Autosomal Dominant Hypocalcemia Type Research Articles

CALIBRATE: A phase 3, randomized, open-label study evaluating the efficacy and safety of encaleret (CLTX-305) compared to standard of care in participants with autosomal dominant hypocalcemia type 1 [NCT05680818

CALIBRATE: A phase 3, randomized, open-label study evaluating the efficacy and safety of encaleret (CLTX-305) compared to standard of care in participants with autosomal dominant hypocalcemia type 1 [NCT05680818

Encaleret (CLTX-305) sustained normalization of mineral homeostasis in patients with autosomal dominant hypocalcemia type 1 over 18 months in a phase 2 study [NCT04581629

Encaleret (CLTX-305) sustained normalization of mineral homeostasis in patients with autosomal dominant hypocalcemia type 1 over 18 months in a phase 2 study [NCT04581629

Treatment of Hypoparathyroidism by Re-Establishing the Effects of Parathyroid Hormone.

The conventional treatment of hypoparathyroidism (HypoPT) includes active vitamin D and calcium. Despite normalization of calcium levels, the conventional treatment is associated with fluctuations in calcium levels, hypercalciuria, renal impairment, and decreased quality of life (QoL). Replacement therapy with parathyroid hormone (PTH)(1-84) is an option in some countries. However, convincing beneficial effects have not been demonstrated, which may be due to the short duration of action of this treatment. Recently, palopegteriparatide (also known as TransCon PTH) has been marketed in Europe and is expected also to be approved in other countries. Palopegteriparatide is a prodrug with sustained release of PTH(1-34) designed to provide stable physiological PTH levels for 24 hours/day. A phase 3 study demonstrated maintenance of normocalcemia in patients with chronic HypoPT, with no need for conventional therapy. Furthermore, this treatment lowers urinary calcium and improves QoL. Another long-acting PTH analog with effects on the parathyroid hormone receptor (eneboparatide) is currently being tested in a phase 3 trial. Furthermore, the treatment of autosomal dominant hypocalcemia type 1 with a calcilytic (encaleret) is also being tested. All in all, improved treatment options are on the way that will likely take the treatment of HypoPT to the next level.

OR23-03 Sustained Normalization Of Mineral Homeostasis In Autosomal Dominant Hypocalcemia Type 1: Results From A Phase 2 Study Over 18 Months Of Encaleret (CLTX-305) Treatment (NCT04581629)

Abstract Disclosure: R.I. Gafni: Advisory Board Member; Self; Ascendis Pharma, Hypoparathyroidism Association. Grant Recipient; Self; Calcilytix Therapeutics. I.R. Hartley: Grant Recipient; Self; Calcilytix Therapeutics. K.L. Roszko: Grant Recipient; Self; Calcilytix Therapeutics. E.F. Nemeth: Consulting Fee; Self; Calcilytix Therapeutics. K.A. Pozo: Grant Recipient; Self; Calcilytix Therapeutics. A. Mathew: Employee; Self; Calcilytix Therapeutics. M. Roberts: Employee; Self; Calcilytix Therapeutics. S.H. Adler: Employee; Self; Calcilytix Therapeutics. M.T. Collins: Grant Recipient; Self; Calcilytix Therapeutics. Autosomal dominant hypocalcemia type 1 (ADH1), caused by gain-of-function calcium-sensing receptor gene (CASR) variants, is characterized by low parathyroid hormone (PTH) levels, hypocalcemia, hypercalciuria, hyperphosphatemia and hypomagnesemia. Conventional therapy (calcium and active vitamin D) worsens hypercalciuria, which may result in renal complications. Calcilytics that act as negative allosteric modulators of the calcium-sensing receptor (CaSR), like encaleret, decrease the sensitivity of hyperactive receptors to extracellular calcium and normalize biochemical abnormalities in ADH1 rodent models. This Phase 2b open-label study of the oral investigational calcilytic encaleret was comprised of 3 periods followed by a long-term extension (LTE). Conventional therapy was discontinued prior to encaleret initiation. Periods 1&2 included dose-finding and safety/tolerability evaluation. Period 3 (P3) optimized dosing and assessed safety and efficacy over 24 outpatient weeks; participants were then allowed to continue in the LTE. Thirteen adults with ADH1 were enrolled and encaleret was individually titrated to normalize albumin-corrected calcium (cCa) and minimize hypercalciuria. Encaleret was well-tolerated with no serious adverse events reported. There were no treatment discontinuations or withdrawals prior to the LTE; one participant withdrew during the LTE for family planning. The mean±SD encaleret sulfate dose at the end of P3, Week 24 (P3W24) was 86±70mg BID, remaining stable at LTE Month 12 (LTEM12) (n=11) (71±62mg BID). Mean±SD values taken 4-hours post-dose for P3W24 and LTEM12 compared to baseline (BL) are presented. PTH levels were low at BL (6.3±7.8 pg/mL [nl 10-65]), normal at P3W24 (35.3±10.2), and remained consistent through LTEM12 (36.9±15.2 [p<0.01]). Similarly, hypocalcemia at BL (cCa=7.1±0.4 mg/dL [nl 8.4-10.2]) was normal at P3W24 (9.2±0.5); eucalcemia was maintained through LTEM12 (9.2±0.4 [p<0.01]). BL hypercalciuria (395±216 mg/d [nl <250-300]) decreased to 202±83 at P3W24 and normalization was sustained through LTEM12 (177±94 [p<0.05]). BL blood phosphate (4.5±1.1 mg/dL [nl 2.3-4.7]) decreased by P3W24 (3.4±0.4) and was maintained at LTEM12 (3.4±0.5 [p<0.01]). Blood magnesium increased (BL 1.7±0.2 mg/dL [nl 1.6-2.6]); P3W24 2.0±0.2; LTEM12 2.1±0.2 [p<0.01]). Bone turnover markers increased from BL (n=7) (CTX=253±111 pg/mL; P1NP=34±10 mcg/L) by P3W24 (n=13) (CTX=744±565; P1NP=104±87) and remained elevated at LTEM12 (CTX=988±652; P1NP=83±49 [p<0.01]. This study represents a molecularly targeted, precision medicine approach to the treatment of ADH1. The consistent and sustained results from over 18 months of outpatient encaleret treatment are clinically meaningful and support Phase 3 evaluation of the efficacy and safety of encaleret as the first potential treatment indicated for ADH1. Presentation: Saturday, June 17, 2023

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

SAT218 Refractory Hypocalcemia From Combined Autosomal Dominant Hypocalcemia Type 2 And Postsurgical Hypoparathyroidism

Abstract Disclosure: M. Sonmez Ince: None. F. Hannan: None. N. Esfandiari: None. M. Hussain: None. M.R. Haymart: None. R.V. Thakker: None. G.A. Clines: None. Background: Autosomal dominant hypocalcemia type 2 (ADH2), due to activating mutations in GNA11, is a rare disorder that causes hypocalcemia with low or inappropriately normal PTH. Postsurgical hypoparathyroidism (PSHP) is the most common etiology for hypoparathyroidism. The patient described was afflicted by both conditions and had persistent hypocalcemia despite aggressive management. Clinical Case: A 50-year-old female was found to have an enlarged thyroid on exam and subsequently diagnosed with papillary thyroid cancer (PTC). She underwent a total thyroidectomy without parathyroid autotransplantation since parathyroid glands were not identified during intraoperative pathologic survey. Surgical pathologic examination confirmed PTC with the identification of a single and small intrathyroidal parathyroid gland. Due to the patient’s low risk (T1N0M0), radioactive iodine ablation was not performed. Before thyroidectomy, serum corrected calcium was 6.4-8.5 mg/dL (8.6-10.3 mg/dL) and PTH was 9-21 pg/mL (10-65 pg/mL) during the previous 20 years. Following thyroidectomy, the patient had multiple emergency department visits due to hypocalcemia, hand cramping, and paresthesias. The patient was diagnosed with postsurgical hypoparathyroidism: corrected calcium 5.6-6.7 mg/dL, 24-hour urine calcium 112 mg (100-300 mg/24hour), magnesium 1.4-1.9 mg/dL (1.6-2.6 mg/dL), phosphorus 3-8.2 mg/dL (2.7-4.6 mg/dL). PTH remained <6 pg/mL. The patient was then referred to an academic endocrinology. TSH, AM cortisol, 25-vitamin D, iron, ceruloplasmin, copper, and 21-hydroxylase antibody concentrations were normal. Genetic testing revealed a pathogenic GNA11 variant (c.178C>T, p.(Arg60Cys)); no mutations were identified with CASR or AP2S1. Despite aggressive management with total daily oral calcitriol up to 12 mcg daily, calcium 8 grams, and chlorthalidone, the patient required calcium infusions thrice weekly. Despite the addition of teriparatide 20 mcg BID, the patient remained dependent on calcium infusions, with improvement after the addition of IV calcitriol. Recently, continuous teriparatide delivery was started using an Omnipod insulin pump that has significantly reduced the patient’s dependence on calcium infusions with serum calcium that are now 8-9 mg/dL. Conclusion: ADH2, due to gain-of-function mutations of GNA11, that encodes the Gα11 protein, causes life-long hypocalcemia that is often asymptomatic and undiagnosed. We report here the first documented case of combined ADH2 and PSHP. This case highlights that patients with ADH2 likely have hypoplastic parathyroid glands and that caution is required with procedures that may disrupt parathyroid gland function. Furthermore, the refractory nature of this patient’s hypocalcemia may suggest that GNA11 mutations in the kidney and skeleton reduce the effectiveness of standard hypocalcemia treatments. Presentation: Saturday, June 17, 2023

SAT231 Next-generation Sequencing For Detection Of Underlying Genetic Causes Of Nonsurgical Hypoparathyroidism: Preliminary Results From A Sponsored Testing Program

Abstract Disclosure: M. Mannstadt: Advisory Board Member; Self; Takeda, Calcilytix, Amolyt. Research Investigator; Self; Takeda, Calcilytix, Amolyt. A. Mathew: Employee; Self; BridgeBio Pharma. A. Sridhar: Employee; Self; BridgeBio Pharma. L.S. Smith: Employee; Self; BridgeBio Pharma. M. Roberts: Employee; Self; BridgeBio Pharma. S. Adler: Employee; Self; BridgeBio Pharma. Hypoparathyroidism is a rare endocrine disorder characterized by inadequate production of parathyroid hormone to maintain normal blood calcium levels. Hypoparathyroidism is most frequently caused by damage to or removal of the parathyroid glands but can also be associated with genetic etiologies. Genetic forms of hypoparathyroidism can present as isolated or as part of a syndrome and include disorders of parathyroid gland formation, parathyroid hormone secretion, and damage to the parathyroid gland through autoimmunity. Genetic testing may uncover the underlying etiology of nonsurgical hypoparathyroidism and can help confirm clinical diagnosis, guide medical treatment, and identify affected family members. A sponsored genetic testing program was made available for patients with suspected genetic hypoparathyroidism who met program eligibility criteria. The next-generation sequencing panel has evolved to include 26 genes known to be associated with hypoparathyroidism: ACADM, AIRE, ATP1A1, CASR, CHD7, CLDN16, CLDN19, CNNM2, DHCR7, EGF, FAM111A, FXYD2, GATA3, GCM2, GNA11, HADHA, HADHB, KCNA1, NEBL, PTH, SEMA3E, SLC12A3, SOX3, TBCE, TBX1 and TRPM6. A total of 169 samples between December 2020 and December 2022 were tested from participants with a mean±SD age of 23.4±20.4 (range 0-81) who were diagnosed with nonsurgical/idiopathic hypoparathyroidism (73.9%), hypocalcemia suspected to be of genetic cause (23.7%) or had a relative with a confirmed diagnosis of genetic hypoparathyroidism (2.4%). Pathogenic or likely pathogenic variants, and variants of uncertain significance were identified in 64 individuals (37.9%). Amongst these 64 participants, 77 variants were detected with 46.9% of variant harboring individuals documented as having unknown or no family history. In order of frequency, the relative number of individuals with detected variants are as follows: CASR 56.3% (36/64), AIRE 12.5% (8/64), TBX1 9.38% (6/64), GATA3 7.8% (5/64), GNA11 6.25% (4/64), CHD7 3.13% (2/64), FAM111A 3.13% (2/64), PTH 3.13% (2/64), ACADM 1.6% (1/64), GCM2 1.6% (1/64), HADHB 1.6% (1/64) and TBCE 1.6% (1/64). Of note, 5 individuals had variants identified in more than 1 gene. Notably, these data demonstrate that genetic testing may identify clinically-relevant variants in approximately 2 of 5 individuals with nonsurgical hypoparathyroidism. The most common genetic form of hypoparathyroidism was found to be autosomal dominant hypocalcemia type 1 (21.3% of individuals tested; 36/169), caused by gain-of-function variants in the CASR gene. Overall, this ongoing sponsored testing program provides an efficient path to aid in the diagnosis of genetic causes and may ultimately improve the understanding and management of nonsurgical hypoparathyroidism. Presentation: Saturday, June 17, 2023

Novel Calcium-Sensing Receptor (CASR) Mutation in a Family with Autosomal Dominant Hypocalcemia Type 1 (ADH1): Genetic Study over Three Generations and Clinical Characteristics

Introduction: Activating mutation of the calcium-sensing receptor gene (CASR) reduces parathyroid hormone secretion and renal tubular reabsorption of calcium, defined as autosomal dominant hypocalcemia type 1 (ADH1). Patients with ADH1 may present with hypocalcemia-induced seizures. Calcitriol and calcium supplementation in symptomatic patients may exacerbate hypercalciuria, leading to nephrocalcinosis, nephrolithiasis, and compromised renal function. Methods: We report on a family with seven members over three generations with ADH1 due to a novel heterozygous mutation in exon 4 of CASR: c.416T>C. Results: This mutation leads to substitution of isoleucine with threonine in the ligand-binding domain of CASR. HEK293T cells transfected with wild type or mutant cDNAs demonstrated that p.Ile139Thr substitution led to increased sensitivity of the CASR to activation by extracellular calcium relative to the wild-type CASR (EC50 of 0.88 ± 0.02 mM vs. 1.1 ± 0.23 mM, respectively, p < 0.005). Clinical characteristics included seizures (2 patients), nephrocalcinosis and nephrolithiasis (3 patients), and early lens opacity (2 patients). In 3 of the patients, serum calcium and urinary calcium-to-creatinine ratio levels obtained simultaneously over 49 patient-years were highly correlated. Using the age-specific maximal-normal levels of calcium-to-creatinine ratio in the correlation equation, we obtained age-adjusted serum calcium levels that are high enough to reduce hypocalcemia-induced seizures and low enough to reduce hypercalciuria. Conclusion: We report on a novel CASR mutation in a three-generation kindred. Comprehensive clinical data enabled us to suggest age-specific upper limit of serum calcium levels, considering the association between serum calcium and renal calcium excretion.

PSAT201 Hypoparathyroidism (HypoPT) in 16 Pregnancies in 7 Patients: A Case Series of Maternal and Neonatal Outcomes

Abstract Background We present biochemical and clinical outcomes from 16 pregnancies in 7 patients with HypoPT. Case1 35y.o postsurgical HypoPT diagnosed(Dx) age27. Pregnancy1(P1): c-section(CS) at 34wks due to pre-eclampsia, BW 1995g with normal APGARS. Admitted for maternal hypercalcemia in 3rd trimester(T3). P2: abortion at 24wks (Trisomy21). P3: CS at 39wks, BW 2993g, calcium(Ca) requirements increased in T3 and decreased while breastfeeding(BF). Case2 39y.o postsurgical HypoPT Dx age34. P1: miscarriage at 8wks. P2: premature uterine contractions in T2 but was carried out to 40wks. Requirements decreased (Ca 44%,calcitriol 33%) due to hypercalcemia and hyperphosphatemia. P3: CS at 40wks. Both P2 and P3 complicated by neonatal hypercalcemia and hyperparathyroidism for 6mo. then recovered. Case3 32y.o postsurgical HypoPT, CS at 39wks, no neonatal complications, BW 3910g.Cae4: 32y.o postsurgical HypoPT Dx age24. P1: preterm at 33+4wks 2nd to PPROM, BW 2550g, normal APGARS. NICU x15 days for nutritional support. Maternal hypercalcemia in T2 (TUMS for GERD). Hypocalcemia and hypomagnesemia in T3 required IV replacement and doubling of Ca and calcitriol requirements. BF for 2mo., requirements decreased (Ca 60%,calcitriol 50%). P2: 28wks pregnant, requirements increased in T1 (Ca 18%,calcitriol 100%). Case5 30y.o GATA3 mutation confirmed age30 with bilateral deafness and CKD. P1: preterm at 36+5wks, BW 2850g. In T3, requirements decreased (Ca 25%, calcitriol 70%). Ca requirements unchanged while BF for 12mo. P2: miscarriage at 8wks. P3: CS at 35+6wks, pre-eclampsia, BW 3190g, APGARS 9/9 according to midwife, required NICU for respiratory distress at 10mins. Calcitriol decreased 66% at T2/T3 vs baseline. Postpartum hypocalcemia required 3X increase in Ca. Case6 31y.o idiopathic HypoPT Dx age22. P1: IVF required induction at 36wks for SGA, BW 1814g. Requirements increased during pregnancy (Ca 4%,calcitriol 150%) and decreased (Ca 10%,calcitriol 20%) while BF. P2: 6wks pregnant, Ca requirements unchanged. Case7 24y.o autosomal dominant hypocalcemia type1 (ADH1) Dx age 18mo. P1: induced at 37wks for "abnormal fetal doppler", BW 2825g, NICU x2wks for hypocalcemia 2nd to ADH1, normal APGARS. Ca and calcitriol requirements increased 3X in T2. Ca requirements declined to baseline, and calcitriol declined by 50% in T3. Required 3 admissions for hypocalcemia. P2: CS at 34wks for low BPP 2/8, APGARS 7/9, BW 2540g, required NICU for hypocalcemia. Required doubling of calcitriol in T1. Requirements increased in T2(Ca 50%,calcitriol 20%) and required 2 admissions for hypocalcemia. Requirements decreased during lactation (Ca 50%,calcitriol 60%). Conclusion Although our case series of pregnancy in HypoPT is relatively small, we document a high prevalence of neonatal and maternal morbidity despite close monitoring of serum calcium throughout pregnancy aiming for a normal serum corrected calcium. Poor compliance contributed to poor outcomes. Women with nonsurgical HypoPT had a higher rate of preterm delivery (4/5 deliveries) vs (2/5). Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

PSAT210 A Case of Asymptomatic Severe Hypocalcemia: Consideration of Genetic Causes

Abstract Calcium sensing receptor (CaSR) activating mutations are a rare etiology of calcium dyscrasias in the general population. Of these, hypocalciuric hypocalcemia and autosomal dominant hypocalcemia (ADH) type 1 are the most common subtypes, with a prevalence of 74.1 and 3.9 per 100,000, respectively. Although rare, these mutations should be considered in patients with a family history of hypocalcemia, particularly if asymptomatic, as the treatment goals and replacement strategies differ from typical primary hypoparathyroidism, with which they are often mistaken. We present a case of a 41-year-old male with a history of treated vitamin D deficiency and anxiety who presented to endocrinology clinic for severe asymptomatic hypocalcemia (serum calcium 6.0-7.0). Family history pertinent for a mother, sister, and brother also with hypocalcemia, and brother with single childhood hypocalcemic seizure at age 4. Patient reported being on and off calcium, calcitriol, and ergocalciferol for years and has never had any symptoms regardless of his regimen or serum calcium. Specifically, he had no personal history of paresthesia, muscle cramping, or kidney stones. No family history of osteoporosis, fracture, kidney stone, or renal disease. Laboratory evaluation over the last 30 years most pertinent for serum calcium 6.0-9.5 on varying supplement/medication regimens, low-normal PTH, initially elevated and now normal serum phosphorous, low-normal serum magnesium, and 24h urinary calcium quite variable but as high as &amp;gt;300mg/d (when serum calcium within normal limits). Genetic testing revealed a heterozygous DNA sequence change detected on exon 7 of the CaSR gene, which has been previously found to be a pathogenic cause of ADH. Activating mutations of the CaSR (typically ADH type 1) clinically present as hypocalcemia, low or low-normal PTH, hyperphosphatemia, hypomagnesemia, and increased urinary calcium. When starting the evaluation for these mutations, it is important to note that there are two types of ADH. Type 1 mutations occur as an activating mutation at the CaSR causing hypersensitivity to calcium, while type 2 activating mutations occur at a different locale (G alpha 11 subunit). Despite mutations at different sites, each type leads to a similar gain-of-function mutation and a very similar clinical presentation. The clinical significance of differentiating these diagnoses from primary hypoparathyroidism (PHP) lies in the goals of treatment and in the adverse effects of over-supplementation of calcium in ADH. In PHP, patients generally have symptomatic hypocalcemia, and calcium can and should be supplemented to prevent adverse events of chronic hypocalcemia. Contrastingly, in CaSR mutation conditions, mild and even significant hypocalcemia is well tolerated. If patients’ serum calcium is normalized, they often experience significant hypercalciuria and renal manifestations therein, such has nephrocalcinosis and nephrolithiasis. Therefore, treatment of patients with CaSR activating mutations should be aimed at relieving hypocalcemia symptoms, if any are present. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Autosomal dominant hypocalcemia with a novel CASR mutation: a case study and literature review.

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare inherited disorder characterized by hypocalcemia with low parathyroid hormone (PTH) levels and high urinary calcium. Its clinical presentation varies from mild asymptomatic to severe hypocalcemia. It is caused by gain-of-function mutations in the calcium-sensing receptor gene (CASR) which affect PTH secretion from the parathyroid gland and calcium resorption in the kidney. Here, we describe a case who presented with symptoms of recurrent seizure caused by hypocalcemia with a novel CASR variant. We comprehensively analyzed the phenotypic features of this presentation and reviewed the current literature to better understand clinical manifestations and the genetic spectrum.

Abstract 14476: Effects of Encaleret on Corrected QT Interval in Autosomal Dominant Hypocalcemia Type 1: Early Results From an Ongoing Phase 2b, Open-Label, Dose-Ranging Study

Introduction: Autosomal dominant hypocalcemia type 1 (ADH1) is caused by gain-of-function variants of the calcium-sensing receptor (CaSR) gene, resulting in receptor proteins with increased sensitivity to extracellular calcium. Individuals with ADH1 exhibit hypocalcemia, hypomagnesemia, hyperphosphatemia, and inappropriately low levels of PTH. Hypocalcemia and hypomagnesemia can slow cardiac repolarization and potentially prolong the QT interval in patients with ADH1. Prolongation of the QT interval can lead to potentially malignant ventricular arrhythmias. Calcilytics are antagonists of the CaSR with the potential to restore normal CaSR sensitivity in ADH1 and thereby normalize blood levels of calcium and magnesium. This study investigated the biochemical and ECG effects of encaleret, an investigational oral calcilytic, in individuals with ADH1. Methods: CLTX-305-201 [NCT04581629] is a 3-period, open-label, dose-ranging study of encaleret in adults with ADH1. In Period 1, supplements were discontinued 1 or 2 days prior to administering sequential, increasing daily doses of encaleret over 5 days with frequent biochemical monitoring. Standard 12-lead surface ECGs were recorded at baseline (BL) and on Day 5 (D5). Results: Data (mean±SD) from the first 6 participants are presented. BL and D5 values were compared as follows: • PTH: BL 3.4±4.5; D5 64.8±49.6 (nl 10-65 pg/mL; p&lt;0.01) • Albumin-corrected total calcium: BL 7.6±0.6; D5 9.0±0.5 (nl 8.4-10.2 mg/dL; p&lt;0.01) • Magnesium: BL 1.6±0.4; D5 2.0±0.5 (nl 1.6-2.6 mg/dL; p&lt;0.01) • Phosphate: BL 4.5±0.7; D5 2.9±0.5 (nl 2.3-4.7 mg/dL; p&lt;0.01) • QT c B: BL 452±9; D5 433±11 (nl &lt;440 msec; p&lt;0.01) There were no important changes or trends in heart rate, blood pressure, or other ECG intervals. Encaleret was well-tolerated and without serious adverse events. Conclusion: Hypocalcemic ADH1 study participants experienced abnormal cardiac repolarization manifested as prolongation of the QT interval at baseline. The consistent responses following encaleret treatment ADH1 participants provide preliminary evidence that encaleret, by raising blood levels of calcium and magnesium, may normalize cardiac repolarization in patients with ADH1. Longer-term evaluation of encaleret in ADH1 is ongoing.

A variant in the CASR gene (c.368T>C) causing hypocalcemia refractory to standard medical therapy.

SummaryHypoparathyroidism is characterized by low or inappropriately normal parathormone production, hypocalcemia and hyperphosphatemia. Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of hypoparathyroidism caused by heterozygous activating mutations in the calcium-sensing receptor (CASR) gene. Current treatments for ADH type 1 include supplementation with calcium and active vitamin D. We report a case of hypoparathyroidism in an adolescent affected by syncope without prodrome. The genetic testing revealed a variant in the CASR gene. Due to standard therapy ineffectiveness, the patient was treated with recombinant human parathyroid hormone (1–34), magnesium aspartate and calcitriol. He remained asymptomatic and without neurological sequelae until adulthood. Early diagnosis and treatment are important to achieve clinical stability.Learning pointsAutosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of hypoparathyroidism caused by heterozygous activating mutations in the calcium-sensing receptor (CASR) gene.The variant c.368T>C (p.Leu123Ser) in heterozygosity in the CASR gene is likely pathogenic and suggests the diagnosis of ADH type 1.Teriparatide (recombinant human parathyroid hormone 1–34) may be a valid treatment option to achieve clinical stability for those individuals whose condition is poorly controlled by current standard therapy.

Autosomal Dominant Hypocalcemia Due to a GNA11 Variant: The First Case in Japan

Abstract Background: Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and hyperphosphatemia due to hypoparathyroidism. ADH type 1 is caused by gain-of-function variants in CASR gene coding the calcium-sensing receptor. Recently, ADH type 2 caused by gain-of-function variants in GNA11 gene coding G-protein subunit α11 has been recognized. Case: A 32-year-old female patient visited our hospital because she suffered from hyperhidrosis, exertional dyspnea, and palpitations. She had a past medical history of paroxysmal kinesigenic dyskinesia confirmed by genetic analysis of PRRT2. Although her sister has unspecified epilepsy, no members of her kindred have episodes of tetany. Her height was 155.7 cm and weight was 64.1 kg. She had goiter with tremor and tachycardia and was diagnosed as Graves’ disease (fT3 &amp;gt;32.55 pg/mL, fT4 &amp;gt;7.77 ng/dL, TSH &amp;lt;0.005 µIU/mL, and TRAb 36.9 IU/L). Thiamazole therapy ameliorated her hyperthyroidism, while serum calcium level was low (7.5 mg/dL) and serum phosphate level was slight high (5.1 mg/dL). Hypoparathyroidism was confirmed because intact-PTH was relatively low (20 pg/mL) under the hypocalcemia. Her episode of tetany that she could not sit on her heels from childhood and her basal ganglia calcification in head CT scan suggest the long disease duration. Germline whole exome sequence detected a rare variant in GNA11 gene; c.1023C&amp;gt;A resulted in p.Phe341Leu. There were no relevant pathogenic variants in other candidate genes such as CASR, PTH, and GCM2. Treatment with 2 µg/day of alfacalcidol and 1200 mg/day of calcium aspartate could not normalize serum calcium level (7.0 mg/dL) and serum phosphate level (5.3 mg/dL) even after 1 year. Conclusions: The pathogenicity of the variant, p.Phe341Leu, in GNA11 gene was previously confirmed [1]. ADH type 2 is extremely rare as our literature review found only four previous reports; 17 patients in 5 families [1–4]. Phenotypes of the present case are mild and skeletal growth is normal. Meanwhile, we are having difficulty in management of her hypocalcemia, even though Graves’ disease might affect her bone metabolism. Optimal therapy for ADH type 2 needs further investigation.

A Novel Variant in the CASR Gene c.368T&amp;gt;Cp.(Leu123Ser) in a Case of Hypocalcemia Refractory to Standard Medical Therapy

Introduction: Hypoparathyroidism is characterized by low or inappropriately normal PTH production, hypocalcemia and hyperphosphatemia. Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of this, caused by heterozygous activating mutations in the CASR gene. Some individuals fail to meet treatment goals despite standard therapy. Clinical Case: A 13-year-old male patient was admitted in the emergency department due to syncope during physical activity. There was no reference to seizures or other complaints. Standard screening for metabolic diseases revealed no changes at the 7th day of life and family history was unremarkable. There was a history of febrile seizures up to 5 years of age with several hospitalizations for diagnosis investigation that were inconclusive. Physical examination showed a positive Chvostek signal, without other changes. A basic workup revealed hypocalcemia 1.67mmol/L (NR: 2.19-2.66), hyperphosphatemia 3.06mmol/L (NR: 0.95-1.75), hypomagnesemia 0.62mmol/L (NR: 0.7-1.0), low 25Hydroxyvitamin D 8.7ng/mL (NR: >30ng/mL) and inappropriately low PTH 4.0pg/mL (NR: 16.0-87.0). Cranial computed tomography scan showed bilateral calcifications of the basal ganglia. Dual-energy x-ray absorptiometry revealed bone mineral density z-scores increased 15% in spine lumbar and decreased 7% in left femur. Cardiac ultrasound and electrocardiography were normal. The patient started therapy with intravenous calcium gluconate. During this treatment, he developed significant calcification of the peripheral veins at the site of administration, leading to intravenous therapy suspension. The dose of oral calcium, calcitriol and magnesium was gradually increased and sevelamer started to control hyperphosphatemia. Despite the optimization, the patient maintained hypocalcemia refractory to standard therapy. As a last resource strategy in therapeutic optimization, the patient started on rhPTH (1-34). Ever since, the patient has been clinically asymptomatic with biochemical stability and with a reasonable quality of life. At age 18, renal ultrasound revealed diffuse medullary nephrocalcinosis.The genetic testing revealed a novel variant c.368T>C p.(Leu123Ser) likely pathogenic in heterozygosity in the CASR gene, suggesting the diagnosis of ADH type 1. The patient′s mother did not give her consent for genetic study and patient’s father had already died with a diagnosis of acute leukemia. Conclusion: This case can be explained by the presence of a likely pathogenic variant in heterozygosity in the CASR gene that has been described in the medical literature that has not been identified in gnomAD population database, suggesting the diagnosis of ADH type 1. rhPTH (1-34) may be a treatment option for those individuals who are not well controlled on standard therapy, but long-term follow-up studies are needed to reinforce its safety.

The role of calcium-sensing receptor signaling in regulating transepithelial calcium transport.

The calcium-sensing receptor (CaSR) plays a critical role in sensing extracellular calcium (Ca2+) and signaling to maintain Ca2+ homeostasis. In the parathyroid, the CaSR regulates secretion of parathyroid hormone, which functions to increase extracellular Ca2+ levels. The CaSR is also located in other organs imperative to Ca2+ homeostasis including the kidney and intestine, where it modulates Ca2+ reabsorption and absorption, respectively. In this review, we describe CaSR expression and its function in transepithelial Ca2+ transport in the kidney and intestine. Activation of the CaSR leads to G protein dependent and independent signaling cascades. The known CaSR signal transduction pathways involved in modulating paracellular and transcellular epithelial Ca2+ transport are discussed. Mutations in the CaSR cause a range of diseases that manifest in altered serum Ca2+ levels. Gain-of-function mutations in the CaSR result in autosomal dominant hypocalcemia type 1, while loss-of-function mutations cause familial hypocalciuric hypercalcemia. Additionally, the putative serine protease, FAM111A, is discussed as a potential regulator of the CaSR because mutations in FAM111A cause Kenny Caffey syndrome type 2, gracile bone dysplasia, and osteocraniostenosis, diseases that are characterized by hypocalcemia, hypoparathyroidism, and bony abnormalities, i.e. share phenotypic features of autosomal dominant hypocalcemia. Recent work has helped to elucidate the effect of CaSR signaling cascades on downstream proteins involved in Ca2+ transport across renal and intestinal epithelia; however, much remains to be discovered.

GNA11 Variants Identified in Patients with Hypercalcemia or Hypocalcemia.

Familial hypocalciuric hypercalcemia type 2 (FHH2) and autosomal dominant hypocalcemia type 2 (ADH2) are due to loss- and gain-of-function mutations, respectively, of the GNA11 gene that encodes the G protein subunit Gα11, a signaling partner of the calcium-sensing receptor (CaSR). To date, four probands with FHH2-associated Gα11 mutations and eight probands with ADH2-associated Gα11 mutations have been reported. In a 10-year period, we identified 37 different germline GNA11 variants in >1200 probands referred for investigation of genetic causes for hypercalcemia or hypocalcemia, comprising 14 synonymous, 12 noncoding, and 11 nonsynonymous variants. The synonymous and noncoding variants were predicted to be benign or likely benign by in silico analysis, with 5 and 3, respectively, occurring in both hypercalcemic and hypocalcemic individuals. Nine of the nonsynonymous variants (Thr54Met, Arg60His, Arg60Leu, Gly66Ser, Arg149His, Arg181Gln, Phe220Ser, Val340Met, Phe341Leu) identified in 13 probands have been reported to be FHH2- or ADH2-causing. Of the remaining nonsynonymous variants, Ala65Thr was predicted to be benign, and Met87Val, identified in a hypercalcemic individual, was predicted to be of uncertain significance. Three-dimensional homology modeling of the Val87 variant suggested it was likely benign, and expression of Val87 variant and wild-type Met87 Gα11 in CaSR-expressing HEK293 cells revealed no differences in intracellular calcium responses to alterations in extracellular calcium concentrations, consistent with Val87 being a benign polymorphism. Two noncoding region variants, a 40bp-5'UTR deletion and a 15bp-intronic deletion, identified only in hypercalcemic individuals, were associated with decreased luciferase expression in vitro but no alterations in GNA11 mRNA or Gα11 protein levels in cells from the patient and no abnormality in splicing of the GNA11 mRNA, respectively, confirming them to be benign polymorphisms. Thus, this study identified likely disease-causing GNA11 variants in <1% of probands with hypercalcemia or hypocalcemia and highlights the occurrence of GNA11 rare variants that are benign polymorphisms. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Calcilytic NPSP795 Increases Plasma Calcium and PTH in an Autosomal Dominant Hypocalcemia Type 1 Mouse Model.

ABSTRACTCalcilytics are calcium‐sensing receptor (CaSR) antagonists that reduce the sensitivity of the CaSR to extracellular calcium. Calcilytics have the potential to treat autosomal dominant hypocalcemia type 1 (ADH1), which is caused by germline gain‐of‐function CaSR mutations and leads to symptomatic hypocalcemia, inappropriately low PTH concentrations, and hypercalciuria. To date, only one calcilytic compound, NPSP795, has been evaluated in patients with ADH1: Doses of up to 30 mg per patient have been shown to increase PTH concentrations, but did not significantly alter ionized blood calcium concentrations. The aim of this study was to further investigate NPSP795 for the treatment of ADH1 by undertaking in vitro and in vivo studies involving Nuf mice, which have hypocalcemia in association with a gain‐of‐function CaSR mutation, Leu723Gln. Treatment of HEK293 cells stably expressing the mutant Nuf (Gln723) CaSR with 20nM NPSP795 decreased extracellular Ca2+‐mediated intracellular calcium and phosphorylated ERK responses. An in vivo dose‐ranging study was undertaken by administering a s.c. bolus of NPSP795 at doses ranging from 0 to 30 mg/kg to heterozygous (Casr +/Nuf ) and to homozygous (Casr Nuf/Nuf ) mice, and measuring plasma PTH responses at 30 min postdose. NPSP795 significantly increased plasma PTH concentrations in a dose‐dependent manner with the 30 mg/kg dose causing a maximal (≥10‐fold) rise in PTH. To determine whether NPSP795 can rectify the hypocalcemia of Casr +/Nuf and Casr Nuf/Nuf mice, a submaximal dose (25 mg/kg) was administered, and plasma adjusted‐calcium concentrations measured over a 6‐hour period. NPSP795 significantly increased plasma adjusted‐calcium in Casr +/Nuf mice from 1.87 ± 0.03 mmol/L to 2.16 ± 0.06 mmol/L, and in Casr Nuf/Nuf mice from 1.70 ± 0.03 mmol/L to 1.89 ± 0.05 mmol/L. Our findings show that NPSP795 elicits dose‐dependent increases in PTH and ameliorates the hypocalcemia in an ADH1 mouse model. Thus, calcilytics such as NPSP795 represent a potential targeted therapy for ADH1. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

SAT-347 Diagnosis of Autosomal Dominant Hypocalcemia Type 1 Following the Initiation of Imatinib for Treatment of Chronic Myeloid Leukemia

Background: Autosomal Dominant Hypocalcemia Type 1 is an underdiagnosed condition due to the vast majority of patients being asymptomatic and having mild hypocalcemia. Imatinib has been associated with hypophosphatemia and hypocalcemia. Clinical Case: 69-year-old man who had a long history of asymptomatic mild hypocalcemia, calcium level of 7.9 mg/dL (8.4 – 10.2 mg/dL) diagnosed with chronic myeloid leukemia and developed symptoms of hypocalcemia within 2 months of treatment with imatinib. After the initiation of imatinib, his calcium reduced to 6.8 mg/dL (8.4 – 10.2 mg/dL) with a corresponding ionized calcium of 0.98 mmol/L (1.12–1.32 mmol/L) within 2 months. He developed tetany. With the reduced calcium level his PTH was unexpectedly low-normal at 34 pg/mL (16–62 pg/mL). He also had a higher than expected urinary calcium of 342 mg/24 hours. The PTH and 24-hour urinary calcium levels raised concern for an underlying diagnosis of autosomal dominant hypocalcemia type 1. His phosphorous was normal at 3.3 mg/dL (2.6–4.9 mg/dL). He never had hypophosphatemia, which is common with imatinib.After two doses of IV calcium and initiation of oral calcium replacement, 1000 mg BID, his level continued to be reduced with symptoms. Given his symptoms, laboratory results, and continued hypocalcemia he underwent genetic testing. Results of his genetic testing showed a p.Thr151Met mutation in the CASR gene consistent with autosomal dominant hypocalcemia type 1. With this diagnosis, there is concern for nephrolithiasis with over treatment. His symptoms resolved with treatment with calcium 1000mg TID, calcitriol 0.25 mg BID and vitamin D3 2000 IU daily. He has not developed nephrolithiasis and his urinary calcium increased to 424mg/24 hours. A thiazide diuretic is being considered to decrease urinary calcium excretion.He continues on imatinib with an excellent response to therapy. It is likely that the trigger for symptomatic severe hypocalcemia was initiation of imatinib superimposed on the hypocalcemia type 1. Possible mechanisms for this are decreased intestinal absorption, increased urinary loss, or decreased dissolution from bone. 1 These mechanisms are also associated with hypophosphatemia, which our patient did not have. Another possible cause could be an immune mediated destruction of the parathyroid gland, a rare finding seen with other tyrosine kinase inhibitors.2 Conclusion: This is the first reported case of imatinib triggering severe symptomatic hypocalcemia leading to the diagnosis of underlying autosomal dominant hypocalcemia type 1.

Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population

The calcium-sensing receptor (CaSR) regulates serum calcium concentrations. CASR loss- or gain-of-function mutations cause familial hypocalciuric hypercalcemia type 1 (FHH1) or autosomal-dominant hypocalcemia type 1 (ADH1), respectively, but the population prevalence of FHH1 or ADH1 is unknown. Rare CASR variants were identified in whole-exome sequences from 51,289 de-identified individuals in the DiscovEHR cohort derived from a single US healthcare system. We integrated bioinformatics pathogenicity triage, mean serum Ca concentrations, and mode of inheritance to identify potential FHH1 or ADH1 variants, and we used a Sequence Kernel Association Test (SKAT) to identify rare variant-associated diseases. We identified predicted heterozygous loss-of-function CASR variants (6 different nonsense/frameshift variants and 12 different missense variants) in 38 unrelated individuals, 21 of whom were hypercalcemic. Missense CASR variants were identified in two unrelated hypocalcemic individuals. Functional studies showed that all hypercalcemia-associated missense variants impaired heterologous expression, plasma membrane targeting, and/or signaling, whereas hypocalcemia-associated missense variants increased expression, plasma membrane targeting, and/or signaling. Thus, 38 individuals with a genetic diagnosis of FHH1 and two individuals with a genetic diagnosis of ADH1 were identified in the 51,289 cohort, giving a prevalence in this population of 74.1 per 100,000 for FHH1 and 3.9 per 100,000 for ADH1. SKAT combining all nonsense, frameshift, and missense loss-of-function variants revealed associations with cardiovascular, neurological, and other diseases. In conclusion, FHH1 is a common cause of hypercalcemia, with prevalence similar to that of primary hyperparathyroidism, and is associated with altered disease risks, whereas ADH1 is a major cause of non-surgical hypoparathyroidism.