Primary hyperparathyroidism in pregnancy: a case report highlighting uncommon complication.

Primary hyperparathyroidism (PHPT) is characterized by elevated levels of calcium and parathyroid hormone (PTH). However, the interpretation of diagnostic tests, such as serum calcium and PTH levels, is complex in pregnant women. The aim of this report is to present a case of PHTP in a pregnant adolescent, with a special emphasis on an uncommon complication, as well as diagnostic and treatment strategies. A 17-year-old pregnant female presented with hyperemesis gravidarum and neurological symptoms, leading to the diagnosis of cerebral venous thrombosis. Further investigations revealed hypercalcemia and persistently elevated PTH levels, consistent with PHPT. After localization studies, the patient underwent an emergency parathyroidectomy with a diagnosis of parathyroid adenoma. During follow-up, intrauterine growth restriction and severe preeclampsia developed, necessitating an emergency cesarean section. Both the mother and neonate had favorable outcomes. PHPT is an infrequent condition in the pregnant population, and its diagnosis can be challenging due to the overlap of symptoms with normal physiological changes during pregnancy. The occurrence of uncommon complications, such as thrombotic phenomena, highlights the need for a comprehensive approach to ensure early detection and management. In most cases, parathyroidectomy is the treatment of choice.

El hiperparatiroidismo primario (HPTP) se caracteriza por niveles elevados de calcio y hormona paratiroidea (PTH). Sin embargo, la interpretación de pruebas diagnósticas, como los niveles de calcio sérico y PTH, es compleja en mujeres embarazadas. El objetivo de este reporte es presentar un caso de HPTP en una adolescente embarazada, con especial hincapié en una complicación infrecuente, así como en las estrategias diagnósticas y de tratamiento. Una mujer embarazada de 17 años presentó hiperémesis gravídica y síntomas neurológicos, lo que llevó al diagnóstico de trombosis venosa cerebral. Posteriores investigaciones revelaron hipercalcemia y niveles persistentemente elevados de PTH, consistentes con HPTP. Tras la realización de estudios de localización, la paciente fue sometida a una paratiroidectomía de emergencia con diagnóstico de adenoma de paratiroides. Durante el seguimiento, se desarrolló restricción del crecimiento intrauterino y preeclampsia grave, lo que resultó en la necesidad de realizar una cesárea de emergencia. Tanto la madre como el neonato evolucionaron favorablemente. El HPTP es una condición infrecuente en la población embarazada y su diagnóstico puede ser desafiante por la superposición de síntomas con los cambios fisiológicos normales del embarazo. La aparición de complicaciones infrecuentes, como fenómenos trombóticos, resalta la necesidad de un abordaje integral para garantizar la detección y el manejo temprano. En la mayoría de los casos, la paratiroidectomía es el tratamiento de elección.

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-1ß 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.

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.

Pancreatitis aguda en el escenario de hipercalcemia por hiperparatiroidismo primario / Acute pancreatitis in the setting of hypercalcemia due to primary hyperparathyroidism

Introducción: describir el caso de un paciente con pancreatitis aguda secundaria a hipercalcemia por hiperparatiroidismo prImario. Esta es una causa poco frecuente de pancreatitis, asociada a morbimortalidad significativa en caso de no ser diagnosticada oportunamente Caso clínico: un hombre de 44 años, con antecedente de pancreatitis de presunto origen biliar que había requerido previamente colecistectomía, consultó por dolor abdominal y náuseas. Los estudios complementarios fueron compatibles con un nuevo episodio de pancreatitis aguda. Presentaba hipercalcemia y hormona paratiroidea (PTH) elevada, configurando hiperparatiroidismo primario. La gammagrafía informó hallazgos compatibles con adenoma paratiroideo. Se inició tratamiento con reanimación hídrica y analgesia con adecuada disminución de calcio sérico y resolución de dolor abdominal. Después de la paratiroidectomía se logró normalizar los niveles de calcio y PTH. Discusión: la pancreatitis aguda es una condición potencialmente fatal, por lo que la sospecha de causas poco frecuentes como la hipercalcemia debe tenerse en cuenta. El tratamiento de la hipercalcemia por adenoma paratiroideo se basa en reanimación hídrica adecuada y manejo quirúrgico del adenoma, con el fin de evitar recurrencia de pancreatitis y mortalidad. (AU)

Introduction: we describe the case of a patient with acute pancreatitis secondary to hypercalcemia due to primary hyperparathyroidism. This is a rare cause of pancreatitis associated with significant morbidity and mortality if not diagnosed in time. Clinical case: a 44-year-old man with a history of pancreatitis of presumed biliary origin, which had previously required cholecystectomy, consulted for abdominal pain and nausea. The laboratory findings were compatible with a new episode of acute pancreatitis. He presented hypercalcemia and an elevated parathyroid hormone (PTH), configuring primary hyperparathyroidism. Scintigraphy was performed, yielding findings compatible with parathyroid adenoma. Treatment with fluid resuscitation and analgesia was started, resulting in an adequate decrease in serum calcium and resolution of abdominal pain. After parathyroidectomy, calcium and PTH levels were normalized. Discussion: acute pancreatitis is a potentially fatal condition; therefore the suspicion of rare causes, such as hypercalcemia, should be considered. The treatment of hypercalcemia due to parathyroid adenoma is based on adequate fluid resuscitation and surgical management of the adenoma, to avoid recurrence of pancreatitis and death. (AU)

Hypercalcemia: A Review.

Importance: Hypercalcemia affects approximately 1% of the worldwide population. Mild hypercalcemia, defined as total calcium of less than 12 mg/dL (<3 mmol/L) or ionized calcium of 5.6 to 8.0 mg/dL (1.4-2 mmol/L), is usually asymptomatic but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people. Hypercalcemia that is severe, defined as total calcium of 14 mg/dL or greater (>3.5 mmol/L) or ionized calcium of 10 mg/dL or greater (≥2.5 mmol/L) or that develops rapidly over days to weeks, can cause nausea, vomiting, dehydration, confusion, somnolence, and coma. Observations: Approximately 90% of people with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy. Additional causes of hypercalcemia include granulomatous disease such as sarcoidosis, endocrinopathies such as thyroid disease, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A. Hypercalcemia has been associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, but these account for less than 1% of causes. Serum intact parathyroid hormone (PTH), the most important initial test to evaluate hypercalcemia, distinguishes PTH-dependent from PTH-independent causes. In a patient with hypercalcemia, an elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level (<20 pg/mL depending on assay) indicates another cause. Mild hypercalcemia usually does not need acute intervention. If due to PHPT, parathyroidectomy may be considered depending on age, serum calcium level, and kidney or skeletal involvement. In patients older than 50 years with serum calcium levels less than 1 mg above the upper normal limit and no evidence of skeletal or kidney disease, observation may be appropriate. Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate. In patients with kidney failure, denosumab and dialysis may be indicated. Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas). Treatment reduces serum calcium and improves symptoms, at least transiently. The underlying cause of hypercalcemia should be identified and treated. The prognosis for asymptomatic PHPT is excellent with either medical or surgical management. Hypercalcemia of malignancy is associated with poor survival. Conclusions and Relevance: Mild hypercalcemia is typically asymptomatic, while severe hypercalcemia is associated with nausea, vomiting, dehydration, confusion, somnolence, and coma. Asymptomatic hypercalcemia due to primary hyperparathyroidism is managed with parathyroidectomy or observation with monitoring, while severe hypercalcemia is typically treated with hydration and intravenous bisphosphonates.

A Review of Current Clinical Concepts in the Pathophysiology, Etiology, Diagnosis, and Management of Hypercalcemia.

Calcium is the most abundant extracellular cation in the body, and it is responsible for structural and enzymatic functions. Calcium homeostasis is regulated by 3 factors: calcitonin, vitamin D, and parathyroid hormone (PTH). Hypercalcemia is defined by a serum calcium concentration >10.5 mg/dL, and it is classified into mild, moderate, and severe, depending on calcium values. Most cases are caused by primary hyperparathyroidism and malignancies. Various mechanisms are involved in the pathophysiology of hypercalcemia, such as excessive PTH production, production of parathyroid hormone-related protein (PTHrp), bone metastasis, extrarenal activation of vitamin D, and ectopic PTH secretion. The initial approach is similar in most cases, but a definitive treatment depends on etiology, that is why etiological investigation is mandatory in all cases. The majority of patients are asymptomatic and diagnosed during routine exams; only a small percentage of patients present with severe manifestations which can affect neurological, muscular, gastrointestinal, renal, and cardiovascular systems. Clinical manifestations are related to calcium levels, with higher values leading to more pronounced symptoms. Critically ill patients should receive treatment as soon as diagnosis is made. Initial treatment involves vigorous intravenous hydration and drugs to reduce bone resorption such as bisphosphonates and, more recently, denosumab, in refractory cases; also, corticosteroids and calcitonin can be used in specific cases. This review aims to provide a clinical update on current concepts of the pathophysiology of calcium homeostasis, epidemiology, screening, clinical presentation, diagnosis, and management of hypercalcemia.

Stones left unturned: Missed opportunities to diagnose primary hyperparathyroidism in patients with nephrolithiasis.

BACKGROUND: Nephrolithiasis is a sequela of primary hyperparathyroidism and an indication for parathyroidectomy. The prevalence of primary hyperparathyroidism in patients with nephrolithiasis is 3% to 5%; however, recent studies suggest that many hypercalcemic patients with nephrolithiasis never undergo workup for primary hyperparathyroidism. Our goal is to evaluate primary hyperparathyroidism screening rates at a tertiary academic health institution and identify opportunities to increase referral rates in patients presenting with nephrolithiasis. METHODS: We retrospectively reviewed 15,725 patients across an academic health system who presented with nephrolithiasis between 2012 and 2020. Calcium levels measured within 6 months of presentation were identified, and those with hypercalcemia (≥10.3 mg/dL) were reviewed if parathyroid hormone levels were measured. Patients with primary hyperparathyroidism were evaluated to see if they were referred to a specialist for treatment. RESULTS: Of 15,725 patients presenting with nephrolithiasis, 12,420 (79%) had calcium levels measured; 630 patients (4.0%) were hypercalcemic, and 207 (33%) had parathyroid hormone levels measured. Patients were more likely to have parathyroid hormone levels sent if they were older, had higher calcium levels, or presented to an outpatient clinic (P = .028, P = .002, P < .001). We identified 89 patients (0.6%) with primary hyperparathyroidism, of which only 35 (39%) were referred for treatment. CONCLUSION: The proportion of patients presenting with nephrolithiasis ultimately diagnosed with primary hyperparathyroidism was significantly lower than others have reported. Additionally, a substantial number of patients with nephrolithiasis did not have calcium and/or parathyroid hormone levels measured. These missed opportunities for diagnosis are critical as early definitive management of primary hyperparathyroidism can prevent recurrent nephrolithiasis and other primary hyperparathyroidism-related end organ effects.

Recurrence after successful parathyroidectomy-Who should we worry about?

BACKGROUND: Preventing cervical reoperations is important-especially after parathyroidectomy. We sought to examine early predictors of recurrence of primary hyperparathyroidism after surgical cure. METHODS: Adult patients with sporadic primary hyperparathyroidism treated with parathyroidectomy between September 1, 1997, and September 1, 2019, with confirmed eucalcemia at 6 months postoperatively were identified. Recurrence was defined as hypercalcemia (>10.2 mg/dL) with an elevated or nonsuppressed parathyroid hormone level on subsequent follow-up. RESULTS: Parathyroidectomy was performed in 522 patients (median age, 62.1 years, 77% female) with the majority undergoing planned minimally invasive parathyroidectomy (85.4%, n = 446). After a median follow-up of 30.9 months, 13 patients (2.5%) recurred (median time to recurrence 50.2 months, interquartile range 27.9-66.5), all of whom underwent planned minimally invasive parathyroidectomy (n = 13/446, 2.9%). Recurrence was more common in those with higher (but still normal) 6-month calcium (10.1 vs 9.3 mg/dL, P < .001) or parathyroid hormone values (64 vs 46 pg/mL, P < .01). Multivariate analysis revealed that age >66.5 years, calcium ≥9.8mg/dL and parathyroid hormone ≥80 pg/mL at 6 months were associated with increased risk of recurrence. In addition, the presence of at least 1 preoperative imaging study that conflicted with intraoperative findings among minimally invasive parathyroidectomy patients (n = 446) was associated with increased risk of recurrence (hazard ratio 4.93, 95% confidence interval 1.25-16.53, P = .016). CONCLUSION: Recurrence of sporadic primary hyperparathyroidism after initial surgical cure in the era of minimally invasive parathyroidectomy is 2.5%. Identification of those at risk for recurrence using 6-month serum calcium ≥9.8 mg/dL, parathyroid hormone ≥80 pg/mL, and/or potentially conflicting localization studies may inform surveillance strategies.

Serum Phosphate: A Neglected Test in the Clinical Management of Primary Hyperparathyroidism.

BACKGROUND: Although the inverse correlation between serum PTH and phosphate (P) levels in patients with primary hyperparathyroidism (PHPT) is well known, the relationship between P levels and the clinical picture of the disease has not been well investigated. This was thus the aim of this paper. PATIENTS: A total of 472 consecutive patients with PHPT attending our center were retrospectively evaluated at diagnosis. RESULTS: P levels lower than 2.5 mg/dL (HypoP) were found in 198/472 patients (41.9%). HypoP was mild (2-2.5 mg/dL), moderate (1-1.9 mg/dL), and severe (<1 mg/dL) in 168 (84.9%), 30 (15.1%), and 0 cases, respectively. P levels were lower in males than females. Patients with more severe bone density impairment at the radial (but not the vertebral or femoral) site had P levels significantly lower than other patients. PHPT severity was worse in HypoP patients, both clinically (higher prevalence of renal stones, but not of osteoporosis) and biochemically (higher serum calcium and PTH levels). All patients in the moderate HypoP group were either symptomatic or asymptomatic reaching surgical indication according to the latest guidelines. CONCLUSIONS: We observed a relationship between P levels and biochemical and clinical features of PHPT severity. In asymptomatic PHPT patients, even moderate HypoP is predictive of surgical indication, regardless of age and hypercalcemia severity.

Prevalence and risk factors for tertiary hyperparathyroidism in kidney transplant recipients.

BACKGROUND: Tertiary hyperparathyroidism after kidney transplantation has been associated with graft dysfunction, cardiovascular morbidity, and osteopenia; however, its true prevalence is unclear. The objective of our study was to evaluate the prevalence of and risk factors for tertiary hyperparathyroidism. METHODS: A prospective cohort of 849 adult kidney transplantation recipients (December 2008-February 2020) was used to estimate the prevalence of hyperparathyroidism 1-year post-kidney transplant. Tertiary hyperparathyroidism was defined as hypercalcemia (≥10mg/dL) and hyperparathyroidism (parathyroid hormone≥70pg/mL) 1-year post-kidney transplantation. Modified Poisson regression models were used to evaluate risk factors associated with the development of both persistent hyperparathyroidism and tertiary hyperparathyroidism. RESULTS: Among kidney transplantation recipients, 524 (61.7%) had persistent hyperparathyroidism and 182 (21.5%) had tertiary hyperparathyroidism at 1-year post-kidney transplantation. Calcimimetic use before kidney transplantation was associated with 1.30-fold higher risk of persistent hyperparathyroidism (adjusted prevalence ratio = 1.30, 95% CI: 1.12-1.51) and 1.84-fold higher risk of tertiary hyperparathyroidism (adjusted prevalence ratio = 1.84, 95% CI: 1.25-2.72). Pre-kidney transplantation parathyroid hormone ≥300 pg/mL was associated with 1.49-fold higher risk of persistent hyperparathyroidism (adjusted prevalence ratio = 1.49, 95% CI = 1.19-1.85) and 2.21-fold higher risk of tertiary hyperparathyroidism (adjusted prevalence ratio = 2.21, 95% CI = 1.25-3.90). Pre-kidney transplantation tertiary hyperparathyroidism was associated with an increased risk of post-kidney transplantation tertiary hyperparathyroidism (adjusted prevalence ratio = 1.71, 95% CI = 1.29-2.27), but not persistent hyperparathyroidism. Furthermore, 73.0% of patients with persistent hyperparathyroidism and 61.5% with tertiary hyperparathyroidism did not receive any treatment at 1-year post-kidney transplantation. CONCLUSION: Persistent hyperparathyroidism affected 61.7% and tertiary hyperparathyroidism affected 21.5% of kidney transplantation recipients; however, the majority of patients were not treated. Pre-kidney transplantation parathyroid hormone levels ≥300pg/mL and the use of calcimimetics are associated with the development of tertiary hyperparathyroidism. These findings encourage the re-evaluation of recommended pre-kidney transplantation parathyroid hormone thresholds and reconsideration of pre-kidney transplantation secondary hyperparathyroidism treatments to avoid the adverse sequelae of tertiary hyperparathyroidism in kidney transplantation recipients.

Mechanisms of acute hypercalcemia in pediatric patients following the interruption of Denosumab.

PURPOSE: Denosumab is a fully human monoclonal anti-RANK-L antibody that is clinically used to counteract the bone loss induced by exacerbated osteoclast activity. Indeed, its binding to RANK-L prevents the interaction RANK-L/receptor RANK that is essential for osteoclastogenesis and bone resorbing activity. Although there are many medications available to treat bone loss diseases, including bisphosphonates, Denosumab is highly effective since it reduces the bone erosion. The use in pediatric patients is safe. However, some concerns are related to the interruption of the treatment. Indeed, in this study, we reported hypercalcemia in two pediatric patients and alterations of circulating osteoclast precursors. METHODS: Peripheral Blood Mononuclear Cells (PBMC) were isolated from two pediatric patients with hypercalcemia after Denosumab interruption and from 10 controls. Cytofluorimetric analysis and in vitro osteoclastogenesis experiments were performed. RESULTS: Increase of CD16-CD14+CD11b+ cells was revealed in PBMC from patients reflecting the enhanced in vitro osteoclastogenesis. CONCLUSION: Our data suggest that precautions must be taken when Denosumab therapy is interrupted and gradual decrease of dose and/or timing of treatment should be performed. To prevent the onset of hypercalcemia that could be in the discontinuation phase, cytofluorimetric analysis of PBMC should be performed to evaluate osteoclast precursors.

How and when is multiglandular disease diagnosed in sporadic primary hyperparathyroidism?

BACKGROUND: In total, ∼15% of patients with sporadic primary hyperparathyroidism have multiglandular disease, which may be suspected preoperatively but can only be confirmed intra or postoperatively. The study aim is to determine how and when patients are diagnosed with multiglandular disease and to what extent different modalities contribute. METHODS: Consecutive cases of sporadic primary hyperparathyroidism (2013-2019) undergoing initial exploration were reviewed from a single-institution prospective database. Preoperative single-photon emission tomography/computed tomography and neck ultrasound were routinely performed to help direct either bilateral or unilateral exploration guided by intraoperative parathyroid hormone monitoring using the dual criteria. Multiglandular disease was defined as either resection of >1 enlarged parathyroid or hypercalcemia at ≥6 months after single gland resection. RESULTS: Of 1,890 patients with sporadic primary hyperparathyroidism, multiglandular disease was identified in 254 (13.4%); 244 (96.1%) were diagnosed intraoperatively and 10 (3.9%) postoperatively. In these multiglandular disease patients, single gland disease was suggested on single-photon emission tomography/computed tomography in 54.0%, ultrasound in 49.2%, and both were concordant for single gland disease in 29.4%. Intraoperative multiglandular disease diagnosis was prompted by an inadequate intraoperative parathyroid hormone monitoring drop in 38.5%, by surgeon interpretation of imaging in 38.1%, by observing ipsilateral gland enlargement in 11.0%, by finding an initial gland <200 mg in 10.3%, and 2.0% had unexpected multiglandular disease during thyroidectomy. Multiglandular disease was diagnosed by postoperative hypercalcemia in 10 of 254 patients (4.9%). CONCLUSION: To avoid failure at parathyroidectomy for primary hyperparathyroidism, expert surgeons use multiple approaches to diagnose and manage multiglandular disease. Preoperative localization studies alone are insufficient, missing multiglandular disease in at least 30% of cases. All examined adjuncts are informative, including intraoperative parathyroid hormone monitoring, imaging, and intraoperative visual cues.

Hypercalcemia due to CYP24A1 mutations: a systematic descriptive review.

BACKGROUND AND OBJECTIVES: CYP24A1 encodes a 24-hydroxylase involved in vitamin D catabolism, whose loss-of-function results in vitamin D-dependent hypercalcemia. Since the identification of CYP24A1 variants as a cause of idiopathic infantile hypercalcemia, a large body of literature has emerged indicating heterogeneity in penetrance, symptoms, biochemistry, and treatments. The objectives of the present research work were to investigate the clinical heterogeneity of the disease, the possibility of a relevant phenotype for monoallelic carriers, and to compare the hypocalcemic effect of the available therapies. METHODS: Two reviewers searched different databases for studies published between the identification of CYP24A1 variants and December 31, 2020. Eligible studies included clinical trials and reports describing carriers of CYP24A1 variants. RESULTS: Fifty eligible studies were identified, accounting for 221 patients. Genetic data were retrieved and allele frequencies were calculated. Acute hypercalcemia was the typical presentation during the first year of life (76%, P = 0.0005), and nephrocalcinosis was more frequent in infancy (P < 0.0001). Pregnancy was associated with symptomatic hypercalcemia in 81.8% and high rates of obstetric complications. Monoallelic carriers displayed significant rates of nephrolithiasis (19.4%), nephrocalcinosis (4.9%), and symptomatic hypercalcemia (5.6%). CONCLUSIONS: CYP24A1 loss-of-function results in an age-dependent phenotype, which can be exacerbated by triggering factors, such as pregnancy. Although biallelic carriers present more significant clinical and biochemical features, monoallelic carriers have an increased risk of calcium-related conditions. The highly variable tested therapeutic approaches did not allow to draw conclusions on preferable therapeutic regime.

Persistent hypercalcemia with similar familial Hypocalciuric hypercalcemia features: a case report and literature review.

BACKGROUND: Primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcemia (FHH) are the most important differential diagnosis of parathyroid hormone (PTH)-dependent hypercalcemia. The clinical features of FHH and PHPT can overlap in some cases. Therefore, these two diseases must be differentiated to prevent unnecessary parathyroidectomy. Here, we present a case that was not entirely matched with any of the known differential diagnoses of hypercalcemia. CASE PRESENTATION: A 19-year-old girl with no history of any disease presented with persistent hypercalcemia without any specific musculoskeletal complaint. We found persistent hypercalcemia in her routine laboratory data from 3 years ago; while no data was available during the childhood period. Her dietary calcium intake was normal. She did not mention any history of renal stone, bone fracture as well as family history of hypercalcemia. Biochemical features showed normal values of serum creatinine, high normal serum calcium (range, 10.3-11.3 mg/dL; (normal range: 8.8-10.4)), and non-suppressed PTH levels (range, 37.2-58.1 pg/mL; (normal range: 10-65)). Serum 25 OH vitamin D level at the first visit was 16.1 ng/mL that treated by vitamin D supplementation. Since then, all 25 OH vitamin D levels were in the acceptable range. After correction of vitamin D deficiency during the follow-up period the calcium creatinine clearance ratio(s) (CCCR) were calculated in the range of 0.009 to 0.014 (means below 1%). The clinical and laboratory data indicate more FHH rather than PHPT. Genetic studies were negative for the common genes associated with FHH (CASR, GNA11, and AP2S1 genes) and multiple endocrine neoplasia type1 (MEN1). On the other hand, no evidence of autoimmunity was found in her to support an autoimmune FHH-like syndrome. Hence, the case did not match completely to any diagnosis of FHH and PHPT, so we decided to follow her. CONCLUSION: We presented a patient with FHH phenotype whose common genetic tests were negative. Further research is needed to ascertain other causes leading to similar manifestations.

The influence of parenteral protein intake on electrolyte disturbances in premature infants.

INTRODUCTION: Aggressive parenteral nutrition with delivery of high amino acid and energy doses is used to improve growth and neurodevelopmental outcomes in very low birth weight (VLBW) preterm infants. Recent findings, however, suggest that this approach may cause electrolyte imbalances. The aim of our study was to compare the prevalence of hypercalcaemia, hypophosphataemia, and hypokalaemia in 2 groups of preterm infants that received parenteral nutrition with different amounts of amino acids and to analyse perinatal and nutritional variables associated with the development of electrolyte imbalances. METHODS: We conducted a retrospective observational study comparing 2 groups of preterm infants born before 33 weeks' gestation with birth weights of less than 1500 g managed with parenteral nutrition. One of the groups received less than 3 g/kg/day of amino acids and the other received 3 g/kg//day of amino acids or more. We analysed the prevalence of electrolyte imbalances and possible associations with aggressive parenteral nutrition, adjusting for potential confounders. RESULTS: We studied 114 infants: 60 given less than 3 g/kg/day of amino acids (low-intake group) and 54 given at least 3 g/kg/day (high-intake group). The prevalence of electrolyte imbalances was similar in both groups. The prevalence of hypercalcaemia was 1.67% in the low-intake group and 1.85% in the high-intake group (P > .99), the prevalence of severe hypophosphataemia 11.7% vs 9.3%, and the prevalence of hypokalaemia 15.0% vs 11.1% (P > .99). A calcium to phosphorus ratio greater than 1.05 had a protective effect against hypophosphataemia (P = .007). CONCLUSIONS: We did not find an association between hypercalcaemia, hypophosphataemia, and hypokalaemia and the amino acid dose delivered by PN in the high-intake group of preterm infants.