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Abstract Disclosure: R.I. Gafni: Calcilytix Therapeutics. I.R. Hartley: Calcilytix Therapeutics. K.L. Roszko: Calcilytix Therapeutics. E.F. Nemeth: Calcilytix Therapeutics. K. Pozo: Calcilytix Therapeutics. R. Meadows: Calcilytix Therapeutics. E. Ferguson: Calcilytix Therapeutics. A. Mathew: Calcilytix Therapeutics. M. Roberts: Calcilytix Therapeutics. S. Adler: Calcilytix Therapeutics. M.T. Collins: Calcilytix Therapeutics. Autosomal dominant hypocalcemia type 1 (ADH1), due to activating calcium-sensing receptor gene (CASR) variants, manifests as low PTH, hypocalcemia, hypercalciuria, hyperphosphatemia and hypomagnesemia. Calcium and active vitamin D treatment worsens hypercalciuria, which may result in renal morbidity. Calcilytics are negative allosteric modulators of the calcium-sensing receptor (CaSR) that decrease the sensitivity of hyperactive receptors to extracellular calcium and normalize biochemical abnormalities in ADH1 mouse models. This Phase 2b open-label study (NCT04581629) of the oral investigational calcilytic encaleret included 2 5d inpatient periods followed by a 24W outpatient period and then a long-term extension (LTE). Conventional therapy was stopped prior to encaleret initiation. After about 18 months in Phase 2b LTE, participants continued encaleret treatment in the CALIBRATE study LTE (NCT05680818). Thirteen adults with ADH1 were enrolled and encaleret was individually titrated to normalize albumin-corrected calcium (cCa). Encaleret was well-tolerated. There were 2 unrelated serious adverse events during the LTE: chest pain and post-surgical pain. There were no treatment discontinuations or withdrawals prior to the LTE; one participant withdrew during the LTE for family planning but subsequently re-enrolled without an intervening pregnancy. Mean±SD values taken pre-dose at P3W24 and LTEM36 compared to baseline (BL) are presented. PTH levels were low at BL (6.3±7.8 pg/mL [nl 10-65]) and normal at P3W24 (35.3±10.2) and LTEM36 (23.7±16.8 [p<0.01]). Similarly, hypocalcemia at BL (cCa=7.1±0.4 mg/dL [nl 8.4-10.2]) had normalized at P3W24 (9.0±0.5) and LTEM36 (9.0±0.3 [p<0.01]). BL hypercalciuria (395±216 mg/d [nl <250-300]) normalized to 202±83 at P3W24 and LTEM36 (162±103 [p<0.01]). BL blood phosphate (4.5±1.1 mg/dL [nl 2.3-4.7]) decreased at P3W24 (3.7±0.5) and LTEM36 (3.7±0.7 [p<0.05]). Blood magnesium rose (BL 1.7±0.2 mg/dL [nl 1.6-2.6]); P3W24 2.0±0.2; LTEM36 2.0±0.2 [p<0.01]). Bone turnover markers, adjusted for age, sex, and menopausal status by dividing by the upper limit of normal for each participant [nl 0-1], were low at BL (CTX=0.4±0.3; P1NP=0.3±0.1) and increased at P3W24 (CTX=1.15±1.0; P1NP=1.22±1.05) and LTEM36 (CTX=0.71±0.53; P1NP=1.37±0.98 [p<0.05; p<0.01]). Compared with screening, DXA Z-scores had decreased at LTEM24 but stabilized at LTEM36 (AP spine Z=2.6±1.5→2.2±1.6→2.2±1.6; Total hip Z=2.2±1.4→1.8±1.1→1.7±1.1; 1/3 radius Z=0.2±0.9→ -0.2±0.4→ -0.1±0.5, n=10-11 [p<0.05]). In patients with ADH1, encaleret corrected biochemical abnormalities and increased bone turnover, with stabilization of bone density by 42 months of continuous treatment. These consistent and sustained results are clinically meaningful and support ongoing efficacy and safety evaluation of encaleret as the first potential treatment for ADH1. Presentation: Monday, July 14, 2025

Abstract Disclosure: M.H. Alabdely: None. A.A. Khan: None. Background: Autosomal dominant hypocalcemia (ADH) type 1 and type 2 are rare disorders caused by gain-of-function variants that activate the calcium sensing receptor (CASR) gene, leading to ADH type 1, or its signaling protein Guanine nucleotide-binding protein subunit alpha-11 (GNA11), resulting in ADH type 2. These disorders are inherited in an autosomal dominant pattern and are characterized by hypoparathyroidism, manifesting as hypocalcemia, inappropriately low serum parathyroid hormone (PTH) concentrations and hypercalciuria due to enhanced sensitivity of the CaSR to extracellular calcium concentrations. Clinical features range from asymptomatic to severe. Treatment with calcium and active vitamin D can exacerbate hypercalciuria and nephrocalcinosis. Alternative treatment options that have been used in patients with ADH1 include recombinant human PTH or calcilytic therapy. Here, we describe a male patient with ADH2 harboring a novel GNA11 variant, evaluated at our tertiary center in Canada.Case summary:A 43-year-old male experienced intermittent numbness in hands for 3 years prior to presentation; in association with exercise. Other manifestations include bronchospasm and laryngospasm triggered by wrestling or climbing 2-3 flights of stairs, over the past 15 years. He had no peri oral numbness, muscle spasm, seizures, arrhythmias, brain fog, kidney stones, fractures or osteoporosis. Additionally, he had no clinical features features suggestive of genetic or autoimmune disorders resulting in hypoparathyroidism. There was no history of neck surgery or a family history of endocrine or autoimmune disease. In April 2024, he was incidentally found to have low calcium levels. By July 2024, he was found to have low PTH levels as well as persistently low calcium levels. Medical examination was unremarkable and Chvostek’s sign was negative. Laboratory tests revealed low corrected calcium (1.98 mmol/L, NR: 2.15-2.60), and low or inappropriately normal PTH (2.2 pmol/L, NR:1.6-9.3) on two occasions. The serum phosphorus was (1.03 mmol/L, NR: 0.81-1.45), serum magnesium (0.88 mmol/L, NR: 0.65-1.05), 25OHD (83 nmol/L, NR: 75-250), ALP (56 IU/L, NR: 30-129) and 24 hr urine for calcium collection was inadequate.Genetic testing confirmed a heterozygous variant of uncertain significance (VUS) in GNA11 gene c.1-12C>T pArg338Cys which has not been previously reported. The clinical picture is consistent with ADH2. The patient was started on calcium carbonate 500 mg three times daily with meals with follow up in 4 weeks. Conclusion: We report a male patient with hypoparathyroidism who was found to have a novel VUS in GNA 11 gene. This variant could be pathogenic, as the patient presents with a phenotype consistent with ADH2. To date, six different gain-of-function variants in the GNA11 have been identified. An important contribution to the Literature is identifying several variants in ADH2. Presentation: Saturday, July 12, 2025

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

There are several studies in which a correlation between maternal vitamin D deficiency and serum mineral disorders in the mother and the newborn has been reported. The present randomised clinical trial was designed to investigate the effect of vitamin D administration on maternal and fetal Ca and vitamin D status. The trial was carried out on 160 pregnant women. Vitamin D-deficient (25-hydroxyvitamin D (25(OH)D) < 30 ng/ml) pregnant women were recruited at 26–28 weeks of pregnancy. In the control group, a multivitamin supplement containing 400 IU vitamin D3/d was given. Patients in the treatment group were treated with 50 000 IU vitamin D3 weekly for a total duration of 8 weeks. At delivery, maternal and fetal Ca and 25(OH)D levels in both groups were compared. In total, 81 % of pregnant women were vitamin D deficient. At the time of delivery, Ca and vitamin D levels were higher in the treatment group compared with the control group (92 (sd 3) v. 85 (sd 4) mg/l, respectively, P= 0·001 for serum Ca; 47·8 (sd 11·1) v. 15·9 (sd 6·6) ng/ml, respectively, P< 0·001 for vitamin D). At the time of delivery, 32·7 % of women in the control group had hypocalcaemia, while no hypocalcaemic case was detected in the vitamin D-treated group. Mean neonatal serum 25(OH)D was higher in the treatment group compared with the control group (27·7 (sd 5·2) v.10·9 (sd 4·4) ng/ml, respectively, P< 0·01). The neonatal Ca level in the treatment group was significantly higher than that of the control group (99 (sd 3) v. 91 (sd 3) mg/l, respectively, P< 0·001). The administration of vitamin D to pregnant women with vitamin D deficiency improves both maternal and neonatal Ca levels.

The Ca2+-sensing receptor (CaSR) is a dimeric family C G protein-coupled receptor that is expressed in calcitropic tissues such as the parathyroid glands and the kidneys and signals via G proteins and β-arrestin. The CaSR has a pivotal role in bone and mineral metabolism, as it regulates parathyroid hormone secretion, urinary Ca2+ excretion, skeletal development and lactation. The importance of the CaSR for these calcitropic processes is highlighted by loss-of-function and gain-of-function CaSR mutations that cause familial hypocalciuric hypercalcaemia and autosomal dominant hypocalcaemia, respectively, and also by the fact that alterations in parathyroid CaSR expression contribute to the pathogenesis of primary and secondary hyperparathyroidism. Moreover, the CaSR is an established therapeutic target for hyperparathyroid disorders. The CaSR is also expressed in organs not involved in Ca2+ homeostasis: it has noncalcitropic roles in lung and neuronal development, vascular tone, gastrointestinal nutrient sensing, wound healing and secretion of insulin and enteroendocrine hormones. Furthermore, the abnormal expression or function of the CaSR is implicated in cardiovascular and neurological diseases, as well as in asthma, and the CaSR is reported to protect against colorectal cancer and neuroblastoma but increase the malignant potential of prostate and breast cancers.

Objective To analyze the risk factors associated with the development of severe hypocalcemia (SH) in patients who have undergone parathyroidectomy (PTX). Methods This research involved patients with chronic kidney disease–secondary hyperparathyroidism who underwent PTX between June 1, 2021, and May 31, 2023. SH was characterized by a serum total calcium (tCa) level below 1.8 mmol/L. This study aimed to analyze differences in preoperative laboratory findings and clinical manifestations between patients with and without SH. Logistic regression analysis was used to identify potential risk factors associated with the development of SH. Results The incidence of SH was 23% ( n  = 176). Significant differences were observed in free thyroxine (FT4), free triiodothyronine, alanine aminotransferase, osteocalcin, tCa, alkaline phosphatase (ALP), C-terminal cross-linked telopeptide of type I collagen, and parathyroid hormone between the SH and non-SH groups. The three independent risk factors for SH were tCa [odds ratio ( OR ) 0.063, 95% confidence interval ( 95% CI ) 0.006–0.663], ALP ( OR 1.003, 95% CI 1.001–1.005), and FT4 ( OR 0.439, 95%CI 0.310–0.621). The area under the curve, sensitivity, specificity, and overall accuracy of this model were 0.904 ( 95% CI 0.856–0.952), 46.3%( 95% CI 32.0%-61.3%), 94.8% ( 95% CI 89.7%-97.5%), and 83.5% ( 95% CI 77.3%-88.3%), respectively. Conclusion The preoperative level of FT4 plays a crucial role in predicting the risk of SH after PTX. The combined FT4–ALP–tCa model demonstrates the ability to predict SH risk, providing valuable insights for customizing calcium supplementation strategies and improving clinical decision-making.

Abstract Disclosure: M. Lopez Baez: None. A. Szeinfeld: None. C. Sanchez Perez: None. Y. Benitez: None. S. Hanson-Leal: None. Hypocalcemia is a common finding in acute pancreatitis, with prevalence rates ranging from 15% to 88% in critically ill patients, depending on the setting and diagnostic criteria used. In this case, a 46-year-old female with a history of mixed hyperlipidemia and recurrent pancreatitis presented with left flank pain. Acute pancreatitis was confirmed by an elevated lipase level (3811 U/L) and evidence of pancreatic inflammation on contrast-enhanced CT. Triglycerides were markedly elevated (>1575 mg/dL, exceeding assay limits), and corrected calcium was low at 7.7 mg/dL. Within hours, she developed perioral numbness and tingling in her extremities. During a subsequent clinical assessment, a spontaneous Trousseau’s sign was observed—carpopedal spasm occurring without blood pressure cuff inflation—raising immediate suspicion of worsening hypocalcemia. Arterial blood gas analysis confirmed a profoundly reduced ionized calcium level of 0.77 mmol/L.Recognizing the severity of the metabolic disturbance, the patient was promptly transferred to the intensive care unit for emergent intravenous calcium replacement and an insulin infusion for hypertriglyceridemia management. The presence of spontaneous Trousseau’s sign served as a crucial bedside indicator of life-threatening hypocalcemia, allowing for timely intervention and prevention of further complications.This case underscores the importance of early recognition of severe hypocalcemia in acute pancreatitis. The observation of Trousseau’s sign without external provocation highlights its potential as a critical clinical finding warranting urgent correction. A multidisciplinary approach, including endocrinology and critical care teams, was pivotal in ensuring a favorable outcome. Increased awareness of spontaneous Trousseau’s sign in patients with pancreatitis may improve timely diagnosis and management, reducing morbidity and improving prognosis. Presentation: Saturday, July 12, 2025

Abstract Disclosure: T. Prazeres: None. S. Tariq: None. T. Rave: None. H.D. Sacoto: None. R. Belokovskaya: None. A. Franco-Akel: None. Pseudohypoparathyroidism (PHP) is a rare disorder that affects around 0.79 per 100,000 individuals. It is characterized by organ resistance to parathyroid hormone (PTH) due to a GNAS gene mutation. This can result in low calcium, high phosphorus, and high PTH levels at a young age, which can lead to bone fractures, seizures, or tetany. We present a 42-year-old female known to have PHP after presenting with hypocalcemic seizures at the age of 2. During childhood, she had multiple pathologic fractures and a bilateral hip fracture requiring surgery at the age of 9. She was initially treated with calcitriol but had inconsistent care for more than 10 years. When the patient returned to care, she presented with asymptomatic severe hypocalcemia - 6.7 mg/dL [8.4 - 10.5 mg/dL] and 25-hydroxy vitamin D (VitD25OH) deficiency - 17.2 ng/mL [30 - 80 ng/mL], markedly elevated PTH - 657 pg/mL [15 - 65 pg/mL], hyperphosphatemia - 5.0 mg/dL [2.5 - 4.5 mg/dL], subclinical hypothyroidism (TSH 4.37 uIU/mL [0.27 - 4.20 uIU/mL] with normal free T4). She was clinically euthyroid, with a regular menstrual history, and denied seizures, paresthesia, arthralgia, recent fractures, or a family history of similar disorders. Her BMI was 29.6 kg/m2, with a normal stature and phenotype, no dysmorphism, or signs of osteodystrophy. Treatment was resumed with calcium carbonate, calcitriol, and ergocalciferol, and the patient was referred to genetic medicine for further testing. On follow up VitD 25OH levels improved, and TSH normalized without any treatment, however, she had persistent severe hypocalcemia - 7.7 mg/dL and elevated PTH - 525 pg/mL, even with escalating therapy. She is currently being treated with a total daily amount of 7500 mg of calcium carbonate (elemental calcium 3000 mg), 1 mcg of calcitriol, and 4000 IU of VitD25OH. This case underscores the importance of consistent follow-up in PHP, where gaps in care can lead to severe, persistent biochemical imbalances and increased therapeutic complexity. It reminds us that hypocalcemia should be considered in cases of seizure and bone fractures. The latter is associated with such severe hypocalcemia that very few cases are described, making this case even more unique. Lastly, a detailed history, clinical features, and laboratory tests help suggest that this case can be a type 1B PHP, however, a genetic workup is essential to confirm the definitive diagnosis and provide management guidance. Presentation: Sunday, July 13, 2025

Abstract Disclosure: A. Shahatit: None. A. Banka: None. L. De Mattei: None. B. Celik: None. J. Meireles: None. U. Bin Hameed: None. Introduction: Pseudohypoparathyroidism (PHP) is a rare disorder marked by end-organ resistance to parathyroid hormone (PTH), leading to hypocalcemia and hyperphosphatemia despite elevated PTH. Chronic PHP may result in basal ganglia calcifications (BGC), contributing to neurological complications. Case Presentation: A 44-year-old man with hypertension, hypothyroidism, and prior strokes with residual aphasia and right-sided weakness was referred for severe hypocalcemia. On exam, he had short stature. Labs showed: calcium 4.8 mg/dL (normal: 8.5-10.5), ionized calcium 2.53 mg/dL (4.6-5.3), phosphorus 6.7 mg/dL (2.5-4.5), PTH 218 pg/mL (10-65), vitamin D 66.2 ng/mL (30-100), creatinine 0.87 mg/dL (0.6-1.2), and TSH 9.98 µIU/mL (0.4-4.0). Head CT revealed extensive calcifications in the posterior fossa, deep gray nuclei, subcortical frontal and temporal lobes, and subcutaneous scalp tissues. The patient reported lifelong hypocalcemia and prior imaging showing brain calcifications. He was non-adherent to levothyroxine.He was treated with IV calcium gluconate followed by oral calcium citrate, calcitriol, and levothyroxine. Calcium normalized (to 8.0 mg/dL), and he was discharged on calcium carbonate, calcitriol, and levothyroxine with endocrinology and neurology follow-up. Discussion: This case highlights classic PHP features: hypocalcemia, hyperphosphatemia, elevated PTH, and extensive tissue calcifications. BGC in PHP is linked to seizures, movement disorders, and cognitive deficits. Coexisting hypothyroidism may reflect TSH resistance, often seen in PHP Type 1a due to GNAS mutations, which impair Gs alpha protein signaling in multiple hormone pathways. Learning Points:Suspect PHP with hypocalcemia, hyperphosphatemia, and high PTH in the setting of normal renal function.Intracranial and subcutaneous calcifications may signal long-standing disease.PHP Type 1a may include TSH resistance and other hormone resistance syndromes.Lifelong calcium and active vitamin D therapy is essential. Conclusion: This case emphasizes the importance of recognizing PHP early to prevent irreversible neurologic complications and highlights diagnostic clues from labs and imaging. Presentation: Saturday, July 12, 2025