Hypercalcemia and cancer: Differential diagnosis and treatment.

Incidentally detected hypercalcemia usually presents in an indolent manner and is most likely caused by primary hyperparathyroidism. In contrast, hypercalcemia in the patient with a history of cancer presents in a wide range of clinical settings and may be severe enough to warrant hospitalization. This form of hypercalcemia is usually secondary to hypercalcemia of malignancy and can be fatal. Hypercalcemia of malignancy is most commonly mediated by tumoral production of parathyroid hormone-related protein or by cytokines activating osteoclast degradation of bone. The initial workup, differential diagnoses, confirmatory laboratory testing, imaging, and medical and surgical management of hypercalcemia are described in the patient with cancer.

Testing for Primary Hyperparathyroidism in 17,491 Patients With Hypercalcemia.

BACKGROUND: Primary hyperparathyroidism (PHPT) is underdiagnosed and associated with many adverse health effects. Historically, many hypercalcemic patients have not received parathyroid hormone (PTH) testing; however, underlying reasons are uncertain. Our goals are to determine the PTH testing rate among hypercalcemic individuals at a large academic health system and to assess for characteristics associated with testing versus not testing for PHPT to inform future strategies for closing testing gaps. METHODS: This retrospective study included adult patients with ≥1 elevated serum calcium result between 2018 and 2022. Based on the presence or absence of a serum PTH result, individuals were classified as "screened" versus "unscreened" for PHPT. Demographic and clinical characteristics of these groups were compared. RESULTS: The sample comprised 17,491 patients: 6567 male (37.5%), 10,924 female (62.5%), mean age 59 y. PTH testing was performed in 6096 (34.9%). Characteristics independently associated with the greatest odds of screening were 5+ elevated calcium results (odds ratio [OR] 5.02, P < 0.0001), chronic kidney disease (OR 3.63, P < 0.0001), maximum calcium >12.0 mg/dL (OR 2.48, P < 0.0001), and osteoporosis (OR 2.42, P < 0.0001). Characteristics associated with lowest odds of screening were age <35 y (OR 0.60, P < 0.0001), death during the study period (OR 0.68, P < 0.0001), age ≥85 y (OR 0.70, P = 0.0007), and depression (OR 0.84; P = 0.0081). CONCLUSIONS: Only 35% of hypercalcemic patients received PTH testing. Although the presence of PHPT-associated morbidity was generally associated with increased rates of screening, hypercalcemic patients with depression were 16% less likely to be tested.

Denosumab in a pediatric kidney transplant recipient with late, resistant hypercalcemia secondary to Pneumocystis jirovecii pneumonia.

Kidney transplant recipients (KTR) are at an increased risk of developing Pneumocystis jirovecii pneumonia (PCP), especially during the first year after transplantation. This is the first reported pediatric KTR, with chronic kidney disease (CKD) secondary to kidney dysplasia and vesicoureteral reflux, who developed refractory and symptomatic hypercalcemia 5 years after transplantation. The hypercalcemia was resistant to treatment with intravenous hyperhydration, furosemide, and a low-calcium diet. A respiratory tract infection due to PCP treated with trimethoprim-sulfamethoxazole did not improve calcium levels. Due to the hypercalcemic symptom burden for the patient, a single dose of subcutaneous denosumab was used to achieve sustained clinical and biochemical improvement, without any severe adverse events. This case highlights the potential use of denosumab as a treatment option in pediatric KTR with refractory hypercalcemia related to PCP. Further study of denosumab in young people with CKD or kidney transplants is needed before routine use can be recommended.

Discrepancies in corrected calcium versus ionised calcium in a geriatric population: an observational study.

BACKGROUND: Calcium can be measured as ionised (Ca-ionised) or albumin-adjusted total calcium (Ca-albumin). Current clinical guidelines predominantly utilise Ca-albumin, despite Ca-ionised being the gold standard. Discrepancies can occur between these measurement modalities and can lead to clinical dilemmas. It remains unclear how large these discrepancies are in older patients. This study investigated the discrepancies between Ca-ionised and Ca-albumin in geriatric patients. METHODS: This is an observational study of all geriatric patients (n = 876) in the Jeroen Bosch Hospital (January 2018 and January 2021) in whom both Ca-ionised and Ca-albumin were measured. Misclassification of calcaemic state (i.e. low, normal or high) was calculated (percentages), the measure of agreement was described using Cohen's Kappa and for the continuous data Pearson's correlation coefficient was used. Relevant categories of age and renal function were considered for effect modification effects and studied by interaction terms in a regression model. RESULTS: In one-third of the measurements, there was a misclassification. Ca-albumin measurements failed to identify 28% of hypocalcaemia. In 3.5%, hypercalcemia based on Ca-albumin was not confirmed by Ca-ionised. The correlation coefficient between Ca-ionised and Ca-albumin was 0.743 (P = 0.01) and measure of agreement by Kappa was 0.213 (P < 0.001). In the oldest old (≥ 85 years) and patients with eGFR <30 ml/min/1.73 m2 ,the agreement by Kappa was lower, with values of 0.192 and 0.104, respectively. CONCLUSION: There is a discrepancy between Ca-albumin and Ca-ionised in one-third of the geriatric patients, leading to clinical dilemmas. In the oldest old and patients with renal dysfunction, this problem is most pronounced.

Twenty-four hour Holter ECG in normocalcemic and hypercalcemic patients with hyperparathyroidism.

PURPOSE: To investigate the occurrence of arrhythmias in patients with normocalcemic (NC) primary hyperparathyroidism (PHPT) compared to both hypercalcemic PHPT patients and control subjects by means of 24-h Holter ECG. METHODS: Thirteen NCPHPT postmenopausal patients were enrolled and age-matched with 13 hypercalcemic PHPT patients and 13 controls. Every subject underwent basal ECG, 24-h Holter ECG and mineral metabolism biochemical evaluation. RESULTS: PHPT patients had higher mean serum calcium levels compared to both NCPHPT and controls; there was no difference in mean serum calcium levels between NCPHPT and controls. Both NCPHPT and PHPT patients had significantly higher mean PTH levels compared with controls. There were no differences in ECG parameters between the three groups, except for QTc interval. PHPT patients had normal QTc interval values, but significantly shorter mean values compared with those of controls and NCPHPT patients. During 24-h Holter ECG recording, 100% of PHPT patients had supraventricular premature beats (SVPBs), compared to 46% of NCPHPT (p = 0.005) and to 53% of controls (p = 0.01). PHPT patients experienced ventricular premature beats (VPBs) (69.2%) vs 15% of NCPHPT patients (p = 0.01) and 23% of controls (p = 0.04). There was no difference between NCPHPT and controls subjects concerning occurrence of both VPBs and SVPBs. CONCLUSIONS: NCPHPT patients did not experience an increased occurrence of arrhythmias compared to controls, while PHPT patients showed an increased occurrence compared to both controls and NCPHPT. Our findings are most probably related to the short QTc interval caused by hypercalcemia observed in PHPT patients, but not in NCPHPT.

Measurement of plasma total calcium before plasma free ionized calcium - a possibility with affordable pitfalls.

Free ionized calcium (fCa) is considered the gold standard for assessing calcium status in patients, but it is relatively expensive and is associated with several preanalytical and analytical error sources. We investigated the feasibility of using a reflex test that involves first measuring total calcium (tCa) and if out of reference range, then measure fCa, with expectation of reducing the number of fCa measurements. We used data from 1815 unique patients with concurrent measurement of fCa, tCa and albumin adjusted calcium (aCa). Patients were stratified by albumin level, and the association of fCa to tCa and aCa respectively was assessed with linear regression. The regression analysis showed the best linearity for tCa and aCa at albumin <35 g/L (R2: 0.80-0.90), and the poorest at albumin >40 g/L (R2: tCa 0.58; aCa 0.59). We examined the accuracy of hypo- and hypercalcemia classifications for tCa, aCa and the reflex test. aCa had more misclassifications of hypo- and hypercalcemia than tCa, with respectively 25% and 21%. Implementation of the reflex test would correct any false hypo- or hypercalcemia classified by tCa, leaving only false negative results corresponding to 9% of all tCa measurements. False negative results were on average 0.04 mmol/L above or below the reference range of fCa. Implementation of the reflex test reduces the number of fCa by 68% without major errors diagnosing hyper- or hypocalcemia.

Neurodevelopmental Abnormalities in Patients with Familial Hypocalciuric Hypercalcemia Type 3.

OBJECTIVES: To evaluate the prevalence and degree of any neurodevelopmental abnormalities in children with familial hypocalciuric hypercalcemia type 3 (FHH3). STUDY DESIGN: A formal neurodevelopmental assessment was performed in children diagnosed with FHH3. The Vineland Adaptive Behavior Scales, which is a standardized parent report assessment tool for adaptive behavior, was used to assess communication, social skills, and motor function and to generate a composite score. RESULTS: Six patients were diagnosed with hypercalcemia between 0.1 and 8 years of age. All had neurodevelopmental abnormalities in childhood consisting of either global developmental delay, motor delay, expressive speech disturbances, learning difficulties, hyperactivity, or autism spectrum disorder. Four out of the 6 probands had a composite Vineland Adaptive Behavior Scales SDS of < -2.0, indicating adaptive malfunctioning. Significant deficits were observed in the domains of communication (mean SDS: -2.0, P < .01), social skills (mean SDS: -1.3, P < .05), and motor skills (mean SDS: 2.6, P < .05). Individuals were equally affected across domains, with no clear genotype-phenotype correlation. All family members affected with FHH3 also described evidence of neurodevelopmental dysfunction, including mild-to-moderate learning difficulties, dyslexia, and hyperactivity. CONCLUSION: Neurodevelopmental abnormalities appear to be a highly penetrant and common feature of FHH3, and early detection is warranted to provide appropriate educational support. This case series also supports consideration of serum calcium measurement as part of the diagnostic work-up in any child presenting with unexplained neurodevelopmental abnormalities.

Missed Opportunities to Diagnose and Treat Tertiary Hyperparathyroidism After Transplant.

INTRODUCTION: Tertiary hyperparathyroidism (3HPT) is common after renal transplant. However, guidelines for diagnosis are not clear and few patients are treated surgically. This study aims to determine rates of diagnosis and treatment of 3HPT in renal transplant patients with hypercalcemia. MATERIALS AND METHODS: This retrospective chart review identified all renal transplant recipients at a single tertiary care institution between 2011 and 2021. Patients with post-transplant hypercalcemia (> 10.2 mg/dL) were identified. The time in months of index hypercalcemia was noted. Measurement of parathyroid hormone (PTH) levels after index hypercalcemia was determined and noted as elevated if > 64 pg/mL at least 6 mo after transplant. Documentation of symptoms of hyperparathyroidism, a diagnosis of hyperparathyroidism in the electronic medical record, and medical or surgical management of patients with classic 3HPT (elevated calcium and PTH) were determined. RESULTS: Of 383 renal transplant recipients, hypercalcemia was identified in 132 patients. The majority of hypercalcemic patients had PTH levels measured (127, 96.2%). PTH was elevated in 109 (82.6%). Among the 109 patients with classic 3HPT, 54 (49.5%) had a documented diagnosis of hyperparathyroidism in the electronic medical record (P = 0.01). Kidney stones or abnormal DEXA scan were present in 16 (14.7%) and 18 (16.5%), respectively. Most patients were managed non-surgically (101, 92.6%); calcimimetics were prescribed for 42 (38.5%, P = 0.01). Eight (7.3%) patients with classic 3HPT were referred to a surgeon (P = 0.35); all were initially prescribed calcimimetics (P = 0.001). CONCLUSIONS: 3HPT is underdiagnosed in patients with elevated calcium and PTH levels post-transplant. A significant percentage of these patients go without surgical referral and curative treatment.

Treatment of hypokalemia with amiloride unmasked hypercalcemia and hyperparathyroidism: A case report.

Colonic pseudo-obstruction, also called Ogilvie's syndrome, occurs due to impaired intestinal propulsion, and may be caused by electrolyte imbalances such as hypokalemia and some endocrine disorders such as hyperparathyroidism. Secretory diarrhea due to intestinal pseudo-obstruction can cause hypokalemia. Diuretics such as amiloride can be used to treat hypokalemia, however in this case, treatment with amiloride induced hypercalcemia and unmasked hyperparathyroidism. A 73-year-old female with a history of hypertension and parathyroid adenoma presented with recurrent colonic pseudo-obstruction and chronic hypokalemia. Her hypokalemia was treated with amiloride, causing hypercalcemia of 14.4 mg/dL, elevated PTH, and altered mental status. Amiloride was subsequently discontinued with improvement in her symptoms, and her hyperparathyroidism was treated with cinacalcet. To our knowledge, this is the first report of amiloride unmasking hyperparathyroidism and inducing hypercalcemia.

Renal sarcoidosis presenting with chronic kidney disease and hypercalcemia.

Sarcoidosis is a multisystem inflammatory disease that most frequently affects the lungs, lymph nodes, eyes, and skin. Renal involvement is clinically rare. We describe a 72-year-old male who presented with chronic kidney disease and elevated serum calcium and angiotensin-converting enzyme. Renal biopsy pathology showed chronic granulomatous interstitial nephritis. Renal function was significantly improved after glucocorticoid therapy. This case emphasizes that chronic kidney disease and hypercalcemia can be clues for renal sarcoidosis. Early renal biopsy and projective treatment is beneficial for renal outcome.

Eclampsia as the First Manifestation of Primary Hyperparathyroidism: a Case Report.

BACKGROUND: This study aimed to explore the diagnosis and treatment strategies of eclampsia during pregnancy and postpartum acute pancreatitis caused by primary hyperparathyroidism. METHODS: This study reported a 26-year-old patient who had maternal eclampsia as her first symptom and was admitted to the hospital. The pregnancy was terminated by cesarean section immediately. Postpartum life-threatening complications, such as severe hypercalcemia and acute pancreatitis, occurred afterward. Following completion of the relevant examination, primary hyperparathyroidism was initially considered to be the cause. Symptomatic treatment is ongoing and will be improved, and the patient will be admitted again for parathyroidectomy. RESULTS: The patient gave birth to a premature neonate via cesarean section. The postpartum diagnosis was primary hyperparathyroidism, for which post-surgical pathology showed a parathyroid adenoma. CONCLUSIONS: The clinical manifestations of pregnancy with primary hyperparathyroidism are atypical but may cause serious maternal and fetal complications. Early diagnosis and appropriate treatment can prevent serious prenatal and postnatal complications and foster better pregnancy outcomes.

A Case of Adult Acute B-Cell Lymphoblastic Leukemia with Hypercalcemia and Osteolytic Bone Lesions.

BACKGROUND: We report a rare case of adult acute B-lymphoblastic leukemia (B-ALL) with hypercalcemia and osteolytic bone lesions in a 53-year-old man who died after chemotherapy. METHODS: The bone marrow examination was evaluated by Wright-Giemsa staining, tissue biopsy, immunohistochemical staining, and flow cytometry. Bone imaging was performed using positron emission tomography/computed tomography (PET/CT) technology. Total calcium levels were measured by biochemical analyzer. RESULTS: The result of PET/CT indicated the patient with B-ALL with severe osteolytic bone lesions. The serum total calcium level was as high as 4.09 mmol/L, and the cytokines interleukin-6 and 17A were significantly elevated. The patient was resistant to chemotherapy and had a poor prognosis. CONCLUSIONS: Hypercalcemia and osteolytic bone lesions are rare complications of adult B-ALL, and their co-occurrence may be an indicator of poor prognosis in patients with B-ALL.

The Diagnosis of Gastric Cancer due to a Parathyroid Adenoma Almost Missed in a Hypercalcemia Patient with Severe Vomiting.

BACKGROUND: Hypercalcemia is a relatively common clinical problem. However, the differential diagnosis between hypercalcemia combined with hyperparathyroidism and a malignant tumor is difficult. METHODS: Appropriate laboratory tests, ultrasound and static imaging of the parathyroid, electronic gastroscopy, and histological examinations were used. RESULTS: The patient was found to have primary hyperparathyroidism due to hypercalcemia, with a parathyroid adenoma visible on color Doppler ultrasound and PET. The hypercalcemia was corrected after surgical resection. As the symptoms of nausea and vomiting did not improve, further investigations were undertaken, and gastric cancer was found on gastroscopy. CONCLUSIONS: Both primary hyperparathyroidism and gastric tumors may present with symptoms of nausea and vomiting. Clinically, multiple disease possibilities should be considered to explain a particular symptom.

Steroid responsive idiopathic calcitriol induced hypercalcemia: a case report and review of the literature.

BACKGROUND: Idiopathic Calcitriol Induced Hypercalcemia is a rare cause of a common condition of hypercalcemia. Hypercalcemia is most commonly the result of hyperparathyroidism and together with hypercalcemia of malignancy accounts for over 95% of cases. Idiopathic Calcitriol Induced Hypercalcemia can mimic hypercalcemia secondary to granulomatous diseases like sarcoidosis, but with apparent absences of both imaging and physical exam findings consistent with the disease. We report here a 51-year-old man who presented with recurrent nephrolithiasis, hypercalcemia, and acute kidney injury. CASE PRESENTATION: A 51-year-old man presented with severe back pain and mild hematuria. He had a history of recurrent nephrolithiasis over the course of a 15-year period. On presentation his calcium was elevated at 13.4 mg/dL, creatinine was 3.1 mg/dL (from baseline of 1.2), and his PTH was reduced at 5 pg/mL. CT abdomen and pelvis showed acute nephrolithiasis which was managed medically. Work up for the hypercalcemia included an SPEP which was normal, Vit D,1,25 (OH)2 was elevated at 80.4 pg/mL, CT chest showed no evidence of sarcoidosis. Management with 10 mg prednisone showed marked improvement in the hypercalcemia and he no longer had any symptoms of hypercalcemia. CONCLUSION: Idiopathic Calcitriol Induced Hypercalcemia is a rare cause of hypercalcemia. All reported cases benefit from more intensive long-term immunosuppression. This report helps consolidate the diagnosis of Idiopathic Calcitriol Induced Hypercalcemia and encourages researchers to better investigate its underlying pathogenesis.

Milk-Alkali Syndrome: A Century-old Cause of Hypercalcemia Requires the Addition of Venous Blood Gas in Hypercalcemia Workup.

The Milk-Alkali syndrome (MAS) is identified by the triad of high serum levels of calcium, metabolic alkalosis, and acute kidney injury, usually caused by consuming excessive amounts of calcium and absorbable alkali. If not treated promptly, the syndrome can result in rapid hypercalcemia, acute renal failure, and metastatic calcification. Notably, an increasing number of cases of MAS have been observed, potentially due to the rampant use of calcium-based over-the-counter supplements for the prevention and treatment of osteoporosis in postmenopausal women. Herein, we report a case of severe hypercalcemia due to prolonged intake of calcium carbonate supplements in the absence of any alkali. The case report highlights the importance of including venous blood gas (VBG) analysis as a part of the workup for hypercalcemia, as metabolic alkalosis can help clinch the diagnosis of MAS in the setting of severe hypercalcemia. How to cite this article: Sahu U, Trivedi T, Gupta R. Milk-Alkali Syndrome: A Century-old Cause of Hypercalcemia Requires the Addition of Venous Blood Gas in Hypercalcemia Workup. J Assoc Physicians India 2023;71(9):104-105.

[A case of severe hyperparathyroidism in clinical practice. Case report].

Disorders of the mineral balance often determine the symptoms, the severity of the course and the prognosis of many diseases. Primary hyperparathyroidism (PHPT) is a common endocrine disease caused by increased secretion of parathyroid hormone as a result of primary damage to the parathyroid glands. Diagnosis of PHPT is often difficult. Clinical signs of PHPT appear months or years after the onset of the disease, however, the presence of hypercalcemia serves as an early indication of the disease of the thyroid gland. Often, patients are observed for a long time by related specialists (rheumatologists, traumatologists-orthopedists, oncologists), which gives rise to a lot of problems consisting in the lack of adequate treatment and its result, the progression of the disease, disability, and a decrease in the quality of life. Often, patients are observed for a long time by related specialists (rheumatologists, orthopedic traumatologists, oncologists) under the "masks" of various pathologies (osteoporosis, recurrent urolithiasis, etc.), which gives rise to a lot of problems, consisting in an erroneous diagnosis, lack of adequate treatment and its result, progression of the disease, disability, and a decrease in the quality of life. Late diagnosis of PHPT leads to the development of severe complications (osteoporetic fractures, renal failure) and an increased risk of premature death. A clinical case of late diagnosis of PHPT at the stage of pronounced bone complications of the disease, which proceeded under the guise of osteoarthritis, is considered. According to the results of laboratory and instrumental studies, the following were revealed: hypercalcemia, a significant increase in the concentration of PTH, adenoma of the left lower parathyroid gland, hyperparathyroid osteodystrophy, and a decrease in bone mineral density. Surgical treatment was performed - selective parathyroidectomy with the development of hypocalcemia in the early postoperative period, which was stopped by taking calcium supplements and active vitamin D metabolites and is designed to help practitioners of various specialties to understand the issues of diagnosis of PHPT and effective care for patients.

[Surgical management of primary hyperparathyroidism]. / Prise en charge chirurgicale de l'hyperparathyroïdie primaire.

Primary hyperparathyroidism (PHPT) is characterized by hypercalcemia due to inappropriate parathyroid hormone (PTH) secretion mostly caused by a single adenoma. Clinical manifestations vary and include bone loss (osteopenia, osteoporosis), kidney stones, asthenia and psychiatric disorders. In 80 % of cases PHPT is asymptomatic. Secondary causes of elevated PTH such as renal insufficiency and/or vitamin D deficiency should be excluded, and 24-hour calciuria should be measured to rule out familial hyocalciuric hypercalcemia. Surgery requires radiological tests: a cervical ultrasound to exclude concomitant thyroid pathology and a functional examination (Sestamibi scintigraphy or F-choline PET scan). Management should be discussed in a multidisciplinary team. Treatment is surgical and can also be offered to asymptomatic patients.

L'hyperparathyroïdie primaire (HPTP) est caractérisée par une hypercalcémie causée par une sécrétion inappropriée de parathormone (PTH) due, dans la majorité des cas, à un adénome parathyroïdien unique. Les manifestations cliniques sont variées, comme la perte osseuse (ostéopénie, ostéoporose), les calculs rénaux, l'asthénie et les troubles psychiatriques. Dans 80 % des cas, l'HPTP est asymptomatique. Il faut exclure une cause secondaire d'élévation de la PTH sur une insuffisance rénale ou un déficit en vitamine D et doser la calciurie sur 24 heures pour exclure une hypercalcémie hypocalciurique familiale. La chirurgie nécessite des examens de radiologie au préalable : un ultrason cervical pour exclure une pathologie thyroïdienne concomitante et un examen fonctionnel (scintigraphie au Sestamibi ou PET-scan à la F-choline). Il est important de discuter de la prise en charge de façon multidisciplinaire. Le traitement curatif est chirurgical et peut aussi être proposé aux patients asymptomatiques.

Genetics of monogenic disorders of calcium and bone metabolism.

Disorders of calcium homeostasis are the most frequent metabolic bone and mineral disease encountered by endocrinologists. These disorders usually manifest as primary hyperparathyroidism (PHPT) or hypoparathyroidism (HP), which have a monogenic aetiology in 5%-10% of cases, and may occur as an isolated endocrinopathy, or as part of a complex syndrome. The recognition and diagnosis of these disorders is important to facilitate the most appropriate management of the patient, with regard to both the calcium-related phenotype and any associated clinical features, and also to allow the identification of other family members who may be at risk of disease. Genetic testing forms an important tool in the investigation of PHPT and HP patients and is usually reserved for those deemed to be an increased risk of a monogenic disorder. However, identifying those suitable for testing requires a thorough clinical evaluation of the patient, as well as an understanding of the diversity of relevant phenotypes and their genetic basis. This review aims to provide an overview of the genetic basis of monogenic metabolic bone and mineral disorders, primarily focusing on those associated with abnormal calcium homeostasis, and aims to provide a practical guide to the implementation of genetic testing in the clinic.

Familial hypocalciuric hypercalcaemia type 1 caused by a novel heterozygous missense variant in the CaSR gene, p(His41Arg): two case reports.

BACKGROUND: Familial hypocalciuric hypercalcaemia (FHH) is a rare, inherited disorder of extracellular calcium sensing. It is clinically characterised by mild to moderate parathyroid hormone dependent hypercalcaemia, an autosomal dominant pattern of inheritance, and a normal to reduced urinary calcium excretion in spite of high serum calcium. CASE PRESENTATION: We report two cases of FHH in a family caused by a novel pathogenic missense variant in the CaSR gene, p. His41Arg. Case 1, describes a 17 year old female with no significant past medical history, admitted with acute appendicitis requiring laparoscopic appendectomy and reporting a six month history of polydipsia. Routine investigations were significant for hypercalcaemia, corrected calcium 3.19 mmol/L (2.21-2.52mmol/L), elevated parathyroid hormone of 84pg/ml (15-65pg/ml) and a low 24-hour urine calcium of 0.75mmol/24 (2.50-7.50mmol/24). She was initially managed with intravenous fluids and Zolendronic acid with temporary normalisation of calcium though ultimately required commencement of Cinacalcet 30 mg daily for persistent symptomatic hypercalcaemia. Genetic analysis was subsequently positive for the above variant. Case 2, a 50-year-old female, was referred to the endocrine outpatient clinic for the management of type 2 diabetes and reported a longstanding history of asymptomatic hypercalcaemia which had not been investigated previously. Investigation revealed hypercalcaemia; corrected calcium of 2.6 mmol/L (reference range: 2.21-2.52 mmol/L); PTH of 53.7ng/L (reference range: 15-65 ng/L) and an elevated 24-hour urine calcium of 10 mmol/24 (2.50-7.50 mmol/24hr) with positive genetic analysis and is managed conservatively. Despite sharing this novel mutation, these cases have different phenotypes and their natural history is yet to be determined. Two further relatives are currently undergoing investigation for hypercalcaemia and the family have been referred for genetic counselling. CONCLUSION: Accurate diagnosis of FHH and differentiation from classic primary hyperparathyroidism can be challenging, however it is essential to avoid unnecessary investigations and parathyroid surgery. Genetic analysis may be helpful in establishing a diagnosis of FHH in light of the biochemical heterogeneity in this population and overlap with other causes of hypercalcaemia.

A case of familial hypocalciuric hypercalcemia type 1 due to CASR p.Pro55Leu mutation.

BACKGROUND: Familial hypocalciuric hypercalcemia (FHH) is a rare autosomal dominant disease, which requires differential diagnosis from relatively common primary hyperparathyroidism (PHPT) in order to avoid unnecessary surgery. CASE PRESENTATION: A 16-year-old female had been followed by the department of psychosomatic medicine at our institution. Throughout the follow-up period, her plasma calcium levels were high, plasma Pi levels were relatively low, and plasma intact PTH was relatively high. She was referred to our department to determine the cause of her hypercalcemia. Her 24 h urinary calcium excretion was as low as 100 mg/day, and calcium creatinine clearance ratio was below 0.01. Moreover, she had a family history of hypercalcemia (proband, her brother, and her father). The genetic testing for her family revealed that she, her brother, and her father were definitively diagnosed with FHH type 1 due to the heterozygous calcium-sensing receptor mutation (NM_00388:4:c.164C > T:p.Pro55Leu). CONCLUSION: We experienced a 16-year-old female with FHH, in whom genetic testing identified the heterozygous calcium-sensing receptor mutation (NM_00388:4:c.164C > T:p.Pro55Leu) as pathogenic, permitting a definitive diagnosis of FHH type 1. The genetic testing for calcium sensing receptor is beneficial to distinguish asymptomatic primary hyperparathyroidism from FHH.