Parathyroid Hormone Resistance Research Articles

Secondary hyperparathyroidism: Update

Secondary hyperparathyroidism is a clinical condition characterized by an increase in the synthesis and secretion of parathyroid hormone (PTH). Its presentation will be conditioned by the development of stimuli such as hyperphosphatemia, hypocalcemia, vitamin D deficiency, and PTH resistance. The most common cause of secondary hyperparathyroidism is chronic kidney disease, a pathological condition in which all the afore mentioned stimuli converge. Secondary hyperparathyroidism is evidenced by an increase in the size of the parathyroid glands, favored by cellular hyperplasia and hypertrophy. At the bone level, there will be an increase in the quantity and activity of osteoblasts and osteoclasts, leading to bone with unusual structural characteristics. Symptoms related to the disease include itching, bone pain, concentration alteration, and depression. In the long term, patients have a higher risk of cardiovascular mortality. Therapeutic options include calcimimetics, phosphate binders, vitamin D supplements, and surgery.

GNAS locus: bone related diseases and mouse models.

GNASis a complex locus characterized by multiple transcripts and an imprinting effect. It orchestrates a variety of physiological processes via numerous signaling pathways. Human diseases associated with the GNAS gene encompass fibrous dysplasia (FD), Albright's Hereditary Osteodystrophy (AHO), parathyroid hormone(PTH) resistance, and Progressive Osseous Heteroplasia (POH), among others. To facilitate the study of the GNAS locus and its associated diseases, researchers have developed a range of mouse models. In this review, we will systematically explore the GNAS locus, its related signaling pathways, the bone diseases associated with it, and the mouse models pertinent to these bone diseases.

Mechanistic impact of fibrosis by parathyroid hormone excess

Klotho is a protein that has been found to play a role in regulating parathyroid hormone (PTH) levels. The literature suggests an intricate relationship between Klotho and PTH. Klotho acts as a co-receptor for fibroblast growth factor 23 (FGF23), a hormone that helps regulate phosphate and vitamin D metabolism. Klotho deficiency has been associated with increased PTH levels and secondary hyperparathyroidism. Several studies have investigated the relationship between Klotho and PTH levels. Some studies have shown that Klotho levels are inversely correlated with PTH levels, suggesting that higher Klotho levels may lead to lower PTH levels. Other studies have found that Klotho deficiency can contribute to PTH resistance, leading to persistent hyperparathyroidism. Additionally, the Klotho-PTH axis holds promise as a potential target for therapeutic interventions in calcium and phosphate disorders.

Abstract #1413302: A Case of a 25-Year-Old Woman with Congenital Pseudohypoparathyroidism and Hypothyroidism with Prediabetes

Pseudohypoparathyroidism (PHP) is a group of rare disorders, with fewer than 60 clinically-confirmed cases worldwide by 2016. PHP and related disorders mostly result from the genetic and/or epigenetic changes that cause end-organ parathyroid hormone resistance with a cyclic adenosine monophosphate (cAMP) generator down-regulation. These changes are often associated with the GNAS gene. PHP type IA tends to present with hypocalcemia, hyperphosphatemia, elevated PTH levels and Albright hereditary osteodystrophy (AHO). Clinical features of AHO are obesity, round face, short stature, brachydactyly (BD), subcutaneous ossifications and mental retardation. PHP is associated with increased risk for metabolic syndrome and diabetes with related complications. We present a case of a 25-year-old woman, who was referred to the adult Endocrinology clinic for management of PHP type IA and hypothyroidism by her primary care provider who was managing her condition for the last 7 years. She was last evaluated by her pediatric endocrinologist at age 18. She was initially diagnosed with PHP and hypothyroidism at age 7 after a syncopal episode requiring hospitalization. She had severely low serum calcium and elevated thyroid stimulating hormone levels upon diagnosis. She has a past medical history of seizures as a child. There is no family history of PHP. On physical examination, she had a round face with short stature, shortened chubby extremities and absent knuckles in all except index fingers of both hands. She weighed 173 pounds with a height of 62 inches and a BMI of 31.64. She is currently taking 150 mcg oral once daily levothyroxine, 0.25 mcg oral once daily calcitriol and calcium carbonate 625 mg oral four times per day. Laboratory investigations: Her TSH is 3.4, serum calcium is 8.7mg/dl, intact parathyroid hormone level is 169.4 picograms/milliliter. Her 25-OH-vitamin D level is low at 14.8nanogram/milliliter. Her serum Phosphorus is high at 5.3 mg/dl and her HbA1c is high at 5.8 mg/dl. Her lipid profile is normal except for a low level of HDL at 35 mg/dl. Patients with PHP are at higher risk for weight gain, type 2 diabetes, dyslipidemia and hypertension. Our patient with PHP and prediabetes was referred to the dietitian for nutrition education. Increasing physical activity was recommended. Vitamin D deficiency was treated with a high dose vitamin D course. Calcium and calcitriol treatments were continued. We conclude that patients with PHP should transition from pediatric endocrinology to adult endocrinology in a timely fashion for regular follow-ups to avoid morbidity and mortality. Educational programmes, as well as psychological support, should be provided to patients and families even in the presence of a normal BMI as a preventive strategy.

Neonatal and Early Infancy Features of Patients With Inactivating PTH/PTHrP Signaling Disorders/Pseudohypoparathyroidism.

Pseudohypoparathyroidism (PHP) and related disorders newly referred to as inactivating PTH/PTHrP signaling disorders (iPPSD) are rare endocrine diseases. Many clinical features including obesity, neurocognitive impairment, brachydactyly, short stature, parathyroid hormone (PTH) resistance, and resistance to other hormones such as thyroid-stimulating hormone (TSH) have been well described, yet they refer mainly to the full development of the disease during late childhood and adulthood. A significant delay in diagnosis has been reported; therefore, our objective is to increase awareness on neonatal and early infancy presentation of the diseases. To do so, we analyzed a large cohort of iPPSD/PHP patients. We included 136 patients diagnosed with iPPSD/PHP. We retrospectively collected data on birth and investigated the rate of neonatal complications occurring in each iPPSD/PHP category within the first month of life. Overall 36% of patients presented at least one neonatal complication, far more than the general population; when considering only the patients with iPPSD2/PHP1A, it reached 47% of the patients. Neonatal hypoglycemia and transient respiratory distress appeared significantly frequent in this latter group, ie, 10.5% and 18.4%, respectively. The presence of neonatal features was associated with earlier resistance to TSH (P < 0.001) and with the development of neurocognitive impairment (P = 0.02) or constipation (P = 0.04) later in life. Our findings suggest that iPPSD/PHP and especially iPPSD2/PHP1A newborns require specific care at birth because of an increased risk of neonatal complications. These complications may predict a more severe course of the disease; however, they are unspecific which likely explains the diagnostic delay.

Spectrum of Disorders associated with Tetany.

Awareness regarding the etiological spectrum of tetany is poor among physicians. Because of poor awareness, tetany is underdiagnosed and undertreated. Databases like PubMed, PubMed Central, Scopus, and Google Scholar are searched to identify peer-reviewed articles on tetany. Case reports, case series, and original articles are analyzed to identify different causes of tetany prevalent in the community. Different causes found are analyzed and tabulated, and finally, a flowchart is made on the approach for diagnosing different underlying pathologies of tetany. Both metabolic and respiratory alkalosis are important causes of tetany because of reduced ionized calcium levels. Gitelman syndrome (GS) is associated with metabolic alkalosis, hypokalemia, hypomagnesemia and hypocalciuria, and frequently causes normocalcemic tetany. Recurrent vomiting and primary hyperaldosteronism also cause tetany due to metabolic alkalosis. Hyperventilation syndrome (HVS) leads to respiratory alkalosis and is a frequent cause of tetany. Hyperventilation-induced tetany is also seen after spinal anesthesia and in respiratory disorders like asthma. Vitamin D deficiency (VDD), primary hypoparathyroidism, and pseudohypoparathyroidism (PHP) (1a, 1b, and 2) cause hypocalcemic tetany. Hypomagnesemia causes hypocalcemia and tetany due to peripheral parathyroid hormone resistance and impaired parathyroid hormone secretion. Drugs causing tetany include bisphosphonates, denosumab, cisplatin, antiepileptics, aminoglycosides, diuretics, etc. Tetany is also seen in acute pancreatitis, dengue, falciparum malaria, hyperemesis gravidarum, tumor lysis syndrome (TLS), massive blood transfusion, etc. Conclusion: The spectrum of disorders associated with tetany is diverse. Awareness of different causes will help early and proper diagnosis of tetany.

ODP117 Pseudohypoparathyroidism Type IB: A Rare Cause of Hypocalcemia

Abstract Introduction Pseudohypoparathyroidism (PHP) describes disorders of hypoparathyroidism that are the result of resistance of target tissues to the actions of parathyroid hormone (PTH). Studies have estimated the prevalence of PHP to be 0.34 in 100,000 in Japan and 1.1 in 100,000 in Denmark. The first biochemical abnormalities to become apparent are elevated serum levels of PTH and elevated serum levels of phosphorus, followed by hypocalcaemia. We present a patient diagnosed with PHP Type 1B (PHP1B), which was presented to us many years after her initial diagnosis, with other major comorbidities now present. Case description This patient is an 81 year old female presenting to the clinic to discuss her previously diagnosed PHP1B. Her past medical history revealed she began having symptoms of intermittent muscle cramping at the age of 22, followed by carpopedal spasms and periorbital paresthesia a year later. She has also had a physical examination significant for a positive Trousseau sign, but no phenotypical signs of Albright hereditary Osteodystrophy (AHO). Lab evidence from 1977 was recovered showing urinary cyclic AMP level &amp;lt;20 nmol/mg after administration of PTH, consistent with PHP1B. The family history in her parents and children has revealed no similar genetic history so far. Other comorbidities she has developed since her diagnosis are hypokalemia, hypothyroidism, osteoporosis with a femur fracture, obesity, chronic kidney disease and nephrolithiasis. She has been continuing treatment throughout her life with calcium, calcitriol and vitamin D supplementation for hypocalcemia. She has been mostly eucalcemic since then, and complains of occasional carpopedal spasms and perioral numbness. Discussion PHP1B is isolated resistance to PTH in the kidney and normal PTH response in bone without features of AHO. PHP1A and 1C have PTH resistance in bone, and both express AHO. These various forms of PHP are due to defects in the GNAS gene that lead to decreased expression of the alpha-subunit of G protein (Gsa). In the absence of molecular analysis, the clinical and biochemical overlap between PHP and related disorders can lead to challenges in diagnostic classification. There are 2 types of PHP1B cases- autosomal dominant (AD) and sporadic. However, the majority of Patients with PHP1B do not have mutations within the GNAS but they have methylation and imprinting defects that result in absence of maternal Gsa. To emphasize, epimutation study rather than sequencing of the coding region in GNAS should be performed for genetic investigation, which has now become standard practice. Although there is no difference in clinical presentation between AD PHP1B and sporadic PHP1B, their differentiation early during the disease onset can help providers give patients more reliable genetic and reproductive counseling and provide optimal medical management of complications such as hypocalcemia. Presentation: No date and time listed

ODP076 A Unique Case of Iatrogenic Hypermagnesemia Induced Symptomatic Hypocalcemia

Abstract Introduction Magnesium plays a role in production, release, and end-organ responsiveness of parathyroid hormone (PTH) and calcium homeostasis. Hypomagnesemia has been well documented to cause hypocalcemia by impaired secretion of PTH or PTH resistance. Iatrogenic hypermagnesemia in pregnant patients receiving intravenous magnesium for suppression of premature labor and pre-eclampsia is an uncommon cause of hypocalcemia. We are reporting a case of symptomatic hypocalcemia caused by iatrogenic hypermagnesemia in post-partum mother, who had high PTH in contrast to previous case reports. CaseA 28-year-old G4P1122 female, postpartum day 16 was admitted for headache, slurred speech, and vomiting. She was found to have elevated blood pressures and was started on IV magnesium for postpartum preeclampsia. On her first day, she received a 4g bolus of magnesium sulfate followed by 2g as maintenance for seizure prophylaxis. The following morning, the patient awoke complaining of numbness/tingling in both arms and twitching in her face and eyelids. Later that day, she had developed bilateral spontaneous carpopedal spasm as well. Labs drawn at that time revealed ionized calcium 0.78mmol/L (1.18-1.32 mmol/L), corrected calcium 7.42mg/dL (8.5-10.1), vitamin D 25-OH 45ng/mL (30-100), PTH 149.1pg/mL (18.5-88), phosphorus 2.9mg/dL (2.3-4.6), GFR116mL/min (&amp;gt;60) and magnesium 3.5mg/dL (1.4-2.2). Patient was started on IV calcium gluconate infusion along with calcium carbonate 1g QID and vitamin D3 5000 units daily. By the evening of the second day, patient's carpopedal spasm and paresthesia completely resolved. Repeat labs demonstrated improved ionized calcium of 1.17mmol/L (1.18-1.32), corrected calcium of 9.78mg/dL (8.5-10.1), and magnesium of 1.5mg/dL (1.4-2.2). Patient was discharged on calcium carbonate 1g TID and Vitamin D3 5000 units daily. Patient self-discontinued calcium and vitamin D supplementation a week after discharge. Repeat labs one week later showed normal corrected calcium, magnesium, and PTH levels. Conclusion Our patient developed transient, symptomatic hypocalcemia with elevated PTH secondary to iatrogenic hypermagnesemia, which improved with intravenous calcium. Hypomagnesemia is a known cause of hypocalcemia, but hypermagnesemia is a significantly less recognized etiology. Hypermagnesemia can cause low PTH due to activation of calcium sensing receptors resulting in inhibition of PTH secretion. Hypermagnesemia can also blunt the peripheral effect of PTH and promote hypercalciuria. Previous studies showed PTH can peak by the end of magnesium infusion but still result in hypocalcemia, although this is an uncommon clinical presentation. Our case highlights this aspect of elevated PTH after the completion of IV Magnesium infusion but still unable to correct hypocalcemia due to PTH resistance from hypermagnesemia. This calls attention to another underrecognized sequalae of hypermagnesemia: blunting of peripheral tissues response to PTH. Clinicians should be aware of development of hypocalcemia with both hypo- and hypermagnesemia as well as the underlying pathophysiology. Presentation: No date and time listed

ODP588 A Rare Case Of Infantile Transient Psuedohypoparathyrodism

Abstract Background Pseudohypoparathyroidism (PHP) is a heterogeneous group of disorders in which resistance to parathyroid hormone (PTH) in the proximal renal tubules leads to hypocalcemia, hyperphosphatemia, and impaired 1,25(OH)2 vitamin D production. Clinical Case A 2-month-old child presented with history of recurrent focal seizures since last 10 days. During the first episode, the child was treated with anti- convulsant by paediatrician. Five days later she again developed focal seizures, this time the child was evaluated and serum calcium was 5.6 mg/dl (normal, 8.6-10.2 mg/dl), phosphorus 7.5 mg/dL (normal, 4. 0-7. 0 mg/dL), and magnesium 2. 0 mg/dL (normal 1.8-2.4 mg/dL). In view of symptomatic hypocalcemia, she was treated with I. V. 10% calcium gluconate and oral calcifediol (800 IU/day). The child was seizure free but still had hypocalcemia - serum calcium-6.8 mg/dl, hence the child was evaluated further- serum PTH was 561 pg/mL (normal, 9-91 pg/mL), 25-hydroxyvitamin D was 54.1 ng/mL (normal, 5-60 ng/mL), 1,25 Vit D-6.28 pg/mL (normal, 19.9-79.3pg/mL), TSH-2.69 μUI/mL (normal, 0.35-8. 00 μUI/mL), FT4 was 1.2 ug/dL (normal, 0.9-1.8 ug/dL). Physical examination was unremarkable, and there were no stigmata of AHO, rachitic rosary, or congenital malformations. EEG was normal and CT brain did not show any intraventricular haemorrhage or basal ganglia calcification. Consistent with hypocalcaemia, hyperphosphatemia, high serum PTH levels, and lack of stigmata of AHO, we considered PHP type Ib. Her parents refused further examinations, so PTH infusion and molecular analysis of the GNAS gene could not be performed. The child was discharged in good clinical condition on calcitriol 0.25 ug/day and calcium (elemental calcium 625 mg/day) supplementation. He had no further seizures and normal serum electrolyte levels till 9 months of age. European Pseudohypoparathyroidism Network (EuroPHP Network) has recently proposed a new classification system to cover all disorders of the PTH pathway. Inactivating PTH/PTH-related protein signaling disorder (iPPSD) is the new name proposed for these disorders. iPPSDs can be further divided into subtypes: iPPSD1 to iPPSD6. A minimum of one major criterion is mandatory for the clinical diagnosis of iPPSD. Applying iPPSD criteria to this case, one can observe that they all had persistent hypocalcemia and PTH resistance but no other major or minor criteria. Nevertheless, we speculate whether neonatal transient pseudohypoparathyroidism (ntPHP) could be included among iPPSDs, specifically in the group of unknown molecular defects. Conclusion To the best of our knowledge, this is the second report in which the new classification of iPPSD has been applied and the child has been diagnosed a case of ntPHP. Presentation: No date and time listed

PSAT183 Severe Hypocalcemia Precipitated by COVID-19 Infection in a Patient with Albright Hereditary Osteodystrophy and Pseudohypoparathyroidism

Abstract Background Hypocalcemia is a common endocrine manifestation of COVID 19 infection. We present a rare case of severe hypocalcemia in a patient with a history of Pseudohypoparathyroidism (PHP) type 1A after COVID-19 infection. PHP is a genetic disorder that presents with hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism due to marked target-organ unresponsiveness to parathyroid hormone (PTH). PHP type 1A also has a characteristic somatic phenotype known as Albright Hereditary Osteodystrophy (AHO), including short stature, brachydactyly, shortened metatarsals, and often reduced intelligence. Case Presentation This is a 53-year-old female with PHP type 1A, diabetes mellitus type 2, hypothyroidism, vitamin D deficiency, mild intellectual disability, and hypertension. She presented with new onset of seizures. She was also found to be positive for COVID-19 infection. On Review of systems, she had diarrhea but denied perioral or extremity paresthesia, palpitations, muscle spasms and bone pain. She reported compliance with calcitriol and calcium supplements at home. She had short stature, round face, short neck, obesity, brachydactyly (short digits of right 4th and 5th fingers) and shortened left 4th metacarpal. Labs revealed corrected serum calcium from baseline of 7.8 mg/dL to 4.4 mg/dL, ionized calcium 2.9 mg/dL, vitamin D 12.8ng/ml, PTH 142pg/ml and phosphorus 6.2mg/dl. EKG showed T wave inversions and prolonged QT interval. She did not have tetany, carpopedal spasm, paresthesia, Chvostek's sign, or Trousseau's sign. After receiving a total of 11 grams of elemental calcium, calcitriol, and ergocalciferol, her corrected calcium level improved to 7.4 mg/dL and EKG normalized. She was discharged home with calcium carbonate 1,250 mg twice a day and calcitriol 0.5 mcg daily. Discussion PHP type 1A is an autosomal dominant mutation of the stimulatory G protein alpha subunit (G alpha or GNAS) derived from the mother due to genomic imprinting which leads to PTH resistance in the kidneys and parathyroid glands. Our patient had a long-standing history of mild hypocalcemia with calcium and calcitriol supplements. Sudden worsening of hypocalcemia was likely related poor calcium and calcitriol absorption induced by COVID-19 infection. Patient with chronic hypocalcemia may not present with typical hypocalcemia signs or symptoms due to their tolerance. Conclusion Clinicians should be aware of the risk of developing severe hypocalcemia in patients who are calcium dependent or vitamin D deficient, malnourished during critical illness, or have COVID-19 infection which may decrease serum albumin and reduce total serum calcium level. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Vitamin D Deficiency Mimicking Pseudohypoparathyroidism Type II in an Adolescent Boy: A Case Report

Background: Vitamin D deficiency in children is common and usually characterized by hypocalcemia, hypophosphatemia, and elevated serum parathyroid hormone level. However, vitamin D deficiency can be associated with parathyroid hormone resistance in the kidneys which may cause hyperphosphatemia instead, mimicking thus pseudohypoparathyroidism type II. The exact pathogenesis for parathyroid hormone resistance remains unclear, and the distinction between the two conditions remains difficult. We describe the case of an adolescent who presented with seizures and was found to have biochemical features consistent with pseudohypoparathyroidism, likely related to vitamin D deficiency. Case Report: A 13-year-old previously healthy adolescent presented with seizures. He experienced back pain during the previous month prior to the presentation. He did not have features of Albright hereditary osteodystrophy. His laboratory studies were significant for hypocalcemia, hyperphosphatemia, elevated serum alkaline phosphatase level, elevated parathyroid hormone level, and a deficient vitamin D level. Magnetic resonance imaging of the spine revealed multiple compression fractures. The child was treated with intravenous calcium and vitamin D administration with rapid improvement and his seizures resolved. Conclusion: Hypocalcemia from vitamin D deficiency can mimic pseudohypoparathyroidism type II. The principles of treatment for hypocalcemia in both conditions are similar and patients require timely intervention with close follow-up to ensure the resolution of symptoms. Patients with resolution of symptoms after adequate treatment may not require further evaluation for other types of pseudohypoparathyroidism.

Research on biochemical indexes of bone metabolism in bipolar disorder: A cross-sectional study with newly diagnosed, drug-naïve patients

BackgroundIn recent years, the metabolic abnormalities associated with bipolar disorder (BD) have attracted people's attention. However, clinical studies on bone metabolism in individuals with BD are unavailable. This study was designed to assess biochemical indexes of bone metabolism and related influencing factors. MethodsWe measured bone turnover markers (BTMs), including procollagen Ⅰ N-terminal propeptide (PⅠNP), osteocalcin (OC) and C-terminal cross-linking telopeptide of type I collagen (CTX-I), and index of calcium and phosphorus metabolism in 100 drug-naïve individuals with BD (DSM-5) and 91 healthy volunteers. Besides, sociodemographic and clinical assessment were collected. Between-group comparisons and within subgroup analysis were performed. ResultsThe PⅠNP (t = 3.715, p < 0.001), OC (t = 2.117, p = 0.036), parathyroid hormone (PTH, t = 3.877, p < 0.001), vitamin D (t = 2.065, p = 0.041), insulin (t = 4.208, p < 0.001) and insulin resistance (t = 2.888, p = 0.004) levels in the drug-naive BD group was significantly higher than those in the healthy control (HC) group. The level of calcium (t = −2.124, p = 0.035) in the drug-naive BD group was significantly lower than that of the HC group. But OC and vitamin D loses statistical significance after Bonferroni correction. However, there was no significant difference in the CTX-I level between the two groups. There are gender differences in the level of BMTs in individuals with BD, but this phenomenon was not found in the HC subgroup. It is shown that diagnosed BD, gender, age and BMI may affect the PINP levels through multiple linear regression analysis. ConclusionThe biochemical indexes of bone metabolism in drug-naive individuals with BD were more active than that of the healthy controls in a sample from the Chinese Han nationality. The finding provides new evidence for our understanding of bone metabolism in individuals with BD.

Tertiary hyperparathyroidism in patients with pseudohypoparathyroidism type 1a

Pseudohypoparathyroidism type 1a (PHP1a) is a genetic disorder caused by heterozygous loss-of-function mutations on the maternal allele of the GNAS gene. Patients with PHP1a predominantly exhibit parathyroid hormone (PTH) resistance and physical features of Albright's hereditary osteodystrophy. We report two unrelated cases with PHP1a who developed tertiary hyperparathyroidism (HPT). Molecular analyses of the GNAS gene identified a previously known heterozygous 4-bp deletion (c. 565_568delGACT) in exon 7 in case 1 and a novel heterozygous missense mutation (p.Lys233Glu) in exon 9 in case 2. Both patients developed tertiary HPT associated with hyperfunctioning parathyroid glands during long-term treatment of hypocalcemia. Case 1 had severe osteoporosis and underwent parathyroidectomy. Case 2 was asymptomatic with no evidence of bone diseases associated with tertiary HPT. PHP1a patients are at risk of developing tertiary HPT and should be treated with sufficient doses of calcium and vitamin D to achieve serum PTH levels within the mid - normal to double the upper limit of the normal range, regardless of serum calcium levels.

Clinical and genetic analysis of pseudohypoparathyroidism complicated by hypokalemia: a case report and review of the literature

BackgroundPseudohypoparathyroidism (PHP) encompasses a highly heterogenous group of disorders, characterized by parathyroid hormone (PTH) resistance caused by mutations in the GNAS gene or other upstream targets. Here, we investigate the characteristics of a female patient diagnosed with PHP complicated with hypokalemia, and her family members.Case presentation and gene analysisA 27-year-old female patient occasionally exhibited asymptomatic hypocalcemia and hypokalemia during her pregnancy 1 year ago. Seven months after delivery, she experienced tetany and dysphonia with diarrhea. Tetany symptoms were relieved after intravenous calcium gluconate supplementation and she was then transferred to our Hospital. Laboratory assessments of the patient revealed hypokalemia, hypocalcemia and hyperphosphatemia despite elevated PTH levels. CT scanning of the brain revealed globus pallidus calcification. Possible mutations in GNAS and hypokalemia related genes were identified using WES, exon copies of STX16 were analized by MLPA and the methylation status of GNAS in three differential methylated regions (DMRs) was analyzed by methylation-specific polymerase chain reaction, followed by confirmation with gene sequencing. The patient was clinically diagnosed with PHP-1b. Loss of methylation in the A/B region and hypermethylation in the NESP55 region were detected. No other mutations in GNAS or hypokalemia related genes and no deletions of STX16 exons were detected. A negative family history and abnormal DMRs in GNAS led to a diagnosis of sporadic PHP-1b of the patient.ConclusionsHypokalemia is a rare disorder associated with PHP-1b. Analysis of genetic and epigenetic mutations can aid in the diagnosis and accurate subtyping of PHP.

Evaluating the variety of GNAS inactivation disorders and their clinical manifestations in 11 Chinese children

BackgroundThe GNAS gene on chromosome 20q13.3, encodes the alpha-subunit of the stimulatory G protein, which is expressed in most tissues and regulated through reciprocal genomic imprinting. Disorders of GNAS inactivation produce several different clinical phenotypes including pseudohypoparathyroidism (PHP), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). The clinical and biochemical characteristics overlap of PHP subtypes and other related disorders presents challenges for differential diagnosis.MethodsWe enrolled a total of 11 Chinese children with PHP in our study and analyzed their clinical characteristics, laboratory results, and genetic mutations.ResultsAmong these 11 patients, nine of them (9/11) presented with resistance to parathyroid hormone (PTH); and nine (9/11) presented with an Albright′s hereditary osteodystrophy (AHO) phenotype. GNAS abnormalities were detected in all 11 patients, including nine cases with GNAS gene variations and two cases with GNAS methylation defects. These GNAS variations included an intronic mutation (c.212 + 3_212 + 6delAAGT), three missense mutations (c.314C > T, c.308 T > C, c.1123G > T), two deletion mutations (c.565_568delGACT*2, c.74delA), and two splicing mutations (c.721 + 1G > A, c.432 + 1G > A). Three of these mutations, namely, c.314C > T, c.1123G > T, and c.721 + 1G > A, were found to be novel. This data was then used to assign a GNAS subtype to each of these patients with six cases diagnosed as PHP1a, two cases as PHP1b, one as PPHP, and two as POH.ConclusionsEvaluating patients with PTH resistance and AHO phenotype improved the genetic diagnosis of GNAS mutations significantly. In addition, our results suggest that when GNAS gene sequencing is negative, GNAS methylation study should be performed. Early genetic detection is required for the differential diagnosis of GNAS disorders and is critical to the clinician’s ability to distinguish between heterotopic ossification in the POH and AHO phenotype.

Parathyroid Hormone Resistance and Autoantibodies to the PTH1 Receptor

SummaryWe describe two cases of acquired parathyroid hormone (PTH) resistance consequent to the development of serum PTH type 1 receptor (PTH1R) autoantibodies, which block PTH binding and signaling. Both cases were associated with other autoimmune manifestations, and one case was associated with atypical membranous glomerulonephritis. In vitro binding and signaling assays identified the presence of PTH1R-blocking IgG autoantibodies, which were not present in serum samples from patients with other renal or autoimmune disorders. (Funded by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and others.)

Lack of GNAS Remethylation During Oogenesis May Be a Cause of Sporadic Pseudohypoparathyroidism Type Ib.

Pseudohypoparathyroidism type Ib (PHP1B) is characterized by hypocalcemia and hyperphosphatemia due to parathyroid hormone resistance in the proximal renal tubules. Maternal pathogenic STX16/GNAS variants leading to maternal epigenetic GNAS changes impair expression of the stimulatory G protein alpha-subunit (Gsα) thereby causing autosomal dominant PHP1B. In contrast, genetic defects responsible for sporadic PHP1B (sporPHP1B) remain mostly unknown. Determine whether PHP1B encountered after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) causes GNAS remethylation defects similar to those in sporPHP1B. Retrospective analysis. Nine among 36 sporPHP1B patients investigated since 2000, all with loss of methylation (LOM) at the 3 maternal GNAS differentially methylated regions (DMRs) and gain of methylation at the paternal NESP DMR, had been conceived through IVF or ICSI. Besides abnormal GNAS methylation, IVF/ICSI PHP1B cases revealed no additional imprinting defects. Three of these PHP1B patients have dizygotic twins, and 4 have IVF/ICSI-conceived siblings, all with normal GNAS methylation; 2 unaffected younger siblings were conceived naturally. Sporadic and IVF/ICSI-conceived PHP1B patients revealed indistinguishable epigenetic changes at all 4 GNAS DMRs, thus suggesting a similar underlying disease mechanism. Given that remethylation at the 3 maternal DMRs occurs during oogenesis, male factors are unlikely to cause LOM postfertilization. Instead, at least some of the sporPHP1B variants could be caused by a defect or defects in an oocyte-expressed gene that is required for fertility and for re-establishing maternal GNAS methylation imprints. It remains uncertain, however, whether the lack of GNAS remethylation alone and the resulting reduction in Gsα expression is sufficient to impair oocyte maturation.

Progression of PTH Resistance in Autosomal Dominant Pseudohypoparathyroidism Type Ib Due to Maternal STX16 Deletions.

Maternally inherited STX16 deletions that cause loss of methylation at GNAS exon A/B and thereby reduce Gsα expression are the most frequent cause of autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP1B). Early identification of these disease-causing variants in the children of affected and unaffected female carriers would prompt treatment with calcium and calcitriol once parathyroid hormone (PTH) levels increase, thereby preventing hypocalcemia and associated complications. This study aimed to determine when PTH and calcium abnormalities develop after birth if a STX16 deletion is inherited maternally. Forty-four children of affected (n = 7) or unaffected (n = 7) females with a STX16 deletion were investigated for the presence of these variants. If a deletion was identified, measurement of PTH, calcium, phosphate, and thyrotropin (TSH) was advised. The STX16 deletion that causes AD-PHP1B was identified in 25 children. Pretreatment laboratory results were available for 19 of those cases. Elevated PTH levels were detected by 2 years of age, and these were progressively higher if laboratory testing was first performed after establishing the genetic defect later in life. Total serum calcium levels remained within normal limits until about 5 years of age. TSH levels showed no consistent rise over time. Establishing whether a STX16 deletion is inherited from a female carrier of a disease-causing variant rapidly establishes the diagnosis of AD-PHP1B. Several years before overt hypocalcemia developed, PTH levels increased, thereby establishing the onset of PTH resistance. Our findings provide diagnostic guidance and when treatment with calcium and calcitriol should be considered in order to prevent hypocalcemia and associated sequelae.

Mild progressive osseous heteroplasia overlap syndrome with PTH and TSH resistance appearing during adolescence and not early childhood

Progressive osseous heteroplasia (POH), a genetic disorder, is associated with Albright's hereditary osteodystrophy (AHO), pseudohypoparathyroidism, and primary osteoma cutis and has common features of superficial ossification and GNAS-inactivating mutations. Disorders due to GNAS-inactivating mutations are classified as "inactivating parathyroid hormone (PTH)/PTHrP signaling disorder type 2." This study reports a case of mild POH overlap syndrome to improve understanding of genotype-phenotype correlations. A 13-year and 6-month-old Japanese boy was referred to our hospital with a chief complaint of the lower limb length difference. He underwent clinical, biochemical, radiological, and genetic studies. He showed sporadic GNAS mutation, deep ectopic ossification, small for gestational age (SGA), congenital tooth defect, and lack of AHO features; he met the diagnostic criteria for POH, and mild PTH and TSH resistance was detected. He had constant hyperphosphatasemia and hypocalciuria. At the age of 10 years, he occasionally experienced high iPTH levels. The pituitary stimulation test showed a normal response of all hormones at 3 years of age, but TSH response was decreased (previously 0.770, peak value 4.144 μIU/mL) in the TRH loading test at age 13 years and 6 months. DNA analysis showed a heterozygous p.D189MfsTer14 mutation of GNAS. The parents did not carry this mutation. We report a rare case of POH overlap syndrome with PTH/TSH resistance that appeared in adolescence rather than early childhood. Cases diagnosed with POH in early childhood also require reassessment during adolescence. Further studies of the GNAS heterozygous mutation p.D189MfsTer14 may reveal factors involved in POH overlap syndrome.

PTH resistance

Parathyroid hormone (PTH), which is primarily regulated by extracellular calcium changes, controls calcium and phosphate homeostasis. Different diseases are derived from PTH deficiency (hypoparathyroidism), excess (hyperparathyroidism) and resistance (pseudohypoparathyroidism, PHP). Pseudohypoparathyroidism was historically classified into subtypes according to the presence or not of inherited PTH resistance associated or not with features of Albright's hereditary osteodystrophy and deep and progressive ectopic ossifications. The growing knowledge on the PTH/PTHrP signaling pathway showed that molecular defects affecting different members of this pathway determined distinct, yet clinically related disorders, leading to the proposal of a new nomenclature and classification encompassing all disorders, collectively termed inactivating PTH/PTHrP signaling disorders (iPPSD).