Familial Hypocalciuric Hypercalcemia Research Articles

Comparison of fractional excretion of calcium from different urine samples in the differentiation between primary hyperparathyroidism and familial hypocalciuric hypercalcemia

Comparison of fractional excretion of calcium from different urine samples in the differentiation between primary hyperparathyroidism and familial hypocalciuric hypercalcemia

Molecular regulation of calcium‐sensing receptor (CaSR)‐mediated signaling

AbstractCalcium‐sensing receptor (CaSR), a family C G‐protein‐coupled receptor, plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca2+, Mg2+, amino acids (e.g., L‐Trp and L‐Phe), small peptides, anions (e.g., HCO3− and PO43−), and pH. CaSR‐mediated intracellular Ca2+ signaling regulates a diverse set of cellular processes including gene transcription, cell proliferation, differentiation, apoptosis, muscle contraction, and neuronal transmission. Dysfunction of CaSR with mutations results in diseases such as autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia, and neonatal severe hyperparathyroidism. CaSR also influences calciotropic disorders, such as osteoporosis, and noncalciotropic disorders, such as cancer, Alzheimer's disease, and pulmonary arterial hypertension. This study first reviews recent advances in biochemical and structural determination of the framework of CaSR and its interaction sites with natural ligands, as well as exogenous positive allosteric modulators and negative allosteric modulators. The establishment of the first CaSR protein–protein interactome network revealed 94 novel players involved in protein processing in endoplasmic reticulum, trafficking, cell surface expression, endocytosis, degradation, and signaling pathways. The roles of these proteins in Ca2+‐dependent cellular physiological processes and in CaSR‐dependent cellular signaling provide new insights into the molecular basis of diseases caused by CaSR mutations and dysregulated CaSR activity caused by its protein interactors and facilitate the design of therapeutic agents that target CaSR and other family C G‐protein‐coupled receptors.

Familial states of primary hyperparathyroidism: an update.

Familial primary hyperparathyroidism (PHPT) includes syndromic and non-syndromic disorders. The former are characterized by the occurrence of PHPT in association with extra-parathyroid manifestations and includes multiple endocrine neoplasia (MEN) types 1, 2, and 4 syndromes, and hyperparathyroidism-jaw tumor (HPT-JT). The latter consists of familial hypocalciuric hypercalcemia (FHH) types 1, 2 and 3, neonatal severe primary hyperparathyroidism (NSHPT), and familial isolated primary hyperparathyroidism (FIHP). The familial forms of PHPT show different levels of PHPT penetrance, developing earlier and with multiglandular involvement compared to sporadic counterpart. All these diseases exhibit Mendelian inheritance patterns, and for most of them, the genes responsible have been identified. DNA testing for predisposing mutations is helpful in index cases or in individuals with a high suspicion of the disease. Early recognition of hereditary disorders of PHPT is of great importance for the best clinical and surgical approach. Genetic testing is useful in routine clinical practice because it will also involve appropriate screening for extra-parathyroidal manifestations related to the syndrome as well as the identification of asymptomatic carriers of the mutation. The aim of the review is to discuss the current knowledge on the clinical and genetic profile of these disorders along with the importance of genetic testing in clinical practice.

Gα11 deficiency increases fibroblast growth factor 23 levels in a mouse model of familial hypocalciuric hypercalcemia.

Fibroblast growth factor 23 (FGF23) production has recently been shown to increase downstream of Gαq/11-PKC signaling in osteocytes. Inactivating mutations in the gene encoding Gα11 (GNA11) cause familial hypocalciuric hypercalcemia (FHH) due to impaired calcium-sensing receptor signaling. We explored the effect of Gα11 deficiency on FGF23 production in mice with heterozygous (Gna11+/-) or homozygous (Gna11-/-) ablation of Gna11. Both Gna11+/- and Gna11-/- mice demonstrated hypercalcemia and mildly raised parathyroid hormone levels, consistent with FHH. Strikingly, these mice also displayed increased serum levels of total and intact FGF23 and hypophosphatemia. Gna11-/- mice showed augmented Fgf23 mRNA levels in the liver and heart, but not in bone or bone marrow, and also showed evidence of systemic inflammation with elevated serum IL-1β levels. Furin gene expression was significantly increased in the Gna11-/- liver, suggesting enhanced FGF23 cleavage despite the observed rise in circulating intact FGF23 levels. Gna11-/- mice had normal renal function and reduced serum levels of glycerol-3-phosphate, excluding kidney injury as the primary cause of elevated intact FGF23 levels. Thus, Gα11 ablation caused systemic inflammation and excess serum FGF23 in mice, suggesting that patients with FHH - at least those with GNA11 mutations - may be at risk for these complications.

A novel mouse model for familial hypocalciuric hypercalcemia (FHH1) reveals PTH-dependent and independent CaSR defects

The Calcium-sensing receptor (CaSR) senses extracellular calcium, regulates parathyroid hormone (PTH) secretion, and has additional functions in various organs related to systemic and local calcium and mineral homeostasis. Familial hypocalciuric hypercalcemia type I (FHH1) is caused by heterozygous loss-of-function mutations in the CaSR gene, and is characterized by the combination of hypercalcemia, hypocalciuria, normal to elevated PTH, and facultatively hypermagnesemia and mild bone mineralization defects. To date, only heterozygous Casr null mice have been available as model for FHH1. Here we present a novel mouse FHH1 model identified in a large ENU-screen that carries an c.2579 T > A (p.Ile859Asn) variant in the Casr gene (CasrBCH002 mice). In order to dissect direct effects of the genetic variant from PTH-dependent effects, we crossed CasrBCH002 mice with PTH deficient mice. Heterozygous CasrBCH002 mice were fertile, had normal growth and body weight, were hypercalcemic and hypermagnesemic with inappropriately normal PTH levels and urinary calcium excretion replicating some features of FHH1. Hypercalcemia and hypermagnesemia were independent from PTH and correlated with higher expression of claudin 16 and 19 in kidneys. Likewise, reduced expression of the renal TRPM6 channel in CasrBCH002 mice was not dependent on PTH. In bone, mutations in Casr rescued the bone phenotype observed in Pth null mice by increasing osteoclast numbers and improving the columnar pattern of chondrocytes in the growth zone. In summary, CasrBCH002 mice represent a new model to study FHH1 and our results indicate that only a part of the phenotype is driven by PTH.

GCM2 p.Tyr394Ser variant in Ashkenazi Israeli patients with suspected familial isolated hyperparathyroidism.

A germline mutation can be identified in up to 10% of patients with primary hyperparathyroidism (PHPT). In 2017, a high frequency of the GCM2 [(NM_ 004752.4) c.1181A> C; p.Tyr394Ser; rs142287570] variant was reported in PHPT Ashkenazi Jews (AJ). To evaluate the presence of the GCM2 p.Tyr394Ser variant in Israeli patients addressed for genetic evaluation to characterize their phenotype and clinical management. Patients with PHPT who underwent addressed for genetic screening for suspected familial hypocalciuric hypercalcemia (FHH), a family history of isolated hyperparathyroidism (FIHP), or failed parathyroidectomy with persistent PHPT were recruited. Those with normal initial selected gene sequencing or hyperparathyroid genetic panel completed the GCM2 p.Tyr394Ser variant sequencing. The prevalence of this variant was evaluated using our local genomic database. A total of 42 single individuals from unrelated kindreds were evaluated. A disease-causing mutation was found in 11 (26.1%) patients: 10 were diagnosed with FHH (eight CASR and two AP2S1 mutations), and one patient had a CKN2B mutation. In 28 of the remaining patients, the GCM2 p.Tyr394Ser variant was positive in three (10.7%), and all were AJ. Within AJ (15/28, 53.5%), the rate of the p.Tyr394Ser variant was 3/15 (20%), and of those, two had a history of familial isolated hyperparathyroidism. Multi-glandular parathyroid adenoma/hyperplasia was also observed in two of these patients. No clinical or laboratory findings could discriminate patients with the GCM2 p.Tyr394Ser variant from those with FHH. Cinacalcet normalized the calcium levels in one patient. The prevalence of the GCM2 p.Tyr394Ser variant in 15,407 tests in our local genomic database was 0.98%. In contrast to previous observations, the GCM2 p.Tyr394Ser variant-associated phenotype may be mild in AJ with FIHP, sometimes mimicking FHH. Because surgery may be curative, surgeons should be aware of the possibility of multiple gland diseases in these patients. The clinical spectrum and clinical utility of screening for this variant warrant further investigation.

Two cases of familial hypocalciuric hypercalcaemia (FHH) due to a homozygous CaSR gene mutation (c.-10C>T)

Two cases of familial hypocalciuric hypercalcaemia (FHH) due to a homozygous CaSR gene mutation (c.-10C>T)

A large in-frame deletion of the calcium-sensing receptor extracellular domain causes familial hypocalciuric hypercalcaemia type 1 (FHH1) and is partially responsive to cinacalcet

A large in-frame deletion of the calcium-sensing receptor extracellular domain causes familial hypocalciuric hypercalcaemia type 1 (FHH1) and is partially responsive to cinacalcet

THU236 Mild Asymptomatic Hypercalcemia Secondary To A Novel Calcium-sensing Receptor Mutation

Abstract Disclosure: J. Tarkoff: None. Background: Familial hypocalciuric hypercalcemia (FHH) is a rare cause of mild hypercalcemia that is usually secondary to heterozygous mutations of the calcium-sensing receptor (CaSR) with autosomal dominant inheritance. The distinction between this entity and primary hyperparathyroidism can be difficult. Clinical Case: A 15-year-old female presented to the endocrinology clinic for an incidentally found elevated total calcium of 10.9 mg/dl (8.9-10.4) and elevated ionized calcium 5.5 mg/dl (4.8-5.3 mg/dl). Her labs at that time also showed a PTH of 29 pg/mL (12-71) and phosphorus 3.5 mg/dl (2.5-4.5 mg/dl). She denied any symptoms of hypercalcemia and there is no reported family history of mineral disorders or fractures. She does not take any medications. Her physical exam was unremarkable. Our evaluation showed calcium 10.5 mg/dl, phosphorus 4 mg/dl, magnesium 2.2 mg/dl (1.5-2.5 mg/dl) 25-hydroxyvitamin D 32 ng/ml (30-100 ng/ml), fractional excretion of calcium (FeCa) based upon spot urine sample = 0.0104, TSH 1.29 mIU/L (0.5-4.3 mIU/L), alkaline phosphatase 79 U/L (45-150 U/L), and normal renal function. Given her spot FeCa being <0.02, sequencing of the CASR gene was offered to the family because of potential overlap of her FeCa with primary hyperparathyroidism for which the treatment would be surgical (1). Commercial genetic testing was notable for a previously unreported heterozygous nonsense mutation, c.3001C>T (p.Gln1001X). It is expected to disrupt the final 78 amino acids of the protein in its intracellular domain and may play a role in preventing downstream signaling. At follow-up without treatment, her calcium has ranged between 10-10.9 mg/dl and she remains asymptomatic. Clinical lesson/conclusion: Hypocalciuria in the setting of hypercalcemia should raise the suspicion of FHH even without family history. Genetic testing of the CaSR is a crucial step in facilitating the diagnosis of FHH, especially given the importance of distinguishing it from primary hyperparathyroidism. Reference: (1) Christensen, S.E., Nissen, P.H., Vestergaard, P., Heickendorff, L., Brixen, K. and Mosekilde, L. (2008), Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcemia and primary hyperparathyroidism: a follow-up study on methods. Clinical Endocrinology, 69: 713-720. Presentation: Thursday, June 15, 2023

SAT250 A Case Of Hypercalcemia In Pregnancy - A Diagnostic And Management Challenge

Abstract Disclosure: W. Cheng: None. Y. Kuan: None. Hypercalcemia in pregnancy is rare and poses significant diagnostic and management challenges especially in a low resource setting. Although primary hyperparathyroidism (PHPT) is the main cause, physiological changes in calcium homeostasis make it difficult to distinguish from familial hypocalciuric hypercalcemia (FHH) unless genetic testing is done. Furthermore uncertainty exists on the safety of pharmacotherapy for hypercalcemia in pregnancy which if untreated, can be detrimental to both mother and child. Described herein a 17 year-old primigravida who presented at 32 weeks of gestation for asthma exacerbation precipitated by COVID-19 infection. She was incidentally found to have PTH-dependent hypercalcemia with albumin-corrected calcium 3.42 mmol/L [2.10-2.55] associated with raised intact parathyroid hormone (iPTH) 15 pmol/L [1.6 - 6.0] and deficient serum 25OH Vitamin D at 19.95 nmol/L [50-125]. She was given IV saline of 3-3.5L/day but to no avail as her serum calcium was persistently above 3 mmol/L with an episode of premature uterine contraction. Calcitonin was given in short courses and withheld once albumin-corrected calcium dropped below 3 mmol/L but rebound within three days. As bisphosphonates is contraindicated in pregnancy, we introduced cinacalcet, up to 75mg/day after discussion with the patient and her family. Meanwhile, investigations were done to ascertain underlying cause. Fractional urine calcium excretion ranged from 0.0068 (spot urine sample) to 0.0568 (24-hour urine sample). Ultrasound neck did not reveal enlarged parathyroid glands or an adenoma. Sestamibi scan was contraindicated in pregnancy. Genetic testing for FHH was too costly but all her first-degree relatives tested to have normocalcemia. Blood pressure remained normal throughout pregnancy. She was discharged with cinacalcet at calcium level of 2.7 mmol/L. However she defaulted follow-up and medications and presented at 36 weeks of gestation for preterm labour. She gave birth to a healthy, 2.46kg baby girl. The baby had neonatal jaundice but normal calcium level. Postpartum, the patient was asymptomatic despite persistent hypercalcemia 3.12 - 3.15nmol/L. As she was non-compliant to cinacalcet it was stopped and serum calcium did not worsen. Sestamibi scan is planned after she stops breastfeeding and a reassessment of the urine calcium once vitamin D is adequately replenished. She refused exploratory parathyroidectomy. She continued to be followed up at the endocrine clinic while her baby at primary care. Contraception is advised untill definitive diagnosis and treatment of hypercalcemia. This case illustrates the challenges in managing hypercalcemia in pregnancy and difficulty in distinguishing PHPT vs FHH without genetic testing. Presentation: Saturday, June 17, 2023

THU473 Acute Hypercalcemia In The Setting Of Acute Fatty Liver Of Pregnancy, A Case Report

Abstract Disclosure: M. Ahmad: None. M. Mack: None. A. Arif: None. L.A. Tejada: None. U. Siddiqui: None. Introduction: Hypercalcemia in pregnancy is rare and often goes unrecognized due to the overlapping symptoms of hypercalcemia and pregnancy. The most common cause of hypercalcemia in pregnant patients is primary hyperparathyroidism, with malignancy, milk alkali syndrome and familial hypocalciuric hypercalcemia being less common. Additionally, endogenous PTHrP production by breast and placental tissue have also been described as rare causes of hypercalcemia in pregnancy. We describe an interesting case of severe hypercalcemia in a pregnant woman presenting with acute fatty liver of pregnancy (AFLP) which rapidly corrected after delivery. Case description: The patient was a 32-year-old female with a past medical history of hypothyroidism and type 2 diabetes mellitus who presented to the emergency department at 32 weeks gestation due to four days of nausea, vomiting and epigastric pain. The patient’s vital signs were as follows: blood pressure: elevated to 133/79 mmHg, heart rate: 75 beats per minute, temperature: 36.7 C, and respiratory rate: 12 breaths per minute. On physical exam, the patient had diffuse abdominal tenderness with no vaginal bleeding. The patient’s blood work was significant for: bicarbonate: 17 mmol/L, creatinine: 1.26 mg/dL (baseline 0.7 mg/dL), corrected calcium of 15.1 mg/dL, ALP: 438 IU/L, AST: 653 IU/L, ALT: 666IU/L, total bilirubin: 2.3 mg/dL, INR 1.3, and ammonia: 43 mcmol/L. She was taken to the operating room for emergent cesarian delivery for concerns of AFLP. Further workup of the patient’s hypercalcemia, revealed a low normal PTH level of 11 pg/dL (normal 11-65 mg/dL), PTHrP level of <5 mg/dL, TSH of 1.37 uIU/ml, 25-OH vitamin D 55 ng/ml, and 1,25-OH vitamin D: 20 pg/ml. After delivery, the patient had alleviation of her symptoms and was kept on dextrose 5% with lactated ringers at 100 cc/h for a total of two days and had complete resolution of her hypercalcemia (corrected calcium of 10.2 mg/dL on discharge). The patient follows with endocrinology as an outpatient and since has had normal calcium levels. Discussion: Hypercalcemia in pregnancy is rare, only affecting 0.03% of women in the reproductive age group, with primary hyperparathyroidism being the most common cause. Hypercalcemia in pregnancy can often be missed due to the hemodilution of serum calcium in pregnancy and also the nonspecific symptoms present in pregnant patients. Our case describes a patient presentation of severe hypercalcemia with AFLP, who had rapid correction of her calcium levels after delivery. The exact mechanism of her severe hypercalcemia developed remains unclear, however, given its rapid resolution with delivery of the placenta potential etiologies include the AFLP itself or possibly the placenta contributing to hypercalcemia. Through this case report, we hope to highlight a possible association between AFLP and hypercalcemia. Presentation: Thursday, June 15, 2023

OR03-05 Cinacalcet Acts As A Spatially Biased Allosteric Modulator To Enhance CaSR Signaling From Endosomal Membranes

Abstract Disclosure: R. Wyatt: None. C.M. Gorvin: None. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor that plays a fundamental role in extracellular calcium homeostasis by activating Gαq/11 and Gαi/o signaling to regulate parathyroid hormone (PTH) release. CaSR can also continue signaling once internalised (known as sustained signaling) to elicit responses that are distinct from those at the plasma membrane. Loss-of-function mutations of CaSR cause familial hypocalciuric hypercalcemia type 1 (FHH1), while Arg15 mutations in the adaptor protein-2 σ-subunit (AP2σ) cause FHH3, by impairing CaSR internalisation and disrupting sustained signaling. However, the sustained signaling pathway has been incompletely defined and the effects of allosteric modulators on the process are unknown. Here we examined CaSR membrane trafficking and G protein activation in different endomembrane compartments using bystander BRET and HILO advanced imaging in HEK293 cells. This showed that internalised CaSR is targeted to Rab5-positive early endosomes and Rab4-positive early-to-recycling membranes, and not to degradation pathways as previously hypothesised. CaSR exclusively recruits active Gq/11 to early endosome membranes to drive sustained signals that produce distinct transcriptional profiles than those from plasma membranes. We next mutated a C-terminal region within CaSR predicted to form a dileucine endocytic motif that interacts with AP2σ. NanoBiT assays confirmed that the CaSR-dileucine mutant disrupted interactions between CaSR and AP2σ to the same magnitude as AP2σ-Arg15 mutations. Moreover, this CaSR-dileucine mutant impaired CaSR internalisation and reduced Gq/11 sustained signals from Rab5 and Rab4 endosomes to similar levels to those observed in cells expressing the FHH3-associated AP2σ-Arg15 mutant. Gi/o and G12/13 responses from plasma membranes were not affected by the CaSR-dileucine mutant. Finally, we assessed whether the CaSR positive allosteric modulator, cinacalcet, affects sustained signalling. When exposed to cinacalcet CaSR significantly increased the recruitment of active Gq/11 to early endosomes, resulting in a significant increase in signaling, while signals from the plasma membrane were not different to vehicle-treated cells. In summary, we have demonstrated that CaSR is targeted to an early-to-recycling endosomal pathway, which could explain how CaSR responds rapidly to fluctutations in serum calcium to maintain calcium homeostasis. Moreover, we have defined the endocytic motif within the CaSR required for sustained signaling and shown that cinacalcet is a spatially-biased allosteric modulator of the CaSR that preferentially enhances signaling from endosomal membranes. Thus, FHH3-associated AP2σ mutations, CaSR dileucine mutants and cinacalcet can be used as tools to better understand CaSR spatiotemporal signaling and define its physiological significance. Presentation: Thursday, June 15, 2023

Hypercalcemia – an underestimated medical problem

Hypercalcemia affects approximately 1% of the worldwide population. This electrolyte abnormality is frequent both in out and inpatients (varies from 0,17 to 5% in hospitalized, however incidence increases even up to 7,5% in emergency departments in some populations). Primary hyperparathyroidism (PHPT) and hypercalcemia of malignancy (HCM), account for more than 90 percent of all causes of hypercalcemia. Other causes of hypercalcemia, such as vitamin D intoxication, granulomatous disorders, milk-alkali syndrome, medications, familial hypocalciuric hypercalcemia and immobilization amount to less than 10% of all causes of hypercalcemia. However, once primary hyperparathyroidism or cancer has been excluded, other causes of hypercalcemia, often life-threatening and requiring appropriate causal management, should be considered. Considering rare etiologies is important, nevertheless, when primary hyperparathyroidism or malignancy do not account for the hypercalcemia. The review describes patophysiology, symptoms and diagnostic approach to the most relevant causes of hypercalcemia.

Cinacalcet Reverses Short QT Interval in Familial Hypocalciuric Hypercalcemia Type 1.

Familial hypocalciuric hypercalcemia type 1 (FHH-1) defines an autosomal dominant disease, related to mutations in the CASR gene, with mild hypercalcemia in most cases. Cases of FHH-1 with a short QT interval have not been reported to date. Three family members presented with FHH-1 and short QT interval (<360 ms), a condition that could lead to cardiac arrhythmias, and the effects of cinacalcet, an allosteric modulator of the CaSR, in rectifying the abnormal sensitivity of the mutant CaSR and in correcting the short QT interval were determined. CASR mutational analysis was performed by next-generation sequencing and functional consequences of the identified CaSR variant (p.Ile555Thr), and effects of cinacalcet were assessed in HEK293 cells expressing wild-type and variant CaSRs. A cinacalcet test consisting of administration of 30 mg cinacalcet (8 Am) followed by hourly measurement of serum calcium, phosphate, and parathyroid hormone during 8 hours and an electrocardiogram was performed. The CaSR variant (p.Ile555Thr) was confirmed in all 3 FHH-1 patients and was shown to be associated with a loss of function that was ameliorated by cinacalcet. Cinacalcet decreased parathyroid hormone by >50% within two hours, and decreases in serum calcium and increases in serum phosphate occurred within 8 hours, with rectification of the QT interval, which remained normal after 3 months of cinacalcet treatment. Our results indicate that FHH-1 patients should be assessed for a short QT interval and a cinacalcet test used to select patients who are likely to benefit from this treatment.

Posterior reversible encephalopathy syndrome in malignancy: Hypercalcemic storm?

e17559 Background: Posterior reversible encephalopathy syndrome (PRES) is a clinical-radiological entity characterized by seizures, headaches, altered mental status and visual anomalies associated with vasogenic edema affecting the parietal-occipital lobes on brain magnetic resonance imaging. PRES is rarely described in hypercalcemia of malignancy although multiple mechanisms have been postulated in various case reports. Hence, we conducted this study to evaluate whether there is an increased risk of PRES with hypercalcemia of malignancy. Methods: We analyzed the 2016-2020 National Inpatient Sample (NIS) and extracted patient data with a diagnosis of ovarian cancer, lung cancer, multiple myeloma (MM), breast cancer, diffuse large B-cell lymphoma (DLBCL), and secondary bone cancer. Cases with a history of primary hyperparathyroidism, vitamin D intoxication and familial hypocalciuric hypercalcemia were excluded. The presence of hypercalcemia and PRES were estimated (per 10,000 cases), and their respective adjusted odds ratios (aOR) were calculated via multivariate regression analysis. Results: We identified 1,775 PRES cases in 3,781,899 cancer patients studied. Patients with breast cancers (26 per 10,000 hypercalcemia cases vs. 4 per 10,000 cases with no hypercalcemia, aOR 4.523, 95% CI 3.418-5.984, p &lt; 0.01), ovarian cancers (41 per 10,000 hypercalcemia cases vs. 8 per 10,000 cases with no hypercalcemia, aOR 5.224, 95% CI 3.075-8.875, p &lt; 0.010), and secondary bone neoplasms (14 per 10,000 hypercalcemia cases vs. 5 per 10,000 cases with no hypercalcemia, aOR 2.160, 95% CI 1.671-2.793, p &lt; 0.01) exhibited a statistically significant increased outcome of PRES in association with hypercalcemia. The presence of hypercalcemia among lung cancer patients (aOR 0.755, 95% CI 0.451-1.263, p = 0.284), MM (aOR 1.005, 95% CI 0.751-1.346, p = 0.973), and DLBCL (aOR 1.393, 95% CI 0.806-2.408, p = 0.236) did not show a valid odds ratio for PRES. Conclusions: Our study found a higher association of PRES among hypercalcemia patients with ovarian cancer, breast cancer and secondary bone neoplasms. Prompt recognition of PRES and hypercalcemia-directed treatment can allay the morbidity related to PRES. While our study was limited in quantifying the cut-off values of hypercalcemia causing PRES, designated protocols entitled solely to determining serum calcium thresholds in these cancers warranting rigorous treatments are needed. PRES’s association with hypercalcemia in female-dominant cancers also paves way for further studies looking into the influences of sex hormones and hormonal therapies on the development of PRES with hypercalcemia.

Familial Hypocalciuric Hypercalcemia: the importance of taking detailed family history when assessing patients

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Differentiating Primary Hyperparathyroidism from Familial Hypocalciuric Hypercalcaemia Can Be Difficult: A Misleading Urinary Calcium to Creatinine Clearance Ratio

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract #1408170: Familial Hypocalciuric Hypercalcemia, Primary Hyperparathyroidism, or Both?

Primary hyperparathyroidism (PHPT) is the leading cause of hypercalcemia, and it is characterized by hypercalcemia and normal or inappropriately high levels of parathyroid hormone (PTH). Familial Hypocalciuric hypercalcemia (FHH) is a rare autosomal dominant benign disease caused by inactivating genetic mutations in the calcium sensing receptor. Genetic analyses are expensive and not widely available, making the differential diagnosis challenging. A 77-year-old male with a past medical history of hypertension and chronic kidney disease was referred to the endocrinology clinic for evaluation of hypercalcemia. Routine tests showed total corrected calcium level of 10.5 mg/dL, hypophosphatemia 2.6 mg/dL and low 24h urinary calcium of 79 mg/24h with calcium creatinine clearance ratio (CCCR) of 0.008. 25 hydroxyvitamin D, 1,25 Dihydroxyvitamin D and magnesium were normal. PTH level was 33 pg/dL (normal 15-65 pg/dL). Patient had no hypercalcemic symptoms, history of nephrolithiasis, or bone fractures. No family history of hypercalcemia. Cancer screening and PTH related peptide were normal. He was not taking hydrochlorothiazide or lithium. Renal ultrasound showed no nephrolithiasis and DXA revealed no osteoporosis. Thyroid ultrasound showed a right 1.2cm thyroid nodule without visualization of parathyroid glands. Fine-needle aspiration biopsy (FNA) of the nodule with PTH washout was benign with PTH<10. The patient was diagnosed with FHH and was monitored semiannually. Four years after the initial evaluation, total corrected calcium level was elevated at 14 mg/dL with PTH of 378 despite 25 hydroxyvitamin D level >40, repeated urinary calcium 90 mg/24h, and CCCR 0.01. His renal function was unchanged. Parathyroid scintigraphy revealed increased uptake in the right upper thyroid lobe, and thyroid ultrasound revealed increased right thyroid nodule volume. Repeat FNA was benign, this time with a PTH washout >200. The patient opted against surgical consultation for parathyroidectomy. He was treated with cinacalcet 30 mg twice daily. The co-existence of FHH and PHPT is rare. The few reported cases include patients who maintained hypercalcemia after surgical treatment of PHPT. The best cost-effective test available is a CCCR < 0.02. Our patient had CCCR measured at different times with values < 0.01 and a PTH level that over time increased by 900%. The overlap of biochemical values in patients with FHH and PHPT contributes to the challenges in the differential diagnosis and highlights the importance of close follow up with a high degree of clinical suspicion.

Neurodevelopmental Abnormalities in Patients with Familial Hypocalciuric Hypercalcemia Type 3

To evaluate the prevalence and degree of any neurodevelopmental abnormalities in children with familial hypocalciuric hypercalcemia type 3 (FHH3). 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. Six patients were diagnosed with hypercalcemia between 0.1 and 8years 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. 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.

Scintigraphy Negative Ultrasound positive parathyroid adenoma in familial hypocalciuric hypercalcemia

Familial hypocalciuric hypercalcemia (FHH) is a rare, lifelong, benign condition with an autosomal dominant pattern of inheritance. FHH is clinically distinguished by mild to moderate PTH-dependent hypercalcemia and normal to significantly reduced urinary calcium excretion despite elevated serum calcium. FHH is usually caused by a heterozygous loss-of-function mutation in the calcium-sensing receptor gene (CASR). It should be differentiated from primary hyperparathyroidism (PHPT). The reported case of a 10-year-old girl presented with symptomatic hypercalcemia, elevated intact parathyroid hormone, and a vitamin D deficiency. 99mTc-Sestamibi scan failed to detect any abnormalities, but high-resolution ultrasound (HRUS) of the neck revealed a right inferior parathyroid adenoma, which was excised with a focused parathyroidectomy. Although the patient’s calcium and iPTH levels normalized initially, they started rising within a few days. Bangladesh J. Nuclear Med. 26(1): 62-65, 2023