RARE DISEASE
Autosomal dominant hypocalcemia
Autosomal dominant hypocalcemia
Autosomal dominant hypocalcemia
Synonyms: AD hypocalcemia
Synonyms: AD hypocalcemia
Synonyms: AD hypocalcemia
Drug discovery
1
drug
With orphan designation
Overview
Autosomal dominant hypocalcemia (ADH) is a genetic disorder caused by activating mutations in CASR (type 1) or GNA11 (type 2), leading to hypocalcemia, inappropriately low/normal PTH, hyperphosphatemia, and hypercalciuria. Symptoms range from asymptomatic presentations to neuromuscular irritability, seizures, and renal complications. Overactive calcium-sensing receptors suppress PTH secretion and promote urinary calcium excretion, increasing risks of nephrocalcinosis and chronic kidney disease [1][2][5][15].
Therapies
Conventional: Calcium supplements and activated vitamin D (e.g., calcitriol), but exacerbate hypercalciuria [3][8][15].
Emerging: Calcilytics (e.g., NPSP795) show promise in trials, increasing PTH and reducing urinary calcium [3][8][11].
Monitoring: Regular assessment of serum calcium, urinary calcium excretion, and renal imaging to mitigate complications [4][15].
Categories: rare endocrine diseases, rare genetic diseases, rare neurological diseases, rare ophthalmic disorders
Research Papers
167 drug discovery papers about Autosomal dominant hypocalcemia, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
167 drug discovery papers about Autosomal dominant hypocalcemia, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-05-21 | Continuous subcutaneous recombinant PTH(1-34) infusion improves serum calcium and phosphate homeostasis in children with autosomal dominant hypocalcemia type 1 refractory to standard-of-care treatment.
Autosomal dominant hypocalcemia type 1 (ADH1) results from activating CASR variants, causing parathyroid hormone (PTH) suppression and abnormal renal calcium handling. Management is challenging, as hypoparathyroidism is associated with inappropriate renal calcium wasting, leading to hypercalciuria, nephrocalcinosis, and renal impairment. We evaluated long-term outcomes of continuous subcutaneous PTH(1-34) infusion (CSPI) in children with ADH1 refractory to standard of care therapy (SOC). Single-center observational study. Five children with genetically confirmed ADH1 were treated with CSPI between 2012 and 2017 and followed for up to 11 years. Clinical outcomes, biochemical parameters, and renal findings were assessed under SOC and CSPI. Serum calcium, phosphate (standard deviation score, SDS), magnesium, alkaline phosphatase, eGFR, urinary calcium/creatinine ratio (relative to the age-specific 95th percentile), and fractional calcium excretion (FECa) were analyzed using linear mixed-effects models. Hypocalcemic seizures and emergency visits decreased, growth was appropriate, and no treatment-related adverse events occurred over a median 7-year follow-up. CSPI was associated with higher serum calcium (P < .001) and lower serum phosphate (P < .001). Urinary calcium/creatinine ratios, expressed relative to the age-specific 95th percentile, were lower under CSPI (P < .001). FECa was approximately 8% lower under CSPI (P = .014), suggesting improved renal calcium handling. Renal function remained stable despite progression of nephrocalcinosis in 4/5 patients. SPI appears to be a safe and effective long-term treatment in pediatric ADH1, improving mineral homeostasis and renal calcium handling. Prospective multicenter studies are needed to assess long-term skeletal outcomes and optimize dosing strategies.
2026-02-19 | Long-acting parathyroid hormone receptor agonist rectifies hypocalcemia in autosomal dominant hypocalcemia type 1 mice.
Eneboparatide, a long-acting modified form of parathyroid hormone, increases serum calcium levels without increasing urine calcium in mice with autosomal dominant hypocalcemia type 1.
2024-10-08 | Efficacy and Safety of TransCon PTH in Adults With Hypoparathyroidism: 52-Week Results From the Phase 3 PaTHway Trial.
Conventional therapy for hypoparathyroidism aims to alleviate symptoms of hypocalcemia but does not address insufficient parathyroid hormone (PTH) levels. Assess the long-term efficacy and safety of TransCon PTH (palopegteriparatide) for hypoparathyroidism. Phase 3 trial with a 26-week, double-blind, placebo-controlled period followed by a 156-week, open-label extension (OLE). Twenty-one sites across North America and Europe. A total of 82 adults with hypoparathyroidism were randomized and received study drug and 78 completed week 52. All OLE participants received TransCon PTH administered once daily. Multicomponent efficacy endpoint: proportion of participants at week 52 who achieved normal serum calcium (8.3-10.6 mg/dL) and independence from conventional therapy (≤600 mg/day of elemental calcium and no active vitamin D). Other efficacy endpoints included patient-reported outcomes and bone mineral density. Safety was assessed by 24-hour urine calcium and treatment-emergent adverse events. At week 52, 81% (63/78) met the multicomponent efficacy endpoint, 95% (74/78) achieved independence from conventional therapy, and none required active vitamin D. Patient-reported outcomes showed sustained improvements in quality of life, physical functioning, and well-being. Mean bone mineral density Z-scores decreased toward age- and sex-matched norms from baseline to week 52. Mean (SD) 24-hour urine calcium excretion decreased from 376 (168) mg/day at baseline to 195 (114) mg/day at week 52. Most treatment-emergent adverse events were mild or moderate and none led to trial discontinuation during the OLE. At week 52 of the PaTHway trial, TransCon PTH showed sustained efficacy, safety, and tolerability in adults with hypoparathyroidism.
2024-08-08 | Injection of luteinizing hormone or human chorionic gonadotropin increases calcium excretion and serum PTH in males.
Animal and human studies have suggested that sex steroids have calciotropic actions, and it has been proposed that follicle-stimulating hormone (FSH) may exert direct effects on bone. Here, we demonstrate the expression of the receptor for Luteinizing hormone (LH) and human choriogonadotropin (hCG), LHCGR, in human kidney tissue, suggesting a potential influence on calcium homeostasis. To investigate the role of LHCGR agonist on calcium homeostasis in vivo, we conducted studies in male mice and human subjects. Male mice were treated with luteinizing hormone (LH), and human extrapolation was achieved by injecting 5000 IU hCG once to healthy men or men with hypergonadotropic or hypogonadotropic hypogonadism. In mice, LH treatment significantly increased urinary calcium excretion and induced a secondary increase in serum parathyroid hormone (PTH). Similarly, hCG treatment in healthy men led to a significant increase in urinary calcium excretion, serum PTH levels, and 1,25 (OH)2D3, while calcitonin, and albumin levels were reduced, possibly to avoid development of persistent hypocalcemia. Still, the rapid initial decline in ionized calcium coincided with a significant prolongation of the cardiac QTc-interval that normalized over time. The observed effects may be attributed to LH/hCG-receptor (LHCGR) activation, considering the presence of LHCGR expression in human kidney tissue, and the increase in sex steroids occurred several hours after the changes in calcium homeostasis. Our translational study shed light on the intricate relationship between gonadotropins, sex hormones and calcium, suggesting that LHCGR may be influencing calcium homeostasis directly or indirectly.
2020-11-17 | Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
Gain-of-function mutations in the CASR gene cause Autosomal Dominant Hypocalcemia Type 1 (ADH1), the most common genetic cause of isolated hypoparathyroidism. Subjects have increased calcium sensitivity in the renal tubule, leading to increased urinary calcium excretion, nephrocalcinosis and nephrolithiasis when compared with other causes of hypoparathyroidism. The traditional approach to treatment includes activated vitamin D but this further increases urinary calcium excretion. In this case series, we describe the use of recombinant human parathyroid hormone (rhPTH)1-84 to treat subjects with ADH1, with improved control of serum and urinary calcium levels. We describe two children and one adult with ADH1 due to heterozygous CASR mutations who were treated with rhPTH(1-84). Case 1 was a 9.4-year-old female whose 24-h urinary calcium decreased from 7.5 to 3.9 mg/kg at 1 year. Calcitriol and calcium supplementation were discontinued after titration of rhPTH(1-84). Case 2 was a 9.5-year-old male whose 24-h urinary calcium decreased from 11.7 to 1.7 mg/kg at 1 year, and calcitriol was also discontinued. Case 3 was a 24-year-old female whose treatment was switched from multi-dose teriparatide to daily rhPTH(1-84). All three subjects achieved or maintained target serum levels of calcium and normal or improved urinary calcium levels with daily rhPTH(1-84) monotherapy. We have described three subjects with ADH1 who were treated effectively with rhPTH(1-84). In all cases, hypercalciuria improved by comparison to treatment with conventional therapy consisting of calcium supplementation and calcitriol.
small molecules
2026-06-01 | Clinical and genetic insights into Autosomal Dominant Hypocalcemia type 1: a single-center case series including genotype-phenotype correlations, pregnancy outcomes, and novel CASR variants.
The main purpose of this study was to provide a comprehensive characterization of adult patients with Autosomal Dominant Hypocalcemia type 1 (ADH1), focusing on clinical and biochemical features, with particular attention to renal involvement, skeletal features and ectopic calcifications. The secondary aims were to explore potential genotype-phenotype correlations, describe two previously unreported CASR variants, and report pregnancy outcomes in affected women. We conducted a retrospective, single-centre study of 11 adults with genetically confirmed ADH1 followed at a tertiary Endocrinology Unit between March 2012 and May 2025. Clinical presentation, biochemical data, renal and cerebral involvement, skeletal status and treatment history were collected at first evaluation and during follow-up. CASR variants were identified by next-generation sequencing with Sanger confirmation, and genotype-phenotype relationships were explored. At diagnosis, 64% of patients reported hypocalcemia-related symptoms, while 36% were asymptomatic. Nephrolithiasis, nephrocalcinosis and basal ganglia calcifications were frequent, in patients exposed to long-term calcium and active vitamin D therapy, although causal relationships cannot be established. Axial BMD was normal or increased, whereas radial BMD was often reduced and bone turnover markers were low-normal; no fragility fractures were documented. We identified two novels CASR missense variants and observed marked intra- and interfamilial variability. Four pregnancies in three women with ADH1 resulted in favourable maternal and neonatal outcomes. In our ADH1 patients we found a wide clinical variability, from asymptomatic hypocalcemia to severe early-onset disease, with a high burden of renal complications and ectopic calcifications. Genotype alone does not fully predict clinical severity, even for the same CASR variant. Pregnancies can have good outcomes under close biochemical monitoring and tailored therapy but should be managed as high-risk.
2026-02-13 | Peri-kidney transplant management in autosomal dominant hypocalcaemia type 1.
Autosomal dominant hypocalcaemia type 1 is rare and clinically challenging. Altered calcium handling may lead to progressive nephrocalcinosis and chronic kidney disease. We present the first known report of a child with ADH1 caused by the genetic variant c.2528C > A; p.Ala843Glu, who successfully underwent kidney transplantation without simultaneous parathyroid gland transplant aged 11yrs. We outline our reasoning for this and our management strategy for maintaining calcium homeostasis post-transplant over a 4-year period.
2025-10-01 | MON-743 Autosomal Dominant Hypocalcemia Type 1 or Type 2: Baseline Characteristics of Pediatric Participants in the CLARIFY Disease Monitoring Study
Abstract Disclosure: J. Bacchetta: None. C. Jacobsen: None. T. Kubota: None. Autosomal dominant hypocalcemia type 1 (ADH1) and type 2 (ADH2) are rare disorders caused by activating variants of the CASR and GNA11 genes, respectively. The calcium-sensing receptor (CaSR) plays a critical role in calcium homeostasis by signaling parathyroid hormone (PTH) secretion and urinary calcium (uCa) reabsorption in response to variations in blood calcium. The CaSR signals by coupling to G-proteins, including GNA11-encoded Gα11. The CLARIFY disease monitoring study [NCT05227287] is an ongoing global, multicenter, longitudinal, observational study to characterize disease burden, management, and progression in children and adults with ADH1/2 over a 5-year period. Of 25 pediatric participants (birth to <18y) enrolled (Mar 2022 to Jun 2024), 22 were diagnosed with ADH1 and 3 with ADH2; 64% are females. Median age at enrollment was 9 years (IQR 5-13). Median age at hypocalcemia presentation and ADH1/2 diagnosis were 0.8 years (IQR 0.0-3.0) and 1.0 year (IQR 0.5-3.0), respectively. Family history of ADH1/2 was reported in 64% of participants. 16 unique CASR and 2 unique GNA11 variants were present, with CASR E767K (3) and F788C (3) the most frequent. Treatment regimen varied at baseline (Day 1 study visit): 32% (8) were on Ca and active vitamin D, 24% (6) on Ca alone, 8% (2) on active vitamin D alone, 20% (5) on PTH replacement, 20% (5) on magnesium, 12% (3) on thiazide diuretics, 12% (3) on potassium, 12% (3) on phosphate binder, 32% (8) on cholecalciferol, and 20% (5) without treatment. At baseline, 92% (23) had hypocalcemia (0-<1y <8.4 mg/dL; 1-17y <8.6 mg/dL), 83% (20) had low iPTH (<15 pg/mL), 84% (21) had hyperphosphatemia (0-<1y >7.8 mg/dL; 1-12y >6.0 mg/dL; 13-17y >4.8 mg/dL), 8% (2) had hypomagnesemia (<1.5 mg/dL), and 84% (21) had normal total 25-OH Vitamin D (20-50 ng/mL). 32% (6) of 19 participants with 24hr uCa collected were hypercalciuric (>4 mg/kg/day); and 0% of 5 participants with spot urine collections had Ca/Cr above the aged-defined reference range (7-18mo <0.60 mg/mg; 19mo – 6y <0.41 mg/mg; adults <0.21 mg/mg). Baseline eGFR by Schwartz equation was 117±25 mL/min/1.73m² (range: 69-175). Common (proxy) self-reported ADH1-related comorbidities were seizures (36%), nephrocalcinosis (32%), dental abnormalities (20%), and long QT syndrome (16%). This study represents the largest pediatric cohort of ADH1/2 described to date. Persistent hypocalcemia and hypercalciuria, along with the high prevalence of comorbidities, highlights the ongoing medical need in this population. Long-term prospective data are needed to better understand disease progression and burden of ADH1/2. Presentation: Monday, July 14, 2025
2025-10-01 | SAT-739 Case Report: Autosomal Dominant Hypocalcemia Type 2 In A 43-year-old Male Presenting At A Tertiary Canadian Medical Center
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
2025-07-31 | Prophylactic effect of nano vitamin D3 against fatty degeneration caused by calcium-deficient diet in parotid salivary gland: a histological and ultrastructural study.
Poor dietary habits, such as a calcium-deficient diet, negatively impact oral health by impairing salivary gland function due to hypocalcemia. If left untreated, calcium deficiency can lead to fatal consequences. Several nano-formulations, including nano vitamin D3 supplements, have recently been introduced. However, there is limited research on the impact of vitamin D3-loaded lipid nano capsules (LNCs) on dental health maintenance. This study evaluated the protective potential of vitamin D3-loaded lipid nano capsules (LNCs) versus conventional vitamin D3 in countering fatty degeneration in parotid salivary glands caused by a calcium-deficient diet. Thirty-six male mature albino rats were randomly split into three groups: a calcium-deficient group, a calcium-deficient group treated with conventional vitamin D3, and another receiving vitamin D3-loaded lipid nano capsules (LNCs). The body weight was calculated weekly throughout the experimental duration. At the end of the experiment, blood samples were obtained for serological analysis of serum calcium and insulin concentration as well as blood glucose levels. Parotid glands were harvested for histological and ultrastructural examination. Digital morphometry was used to assess the number of secretory granules. All the data was collected and statistically analyzed using one-way ANOVA and Tukey's honestly significant difference test. The conventional vitamin D3 group showed an incomplete protective effect, while vitamin D3-loaded lipid nano capsules (LNCs) completely preserved cellular structures, preventing the salivary tissue's fatty deterioration. Vitamin D3-loaded lipid nano capsules (LNCs) outperformed conventional vitamin D3 when preserving the quantity of secretory granules. Supplementing calcium-deficient diets with vitamin D3-loaded lipid nano capsules (LNCs) could protect against salivary gland damage caused by calcium deficiency in rats.
antibodies
2023-10-01 | SAT224 Nonsurgical Hypoparathyroidism: 40 Years After Diagnosis
Abstract Disclosure: L.I. Kaplan: None. A. Yuen: None. P.D. Greenberg: None. Background: The majority of cases of hypoparathyroidism occur after neck surgery. The most common nonsurgical cause is autoimmune, either in isolation or part of Autoimmune Polyglandular Syndrome Type 1. Hypomagnesemia is a functional cause. Hypoparathyroidism can occur as part of genetic syndromes that include congenital anomalies, short stature and developmental delay. Non-syndromic genetic etiologies including Autosomal Dominant Hypocalcemia type 1 (ADH1), a gain of function mutation in the calcium sensing receptor (CaSR) that can present in infancy, childhood or adulthood with hypocalcemia (50% symptomatic), hypercalcuria (10%) and basal ganglia calcification (35%). For ADH1, targeted therapies are being developed. Clinical Case: A 90-year-old male was diagnosed with hypoparathyroidism at age 50 when he presented with hand cramping and was found to have hypocalcemia with low PTH. He was started on calcitriol and calcium supplementation. Many years later he started following at our endocrine clinic. Past medical history includes prostate cancer treated with radiation and androgen deprivation therapy, HTN, and pre-diabetes. He has no history of neck surgery, other endocrinopathies, candidiasis, vitiligo or congenital anomalies. He has no family history of hypocalcemia and has two children without calcium abnormalities. His DEXA shows stable +T scores in LS spine and bilateral hips. He has not had brain imaging. Nephrocalcinosis was not reported on renal ultrasound. More than 10 years ago, he presented with severe hypercalcemia, acute renal failure (Ca 13.5 mg/dl, Cr 6.0mg/dl, Phos 5.5mg/dl) and ureteral stones after taking over the counter calcium supplements in excess. He underwent stone removal with return to baseline renal function. Subsequently, he underwent knee replacement surgeries and required IV calcium until he was able to swallow pills. Since this time, he has been managed on calcitriol, calcium carbonate, vitamin D3, and chlorthalidone with close follow up for adjustment of regimen to target Ca 8.0-8.5 mg/dl. He has not had a recurrence of severe hypercalcemia, hyperphosphatemia or nephrolithiasis. He feels well and lives at home with his wife. Lab values over the past 10 years are as follows: Ca 8.1-10.6 mg/dl (8.5-10.5), Alb 4.0-4.6 g/dl (3.5-5.4), Phos 4.3-5.5 mg/dl (2.8-4.5), Mg 1.7-1.9 mg/dl (1.3-2.1), K 3.7-4.4 mEq/L (3.6-5.2), Cr 1.0-1.5 mg/dl (0.5-1.3), PTH 0.00-1.4 pg/ml (10-55), 25 OH Vit D 18-58 ng/ml (32-100), 1,25 OH Vit D3 25.5-37.2 pg/ml (19.9-79.3), 24hr Urine Ca 162- 384 mg/24 hrs (50-400). Clinical lessons: Chronic hypoparathyroidism can be well managed with close follow up and frequent lab monitoring. This patient should be referred for genetic testing, particularly to look for ADH1 mutation in the CaSR gene as targeted treatments are being developed. His children should be tested for any mutations found in him. Presentation: Saturday, June 17, 2023
proteins
2026-05-21 | Continuous subcutaneous recombinant PTH(1-34) infusion improves serum calcium and phosphate homeostasis in children with autosomal dominant hypocalcemia type 1 refractory to standard-of-care treatment.
Autosomal dominant hypocalcemia type 1 (ADH1) results from activating CASR variants, causing parathyroid hormone (PTH) suppression and abnormal renal calcium handling. Management is challenging, as hypoparathyroidism is associated with inappropriate renal calcium wasting, leading to hypercalciuria, nephrocalcinosis, and renal impairment. We evaluated long-term outcomes of continuous subcutaneous PTH(1-34) infusion (CSPI) in children with ADH1 refractory to standard of care therapy (SOC). Single-center observational study. Five children with genetically confirmed ADH1 were treated with CSPI between 2012 and 2017 and followed for up to 11 years. Clinical outcomes, biochemical parameters, and renal findings were assessed under SOC and CSPI. Serum calcium, phosphate (standard deviation score, SDS), magnesium, alkaline phosphatase, eGFR, urinary calcium/creatinine ratio (relative to the age-specific 95th percentile), and fractional calcium excretion (FECa) were analyzed using linear mixed-effects models. Hypocalcemic seizures and emergency visits decreased, growth was appropriate, and no treatment-related adverse events occurred over a median 7-year follow-up. CSPI was associated with higher serum calcium (P < .001) and lower serum phosphate (P < .001). Urinary calcium/creatinine ratios, expressed relative to the age-specific 95th percentile, were lower under CSPI (P < .001). FECa was approximately 8% lower under CSPI (P = .014), suggesting improved renal calcium handling. Renal function remained stable despite progression of nephrocalcinosis in 4/5 patients. SPI appears to be a safe and effective long-term treatment in pediatric ADH1, improving mineral homeostasis and renal calcium handling. Prospective multicenter studies are needed to assess long-term skeletal outcomes and optimize dosing strategies.
2026-02-19 | Long-acting parathyroid hormone receptor agonist rectifies hypocalcemia in autosomal dominant hypocalcemia type 1 mice.
Eneboparatide, a long-acting modified form of parathyroid hormone, increases serum calcium levels without increasing urine calcium in mice with autosomal dominant hypocalcemia type 1.
2024-10-08 | Efficacy and Safety of TransCon PTH in Adults With Hypoparathyroidism: 52-Week Results From the Phase 3 PaTHway Trial.
Conventional therapy for hypoparathyroidism aims to alleviate symptoms of hypocalcemia but does not address insufficient parathyroid hormone (PTH) levels. Assess the long-term efficacy and safety of TransCon PTH (palopegteriparatide) for hypoparathyroidism. Phase 3 trial with a 26-week, double-blind, placebo-controlled period followed by a 156-week, open-label extension (OLE). Twenty-one sites across North America and Europe. A total of 82 adults with hypoparathyroidism were randomized and received study drug and 78 completed week 52. All OLE participants received TransCon PTH administered once daily. Multicomponent efficacy endpoint: proportion of participants at week 52 who achieved normal serum calcium (8.3-10.6 mg/dL) and independence from conventional therapy (≤600 mg/day of elemental calcium and no active vitamin D). Other efficacy endpoints included patient-reported outcomes and bone mineral density. Safety was assessed by 24-hour urine calcium and treatment-emergent adverse events. At week 52, 81% (63/78) met the multicomponent efficacy endpoint, 95% (74/78) achieved independence from conventional therapy, and none required active vitamin D. Patient-reported outcomes showed sustained improvements in quality of life, physical functioning, and well-being. Mean bone mineral density Z-scores decreased toward age- and sex-matched norms from baseline to week 52. Mean (SD) 24-hour urine calcium excretion decreased from 376 (168) mg/day at baseline to 195 (114) mg/day at week 52. Most treatment-emergent adverse events were mild or moderate and none led to trial discontinuation during the OLE. At week 52 of the PaTHway trial, TransCon PTH showed sustained efficacy, safety, and tolerability in adults with hypoparathyroidism.
2024-08-08 | Injection of luteinizing hormone or human chorionic gonadotropin increases calcium excretion and serum PTH in males.
Animal and human studies have suggested that sex steroids have calciotropic actions, and it has been proposed that follicle-stimulating hormone (FSH) may exert direct effects on bone. Here, we demonstrate the expression of the receptor for Luteinizing hormone (LH) and human choriogonadotropin (hCG), LHCGR, in human kidney tissue, suggesting a potential influence on calcium homeostasis. To investigate the role of LHCGR agonist on calcium homeostasis in vivo, we conducted studies in male mice and human subjects. Male mice were treated with luteinizing hormone (LH), and human extrapolation was achieved by injecting 5000 IU hCG once to healthy men or men with hypergonadotropic or hypogonadotropic hypogonadism. In mice, LH treatment significantly increased urinary calcium excretion and induced a secondary increase in serum parathyroid hormone (PTH). Similarly, hCG treatment in healthy men led to a significant increase in urinary calcium excretion, serum PTH levels, and 1,25 (OH)2D3, while calcitonin, and albumin levels were reduced, possibly to avoid development of persistent hypocalcemia. Still, the rapid initial decline in ionized calcium coincided with a significant prolongation of the cardiac QTc-interval that normalized over time. The observed effects may be attributed to LH/hCG-receptor (LHCGR) activation, considering the presence of LHCGR expression in human kidney tissue, and the increase in sex steroids occurred several hours after the changes in calcium homeostasis. Our translational study shed light on the intricate relationship between gonadotropins, sex hormones and calcium, suggesting that LHCGR may be influencing calcium homeostasis directly or indirectly.
2020-11-17 | Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
Gain-of-function mutations in the CASR gene cause Autosomal Dominant Hypocalcemia Type 1 (ADH1), the most common genetic cause of isolated hypoparathyroidism. Subjects have increased calcium sensitivity in the renal tubule, leading to increased urinary calcium excretion, nephrocalcinosis and nephrolithiasis when compared with other causes of hypoparathyroidism. The traditional approach to treatment includes activated vitamin D but this further increases urinary calcium excretion. In this case series, we describe the use of recombinant human parathyroid hormone (rhPTH)1-84 to treat subjects with ADH1, with improved control of serum and urinary calcium levels. We describe two children and one adult with ADH1 due to heterozygous CASR mutations who were treated with rhPTH(1-84). Case 1 was a 9.4-year-old female whose 24-h urinary calcium decreased from 7.5 to 3.9 mg/kg at 1 year. Calcitriol and calcium supplementation were discontinued after titration of rhPTH(1-84). Case 2 was a 9.5-year-old male whose 24-h urinary calcium decreased from 11.7 to 1.7 mg/kg at 1 year, and calcitriol was also discontinued. Case 3 was a 24-year-old female whose treatment was switched from multi-dose teriparatide to daily rhPTH(1-84). All three subjects achieved or maintained target serum levels of calcium and normal or improved urinary calcium levels with daily rhPTH(1-84) monotherapy. We have described three subjects with ADH1 who were treated effectively with rhPTH(1-84). In all cases, hypercalciuria improved by comparison to treatment with conventional therapy consisting of calcium supplementation and calcitriol.
small molecules
2026-06-01 | Clinical and genetic insights into Autosomal Dominant Hypocalcemia type 1: a single-center case series including genotype-phenotype correlations, pregnancy outcomes, and novel CASR variants.
The main purpose of this study was to provide a comprehensive characterization of adult patients with Autosomal Dominant Hypocalcemia type 1 (ADH1), focusing on clinical and biochemical features, with particular attention to renal involvement, skeletal features and ectopic calcifications. The secondary aims were to explore potential genotype-phenotype correlations, describe two previously unreported CASR variants, and report pregnancy outcomes in affected women. We conducted a retrospective, single-centre study of 11 adults with genetically confirmed ADH1 followed at a tertiary Endocrinology Unit between March 2012 and May 2025. Clinical presentation, biochemical data, renal and cerebral involvement, skeletal status and treatment history were collected at first evaluation and during follow-up. CASR variants were identified by next-generation sequencing with Sanger confirmation, and genotype-phenotype relationships were explored. At diagnosis, 64% of patients reported hypocalcemia-related symptoms, while 36% were asymptomatic. Nephrolithiasis, nephrocalcinosis and basal ganglia calcifications were frequent, in patients exposed to long-term calcium and active vitamin D therapy, although causal relationships cannot be established. Axial BMD was normal or increased, whereas radial BMD was often reduced and bone turnover markers were low-normal; no fragility fractures were documented. We identified two novels CASR missense variants and observed marked intra- and interfamilial variability. Four pregnancies in three women with ADH1 resulted in favourable maternal and neonatal outcomes. In our ADH1 patients we found a wide clinical variability, from asymptomatic hypocalcemia to severe early-onset disease, with a high burden of renal complications and ectopic calcifications. Genotype alone does not fully predict clinical severity, even for the same CASR variant. Pregnancies can have good outcomes under close biochemical monitoring and tailored therapy but should be managed as high-risk.
2026-02-13 | Peri-kidney transplant management in autosomal dominant hypocalcaemia type 1.
Autosomal dominant hypocalcaemia type 1 is rare and clinically challenging. Altered calcium handling may lead to progressive nephrocalcinosis and chronic kidney disease. We present the first known report of a child with ADH1 caused by the genetic variant c.2528C > A; p.Ala843Glu, who successfully underwent kidney transplantation without simultaneous parathyroid gland transplant aged 11yrs. We outline our reasoning for this and our management strategy for maintaining calcium homeostasis post-transplant over a 4-year period.
2025-10-01 | MON-743 Autosomal Dominant Hypocalcemia Type 1 or Type 2: Baseline Characteristics of Pediatric Participants in the CLARIFY Disease Monitoring Study
Abstract Disclosure: J. Bacchetta: None. C. Jacobsen: None. T. Kubota: None. Autosomal dominant hypocalcemia type 1 (ADH1) and type 2 (ADH2) are rare disorders caused by activating variants of the CASR and GNA11 genes, respectively. The calcium-sensing receptor (CaSR) plays a critical role in calcium homeostasis by signaling parathyroid hormone (PTH) secretion and urinary calcium (uCa) reabsorption in response to variations in blood calcium. The CaSR signals by coupling to G-proteins, including GNA11-encoded Gα11. The CLARIFY disease monitoring study [NCT05227287] is an ongoing global, multicenter, longitudinal, observational study to characterize disease burden, management, and progression in children and adults with ADH1/2 over a 5-year period. Of 25 pediatric participants (birth to <18y) enrolled (Mar 2022 to Jun 2024), 22 were diagnosed with ADH1 and 3 with ADH2; 64% are females. Median age at enrollment was 9 years (IQR 5-13). Median age at hypocalcemia presentation and ADH1/2 diagnosis were 0.8 years (IQR 0.0-3.0) and 1.0 year (IQR 0.5-3.0), respectively. Family history of ADH1/2 was reported in 64% of participants. 16 unique CASR and 2 unique GNA11 variants were present, with CASR E767K (3) and F788C (3) the most frequent. Treatment regimen varied at baseline (Day 1 study visit): 32% (8) were on Ca and active vitamin D, 24% (6) on Ca alone, 8% (2) on active vitamin D alone, 20% (5) on PTH replacement, 20% (5) on magnesium, 12% (3) on thiazide diuretics, 12% (3) on potassium, 12% (3) on phosphate binder, 32% (8) on cholecalciferol, and 20% (5) without treatment. At baseline, 92% (23) had hypocalcemia (0-<1y <8.4 mg/dL; 1-17y <8.6 mg/dL), 83% (20) had low iPTH (<15 pg/mL), 84% (21) had hyperphosphatemia (0-<1y >7.8 mg/dL; 1-12y >6.0 mg/dL; 13-17y >4.8 mg/dL), 8% (2) had hypomagnesemia (<1.5 mg/dL), and 84% (21) had normal total 25-OH Vitamin D (20-50 ng/mL). 32% (6) of 19 participants with 24hr uCa collected were hypercalciuric (>4 mg/kg/day); and 0% of 5 participants with spot urine collections had Ca/Cr above the aged-defined reference range (7-18mo <0.60 mg/mg; 19mo – 6y <0.41 mg/mg; adults <0.21 mg/mg). Baseline eGFR by Schwartz equation was 117±25 mL/min/1.73m² (range: 69-175). Common (proxy) self-reported ADH1-related comorbidities were seizures (36%), nephrocalcinosis (32%), dental abnormalities (20%), and long QT syndrome (16%). This study represents the largest pediatric cohort of ADH1/2 described to date. Persistent hypocalcemia and hypercalciuria, along with the high prevalence of comorbidities, highlights the ongoing medical need in this population. Long-term prospective data are needed to better understand disease progression and burden of ADH1/2. Presentation: Monday, July 14, 2025
2025-10-01 | SAT-739 Case Report: Autosomal Dominant Hypocalcemia Type 2 In A 43-year-old Male Presenting At A Tertiary Canadian Medical Center
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
2025-07-31 | Prophylactic effect of nano vitamin D3 against fatty degeneration caused by calcium-deficient diet in parotid salivary gland: a histological and ultrastructural study.
Poor dietary habits, such as a calcium-deficient diet, negatively impact oral health by impairing salivary gland function due to hypocalcemia. If left untreated, calcium deficiency can lead to fatal consequences. Several nano-formulations, including nano vitamin D3 supplements, have recently been introduced. However, there is limited research on the impact of vitamin D3-loaded lipid nano capsules (LNCs) on dental health maintenance. This study evaluated the protective potential of vitamin D3-loaded lipid nano capsules (LNCs) versus conventional vitamin D3 in countering fatty degeneration in parotid salivary glands caused by a calcium-deficient diet. Thirty-six male mature albino rats were randomly split into three groups: a calcium-deficient group, a calcium-deficient group treated with conventional vitamin D3, and another receiving vitamin D3-loaded lipid nano capsules (LNCs). The body weight was calculated weekly throughout the experimental duration. At the end of the experiment, blood samples were obtained for serological analysis of serum calcium and insulin concentration as well as blood glucose levels. Parotid glands were harvested for histological and ultrastructural examination. Digital morphometry was used to assess the number of secretory granules. All the data was collected and statistically analyzed using one-way ANOVA and Tukey's honestly significant difference test. The conventional vitamin D3 group showed an incomplete protective effect, while vitamin D3-loaded lipid nano capsules (LNCs) completely preserved cellular structures, preventing the salivary tissue's fatty deterioration. Vitamin D3-loaded lipid nano capsules (LNCs) outperformed conventional vitamin D3 when preserving the quantity of secretory granules. Supplementing calcium-deficient diets with vitamin D3-loaded lipid nano capsules (LNCs) could protect against salivary gland damage caused by calcium deficiency in rats.
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2023-10-01 | SAT224 Nonsurgical Hypoparathyroidism: 40 Years After Diagnosis
Abstract Disclosure: L.I. Kaplan: None. A. Yuen: None. P.D. Greenberg: None. Background: The majority of cases of hypoparathyroidism occur after neck surgery. The most common nonsurgical cause is autoimmune, either in isolation or part of Autoimmune Polyglandular Syndrome Type 1. Hypomagnesemia is a functional cause. Hypoparathyroidism can occur as part of genetic syndromes that include congenital anomalies, short stature and developmental delay. Non-syndromic genetic etiologies including Autosomal Dominant Hypocalcemia type 1 (ADH1), a gain of function mutation in the calcium sensing receptor (CaSR) that can present in infancy, childhood or adulthood with hypocalcemia (50% symptomatic), hypercalcuria (10%) and basal ganglia calcification (35%). For ADH1, targeted therapies are being developed. Clinical Case: A 90-year-old male was diagnosed with hypoparathyroidism at age 50 when he presented with hand cramping and was found to have hypocalcemia with low PTH. He was started on calcitriol and calcium supplementation. Many years later he started following at our endocrine clinic. Past medical history includes prostate cancer treated with radiation and androgen deprivation therapy, HTN, and pre-diabetes. He has no history of neck surgery, other endocrinopathies, candidiasis, vitiligo or congenital anomalies. He has no family history of hypocalcemia and has two children without calcium abnormalities. His DEXA shows stable +T scores in LS spine and bilateral hips. He has not had brain imaging. Nephrocalcinosis was not reported on renal ultrasound. More than 10 years ago, he presented with severe hypercalcemia, acute renal failure (Ca 13.5 mg/dl, Cr 6.0mg/dl, Phos 5.5mg/dl) and ureteral stones after taking over the counter calcium supplements in excess. He underwent stone removal with return to baseline renal function. Subsequently, he underwent knee replacement surgeries and required IV calcium until he was able to swallow pills. Since this time, he has been managed on calcitriol, calcium carbonate, vitamin D3, and chlorthalidone with close follow up for adjustment of regimen to target Ca 8.0-8.5 mg/dl. He has not had a recurrence of severe hypercalcemia, hyperphosphatemia or nephrolithiasis. He feels well and lives at home with his wife. Lab values over the past 10 years are as follows: Ca 8.1-10.6 mg/dl (8.5-10.5), Alb 4.0-4.6 g/dl (3.5-5.4), Phos 4.3-5.5 mg/dl (2.8-4.5), Mg 1.7-1.9 mg/dl (1.3-2.1), K 3.7-4.4 mEq/L (3.6-5.2), Cr 1.0-1.5 mg/dl (0.5-1.3), PTH 0.00-1.4 pg/ml (10-55), 25 OH Vit D 18-58 ng/ml (32-100), 1,25 OH Vit D3 25.5-37.2 pg/ml (19.9-79.3), 24hr Urine Ca 162- 384 mg/24 hrs (50-400). Clinical lessons: Chronic hypoparathyroidism can be well managed with close follow up and frequent lab monitoring. This patient should be referred for genetic testing, particularly to look for ADH1 mutation in the CaSR gene as targeted treatments are being developed. His children should be tested for any mutations found in him. Presentation: Saturday, June 17, 2023
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Drug Discovery Landscape
1 orphan drug designation for Autosomal dominant hypocalcemia.
1 orphan drug designation for Autosomal dominant hypocalcemia.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Encaleret sulfate | small molecules | FDA | Calcilytix Therapeutics, Inc. a BridgeBio Company |
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