Oral Calcium Research Articles

A Novel GATA3 Variant Causing Familial Hypoparathyroidism, Renal Agenesis and Sensorineural Deafness Presenting With Atypical Symptoms of Chronic Hypocalcaemia

Introduction: Familial hypoparathyroidism is a rare cause of hypocalcaemia. We report a case of long-standing hypocalcaemia secondary to hypoparathyroidism caused by a novel GATA3 variant resulting in multiple organ involvement. Case: A 20 year old girl was referred to our bone metabolic clinic for hypocalcaemia. Her past medical history included Bechet’s disease, epilepsy and depression. She had bilateral sensorineural hearing loss and encephalitis as a child. She underwent right nephrectomy for an atrophic non-functioning kidney at the age of 16. Current medication included hydroxychloroquine, diazepam, oral calcium and cholecalciferol. It was noted that the hypocalcaemia dated back to 8 years, she denied any typical symptoms of hypocalcaemia but she did report visual and auditory hallucinations, fatigue and had low seizure threshold. She sustained recurrent fractures of her arm, elbow and wrist. Initial investigations: Corrected calcium 1.88 (2.20-2.60mmol/L), Phosphate 1.54 (0.80–1.50mmol/L), PTH 1.2 (1.6–6.9pmol/), 25-OH vitamin D 37 (50-120nmol/L). Myeloma screen, thyroid, renal and liver functions were all within the normal reference range. Other bone markers: Serum Procollagen Type 1 Amino Terminal Peptide was mildly raised at 82 (19-69ug/L), CTX 0.42 (0.1-0.5ug/L), 1,25 OH Vitamin D 29 (55-139pmol/L), 24,25-dihydroxyvitamin D was normal with normal 25:24,25 Dihyroxyvitamin D ratio at 18 normal. Bone density was in the normal range for her age. MRI of the brain was normal with no evidence of calcification. There was a family history of hypocalcemia in her estranged father. Subsequent genetic analysis showed a novel likely pathogenic GATA3 missense variant (c.961T>C p.(Cys321Arg). She was started on alfacalcidol and achieved near normocalcemia with adjusted calcium levels of 2.18nmol/L. Conclusion: Pathogenic variants in the GATA3 gene are responsible for Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome. In our patient, a novel missense variant in GATA3, p.(Cys321Arg), has been detected. This variant disrupts one of four conserved cysteine residues within a zinc-finger domain, which is involved in DNA binding and is presumed to have a deleterious effect on protein function. Patients may have longstanding asymptomatic hypocalcaemia with atypical features hence genetic testing is recommended in patient with multi-organ involvement. Alfacalcidol successfully restored calcium homeostasis in this case.

Rare Case of Severe Hypocalcemia Due to PTH Resistance Related to Diet Pill

Introduction: The production of parathyroid hormone (PTH) is essential for calcium the maintenance of normal mineral metabolism. Parathyroid cells have cell-surface calciumsensing receptors, even small changes in extracellular Ca induce rapid changes in PTH secretion. Hypocalcaemia is a well-recognized manifestation of magnesium deficiency. We present rare case of severe hypocalcemia due to PTH resistance caused by hypomagnesemia related to diet pill. Case Report: 61 year old Hispanic obese female with chronic gastritis on omeprazole 20 mg daily, no other significant past medical and surgical history, not taking any prescribed medications presents to ED with complaints of tingling and numbness around the mouth, abdominal cramps, chest pain, shortness of breath and anxiety. On arrival calcium was found to be 6.0mg/dl(8.2–10.2mg/dl) with ionized calcium of 0.60mmol/l(1.13-1.32mmol/l) and EGFR>90ml/min, Albumin-4.0g/l, Magnesium-1.1mg/dl(1.6–2.3mg/dl), Phosphorus-6.1mg/dl(2.4–4.5mg/dl),rest of the electrolytes were normal. Patient was given IV calcium gluconate 2g and magnesium which helped improving her symptoms. PTH was 1700pg/ml(23-73pg/ml), low Vitamin D 25-hydroxy 20ng/dl(30-100ng/dl). Urinary calcium was <1mg/dl(2.0–17.5mg/dl). Vitamin D1,25- dihydroxy 34pg/ml(18-78pg/ml), PTH-like peptide levels 0.6pmol/l(<4.2pmol/l). EKG was normal no QT interval changes. For 4 weekspatient was taking weight loss medication was given to her by her brother called nucific-bio-x4. Patient had lost 4 pounds while taking the medication and had suppression of appetite. Physical features of pseudohypoparathyroidism were not seen. Patient had poor dietary intake of calcium, denied taking vitamin D supplements. Patient was given calcium acetate 2001 mg TID with meals, calcitriol 0.5mcg daily and calcium gluconate 2g IV intermittently was given. That improved her calcium levels to 6.8mg/dl with ionized calcium-0.90mmol/l. Magnesium was replaced IV and discharged on magnesium oxide 400mg BID to maintain magnesium the normal range. The patient was given loading dose of ergocalciferol 50,000 IUfor 8 weeks. At the time of discharge repeat PTH levels were 1600 pg/ml and calcium levels were 8.2mg/dl. 3D CT of the neck did not parathyroid mass. After discharge patient continued on oral calcium and magnesium to maintain calcium levels between 8.4–10.2mg/dl. After discharge calcium levels were 8.6mg/dl, vitamin D 25-hydroxy levels were 32ng/dl and maintenance dose of vitamin D3 2000 IU daily also continued. Nucific-bio-x4 pill was discontinued. Conclusion: In conclusion, severe life threatening hypocalcemia can occur with unsupervised weight lossmedications due to malabsorption of magnesium in patient with likely mutation in magnesium receptors causing PTH resistance. Vitamin D deficiency worsens hypocalcemia resulting into secondary hyperparathyroidism.

Denosumab Induced Severe Prolonged Hypocalcemia in Metastatic Prostate Cancer

Background: Denosumab is a RANK-l inhibitor that, in addition to the treatment of osteoporosis, is used in patients with advanced cancer and metastatic bone disease to prevent skeletal-related events. Although denosumab is generally safe and effective, it can cause hypocalcemia which in some patients can be severe and life threatening. We present a case of severe prolonged hypocalcemia after a single dose of denosumab in a patient with metastatic prostate cancer. Case: A 78-year-old male with a past medical history of stage 4 prostate cancer on antiandrogen treatment with GnRH antagonist presented with severe hypocalcemia. Physical exam revealed a blood pressure 125/80 mm Hg, pulse 115 per min and weight 135 lb with negative Chvostek’s and Trousseau’s signs. The electrocardiogram showed supraventricular tachycardia with prolonged QTc interval of 503 ms (<430 ms). Labs showed serum calcium 4.9mg/dL (8.5–10.5), albumin 2.5g/dL (3.6–5.1), corrected calcium 5.7 mg/dL, ionized serum calcium 0.64mmol/L (1.05–1.3), creatinine 1.10mg/dL (0.7–1.2), eGFR >60, phosphorus 2.0mg/dL (2.5–4.5), magnesium 1.9 mg/dL (1.6–2.6), 25-OH vitamin D 29.7 ng/mL (30–100), 1,25 dihydroxy vitamin D 174 pg/mL (18–64), iPTH 244.0 pg/mL (11–68) and PSA 1860 ng/mL. Three weeks prior to presentation, the patient received 120 mg of subcutaneous denosumab. Pre-treatment serum calcium was 9.2 mg/dL (8.5–10.5), and Tc-99m bone scan showed multiple osteoblastic osseous metastatic lesions involving both axial and appendicular skeleton. The patient was diagnosed with denosumab-induced severe hypocalcemia and started on intravenous (IV) calcium gluconate infusion, oral phosphate 250 mg twice daily, and ergocalciferol 50,000 IU twice weekly. He required IV calcium gluconate up to 10 g per day in addition to oral calcium carbonate 2 g t.i.d. for 2 weeks to resolve hypocalcemia and normalize QTc interval. Patient was discharged to nursing home on calcium carbonate 2 g q.i.d. with IV calcium gluconate as needed to keep corrected calcium >8.0 mg/dL. After discharge he required up to 4 g of IV calcium and 8 g of oral calcium per day. Unfortunately, he presented again with severe hypocalcemia 5 weeks after discharge. In addition to current regimen of oral and IV calcium boluses, low dose calcitriol was started. We were only able to maintain his serum calcium>8.0 mg/dL by administering high daily dose of oral calcium carbonate 8 g /day and calcitriol 2 mcg daily. Due to poor prognosis, he was transitioned to hospice care and died 2 weeks later. Discussion: There are not many case reports on severe prolonged hypocalcemia secondary to denosumab in cancer patients but normal kidney function. Our patient remained on high dose of calcium even 101 days after denosumab administration. Reference: 1. Milat F et al. Prolonged hypocalcemia following denosumab therapy in metastatic hormone refractory prostate cancer. Bone. 2013 Aug 1;55(2):305–8.

Effect of Oral Calcium Supplementation on Insulin Sensitivity in Patients With Metabolic Syndrome

Background: Evidence from epidemiological research suggests that dietary calcium may protect against metabolic abnormality in populations at high risk. Observational studies show the relationship between dietary calcium intake and metabolic syndrome. However evidence for beneficial effect of elemental calcium supplementation on metabolic syndrome is limited. Aims: Present studydetermined whether oral calcium supplementation reduced insulin resistance in patients with metabolic syndrome or not. Methods; Hundred patients who have metabolic syndrome without diabetes mellitus, parathyroid disease, chronic renal failure, pregnancy and lactationwere randomly allocated to the group receiving 1500 mg/ day of elemental calcium as calcium carbonate for 8 weeks and the control group. The primary outcome was change in insulin resistance as measured by homeostasis model assessment of insulin resistance (HOMA-IR). Other outcomes were changes of serum free ionized calcium (FiCa) level with accompanying serum parathyroid hormone (PTH) level. Fasting serum glucose was measured by glucose oxidase method. Serum insulin and PTH level were measured by enzyme linked immunoassay. Total serum ionized calcium was analyzed by Atomic Absorption Spectrophotometry. Serum FiCa(mg/dl) level was calculated by using following formula = [6Ca-(K/3)]/(K+6). Results: Mean age of participants was 47.38±13.2 years in calcium supplement group (n = 50) and 49.46±12.9 years in control group (n=50). Mean body mass index was not significant different between two groups (30.91 ±4.23 vs 30.37 ± 4.62 kg/m2). More female were involved in both group, 72% vs 62% respectively. Baseline biochemical parameters of the participants between two groups were not significantly different. After 8 week intervention period, mean serum FiCa increased significantly from 2.64±1.19 mg/dl to 5.82± 5.59 mg/dl, p<0.0001, serum PTH decreased significantly from 57.88 ±17.05 pg/ml to 35.7±23.12 pg/ml, p<0.0001, HOMA-IR decreased significantly from 5.14 ± 3.71 to 2.94±1.51, p<0.0001. None of these parameters were significantly affected in control group. By comparing biochemical changes of calcium supplement group to control group, Mean (SEM) of paired difference changes were observed in serum FiCa level [3.18(0.81) vs 0.81(0.25)mg/dl, p<0.05], serum PTH level [22.18(3.24) vs 3.58(1.99)pg/ml, p<0.0001] and HOMA-IR [2.19(0.45) vs 0.43(0.21), p<0.05]. It indicated that elemental calcium supplementation not only reduced insulin resistance but also decompensated the higher level of PTH to normal range by replenishing FiCa significantly. Conclusion: Eight-week oral elemental calcium supplementation of 1500mg/day showed beneficial effect on insulin sensitivity in patients with metabolic syndrome.

Prolonged Hypocalcemia After a Single Dose of Denosumab in Chronic Kidney Disease

Introduction: Denosumab, a monoclonal antibody that inhibits RANK L (receptor activator nuclear factor-kappa beta ligand), is one of the few medications that can be used to treat osteoporosis in patients with chronic kidney disease (CKD). However, its use is associated with a much higher incidence of hypocalcemia in this patient population. What remains unclear is the duration of hypocalcemia after denosumab use. We describe a case of prolonged hypocalcemia of 9 months in a patient with CKD after a single dose of denosumab. Case: A 64-year-old Caucasian man with a history of bilateral lung transplant for interstitial pulmonary fibrosis and CKD Stage IV was referred to the Endocrinology clinic for evaluation of steroid-induced osteoporosis. Bone density scan was consistent with osteoporosis with the lowest T-score of -2.8 at the left femoral neck, which showed a 25.3% decline from a previous one two years prior. His labs upon initial visit: 25 hydroxy Vitamin D: 36.5 ng/mL (30–100), 1, 25 hydroxy vitamin D 32 pg/ml (19.9–79.3), corrected Serum Calcium 8.9 mg/dL (8.5–10.5), Serum Cr 4.38 mg/dL (0.6–1.4), PTH 157 pg/mL (10–65), Serum Alkaline Phosphatase 61 Units/L (25–125), Urine NTX 39 nM BCE/mM creatinine (21–83). After discussing risks and benefits, he was given a dose of subcutaneous denosumab 60 mg. He had been started on Calcium/Vitamin D (600 mg/400 IU BID) prior to receiving his dose. Keeping in mind the increased risk of hypocalcemia given his history of CKD, his corrected serum calcium was checked one week later, and it was 6.5 mg/dL. The patient was asymptomatic. However, given the severity of his hypocalcemia, he was started on calcitriol 0.25 mcg oral BID and calcium carbonate 1200 mg daily. He did show mild improvement in three days to a corrected calcium of 7.0 mg/dL. His calcitriol was briefly increased to 0.5 mcg BID and calcium carbonate was increased to 1800 mg daily. The regimen was weaned to calcitriol 0.25 mcg daily and previous calcium/Vitamin D dosing later that month. Thereafter, his labs were monitored regularly and there were several unsuccessful attempts made to decrease the calcitriol/calcium carbonate. Given persistent hypocalcemia, other bloodwork including a bone specific alkaline phosphatase and celiac screen were checked which were unremarkable. Finally, nine months after his denosumab dose, calcitriol was discontinued safely. Serum calcium levels have remained stable thereafter. Given prolonged hypocalcemia, it was decided not to administer another dose of denosumab. Conclusion: Patients with CKD who receive denosumab are not only at risk for developing severe, but also prolonged hypocalcemia. Therefore, it is imperative to monitor serum calcium levels, not only immediately after receiving a dose, but serially.

Tumor Induced Osteomalacia - Long Term Medical Treatment When Surgery Is Risky

Introduction: Tumor induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by bone pain, muscle weakness and fractures caused by production of a phosphaturic factor by rare mesenchymal bone or soft tissue tumors that causes isolated renal phosphate loss and osteomalacia. Low phosphate (iP), high bone alkaline phosphatase (BAP), and normal or low 125 dihydroxy D, are salient biochemical findings. Fibroblast derived growth factor (FGF 23) may be high or inappropriately normal. Gallium-68 Dotatate (DoT) imaging has become the imaging method of choice. Long term medical management may be required when removal of the tumor is risky or not feasable. Case Report: 65 yr old woman with carcinoid tumor of the right lung and a bony lesion in the T3 vertebral body diagnosed with TIO. She was initially screened for osteoporosis after traumatic rib fractures. Bone scan and SPECT-CT revealed numerous foci of increased uptake. She had elevated alkaline phosphatase 186 IU/L (0–140) and PTH 83 pg/ml (15–65) with a low phosphate 1.5 mg/dl (2.5–4.5), along with normal FGF23 level 102 RU/ml Ref Range < + 180 RU/ml. DoT and PET CT imaging for TIO evaluation showed a foci of increased uptake right lower lobe of her lung, and “osseous metastatic disease” in the right scapula, vertebral body, iliac, and pubic ramus. Sclerosis of T3 vertebral body was noted in the area of intense Gallium Dotatate uptake. Transbronchial excision of the lesion showed a well differentiated neuroendocrine carcinoma. Chromogranin A and 24 hour urine for 5HIAA were normal. She responded well to medical therapy with oral phosphate, calcium and calcitriol. Follow up, DoT and FDG PET showed persistent intense uptake in the sclerotic lesion on T3 vertebral body, while the rest of the hot spots resolved. Sclerotic T3 lesion is likely the primary lesion that is responsible for the TIO. Neuroendocrine tumor of the lung may be a mere association. Biopsy of the T3 lesion was not feasible and excision was considered risky to the patient. Discussion: Our case illustrates that awareness is the key to early diagnosis of TIO. FGF 23 in some TIO cases may be inappropriately normal in commercial assays and even in research labs. Measurement of fibronectin 1 (FN1) and FGF receptor 1 fusion gene which is noted in up to 60% of tumors are not commercially available. While DoT and PET CT are imaging modality of choice, CT and MRI may be useful to define the anatomy of the lesion. Long term medical management may be necessary when removal of primary lesion is not possible or risky. Most tumors are benign while some may prove to be malignant.

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.

Ectopic Cushing’s Syndrome and Severe Hypocalcemia Due to Medullary Thyroid Cancer Responsive to Selpercatinib

Introduction: Cushing’s syndrome (CS) due to ectopic ACTH production from medullary thyroid carcinoma (MTC) is characterized by rapid progression of disease, leading to hyperglycemia and hypokalemia. However, hypercortisolemia leading to hypocalcemia is rarely seen. Initiation of selpercatinib greatly improved hypocalcemia and ectopic CS in this case. Clinical Case: A 41-year-old man with a history of MTC (variant RET p.M918T) post thyroidectomy in 2018 developed progressive weight gain, lower extremity edema, weakness, new onset diabetes, severe refractory hypocalcemia and hypokalemia requiring multiple hospitalizations. On initial presentation to our institution, he was lethargic, had multiple ecchymoses, peripheral edema and proximal myopathy. Laboratory evaluation revealed Ca 5.4 mg/dL (NR 8.9 - 10.3), albumin 3 g/dL (NR 3.5 - 5.1), iPTH 1.4 pmol/L (NR 1.6 - 6.9), 25-OH vitamin D 23 pg/mL (NR 25–80) while taking elemental calcium 1500 mg every 6h, calcitriol 0.25 mcg/d and vitamin D3 1000 IU/d. Serum cortisol measured at 9:30 pm was 136 ug/dL (NR 2.5–11.9), ACTH 1,145 pg/mL (NR 7.2–63.3) and 24-h UFC 27,629 ug/d consistent with CS due to ectopic ACTH production. Calcitonin and CEA were 18,687 pg/mL (NR 0–7.5) and 3,766 ng/mL (NR 0–4.7). CT abdomen revealed numerous bilateral liver lesions and bilateral adrenal hyperplasia. In addition to high doses of oral calcium and calcitriol, he required calcium drip up to 1.5mg/kg/hr for about 1 week. He simultaneously began cabozantinib, ketoconazole and metyrapone. Hospital course was complicated by infections and recurrent scrotal bleeding, so he was switched to selpercatinib. Two days after starting selpercatinib, ketoconazole was discontinued, and metyrapone has been gradually reduced. Most recent calcitonin was 149 pg/mL, CEA 97.8 ng/mL and 24-h UFC 10 ug/d on metyrapone 250 mg twice daily. Similarly, refractory hypocalcemia greatly improved, last serum Ca was 8.3 mg/dL on elemental calcium 480 mg/d. He has made significant clinical gains and has returned home from rehab. Clinical Lesson: Hypocalcemia is rarely described as a complication in patients with CS. Our patient had underlying hypoparathyroidism and vitamin D deficiency; however, hypocalcemia was initially refractory to high doses of calcium and calcitriol and only improved with treatment of CS. We suspect hypercortisolemia impaired 25 to 1,25 D activation, thereby reducing calcium absorption, and likely inducing hypercalciuria. These deleterious effects of severe hypercortisolemia combined with underlying hypoparathyroidism led to severe and refractory hypocalcemia requiring repeated admissions, and only improved once his ectopic CS due to MTC was recognized and controlled. The RET kinase inhibitor, selpercatinib, induced a rapid decline in calcitonin, CEA and ACTH levels, and with metyrapone, enabled control of hypercortisolemia and its complications.

Profound Hypocalcemia Following Thyroidectomy for Graves’ Disease

Abstract Introduction: While transient parathyroid insufficiency is not an uncommon complication of thyroidectomy, severe and prolonged hypocalcemia attributed to a combination of post-surgical hypoparathyroidism, hungry bone syndrome (HBS) and hypovitaminosis D is unusual. Clinical Case: A 17-year-old female from a remote community in Australia with Graves’ disease, complicated by exophthalmos and atrial flutter, underwent total thyroidectomy due to challenges with medication adherence leading to persistent thyrotoxicosis. FT4 was &amp;gt;150 pmol/L (normal 10–20 pmol/L) almost two years after diagnosis. Pre-operatively, she received Lugol’s iodine, carbimazole and beta-blockade. The operation was uncomplicated and three parathyroid glands were preserved. Within six hours of thyroidectomy, she developed symptomatic hypocalcemia with corrected calcium 1.9 mmol/L (7.6 mg/dL) (normal 2.2–2.65 mmol/L). PTH level was 0.8 pmol/L (normal 1.4–9.0 pmol/L). Magnesium and phosphate levels were initially normal but hyperphosphatemia developed the following day. 25-OH vitamin D was low (29 nmol/L, normal 50–150 nmol/L) and was corrected with high dose cholecalciferol. Despite use of continuous intravenous calcium gluconate in addition to oral calcium carbonate, as well as both intravenous and oral calcitriol and magnesium, urinary calcium excretion remained undetectable. Teriparatide 20 mcg BD was commenced on post-operative day 14 with no demonstrable improvement in serum calcium. Less than 48 hours after cessation of parenteral calcium on day 18 post-operation, corrected calcium and ionised calcium declined to 1.47 mmol/L (5.9 mg/dL) and 0.46 mmol/L (normal 1.15–1.33 mmol/L) respectively, prompting recommencement of calcium infusion. Her remarkably high requirement for calcium replacement with negligible urinary calcium excretion for at least one month in spite of parenteral calcium infusion for a total of three weeks’ duration is highly suggestive of HBS which became evident due to post-surgical hypoparathyroidism. She had elevated ALP (618 U/L, normal 35–140 U/L) and increased bone resorption marker (N-telopeptide/creatinine 262 nmol BCE/mmol, normal &amp;lt;100 nmol BCE/mmol), with osteopenia at lumbar spine (Z-score -1.7) and femur (Z-score -1.3). Additionally, vitamin D deficiency is likely to have contributed to the severity of hypocalcemia. 60 days after surgery, she was still requiring calcium carbonate 2500 mg QID (4 g/day elemental calcium) and calcitriol 1 mcg TDS. Her phosphate level had normalised and ALP gradually declined to 241 U/L. Clinical Lesson: This case highlights the importance of attaining euthyroid status as early as possible pre-operatively to allow near-complete reversal of thyrotoxicosis-induced osteodystrophy, as indicated by normalisation of serum ALP, and ensuring vitamin D levels are replete prior to thyroidectomy for Graves’ disease.

A Case Report on Parathyroid Carcinoma - an Extremely Rare Endocrine Malignancy

Abstract Background: Parathyroid carcinoma is an extremely rare endocrine malignancy with a prevalence of &amp;It 1%. It is associated with hyperparathyroidism-jaw tumor syndrome (HJTS), multiple endocrine neoplasia (MEN) type 1 or 2A syndromes, secondary hyperparathyroidism, and chronic kidney disease. Incidence is equal in both men and women. Patients may present with symptoms of hypercalcemia, and should be further worked up with neck ultrasound, Tc-99m sestamibi imaging, single-photon emission computed tomography, magnetic resonance imaging, positron emission tomography combined with CT scan, and biopsy of the parathyroid mass. Parathyroid carcinoma can be treated surgically with complete resection. Patients treated with En-bloc resection with microscopically negative margins remain cancer-free for at least three years to a maximum of twenty years. Case Report: A 50-year-old female treated with laparoscopic sleeve gastrectomy for morbid obesity, came for the follow-up visit. She denied any active complaint. Routine Lab work showed mild hypercalcemia, hypophosphatemia, elevated PTH, and alkaline phosphatase. Neck ultrasound showed a cystic lesion adjacent to the right thyroid lobe. Sestamibi (MIBI) parathyroid scintigraphy showed increased radiopharmaceutical uptake by the right superior parathyroid gland without any enlarged or suspicious lymph nodes. Dexa scan was positive for osteopenia. The patient underwent right superior parathyroidectomy along with en-bloc right thyroid lobectomy. Histological examination revealed anaplastic regions, giant cells with abundant cytoplasm, and polymorphous nuclei with a Ki-67 labeling index of 10% consistent with parathyroid carcinoma. Post-surgery imaging with ultrasound and magnetic resonance imaging of the neck computed tomography of the chest, and abdomen, whole-body MIBI scintigraphy was negative for residuals or metastatic disease. She was started on oral calcium carbonate and was monitored regularly with routine lab work. The most recent lab work was within normal limits. Conclusion: Most of the patients with parathyroid carcinoma present in the early stage with the symptoms of hypercalcemia. Many of them do not have symptoms of mass or tumor effects. Parathyroid cancer is a rare malignancy and can be missed, therefore all patients with hypercalcemia should be further evaluated with lab work, imaging, and biopsy to rule out parathyroid carcinoma. Early diagnosis and treatment have a better outcome.

Primary Hyperparathyroidism From Ectopic Parathyroid Adenoma in a Patient With Bilateral Slipped Capital Femoral Epiphysis

Background: Primary hyperparathyroidism has been reported in 13 pediatric patients presenting with slipped capital femoral epiphysis (SCFE), but never in patients with ectopic parathyroid adenoma [1]. Case report: A 12-year-old boy with obesity (BMI 99th percentile) and autism spectrum disorder presented with a limp and was found to have bilateral SCFE. Calcium was elevated to 12.3 mg/dL (reference range 8.0–10.5) with phosphorus of 3.2 mg/dL (3.0–5.7), alkaline phosphatase 775 units/L (40–360), tubular reabsorption of phosphorus 89% (> 95%), 25OH-vitamin D 12.1 ng/mL (30–80), 1,25OH-vitamin D 246.6 pg/mL (19.9–79.3), and PTH 1191 pg/mL (10–65). He had significant neuropsychiatric agitation but denied constipation, polyuria, and other symptoms of hypercalcemia. He had in situ pinning of the SCFE bilaterally and was hyperhydrated with minimal improvement in his calcium level. Neck ultrasound revealed no parathyroid adenoma. He was discharged on cholecalciferol 1000 IU daily with plans for outpatient Tc-99m Sestamibi scintigraphy. Following discharge, he developed significant nausea, did not tolerate the cholecalciferol, and was non-weight bearing. Repeat labs and imaging 5 days later demonstrated calcium had risen to 16.7 mg/dL with phosphorus of 2.2 mg/dL. He was admitted and calcium improved transiently to less than 12 mg/dL with intranasal calcitonin therapy. Sestamibi and subsequent CT scan revealed a 2.7x1.6x1.9 cm ectopic parathyroid adenoma in the upper anterior mediastinum. He had thoracoscopic resection of the mass, which was revealed to be intrathymic, and PTH levels fell from 1613 pg/mL pre-operatively to 76 pg/mL 30 minutes post-resection. Post-operatively, he developed hungry bone syndrome with a calcium nadir of 7.6 mg/dL and phosphorus nadir of 1.6 mg/dL, which required oral calcium and calcitriol for 10 days. With normalization of his calcium, his neuropsychiatric symptoms improved. Pathology revealed a parathyroid adenoma. Conclusion: Primary hyperparathyroidism can be associated with SCFE and should be considered even in patients with traditional risk factors for SCFE, especially with bilateral disease. Pediatric patients with primary hyperparathyroidism and negative neck imaging should be further evaluated for ectopic parathyroid adenomas.

Hypocalcemia in a 15 Year Old With New Onset Type 2 Diabetes Mellitus

Abstract Background: Diabetic ketoacidosis and significant hyperglycemia are associated with known electrolyte derangements in sodium, potassium, and phosphorus. Hypocalcemia and hypoparathyroidism occurring in uncontrolled diabetes are rare. We present a case of new-onset diabetes with severe hypocalcemia. Case: A 15-year-old obese Caucasian male with ADHD and autism presented to the Emergency room due to hyperglycemia found on laboratory evaluation for hypertension. Serum glucose was 563 mg/dL, serum bicarbonate 24 meq/L (21 - 31 meq/L), and HgbA1C 11.4% (4.0 - 5.6%). He was admitted to initiate insulin and for diabetes education. On admission, hypocalcemia was noted: serum calcium 6.6 mg/dL (8.5 - 10.5 mg/dL), alkaline phosphatase 352 units/L (48 - 277 units/L), and albumin 4.6 g/dL (3.5 - 5.0 g/dL). Repeat testing revealed serum calcium 5.1 mg/dL, phosphorus 4.3 mg/dL (2.5 - 4.5 mg/dL), and magnesium 1.7 mg/dL (1.6 - 2.9 mg/dL). He endorsed a 2 month history of tetany, paresthesia, and muscle weakness. Due to food aversions, his dietary intake of calcium and vitamin D was minimal. He had limited sun exposure. Subsequent PTH was 40 pg/mL (10 - 65 pg/mL) with concurrent serum calcium of 6.5 mg/dL. QTc was prolonged [529 msec (&amp;lt;440 msec)], prompting transfer to the intensive care unit for telemetry, intravenous calcium gluconate, and regular calcium monitoring. Treatment was commenced with cholecalciferol 2000 international units daily and oral calcium carbonate (50 mg elemental calcium/kg/day) in divided doses for presumed Vitamin D deficiency. After several intravenous calcium gluconate doses over 24 hours, the patient’s QTc and ionized calcium normalized. At discharge, calcium was 8.5 mg/dL. He was discharged on the above regimen of calcium and cholecalciferol, and basal and bolus insulin. After discharge, laboratory results returned indicating negative diabetes autoantibodies (GAD 65, Insulin, IA-2) and 25-OH Vitamin D &amp;lt;10 ng/mL (30 - 100ng/mL). Two days after discharge, calcium was 7.3 mg/dL. Two weeks later, labs were: 25-OH Vitamin D 11.3 ng/mL, PTH 10.4 pg/mL, and calcium 9.6 mg/dL. Conclusion: This teen presented with new-onset type 2 diabetes and symptomatic hypocalcemia, an atypical feature of new-onset diabetes. This patient’s hypocalcemia was likely due to both vitamin D deficiency and hypoparathyroidism. He had a low vitamin D level and poor calcium intake with elevated alkaline phosphatase; however, his high normal serum phosphorus and inappropriately normal PTH (instead of elevated in the setting of severe hypocalcemia) indicated a component of hypoparathyroidism. Calcium normalized with detectable 25-OH Vitamin D levels but PTH remained low. Our case highlights the importance of recognizing both that electrolyte abnormalities at diabetes onset may not be directly attributable to diabetes/hyperglycemia and that vitamin D deficiency and hypoparathyroidism may co-exist.

Benign, Malignant or Something in Between: A Rapidly Developing Atypical Parathyroid Adenoma

Introduction: Although Primary Hyperparathyroidism (PHPT) is the third most common endocrine disorder, parathyroid carcinoma and atypical parathyroid adenoma are the rarest of endocrine tumours. The true incidence of atypical parathyroid adenomas has been elusive to endocrinologists since it is not possible to differentiate clinically between parathyroid carcinoma and atypical parathyroid adenomas before histological analysis. Atypical parathyroid adenoma represents a group of an intermediate form of parathyroid neoplasms with uncertain malignant potential. The majority of patients present with hypercalcaemia, however the development of atypical adenoma in patients with known PHPT is extremely rare. Clinical Case: A 78-year-old gentleman presented at the emergency department with lethargy and slurred speech which had started 1 week ago. Blood tests revealed severe hypercalcaemia. (Ca 4.98 mmol/L, PTH 114.2 pmol/L). The patient had a background of primary hyperparathyroidism which was diagnosed due to incidental mild hypercalcaemia (Ca 2.71 mmol/L, PTH 17.57 pmol/L, 25OH-vitamin D3 55 nmol/L). 2 weeks prior to presentation to the Emergency Department calcium and PTH levels were stable. On clinical examination, he was found mildly confused with no other clinical findings. No precipitating factors were identified. Hydration with IV crystalloids commenced and bisphosphonate IV was given. In view of PHPT Cinacalcet was added to treatment (30 mg BD). While the calcium levels seemed to improve initially, (lowest level achieved Ca 3.05 mmol/L) a week later they started to rise gradually. Hypercalcaemia proved refractory to medical treatment despite concomitant use of aggressive hydration, increased cinacalcet dose, second intravenous bisphosphonate, and intravenous calcitonin. Neck U/S revealed a probable parathyroid adenoma measuring 2cm axially at the inferior pole of the left thyroid lobe. In view of the severity and refractory nature of hypercalcaemia, a PET CT was requested which identified an 18 mm soft tissue mass in the left lower neck posterior to the left thyroid lobe with moderate to intense FDG uptake. There was no evidence of increased uptake elsewhere. The patient required 2 sessions of haemodialysis to maintain calcium levels around 3.5 preoperatively. He underwent parathyroidectomy with histological findings in keeping with atypical parathyroid adenoma. Gradual reduction of calcium levels was noted post-operatively with the lowest on day 10 (1.99) when he was started on oral calcium supplementation. The patient remains under follow-up with normal calcium levels 6 months postoperatively while remains on calcium and vitamin D3 supplements. Conclusion: To our knowledge, this is the only case of a patient with known primary hyperparathyroidism and mild hypercalcaemia, to develop severe parathyroid crisis with refractory to medical management hypercalcaemia within 2 weeks. Prompt surgical intervention remains of paramount importance in the management of these patients. They should have lifelong follow up in the view of uncertain malignant potential of the atypical parathyroid adenoma.

Diagnostic Accuracy of Different Screening Tools for Identifying Osteoporosis Risk Among Post-Menopausal Filipino Women Aged 45–65 Years

Abstract Early screening of osteoporosis decreases fracture risk. Several identified clinical risk factors led to the development of screening tools to estimate osteoporosis risk. Bone Mineral Densitometry (BMD) as a diagnostic tool for screening is not practical because of high cost and poor availability. The extensively studied osteoporosis screening tools are: Simple Calculated Osteoporosis Risk Estimation (SCORE), the Osteoporosis Risk Assessment Instrument (ORAI), the Age Bulk One or Never Estrogen (ABONE), body weight (WEIGHT), and the Osteoporosis Risk Index (OSIRIS). These tools were developed and validated in Caucasians. Validation of these tools for specific populations is necessary because of the observed variations in BMD across geographic and ethnic groups. To date, the utility of these screening tools in the Philippines is unknown. We conducted a cross-sectional analysis of all patients who underwent BMD screening for osteoporosis in a tertiary hospital from January 2015 to September 2020. The study participants were postmenopausal Filipino women aged 45 to 65 years. The subjects had no history of osteopenia, osteoporosis, hip or spine fractures, use of osteoporosis medications, renal insufficiency, bilateral oophorectomy, hysterectomy, or early menopause. We identified demographic and clinical risk factors. These risk factors were used to calculate the risk score of five osteoporosis risk assessment tools: ORAI, ABONE, WEIGHT, OSTA, and ORISIS. Using the DEXA T-score as an external criterion, the sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, and diagnostic accuracy for each tool were calculated. Included were 1869 subjects with a mean age of 57.9 + 4.3 years old. Osteoporosis, with a T-score of &amp;lt;-2.5 at the lumbar or femoral neck area, was seen in 665 (35.58%). Risk factors such as weight, height, BMI, menopausal years, history of previous fractures, and intake of oral calcium supplements correlated significantly with a higher risk (OR=1.025, 95%CI: 0.974–1.079; OR=1.059, 95%CI: 0.84–1.338; OR=1.063, 95%CI: 0.817–1.383; OR=1.74, 95%CI: 1.198–2.528; and OR=1.088, 95%CI: 0.869–1.319), of having osteoporosis in the said population. ORAI and WEIGHT have the highest probability of identifying patients with a sensitivity of 88.42% and 91.28%, and accuracy of 85.71% and 87.98%. Both performed equally in screening for osteoporosis in this setting. However, ABONE, OSTA, and ORISIS underestimated the number of high-risk osteoporosis patients, because of their low sensitivity and diagnostic accuracy. Both ORAI and WEIGHT are simple and easy to calculate and can serve as an initial screening tool to identify Filipino postmenopausal women who are at high risk for osteoporosis. A prospective study with a correlation of fracture occurrences may provide evidence for the value of these tools as a screening test.

TransCon PTH as a Hormone Replacement Therapy for Patients with Hypoparathyroidism: 6-Month Update from the PaTH Forward Open-Label Extension

Background: Hypoparathyroidism (HP) is characterized by insufficient levels of parathyroid hormone (PTH), resulting in hypocalcemia, hyperphosphatemia, hypercalciuria, and a reduced quality of life (QoL). PTH replacement therapy should restore physiologic levels of PTH and restore downstream physiologic levels of calcitriol, promoting independence from Ca and active vitamin D supplements and normalization of QoL.TransCon PTH is an investigational long-acting prodrug of PTH(1–34) for the treatment of HP. During the initial 4-week fixed-dose period of the PaTH Forward Trial, TransCon PTH enabled 82% of subjects to achieve independence from standard of care (SoC; no active vitamin D and Ca ≤ 500 mg/day) compared to 15% with placebo. Here, we report 6-month (Week 26) results from the open-label extension (OLE). Methods: PaTH Forward is a phase 2, double-blind, placebo-controlled trial evaluating TransCon PTH in adult HP patients treated with SoC. Subjects received fixed doses of TransCon PTH 15, 18, or 21 µg PTH(1–34)/day or placebo for 4 weeks, followed by an OLE period during which TransCon PTH dose was titrated (6–30 µg PTH[1–34]/day) per individual dosing requirement. Safety and efficacy endpoints were evaluated at predefined timepoints over the OLE. Endpoints were evaluated at Week 26 including 1) sCa, 2) 24-hour uCa, 3) independence from active vitamin D, and 4) independence from therapeutics doses of oral calcium. QoL was assessed by the SF-36 and the Hypoparathyroidism Patient Experience Scales (HPES). Results: All 59 subjects completed the initial 4-week period and continued in the OLE; 58 subjects continue in the OLE beyond 6 months (1 withdrew unrelated to safety or efficacy). TransCon PTH enabled independence from SoC (no active vitamin D and Ca ≤ 500 mg/day) in 91% of subjects and independence from all supplements (no active vitamin D and no Ca) in 76% of subjects by Week 26. Mean 24-hour uCa decreased from a baseline mean of 415 mg/24h to 178 mg/24h by Week 26 (n = 44) while maintaining sCa, and reducing sP and CaxP to fall within the normal range. The mean scores for all SF-36 summary and domains increased from below normal at baseline to within the normal range by Week 26. The HPES Symptom and Impact scores continuously improved through 26 weeks for TransCon PTH and placebo subjects switching to TransCon PTH. TransCon PTH continued to be well-tolerated with no treatment-related serious or severe adverse events. Conclusions: Results from the OLE of the PaTH Forward Trial demonstrated that TransCon PTH continued to enable independence from active vitamin D and Ca supplements for most subjects while maintaining normal sCa, sP, uCa, and demonstrating enhanced quality of life, supporting its potential as a hormone replacement therapy for patients with HP. TransCon PTH will be further evaluated in the phase 3 PaTHway Trial.

Severe Hypophosphatemia and Elevated FGF23 Level Following Zoledronic Acid Infusion

Background: Severe hypophosphatemia may be seen following zoledronic acid infusion, however FGF23 elevation has not been previously reported. Clinical Case: A 67-year-old man with Crohn’s disease status post remote ileocolonic resection, malnutrition (BMI 16.7), anemia, history of hypovitaminosis D, secondary hyperparathyroidism, and severe osteoporosis, was advised to present to the emergency room for hypocalcemia and hypophosphatemia after routine lab draw. His initial ionized calcium was 0.89 mmol/L (1.09–1.29 mmol/L) and phosphorus was 0.9 mg/dL (2.3–4.4 mg/dL), with a 25-hydroxyvitamin D level of 62 ng/mL (20–50 ng/mL), PTH of 132 pg/mL (11–51 pg/mL), and normal renal function. Hemoglobin was stable between 8–9 g/dL (13.5–17.1 g/dL). He endorsed ongoing fatigue, oral ulcers, and perioral numbness, which had been attributed to Humira infusion 2 months prior. He denied other paresthesias, carpopedal spasms, seizures, bone pain, or confusion. He reported receiving his second annual infusion of zoledronic acid 10 days prior in Turkey. He was started on high-dose oral calcium, calcitriol, and phosphate, which were continued on discharge 5 days later. Several days into his hospitalization, the patient spoke with his wife in Turkey who confirmed that his calcium and phosphorus were both within normal limits immediately prior to his infusion. A 1,25-hydroxyvitamin D level obtained during his workup was normal at 42.5 pg/mL (19.9–79.3 pg/mL), however an FGF23 level, which returned 2 weeks later, was elevated at 287 RU/mL (<=180 RU/mL). Dotatate PET to rule out oncogenic osteomalacia was negative. One month later, after normalization of calcium and phosphorus levels, repeat PTH and FGF23 levels were both within normal limits. Conclusion: This case demonstrates that a transient increase in FGF23 levels may accompany and exacerbate hypophosphatemia following zoledronic acid infusion. The mechanism for this elevation is unclear, though we speculate that in the setting of acute hypocalcemia and hypophosphatemia due to zoledronic acid infusion, secondary hyperparathyroidism may upregulate FGF23 production, which further decreases phosphorus levels. If this scenario is accurate, the transient FGF23 elevation seen is not pathologic, but physiologic. Indeed, in the patient above, calcium and phosphorus repletion lead to normalization of both PTH and FGF23.

A Single Administration of AZP-3601, a Novel, Long-Acting PTH Analog, Induces a Significant and Sustained Calcemic Response: Preliminary Data From a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study

Hypoparathyroidism is a rare disease characterized by a deficiency in parathyroid hormone (PTH) that results in hypocalcemia and hyperphosphatemia. Current treatment approaches, including high dose oral calcium and active vitamin D, as well as recombinant human PTH (1–84), do not provide adequate or consistent control of either serum calcium or clinical symptoms over a full 24-hour period. AZP-3601 is a novel 36 amino-acid PTH analog that has been designed to potently bind to the R0 conformation of the PTH1 receptor, which results in prolonged signaling responses in vitro and prolonged calcemic responses in animals despite having a short circulating half-life. A Phase 1 double-blind, placebo-controlled, single and multiple ascending dose study is being conducted to evaluate the safety, tolerability and pharmacodynamics of AZP-3601 in healthy adults. Here we report data from the first cohorts of the single ascending dose portion of the study. Sequential cohorts of 4 (cohort 1) to 8 (cohort 2 to 4) healthy male subjects aged 18–60 years, with a body mass index of 19–28 kg/m2, were assigned to receive 5, 10, 20 or 40μg of AZP-3601 or placebo at a ratio of 3:1. The study drug was administered in the morning by subcutaneous injection in the abdominal wall and was well tolerated with no remarkable adverse events. As compared with placebo controls, AZP-3601 treatment produced a clear, dose-dependent increase in mean albumin-adjusted serum calcium values from baseline. The normal physiological diurnal variation of albumin-adjusted serum calcium was gradually attenuated with 5 and 10μg AZP-3601, and was completely eliminated with 20μg. With the dose of 40μg AZP-3601, mean albumin-adjusted serum calcium values were significantly increased but stayed within normal laboratory range and remained elevated through at least 24 hours post-administration. We observed a dose-dependent decrease in mean endogenous serum PTH that was significantly correlated with the concomitant increase in mean serum calcium. These data provide initial evidence of the pharmacodynamic effect of AZP-3601 in healthy humans characterized by a sustained calcemic response for at least 24 hours following a single administration.

The Effects of Encaleret (CLTX-305) on Mineral Physiology in Autosomal Dominant Hypocalcemia Type 1 (ADH1) Demonstrate Proof-of-Concept: Early Results From an Ongoing Phase 2b, Open-Label, Dose-Ranging Study

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism caused by gain-of-function pathogenic variants in the gene (CASR) encoding the calcium-sensing receptor (CaSR). It is characterized by variable degrees of hypocalcemia, hyperphosphatemia, and hypomagnesemia, inappropriately low levels of parathyroid hormone (PTH) and hypercalciuria. Conventional therapy includes oral calcium and activated Vitamin D, targeting blood calcium at or slightly below the low-normal level to minimize hypocalcemic symptoms. This supplementation typically causes or exacerbates hypercalciuria, which may lead to nephrolithiasis, nephrocalcinosis, and renal insufficiency. It has been demonstrated in in vitro and in vivo models of ADH1, as well as in a Phase 2b clinical study (Roberts et al, JBMR 2019) that calcilytics (negative allosteric modulators of the CaSR), have the ability to shift the concentration-response relationship between extracellular calcium and the mutant CaSR towards normal.Six adults with ADH1 due to four distinct activating variants of the CASR were studied in an ongoing, three period, Phase 2b, open-label, dose-ranging study [NCT04581629] of the calcilytic encaleret (CLTX-305). Calcium, magnesium, and calcitriol supplements were discontinued at the start of Period 1, and subjects received sequential, increasing daily doses of encaleret for 3d (30 mg, 90 mg, 180 mg) followed by 120 or 180 mg twice daily on day 4 and 5, while undergoing frequent blood and urine sampling. The mean baseline PTH was 3.4 ± 4.5 pg/mL (mean ± SD; nl 10–65); on encaleret, there was a rapid, dose-dependent increase in PTH to a mean level of 64.8 ± 49.6 pg/mL over 24 hours by day 5. Albumin-corrected blood calcium (cCa) increased from a baseline of 7.6 ± 0.6 mg/dL (nl 8.4–10.2) to a 24-hour mean on day 5 of 9.0 ± 0.5 mg/dL. Phosphorus decreased from a baseline of 4.5 ± 0.7 mg/dL (nl 2.3–4.7) to a 24-hour day 5 mean of 2.9 ± 0.5 mg/dL. Magnesium increased from a baseline of 1.6 ± 0.4 mg/dL (nl 1.6–2.6) to a 24-hour day 5 mean of 2.0 ± 0.5 mg/dL. Blood calcium, phosphorus and magnesium were mostly maintained within the normal range in ADH1 subjects by days 4 and 5. Twenty-four hour urine calcium was elevated at the screening visit while subjects were on conventional therapy (436 ± 255 mg/day, nl < 250–300) and decreased with increasing doses of encaleret to 63 ± 127 mg/day on day 5. Urinary calcium excretion became normal in 3 subjects and undetectable in 3 subjects while on encaleret. Encaleret was well-tolerated, with no serious adverse events reported.The consistent mineral responses following encaleret administration in all six ADH1 subjects with four distinct CASR genotypes represents preliminary proof-of-concept that encaleret may be an efficacious treatment for ADH1. The longer-term evaluation of encaleret in ADH1 subjects is ongoing.

The “Eyes” Have It. Ophthalmological Findings of Bilateral Cataract in a Boy with Hypoparathyroidism

Background: Hypoparathyroidism is a relatively rare pediatric endocrine disorder in which parathyroid hormone (PTH) production is low or absent, resulting in low serum calcium and high phosphorus. In children, hypoparathyroidism is either congenital or acquired and is often associated with a genetic syndrome. Clinical manifestations include neuromuscular hyperexcitability, tetany, cardiac arrhythmias, and seizure. Radiographic findings include basal ganglia calcifications. In adult literature, ophthalmological findings of lenticular opacities and cataract have also been reported in hypoparathyroidism. Due to the rarity of this condition, there is a paucity of ophthalmological findings in children. We report a pediatric case with severe hypocalcemia, recurrent generalize seizures, intracranial calcifications and bilaterally cataracts secondary to hypoparathyroidism. Case: A 7-year-old boy, from a remote area in China, presented to a local hospital with one-year history of paresthesia in hands and feet. Initial lab evaluation revealed hypocalcemia with serum calcium of 1.76 mmol/L (2.03-2.68). Oral calcium supplement was started but symptoms progressively worsened. He was transferred to a tertiary hospital for further evaluation. On admission, physical exam was significant for positive Chvostek and Trousseau signs and lab evaluation showed serum calcium: 1.28 mmol/L (2.15-2.57), phosphorus: 4.2 mmol/L (0.95-1.75), magnesium: 0.97 mmol/L (0.73-1.06), PTH: 2.2 pg/mL (8.7-79), and 25(OH)Vit D: 97.1 mmol/L (36-126). Multiple symmetrical calcifications were found in the frontal lobe and basal ganglia. Ophthalmology consultation revealed bilateral cataracts with impaired vision. Trio whole exome sequencing with copy number variation testing reveled no pathogenic or likely pathogenic copy number and sequence level variants. He was diagnosed with idiopathic acquired hypoparathyroidism. The seizure disorder, intracranial calcification, and bilateral cataracts were attributed to severe and prolonged hypocalcemia secondary to hypoparathyroidism. He had a second episode of seizure after he was admitted, and seizure resolved after treated with midazolam and IV calcium gluconate. He was started on 1,25 (OH)2 vitamin D. Clinical symptoms resolved and he became biochemically eucalcemic with titrated therapy. Summary: Although lenticular changes have been observed in adults with hypoparathyroidism since the 1950’s, hypoparathyroidism and resulting cataract formations are relatively rare. Proposed mechanism of cataract formation in hypoparathyroidism is prolonged hypocalcemia resulting in membrane damage in the aqueous humor and subsequent sodium content increase in the lens. To our knowledge there are no prior pediatric reports of cataracts associated with hypoparathyroidism and signifies the importance of ophthalmologic referral and evaluation.

A Phase 2B, Open-Label, Dose-Ranging Study of Encaleret (CLTX-305) in Autosomal Dominant Hypocalcemia Type 1 (ADH1)

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism caused by gain-of-function pathogenic variants in the gene encoding the calcium-sensing receptor (CaSR). It is characterized by variable degrees of hypocalcemia, hyperphosphatemia, and hypomagnesemia, with inappropriately low levels of parathyroid hormone (PTH) and hypercalciuria. Conventional therapy includes oral calcium and activated Vitamin D supplementation, which can lead to or exacerbate hypercalciuria. As a result, patients may develop nephrolithiasis and/or nephrocalcinosis, which can progress to renal insufficiency. Calcilytics (antagonists of the CaSR) have demonstrated in in vitro and in vivo models of ADH1, as well as in a small clinical trial (Roberts et al, JBMR 2019), the ability to shift the dose-response relationship between extracellular calcium and the cellular response of cells bearing the mutant CaSR towards normal. This shift has the potential to increase endogenous PTH secretion which in turn may promote skeletal release of calcium into the bloodstream, production of endogenous calcitriol, renal excretion of phosphate, and renal reabsorption of calcium. Additionally, direct effects of calcilytics on renal CaSRs may further reduce renal calcium and magnesium excretion in ADH1. Taken together, this class of drugs has the capacity to restore normal mineral homeostasis, without calcium and activated vitamin D supplements and without attendant risks of iatrogenic hypercalciuria. This Phase 2b, open-label, dose-ranging study will evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of the calcilytic encaleret (CLTX-305) in up to 16 participants with ADH1 (NCT04581629). The study will consist of 3 periods. In periods 1 and 2, participants will undergo a 1-week inpatient evaluation to study the safety and tolerability of daily and twice-daily doses of encaleret. Period 3 will follow participants for up to 24 weeks of continuous outpatient dosing, with periodic inpatient and outpatient assessments. The primary endpoint of period 3 is the change from baseline in albumin-corrected blood calcium concentration. Secondary endpoints of the study include the change in urine calcium (fractional and 24-hour excretion), 1,25-dihydroxy-Vitamin D, phosphate, magnesium, and other blood/urine biomarkers. Enrollment for this study at the National Institutes of Health (NIH) began in September 2020 with topline results expected in 2021. This study is supported by Calcilytix Therapeutics, Inc. and the NIH Intramural Research Program.