PTH Resistance Research Articles

SUN-510 Pseudohypoparathyroidism Type 1b Presenting With Fahr Syndrome In An Adolescent.

Background: Fahr syndrome is a condition characterized by the presence of abnormal calcifications in the basal ganglia and cerebral cortex, and has been linked with parathyroid disorders. We report a case of pseudohypoparathyroidism (PHP) type 1b in an adolescent presenting with recurrent seizures and intracranial calcifications. Clinical Case: A 15-year old boy presented with recurrent seizures that were uncontrolled despite treatment with anti-epileptic medications. He was diagnosed with epilepsy at the age of 9 overseas and had also been started on levothyroxine 25 mcg daily for hypothyroidism. He arrived in the US for further evaluation and management. He was initially seen by pediatric neurology wherein lab work-up showed hypocalcemia with a total calcium of 6.6 mg/dL (n 8.5-10.5). CT scan of the brain showed disseminated intracranial cortical and basal ganglia calcifications, consistent with Fahr syndrome. EEG showed generalized background slowing compatible with mild diffuse cerebral dysfunction. He was referred to pediatric endocrinology. At his endocrine visit, growth parameters were normal with height at 81st percentile, weight at 88th percentile, and BMI at 84th percentile. Family history was negative of seizures, thyroid or calcium disorders. He does not have intellectual disability. Physical exam did not reveal any features of Albright hereditary osteodystrophy. Additional lab testing showed ionized calcium 0.79 mmol/L (n 1.1-1.35), phosphorus 8.7 mg/dL (n 2.9-5.1), PTH 439 pg/mL (n 10.0-65.0), alkaline phosphatase (ALP) 308 U/L (n 60-270) and 25-hydroxy vitamin D 25.8 ng/mL (n 30-83). Renal function was normal. Findings were suggestive of PTH resistance. Thyroid function showed TSH 4.74 uU/mL (n 0.4-4.6), free T4 1.15 ng/dL (n 0.8-1.7) and negative thyroid antibodies (TPO, TG), suggestive of partial TSH resistance. He was treated with calcium carbonate, calcitriol and ergocalciferol. Levothyroxine was continued. Genetic testing was done which showed a partial loss of methylation in the GNAS exon 1A locus (patient 28%, [normal methylation ≥44%, complete loss of methylation ≤ 12%]), confirming the diagnosis of PHP type 1b. Calcium, phosphorus and ALP levels subsequently normalized with calcium and vitamin D supplementation. PTH improved though remains to be elevated (PTH 67.9 pg/mL). Anti-epileptic medications were weaned off after being seizure-free for more than 2 years. Conclusion: In this case, our patient presented with a distinct triad of epileptic seizure, extensive brain calcification, and hypocalcemia. This clinical scenario should prompt diagnostic evaluation for PHP as a treatable cause of epileptic seizures in children. Genetic testing for PHP type 1b showed partial loss of methylation in the GNAS locus, which was sufficient to cause disease.

Bone Status Among Patients With Nonsurgical Hypoparathyroidism, Autosomal Dominant Hypocalcaemia, and Pseudohypoparathyroidism: A Cohort Study.

Nonsurgical hypoparathyroidism (Ns-HypoPT) and pseudohypoparathyroidism (PHP) are both rare diseases, characterized by hypocalcemia. In Ns-HypoPT, PTH levels are low, whereas patients with PHP often have very high levels due to receptor-insensitivity to PTH (PTH-resistance). Accordingly, we hypothesized that indices of bone turnover and bone mineralization/architecture are similar in Ns-HypoPT and PHP despite marked differences in PTH levels. We studied 62 patients with Ns-HypoPT and 31 with PHP as well as a group of age- and sex-matched healthy controls. We found a significantly higher areal BMD (aBMD) by DXA among patients with Ns-HypoPT, both compared with PHP and the background population. Compared with Ns-HypoPT, PHP patients had significantly lower total and trabecular volumetric BMD (vBMD) assessed by quantitative computed tomography (QCT) scans at the spine and hip. High-resolution peripheral quantitative computed tomography (HRpQCT) scans showed a lower trabecular area and vBMD as well as a lower trabecular number at the tibia in PHP compared to Ns-HypoPT and matched controls. In PHP, PTH levels correlated with levels of markers of bone formation (osteocalcin, bone-specific alkaline phosphatase, P1NP), and bone resorption (CTx). In adult males, levels of bone markers were significantly higher in PHP compared with Ns-HypoPT. Levels of procalcitonin and calcitonin were significantly higher in PHP compared with Ns-HypoPT. In conclusion, indices of bone turnover, density, and microarchitecture differ between patients with Ns-HypoPT and PHP. Our data suggest that patients with PHP do not have a complete skeletal resistance to PTH and that the effects of chronically high PTH levels in PHP are mostly confined to the trabecular tissue. © 2017 American Society for Bone and Mineral Research.

Variable phenotype of pseudohypoparathyroidism in children

Background. Pseudohypoparathyroidism (PHP) is a heterogeneous group of disorders associated with tissue insensitivity to parathyroid hormone. PHP is characterized by genetic heterogeneity and variable phenotype. In addition to the hypocalcemic syndrome and resistance to parathyroid hormone, PHP is also characterized by phenotypic features and resistance to other hormones (TSH, LH, FSH, and GHRH), which are known as Albright Hereditary Osteodystrophy (AHO). Until recently, no analysis of large cohorts of patients with PHP has been performed in Russian literature.
 Objective — to examine a large cohort of patients with PHP and assess the clinical features of PHP.
 Material and methods. A group consisting of 32 patients with different variants of course of the disease who had been examined at the Endocrinology Research Center in 2014—2016 was analyzed.
 Results. Features of AHO phenotype in addition to hormonal resistance were identified in 16 (50%) patients; one of them had one feature (brachydactyly) and 15 patients had two and more features of AHO. Besides insensitivity to PTH, TSH resistance was found in 22 (68.75%) patients and one patient had resistance to PTH, TSH and LH/FSH. Hypothyroidism manifested before hypocalcaemia in 4 patients. Obesity was the first complaint in 8 patients; 5 of them had subclinical hypocalcaemia and the remaining 3 patients had an elevated PTH level with the normal level of calcium at the time of first examination. The most typical clinical signs of hypocalcaemia in 23 (72%) patients were seizures. Thirteen of them were misdiagnosed with epilepsy and had been followed by a neurologist for a period ranging between 2 months and 7 years before hypocalcaemia was revealed.
 Conclusions. Pseudohypoparathyroidism is a rare genetic disorder associated with resistance to parathyroid hormone, which can have a lot of other clinical features in addition to the symptoms of PTH resistance. Obesity or hypothyroidism can be the earliest manifestation of PHP preceding hypocalcaemia. Evaluation of serum calcium level is important for all pediatric patients with seizures to timely diagnose hypocalcaemia and avoid misdiagnosing.

Endocrinological and phenotype evaluation in a patient with acrodysostosis.

.Acrodysostosis is characterized by distinctive facial features and severe brachydactyly. Mutations in PRKAR1A or PDE4D are known to be responsible for this disease. Cases of hormonal resistance have been reported, particularly in patients with PRKAR1A mutations. The physical characteristics and endocrine function of pseudohypoparathyroidism type Ia is known to resemble acrodysostosis. We report the case of a 4-yr-old patient with a PRKAR1A mutation. He had characteristic facies with an upturned nose and cone-shaped epiphyses of most phalanges. These findings have not been reported as extensive for cases of pseudohypoparathyroidism type Ia. He also had TSH resistance from birth. We performed endocrinological stimulation tests to further evaluate his endocrine status. These examinations revealed resistance to TSH and PTH, but there was normal secretion of ACTH, GH, and cortisol. An Ellsworth-Howard test resulted in normal urinary cAMP excretion. This response differs from that of pseudohypoparathyroidism type Ia. In summary, the constellation of an upturned nose, cone-shaped epiphyses of most if not all phalanges, and PTH resistance with a normal urinary cAMP response may satisfactorily enable clinical diagnosis of acrodysostosis.

Isolated PTH Renal Resistance Pseudo Hypo Parathyroidism 1b: A Rare Cause of Hypocalcemia

A case of Pseudohypoparathyroidism 1b is reported, who presented with signs and symptoms of hypocalcemia. Causes, diagnosis and management with new insight into genetic novel mutations in PHP are discussed. The objectives are to provide information regarding problems of Calcium balance, causes and making diagnosis of pseudohypoparathyroidism, learn complexities of PTH cellular interactions and calcium homeostasis and learn the genetic novel mutations of various types of PHP.

Bone loss in KLHL3 knock-in mice characterized by a pseudohypoaldosteronism type II-like phenotype is mediated by renal PTH resistance

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Bone loss in KLHL3 knock-in mice characterized by a pseudohypoaldosteronism type II-like phenotype is mediated by renal PTH resistance

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Evidence of hormone resistance in a pseudo-pseudohypoparathyroidism patient with a novel paternal mutation in GNAS

ContextLoss-of-function GNAS mutations lead to hormone resistance and Albright's hereditary osteodystrophy (AHO) when maternally inherited, i.e. pseudohypoparathyroidism-Ia (PHPIa), but cause AHO alone when located on the paternal allele, i.e. pseudoPHP (PPHP). ObjectiveWe aimed to establish the molecular diagnosis in a patient with AHO and evidence of hormone resistance. CaseThe patient is a female who presented at the age of 13.5years with short stature and multiple AHO features. No evidence for TSH or gonadotropin-resistance was present. Serum calcium and vitamin D levels were normal. However, serum PTH was elevated on multiple occasions (64–178pg/mL, normal: 9–52) and growth hormone response to clonidine or L-DOPA was blunted, suggesting hormone resistance and PHP-Ia. The patient had diminished erythrocyte Gsα activity and a novel heterozygous GNAS mutation (c.328 G>C; p.A109P). The mother lacked the mutation, and the father's DNA was not available. Hence, a diagnosis of PPHP also appeared possible, supported by low birth weight and a lack of AHO features associated predominantly with PHP-Ia, i.e. obesity and cognitive impairment. To determine the parental origin of the mutation, we amplified the paternally expressed A/B and biallelically expressed Gsα transcripts from the patient's peripheral blood RNA. While both wild-type and mutant nucleotides were detected in the Gsα amplicon, only the mutant nucleotide was present in the A/B amplicon, indicating that the mutation was paternal. ConclusionThese findings suggest that PTH and other hormone resistance may not be an exclusive feature of PHP-Ia and could also be observed in patients with PPHP.

Different pattern of epigenetic changes of the GNAS gene locus in patients with pseudohypoparathyroidism type Ic confirm the heterogeneity of underlying pathomechanisms in this subgroup of pseudohypoparathyroidism and the demand for a new classification of GNAS-related disorders.

Disorders characterized by PTH resistance are grouped within the term pseudohypoparathyroidism type I (PHPI). Most subtypes of this disease are caused by genetic or epigenetic changes of the GNAS locus leading to deficiency of the α-subunit of stimulatory G proteins (Gsα). Because the in vitro measured Gsα protein activity is normal in pseudohypoparathyroidism Ic (PHPIc), it had previously been postulated that this subtype is caused by impairment of distinct components of the G protein-signaling pathway. However, recently, pathogenic GNAS mutations in a subset of PHPIc patients were found. To clarify the underlying pathogenic mechanism of GNAS exon 1-13 mutation-negative PHPIc cases by investigating the differentially methylated regions of GNAS for epigenetic abnormalities. The methylation pattern of GNAS exons A/B, AS, XL, and NESP from blood-derived leukocytes of 26 PHPIc patients was assessed by pyrosequencing of bisulfite-converted DNA. Six patients presented with three different patterns of epigenetic changes. One patient had an exclusive loss of methylation of exon A/B associated with a STX16 deletion; four patients had an additional loss of methylation in XL and AS and a gain of methylation in NESP; and one patient presented with partial GNAS methylation changes concerning all differentially methylated regions. Our results confirm that PHPIc is a heterogeneous entity caused in part by impaired Gsα function, not only due to mutations, but also due to abnormal imprinting of GNAS. However, in the majority of cases of PHPIc, the underlying etiopathogenesis remains elusive.

Long-term Fgf23 deficiency induces renal and skeletal PTH resistance in vitamin D receptor-ablated mice

Long-term Fgf23 deficiency induces renal and skeletal PTH resistance in vitamin D receptor-ablated mice

Simultaneous Hyper- and Hypomethylation at Imprinted Loci in a Subset of Patients withGNASEpimutations Underlies a Complex and Different Mechanism of Multilocus Methylation Defect in Pseudohypoparathyroidism Type 1b

Most patients with pseudohypoparathyroidism type 1b (PHP-1b) display a loss of imprinting (LOI) encompassing the GNAS locus resulting in PTH resistance. In other imprinting disorders, such as Russell-Silver or Beckwith-Wiedemann syndrome, we and others have shown that the LOI is not restricted to one imprinted locus but may affect other imprinted loci for some patients. Therefore, we hypothesized that patients with PHP-1b might present multilocus imprinting defects. We investigated, in 63 patients with PHP-1b, the methylation pattern of eight imprinted loci: GNAS, ZAC1, PEG1/MEST, ICR1, and ICR2 on chromosome 11p15, SNRPN, DLK1/GTL2 IG-DMR, and L3MBTL1. We found multilocus imprinting defects in four PHP-1b patients carrying broad LOI at the GNAS locus (1) simultaneous hypermethylation at L3MBTL1 differentially methylated region 3 (DMR3), and hypomethylation at PEG1/MEST DMR (n = 1), (2) hypermethylation at the L3MBTL1 (DMR3) (n = 1) and at the DLK1/GTL2 IG-DMR (n = 1), and (3) hypomethylation at the L3MBTL1 DMR3 (n = 1). We suggest that mechanisms underlying multilocus imprinting defects in PHP-1b differ from those of other imprinting disorders having only multilocus loss of methylation. Furthermore, our results favor the hypothesis of "epidominance", that is, the phenotype is controlled by the most severely affected imprinted locus.

A Case of Primary Hyperparathyroidism due to Ectopic Parathyroid Adenoma in the Thymus, Accompanied With Vitamin D Deficiency

Primary hyperparathyroidism (PHPT) caused by ectopic parathyroid adenoma (EPA) is not rare, whereas the concurrence of PHPT and vitamin D deficiency (VDD) in youth is uncommon. We reported a case of PHPT with EPA in the thymus, accompanied by a very low level of 25-hydroxyvitamin D. A 20-year-old man suffered from bilateral hip fractures under slight force or no force. Biochemical findings were consistent with PHPT and VDD. Examination results showed severe osteoporosis; both technetium-99m-sestamibi scintigraphy and computed tomography showed an abnormal nodule in the mediastinum, which was resected with a thoracoscope and confirmed pathologically as an EPA in the thymus. Hypocalcemia due to hungry bone syndrome (HBS) occurred after surgery and was resolved quickly with large-dose calcium and alfacalcidol supplementation. PHPT is usually a sporadic disease, and VDD is unfortunately a common global problem. Negative family history and no concomitant illness seemed to rule out familiar hyperparathyroidism. VDD with no gastrointestinal symptom and nutritional anemia was caused by long-term inadequate sun exposure before the first fracture and a 2-year absence of sun exposure due to immobilization. Both PHPT and VDD contributed to severe osteoporosis, which could be exacerbated by not attaining his peak bone mass and by immobilization because of a fragile fracture with delayed healing. Large parathyroid adenoma, VDD, overt bone disease, and PTH resistance in the patient were related to postoperative hungry bone syndrome. Any fracture in young adults that has not healed within 3 months should alert physicians to search for some factors or underlying diseases.

Quantitative Analysis of Methylation Defects and Correlation With Clinical Characteristics in Patients With Pseudohypoparathyroidism Type I and GNAS Epigenetic Alterations

Pseudohypoparathyroidism type I (PHP-I) includes two main subtypes, PHP-Ia and -Ib. About 70% of PHP-Ia patients, who show Albright hereditary osteodystrophy (AHO) associated with resistance toward multiple hormones (PTH/TSH/GHRH/gonadotropins), carry heterozygous mutations in the α-subunit of the stimulatory G protein (Gsα) exons 1-13, encoded by the guanine nucleotide binding-protein α-stimulating activity polypeptide 1 (GNAS), whereas the majority of PHP-Ib patients, who classically display hormone resistance limited to PTH and TSH with no AHO sign, have methylation defects in the imprinted GNAS cluster. Recently methylation defects have been detected also in patients with PHP and different degrees of AHO, indicating a molecular overlap between the two forms. The objectives of the study were to collect patients with the following characteristics: clinical PHP-I (with or without AHO), no mutation in Gsα coding sequence, but the presence of GNAS methylation alterations and to investigate the existence of correlations between the degree of the epigenetic defect and the severity of the disease. We quantified GNAS methylation alterations by both PCR-pyrosequencing and methylation specific-multiplex ligation-dependent probe amplification assay in genomic DNA from 63 patients with PHP-I and correlated these findings with clinical parameters (age at diagnosis; calcium, phosphorus, PTH, TSH levels; presence or absence of each AHO sign). By both approaches, the degree of the imprinting defect did not correlate with the onset of the disease, the severity of endocrine resistances, or with the presence/absence of specific AHO signs. Similar molecular alterations may lead to a broad spectrum of diseases, from isolated PTH resistance to complete PHP-Ia, and the degree of methylation alterations does not reflect or anticipate the severity and the type of different PHP/AHO manifestations.

De NovoSTX16 Deletions: An Infrequent Cause of Pseudohypoparathyroidism Type Ib that Should Be Excluded in Sporadic Cases

Maternally inherited 3-kb STX16 deletions cause autosomal dominant pseudohypoparathyroidism type Ib (PHP-Ib) characterized by PTH resistance with loss of methylation restricted to the GNAS exon A/B. The objective of the study was to search for the 3-kb STX16 deletion and to establish haplotypes for the GNAS region for two PHP-Ib patients and their families. The study was conducted at a research laboratory and tertiary care hospitals. The index cases presented at the ages 8 and 9.5 yr, respectively, with hypocalcemia, hyperphosphatemia, and elevated PTH. There were no interventions. DNA analyses of the index cases revealed an isolated loss of the GNAS exon A/B methylation and the 3-kb STX16 deletion. In the first family, the patient's healthy mother and sister showed no genetic or epigenetic abnormality, yet microsatellite analysis of the GNAS region indicated that both siblings share the same maternal allele, with the exception of an allelic loss for marker 261P9-CA1 (located within STX16), leading to the conclusion that a de novo mutation had occurred on the maternal allele. In the second family, three siblings of the index case are also affected, and an analysis of their DNA revealed the 3-kb STX16 deletion, which was also found in the healthy mother and a maternal uncle. Analysis of the siblings of the deceased maternal grandfather and some of their descendants excluded the 3-kb STX16 deletion, but haplotype analysis of the GNAS region suggested that he had acquired the mutation de novo. De novo 3-kb STX16 deletions, reported only once previously, are infrequent but should be excluded in all cases of PHP-Ib, even when the family history is negative for an inherited form of this disorder.

Hipocalcemias

Hypocalcemia can be present in asymptomatic patient as a laboratory finding or as an important event with impact in patient survival which requires rapid treatment. The severity depends of the magnitude of hypocalcemia and the speed of the instauration. Tetany is the must characteristic clinical sing of acute hypocalcemia. Deferent causes can intervene in the etiology of hypocalcemia such as hypoparathyroidism, alteration in vitamin D metabolism, PTH resistance and magnesium depletion.To diagnose hypocalcemia serum calcium should be determinate which must be interpreted in relation of serum albumin. Determination of PTH is the must important initial date for etiologic diagnosis, other laboratory finding could be useful such as serum magnesium, creatinine, phosphorus, vitamin D, etc.The treatment for chronic hypocalcemia in asymptomatic patients should be make with calcium and vitamin D orally. The objective is normalizing serum calcium without hypercalciuria. Intravenous calcium follow to calcium and vitamin D orally must be necessary in the case of severe acute hypocalcemia.

Development and Treatment of Tertiary Hyperparathyroidism in Patients with Pseudohypoparathyroidism Type 1B

Pseudohypoparathyroidism type 1B (PHP1B) patients have PTH resistance at the renal proximal tubule and develop hypocalcemia and secondary hyperparathyroidism. Hyperparathyroid bone disease also develops in some patients. PHP1B patients are at theoretical risk of developing tertiary hyperparathyroidism. Patients were studied in a clinical research center. Five female PHP1B patients presented with hypercalcemia and elevated PTH. Patients either underwent parathyroidectomy (n = 4) or received cinacalcet (n = 1). Serum calcium and PTH were serially measured before and after intervention. Five PHP1B patients developed concomitantly elevated serum calcium and PTH levels (range, 235-864 ng/liter) requiring termination of calcium and vitamin D therapy (time after diagnosis, 21-42 yr; median, 34 yr), consistent with tertiary hyperparathyroidism. Four patients underwent parathyroidectomy with removal of one (n = 2) or two (n = 2) enlarged parathyroid glands. Calcium and vitamin D therapy was reinstituted postoperatively, and at 93-month median follow-up, PTH levels ranged between 56 and 182 (normal, <87) ng/liter. One patient was treated with cinacalcet, resulting in resolution of hypercalcemia. PHP1B patients are at risk of developing tertiary hyperparathyroidism and/or hyperparathyroid bone disease and should therefore be treated with sufficient doses of calcium and vitamin D to achieve serum calcium and PTH levels within or as close to the normal range as possible. Surgery is the treatment of choice in this setting. Cinacalcet may be a useful alternative in those who do not undergo surgery.

Ubiquitination-deubiquitination balance dictates ligand-stimulated PTHR sorting

Parathyroid hormone receptors (PTHR) are promptly internalized upon stimulation by activating (PTH[1-84], PTH[1-34]) and non-activating (PTH[7-84], PTH[7-34]) ligands. Here, we characterized the mechanism regulating the sorting of internalized receptors between recycling and degradative pathways. PTHR recycles faster after challenge with PTH(1-34) than with PTH(7-34). PTHR recycling is complete by 2 h after PTH(1-34) stimulation, but incomplete at this time in cells treated with PTH(7-34). The slower and incomplete recycling induced by PTH(7-34) is due to proteasomal degradation. Both PTH(1-34) and PTH(7-34) induced PTHR polyubiquitination. Ubiquitination by PTH(1-34) was transient, whereas receptor ubiquitination after PTH(7-34) was sustained. PTH(1-34), but not PTH(7-34), induced expression of the PTHR-specific deubiquitinating enzyme USP2. Overexpression of USP2 prevented PTH(7-34)-induced PTHR degradation. We conclude that PTH(1-34) promotes coupled PTHR ubiquitination and deubiquitination, whereas PTH(7-34) activates only ubiquitination, thereby leading to PTHR downregulation. These findings may explain PTH resistance in diseases associated with elevated PTH(7-84) levels.

Madelung-Like Deformity in Pseudohypoparathyroidism Type 1b

Pseudohypoparathyroidism (PHP) types 1a and 1b are distinguished by clinical, biochemical, and molecular features. We report extended kindred with PHP 1b in which many affected members also had growth plate defects, including brachydactyly and a Madelung-like deformity. Analyses included clinical examination, assessment of mineral metabolism, thyroid function, skeletal radiography, and analysis of the GNAS and STX16 genes. Patients were studied in an academic medical center. We studied 37 members of a family in which PHP 1b occurred in 23 individuals. Ten of 17 affected patients who were examined had brachydactyly E, including two subjects with Madelung-like defects. Five of 16 subjects had subclinical hypothyroidism; no subject showed sc ossification or short stature. None of the unaffected members had brachydactyly or an elevated serum level of PTH or TSH. Levels of immunoactive erythrocyte Gα(s) were normal in two affected subjects tested. Linkage analysis indicated linkage between PTH resistance and the GNAS gene locus; however, no mutations were identified in GNAS exons 1-13. Methylation analysis of genomic DNA from affected subjects showed loss of maternal epigenotype in exon 1A with normal methylation of the differentially methylated regions for XLGαs and NESP55, and PCR demonstrated heterozygosity for a 3.0-kb deletion in the STX16 gene. The segregation of brachydactyly with PHP 1b in this family indicates that an imprinting defect in GNAS can lead to growth plate defects, including brachydactyly and Madelung deformity. These features suggest that GNAS signaling plays a more extensive role in chondrocyte maturation than previously thought.

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.

Bone Mineral Density in Pseudohypoparathyroidism Type 1a

The biochemical hallmark of pseudohypoparathyroidism type 1a (PHP1a) is resistance to PTH, but based on tissue-specific imprinting of GNAS, PTH resistance may be limited to the renal cortex. Some studies have shown that bone is responsive to PTH, suggesting that PHP1a patients with chronically elevated PTH levels may have low bone mineral density (BMD). This observational study was conducted at the Institute of Clinical and Translational Research, Johns Hopkins Medical Institutions. Twenty-two children and adults with PHP1a were studied. The main outcome measure was BMD Z-score at the lumbar spine (LS), total hip, femoral neck, and total body using dual-energy x-ray absorptiometry, relative to height, weight, and pubertal status. The mean (+/-SD) Z-score for height was 0.77 +/- 1.66 and 1.85 +/- 1.15 for BMI. The BMD Z-score at each of the four sites studied was as follows: LS, 0.29 +/- 1.08; total hip, 0.27 +/- 1.24; femoral neck, 0.02 +/- 1.26; and total body, 0.98 +/- 1.50. Only two subjects (9%) had BMD Z-scores less than -2, and each had additional risk factors for low BMD. BMD in total body and LS spine corrected for height-for-age Z-score was significantly greater than normal. There was no correlation between PTH level and BMD Z-score or between body mass index and BMD Z-score. Despite secondary hyperparathyroidism, region-specific BMD is not reduced in patients with PHP1a, and total body BMD is significantly greater than normal.