male, presenting with gum swelling at the right mandible, was referred to a dental clinic. A curative surgical resection by segmental mandibulectomy was performed and the pathologic findings of the mass were consistent with osteoblastic osteosarcoma. His laboratory results showed a low calcium level despite high PTH, and he did not have any features of Albright hereditary osteodystrophy; therefore, PHP1b was suspected. Multiplex ligation‐dependent probe amplification and microsatellite marker analyses of chromosome 20 confirmed the diagnosis and identified paternal uniparental disomy of chromosome 20q (patUPD20). To the best of our knowledge, this is the first report of osteosarcoma in a patient with PHP1b due to patUPD20. © 2017 American Society for Bone and Mineral Research.     

Screening for GNAS genetic and epigenetic alterations in progressive osseous heteroplasia: First Italian series

Progressive osseous heteroplasia (POH) is a rare autosomal dominant disorder of mesenchymal differentiation characterized by progressive heterotopic ossification (HO) of dermis, deep connective tissues and skeletal muscle. Usually, initial bone formation occurs during infancy as primary osteoma cutis (OC) then progressively extending into deep connective tissues and skeletal muscle over childhood.Most cases of POH are caused by paternally inherited inactivating mutations of GNAS gene. Maternally inherited mutations as well as epigenetic defects of the same gene lead to pseudohypoparathyroidism (PHP) and Albright's hereditary osteodystrophy (AHO).During the last decade, some reports documented the existence of patients with POH showing additional features characteristic of AHO such as short stature and brachydactyly, previously thought to occur only in other GNAS-associated disorders. Thus, POH can now be considered as part of a wide spectrum of ectopic bone formation disorders caused by inactivating GNAS mutations.Here, we report genetic and epigenetic analyses of GNAS locus in 10 patients affected with POH or primary OC, further expanding the spectrum of mutations associated with this rare disease and indicating that, unlike PHP, methylation alterations at the same locus are absent or uncommon in this disorder.     

The modulatory effect of endogenous parathyroid hormone on the action of hydrochlorothiazide in pseudohypoparathyroidism type I

We compared the effect of orally administered 100 mg of hydrochlorothiazide (HCTZ) among eight patients with pseudohypoparathyroidism (PHP) type I, 11 patients with idiopathic hypoparathyroidism (IHP), and 12 patients with primary hyperparathyroidism (1^oHPT). Patients with PHP type I or with IHP were studied during the treatment with 1-hydroxylated metabolites of vitamin D₃. HCTZ raised serum levels of calcium (Ca) in 1^oHPT (P<0.001) and PHP type I (P<0.01) but did not increase urinary excretion of Ca. Serum parathyroid hormone (PTH) in PHP type I decreased (P<0.02) after HCTZ administration in response to the increase in serum Ca. HCTZ did not raise serum levels of Ca in IHP but increased urinary excretion of Ca in this group (P<0.01). HCTZ suppressed tubular reabsorption of phosphate (P) in IHP (P<0.01) and 1^oHPT (P<0.05) but not in PHP type I. Urinary excretion of cAMP did not change after HCTZ administration in PHP type I, IHP, or 1^oHPT. Endogenous PTH modulated the effects of HCTZ on Ca mobilization from bone and renal reabsorption of Ca in PHP type I with normal or high serum levels of PTH and in 1^oHPT with high serum levels of PTH. The inhibitory effect of HCTZ on renal tubular reabsorption of P (probably from proximal tubules) was independent of PTH. The resistance to this inhibitory effect of HCTZ on P reabsorption in PHP type I suggested a proximal tubular dysfunction in this disorder.     

Efficacy and Safety of Parathyroid Hormone Replacement With TransCon PTH in Hypoparathyroidism: 26-Week Results From the Phase 3 PaTHway Trial

Conventional therapy for hypoparathyroidism consisting of active vitamin D and calcium aims to alleviate hypocalcemia but fails to restore normal parathyroid hormone (PTH) physiology. PTH replacement therapy is the ideal physiologic treatment for hypoparathyroidism. The double-blind, placebo-controlled, 26-week, phase 3 PaTHway trial assessed the efficacy and safety of PTH replacement therapy for hypoparathyroidism individuals with the investigational drug TransCon PTH (palopegteriparatide). Participants (n = 84) were randomized 3:1 to once-daily TransCon PTH (initially 18 μg/d) or placebo, both co-administered with conventional therapy. The study drug and conventional therapy were titrated according to a dosing algorithm guided by serum calcium. The composite primary efficacy endpoint was the proportion of participants at week 26 who achieved normal albumin-adjusted serum calcium levels (8.3–10.6 mg/dL), independence from conventional therapy (requiring no active vitamin D and ≤600 mg/d of calcium), and no increase in study drug over 4 weeks before week 26. Other outcomes of interest included health-related quality of life measured by the 36-Item Short Form Survey (SF-36), hypoparathyroidism-related symptoms, functioning, and well-being measured by the Hypoparathyroidism Patient Experience Scale (HPES), and urinary calcium excretion. At week 26, 79% (48/61) of participants treated with TransCon PTH versus 5% (1/21) wiplacebo met the composite primary efficacy endpoint (p < 0.0001). TransCon PTH treatment demonstrated a significant improvement in all key secondary endpoint HPES domain scores (all p < 0.01) and the SF-36 Physical Functioning subscale score (p = 0.0347) compared with placebo. Additionally, 93% (57/61) of participants treated with TransCon PTH achieved independence from conventional therapy. TransCon PTH treatment normalized mean 24-hour urine calcium. Overall, 82% (50/61) treated with TransCon PTH and 100% (21/21) wiplacebo experienced adverse events; most were mild (46%) or moderate (46%). No study drug-related withdrawals occurred. In conclusion, TransCon PTH maintained normocalcemia while permitting independence from conventional therapy and was well-tolerated in individuals with hypoparathyroidism. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

PTH 1-34 Replacement Therapy Has Minimal Effect on Quality of Life in Patients With Hypoparathyroidism

In addition to hypocalcemia, patients with hypoparathyroidism report poor quality of life (QOL), complaining of fatigue and “brain fog.” Parathyroid hormone (PTH) therapy can effectively manage hypocalcemia; however, the effects of PTH treatment on QOL are unclear. Thirty-one patients with hypoparathyroidism were treated in an open-label study with full replacement subcutaneous PTH 1-34 twice daily for up to 5.3 years, with individualized fine-dosing titration. Prior to initiation of PTH 1-34, conventional therapy was optimized. The 36-Item Short Form (SF-36) Health Survey, Fatigue Symptom Inventory (FSI), and 6-minute walk test (6MWT) were assessed at PTH start (baseline), every 6 months on PTH, and after PTH discontinuation. The SF-36 assesses physical function (PF), physical role limitations (RP), bodily pain (BP), general health (GH), vitality (VT), emotional role limitations (RE), social function (SF), and mental health (MH). Compared to population norms, patients at baseline had lower scores in RP, GH, VT, and MH (p < 0.05), consistent with impaired QOL. With PTH therapy, only GH at 6 months and VT at 12 months improved (p < 0.05). At the last treatment time point, RP, VT, and SF improved compared to baseline (p < 0.05). However, follow-up scores were unchanged from baseline or last PTH treatment, except for SF, which had decreased at follow-up compared to on-PTH (p < 0.05). On the FSI, there were no changes in fatigue frequency; perceived interference was improved at 12 and 18 months and composite severity was improved only at 60 months (p < 0.05). The 6MWT measures did not change. In conclusion, hypoparathyroidism is associated with decreased QOL. Despite the bias in open-label studies to predict improvements in QOL, PTH therapy had limited and non-sustained effects on QOL, inconclusive changes in fatigue experience, and no change in the 6MWT. Although PTH 1-34 can adequately manage the hypocalcemia in hypoparathyroidism, its effects on QOL appear to be minimal. © 2021 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.     

THE VALUE TO THE SURGEON OF PARATHYROID HORMONE ASSAYS IN PRIMARY HYPERPARATHYROIDISM

The role of various parathyroid hormone (PTH) radio-immunoassays in the diagnosis of primary hyperparathy-roidism (PHP) is controversial. A series of 204 patients with surgically proven PHP was studied. Serum total calcium, serum ionized calcium, amino (N)-terminal PTH and carboxyl(C)-terminal PTH were assessed in relation to the volume and weight of adenomatous or hyperplastic parathyroid tissue excised at operation. N-terminal PTH was elevated above the normal laboratory range in only 24% of patients and correlated relatively poorly with the volume of abnormal parathyroid tissue (r = 0.20, P= 0.05). C-terminal PTH was elevated above the normal range in 91% of patients and had a strong correlation with the volume of abnormal parathyroid tissue (r = 0.63, P< 0.001). The correlation coefficients between C-terminal PTH and serum total calcium and serum ionized calcium were both 0.63 (P< 0.001). In contrast, there was no correlation between N-terminal PTH and serum total calcium (r= -0.02), serum ionized calcium (r= -0.04) or C-terminal PTH (r = 0.09). A combination of hypercalcaemia and elevated C-terminal PTH can be regarded as strong diagnostic evidence of PHP. Furthermore, the level of C-terminal PTH can assist the surgeon by approximately predicting the amount of adenomatous or hyperplastic parathyroid tissue that may be expected at surgical exploration.