A Rare Case of Neonatal Hypomagnesemia with Secondary Hypocalcemia Caused by a Novel Homozygous TRPM6 Gene Variant.

BACKGROUND Familial hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disorder (OMIM# 602014) caused by mutations in the gene encoding transient receptor potential melastatin 6 (TRPM6)) on chromosome 9q22, a channel involved in epithelial magnesium resorption. While a plethora of studies have delineated various clinical manifestations pertinent to this mutation, the literature is devoid of connections between TRPM6 mutations and bleeding diathesis, or sudden infant death syndrome (SIDS). This report presents a case of familial HSH associated with the novel homozygous TRPM6 gene variant c.5281C>G p. (Arg1761Gly) chr9: 77354845. CASE REPORT This report details a 26-day-old neonate, born full term with optimal Apgar scores, who experienced an abrupt emergence of apnea, cyanosis, bilateral nasal bleeding, and diminished alertness. Despite the neonate's initially unremarkable clinical birth indicators, a meticulous assessment unveiled a pronounced family history of SIDS, including a sibling previously diagnosed with hypomagnesemia. Laboratory examination of the infant demonstrated severe hypomagnesemia and hypocalcemia, conditions which were promptly ameliorated following intravenous administration of magnesium and calcium. Whole-exome sequencing identified a homozygous TRPM6 gene mutation c.5281C>G p. (Arg1761Gly) at chr9: 77354845. This gene is crucial for magnesium regulation. The mutation involves a cytosine-to-guanine shift, resulting in an arginine to glycine amino acid substitution at position 1761 of the TRPM6 protein. CONCLUSIONS This report has highlighted that infantile hypomagnesemia may be associated with symptoms and signs that can mimic infection, or it can present with seizures. Although familial HSH is a rare genetic disorder that can be identified by genetic testing, correction of hypomagnesemia is the most important and immediate clinical management strategy.

Epileptic seizures and abnormal tooth development as primary presentation of pseudohypoparathyroidism type 1B.

Pseudohypoparathyroidism (PHP) is a rare genetic disorder characterised by a non-functioning PTH. Usually, the diagnosis is made following (symptomatic) hypocalcaemia. We describe a case in which epileptic seizures and abnormalities in dental development were the main clinical manifestation of PHP type 1B. This case demonstrates the importance of screening for hypocalcaemia in patients with de novo epileptic seizures. In addition, antiepileptic medications themselves may interfere with calcium-phosphate metabolism, causing or aggravating a hypocalcaemia as well. By correcting the calcium level, a resolution of these symptoms could be obtained.

Neonatal hypocalcaemic seizures unmasking asymptomatic maternal primary hyperparathyroidism.

Hypocalcaemia is a common cause of neonatal seizures. Here, we present a breastfed neonate with smooth perinatal transition and no family history of seizures presenting at 3 weeks with recurrent multifocal clonic seizures. On evaluation, the neonate was found to have low iCa and total calcium. 25-hydroxy vitamin D (25(OH)D) level was low and intact parathyroid hormone (iPTH) was inappropriately normal. The maternal evaluation revealed high calcium and low phosphate levels. iPTH was very high and 25(OH)D was very low in the mother. Sestamibi scan showed a left inferior parathyroid adenoma in the mother. Maternal primary hyperparathyroidism causing hypercalcaemia can suppress parathyroid activity in the fetus, resulting in inappropriate parathyroid response to hypocalcaemia after birth causing recurrent hypocalcaemic seizures. So neonatal hypocalcaemic seizures need careful evaluation of the neonate and the mother at times and can help both mother and neonate.

A Rare Reason for Severe Hypocalcemia Following Kidney Transplant: Denosumab Treatment.

Deviations of calcium, phosphate, parathyroid hormone, and vitamin D levels are the basis for the diagnosis of calcium-phosphate metabolism disorders. The plasma concentration of the biologically active form known as free calcium is regulated in a harmonious manner by its exchange in the bones and reabsorption by the kidneys. These steps take place under the control of parathyroid hormone and calcitriol. In the process of chronic kidney disease, the kidney cannot synthesize adequate calcitriol, and the resulting hypocalcemia and hyperphosphatemia cause the development of secondary hyperparathyroidism. Osteoporosis is a metabolic bone disease and is essentially the consequence of osteoclastogenesis-induced bone resorption that exceeds bone formation. Osteoporosis is common after kidney transplant. However, hypocalcemia following kidney transplant is rare. The hungry bone syndrome after parathyroidectomy is often responsible for this condition in the pretransplant period. Denosumab is a human monoclonal antibody developed against the receptor activator of nuclear factor kappa-B ligand (known as RANKL). Denosumab exerts an antiresorptive effect on bones by reducing differentiation into osteoclasts. It is an effective treatment option for osteoporosis in the general population. There is insufficient scientific data regarding the use of denosumab in kidney transplant patients. Here, we present the case of a kidney transplant recipient who developed severe hypocalcemia (serum calcium 4.7 mg/dL) after denosumab treatment for osteoporosis.

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.

Predictors of blood ionized calcium concentration in sick adult cattle.

BACKGROUND: Data on the factors affecting blood ionized calcium concentration (ciCa2+ ) and diagnostic performance of serum total calcium concentration (ctCa) measurements to detect abnormal blood iCa2+ status are lacking in sick adult cattle. OBJECTIVE: Assess the association of ciCa2+ with venous blood pH, plasma concentrations of chloride (cCl), sodium (cNa), and potassium (cK), and ctCa, and total protein, albumin, and globulin concentrations in sick adult cattle. ANIMALS: Two-hundred and sixty-five adult cattle (≥1-year-old) with different diseases. METHODS: Prospective study. Whole blood pH, ciCa2+ , cNa, cK, and cCl were measured using a blood gas and electrolyte analyzer, whereas ctCa, and total protein, and albumin concentrations were determined using an autoanalyzer. The relationship between ciCa2+ and venous blood pH, plasma cCl, cNa, cK, and ctCa, and total protein, albumin, and globulin concentrations was investigated. Sensitivity and specificity were calculated for ctCa for diagnosis of abnormal ciCa2+ . RESULTS: Sensitivity of ctCa measurements to detect abnormal ciCa2+ was 66.0% whereas specificity of ctCa measurements was 72.3%. Serum total calcium concentration measurements accounted for 42% of adjusted blood ionized calcium (iCa2+ 7.40 ) concentration variance. Plasma cCl, and cK had explanatory power of ciCa2+ 7.40 , accounting for an additional 21% and 9% of the variance, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Serum tCa measurements failed to accurately predict blood iCa2+ status in ill adult cattle. Serum tCa concentrations and plasma cCl were the strongest predictors of ciCa2+ in sick adult cattle.

Identification of a Novel Homozygous Missense Mutation in the CLDN16 Gene to Decipher the Ambiguous Clinical Presentation Associated with Autosomal Dominant Hypocalcaemia and Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis in an Indian Family.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHNNC) is a rare autosomal recessive renal tubulopathy disorder characterized by excessive urinary loss of calcium and magnesium, polyuria, polydipsia, bilateral nephrocalcinosis, progressive chronic kidney disease, and renal failure. Also, sometimes amelogenesis imperfecta and severe ocular abnormalities are involved. The CLDN-16 and CLDN-19 genes encode the tight junction proteins claudin-16 and claudin-19, respectively, in the thick ascending loop of Henle in the kidney, epithelial cells of the retina, dental enamel, etc. Loss of function of the CLDN-16 and/or CLDN-19 genes leads to FHHNC. We present a case of FHHNC type 1, which was first confused with autosomal dominant hypocalcaemia (ADH) due to the presence of a very low serum parathyroid hormone (PTH) concentration and other similar clinical features before the genetic investigations. After the exome sequencing, FHHNC type 1 was confirmed by uncovering a novel homozygous missense mutation in the CLDN-16 gene (Exon 2, c.374 T > C) which causes, altered protein structure with F55S. Associated clinical, biochemical, and imaging findings also corroborate final diagnosis. Our findings expand the spectrum of the CLDN-16 mutation, which will further help in the genetic diagnosis and management of FHNNC.

Clinical and molecular characteristics of two Italian kindreds with hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome.

PURPOSE: Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome, also known as Barakat syndrome, is a rare autosomal dominant disease characterized by the triad of hypoparathyroidism, deafness, and renal abnormalities. The disorder is caused by the haploinsufficiency of the zinc finger transcription factor GATA3 and exhibits a great clinical variability with an age-dependent penetrance of each feature. We report two unrelated kindreds whose probands were referred to our outpatient clinic for further evaluation of hypoparathyroidism. METHODS: The proband of family 1, a 17-year-old boy, was referred for severe hypocalcemia (5.9 mg/dL) incidentally detected at routine blood tests. Abdomen ultrasound showed bilateral renal cysts. The audiometric evaluation revealed the presence of bilateral moderate hearing loss although the patient could communicate without any problem. Conversely, the proband of family 2, a 19-year-old man, had severe symptomatic hypocalcemia complicated by epileptic seizure at the age of 14 years; his past medical history was remarkable for right nephrectomy at the age of 4 months due to multicystic renal disease and bilateral hearing loss diagnosed at the age of 18 years. RESULTS: Based on clinical, biochemical, and radiologic data, HDR syndrome was suspected and genetic analysis of the GATA3 gene revealed the presence of two pathogenetic variants in exon 3, c.404dupC and c.431dupG, in the proband of family 1 and 2, respectively. CONCLUSION: HDR syndrome is a rare cause of hypoparathyroidism and must be excluded in all patients with apparently idiopathic hypoparathyroidism. A correct diagnosis is of great importance for early detection of other HDR-related features and genetic counseling.

An individual approach to intraoperative parathyroid hormone measurement during total thyroidectomy.

PURPOSE: Hypocalcemia is a common complication of thyroidectomy. Measurement of the intraoperative serum parathyroid hormone (PTH) levels became an established technique but it requires further improvements. We aimed to assess intraoperative PTH level testing results against the hypothesis that the PTH assay may be performed almost immediately after thyroid gland removal. METHODS: A retrospective cohort study. During total thyroidectomy surgery, the patients had PTH levels measured at the cutting time and again immediately after the thyroid gland is removed. Post-operatively, serial total blood calcium levels were obtained twice daily and recorded. RESULTS: Among 63 enrolled patients, 39 had multinodular goiter, 15 thyroid carcinoma, and nine had Graves' disease. The mean age was 59.8 ± 15.3 years, 43 females. The mean PTH level before surgery was 45.8 ± 22.0 pg/mL. Post-operatively, 11/63 patients developed hypocalcemia with serum calcium levels <8 mg/dL. Four patients with ≥50 % decrease in PTH concentration were normocalcemic a day after surgery and were discharged early. Four patients with ≥70 % PTH decrease were treated accordingly during prolonged hospitalization and did not suffer from permanent hypocalcemia. The cut-off value of 70 % decrease after the gland removal was able to predict postoperative hypocalcemia with a sensitivity of 100 %, specificity 82.9 %, PPV 60.0 % and NPV 100 %. CONCLUSION: Measurements of intraoperative PTH may not be performed at fixed time intervals but after 1-2 min after removal of the thyroid gland. Defining those not at risk would allow the majority of patients to be waived from post-operative blood calcium testing and safely discharged early after surgery.

Severe hypocalcaemia mimicking acute coronary syndrome.

Hypocalcaemia is a common electrolyte deficiency that can be found in up to 28% of hospitalised patients. It may affect cardiac and smooth muscle tone, leading to ECG abnormalities and, in rare cases, coronary spasms and heart failure. This is a case of a pregnant woman in preterm labour who developed vasospastic angina and corrected QT interval (QTc) prolongation on ECG from severe hypocalcaemia, which likely occurred due to iatrogenic hypermagnesaemia. She had a negative diagnostic workup for acute coronary syndrome, and her chest pain and QTc prolongation ultimately resolved with intravenous electrolyte repletion. This case highlights the importance of considering hypocalcaemia on the differential of chest pain that is possibly cardiac in origin.

Low serum iPTH at the end of surgery is the earliest predictor of postoperative hypocalcemia after total thyroidectomy.

BACKGROUND: The most frequent complication of total thyroidectomy remains hypocalcemia due to low postoperative levels of serum intact parathyroid hormone (iPTH). The purpose of this study was to investigate the role of decreased iPTH at the end of surgery in predicting hypocalcemia. In addition, we examined the percentage decrease of iPTH as potential indicator of hypocalcemia. METHODS: We retrospectively collected the data of patients who underwent total thyroidectomy for benign and malignant diseases at our institution between 2010 and 2022. The iPTH level was measured before and at the end of surgery, and serum calcium levels on the first postoperative day. Demographic, clinical, and biochemical characteristics of patients with low iPTH were compared with patients with normal iPTH levels using ANOVA for continuous variables and χ2-tests for categorical variables. Multivariable logistic regression analysis evaluated the association of iPTH at the end of surgery and the relative reduction of iPTH with postoperative hypocalcemia. RESULTS: The mean age of the 607 patients in this study was 55.6 years, and the female-to-male ratio was 5:1. Goiter was the most common indication for surgery (N = 382, 62.9%), followed by Graves' disease (N = 135, 22.2%). The mean preoperative iPTH was 49.0 pg/ml, while the mean postoperative iPTH was 29.3 pg/ml. A total of 197 patients (32.5%) had an iPTH level below normal, 77 patients (39%), had iPTH levels of 10-15.0 pg/ml and 120 patients (61%) of < 10.0 pg/ml at the end of surgery. Among all patients, 124 (20.4%) developed hypocalcemia on the first postoperative day. The mean percentage of decrease of iPTH was highest among patients with iPTH < 10 pg/ml (76.9%, p < 0.01); this group of patients had also the highest rate of postoperative hypocalcemia on day one (45.0% vs. 26.0% vs 12.2%, p < 0.01). CONCLUSIONS: Measurement of iPTH at the end of total thyroidectomy predicts patients who are at risk for postoperative hypocalcemia. The combination of low serum iPTH with a decrease in iPTH level of ≥ 50% may improve prediction of hypocalcemia compared to iPTH levels alone allowing for early calcium substitution in these patients at high risk of developing postoperative hypocalcemia.

The utility of parathyroid autofluorescence as an adjunct in thyroid and parathyroid surgery 2023.

Thyroid and parathyroid surgery requires careful dissection around the vascular pedicle of the parathyroid glands to avoid excessive manipulation of the tissues. If the blood supply to the parathyroid glands is disrupted, or the glands are inadvertently removed, temporary and/or permanent hypocalcemia can occur, requiring post-operative exogenous calcium and vitamin D analogues to maintain stable levels. This can have a significant impact on the quality of life of patients, particularly if it results in permanent hypocalcemia. For over a decade, parathyroid tissue has been noted to have unique intrinsic properties known as "fluorophores," which fluoresce when excited by an external light source. As a result, parathyroid autofluorescence has emerged as an intra-operative technique to help with identification of parathyroid glands and to supplement direct visualization during thyroidectomy and parathyroidectomy. Due to the growing body of literature surrounding Near Infrared Autofluorescence (NIRAF), we sought to review the value of using autofluorescence technology for parathyroid detection during thyroid and parathyroid surgery. A literature review of parathyroid autofluorescence was performed using PubMED. Based on the reviewed literature and expert surgeons' opinions who have used this technology, recommendations were made. We discuss the current available technologies (image vs. probe approach) as well as their limitations. We also capture the opinions and recommendations of international high-volume endocrine surgeons and whether this technology is of value as an intraoperative adjunct. The utility and value of this technology seems promising and needs to be further defined in different scenarios involving surgeon experience and different patient populations and conditions.

Hypomagnesemia with Secondary Hypocalcemia (HSH): a Case Report.

BACKGROUND: Hypomagnesemia with secondary hypocalcemia (HSH) is a genetic disorder arising from the body's impaired capacity to absorb and retain magnesium (Mg2+) consumed through diet. Consequently, Mg2+ levels in blood are significantly reduced, a condition referred to as hypomagnesemia. Insufficient levels of Mg2+ and calci-um (Ca2+) can lead to neurological complications that manifest during infancy, such as painful muscle spasms (tet-any) and seizures. METHODS: We reported a case of HSH involving a 10-year-old male patient from a Han Chinese family. He was admitted due to recurrent convulsions experienced over the past two years. The patient's initial episode occurred two years prior, when he collapsed without apparent cause and exhibited limb numbness, convulsions, and a disordered state of consciousness, accompanied by hypocalcemia. Cranial CT scans revealed multiple symmetrical calcifications in the basal ganglia, corona radiata, and cerebellar dentate nucleus. RESULTS: During the hospital stay, the patient was administered the following treatments: Calcium Carbonate and Vitamin D3 Tablets (1.5 g of calcium carbonate and 125 IU of Vitamin D3 per tablet, 1 tablet/time) once daily, Calcitriol Soft Capsules (0.25 µg of calcitriol per capsule, 1 capsule/time) twice daily, Potassium Chloride Sustained-release Tablets (0.5 g of potassium chloride per tablet, 1 tablet/time) thrice daily, Potassium Aspartate and Mag-nesium Aspartate Tablets (158 mg of potassium aspartate and 140 mg of magnesium aspartate per tablet, 1 tablet/ time) thrice daily, and intravenous infusions of Magnesium Sulfate Injection (2.5 g/time) twice daily. After three days in the hospital, the patient's initial symptoms subsided, resulting in discharge with a prescription of ongoing oral medications including Calcium Carbonate and Vitamin D3 Tablets, Calcitriol Soft Capsules, and Potassium Aspartate and Magnesium Aspartate Tablets, with the same usage and dosage as the above three drugs. A month subsequent, the serum levels of Mg2+, Ca2+, potassium (K+), and phosphorus were 0.96 mmol/L, 2.52 mmol/L, 4.06 mmol/L, and 1.63 mmol/L, respectively. CONCLUSIONS: Primary HSH is an uncommon manifestation of parathyroid hypoplasia, clinically characterized by low levels of Mg2+, Ca2+, and K+ in the blood. Our findings serve to enrich and consolidate the knowledge for future case studies and follow-up investigations.

Parathyroid Hormone Resistance: An Uncommon Cause of Hypocalcaemia in an Adult Ghanaian Female.

BACKGROUND AND OBJECTIVE: Parathyroid hormone (PTH) resistance, the main biochemical feature of a rare group of disorders known as Pseudohypoparathyroidism (PHP) is an uncommon cause of hypocalcaemia. In addition to the biochemical abnormalities, some individuals with PHP may have features of Albright Hereditary Osteodystrophy (AHO). Being a rare disorder with a significant level of variation and overlap in its clinical presentation, diagnosis of PHP may be challenging in some clinical settings. This case report highlights the diagnosis of this rare disorder. CASE REPORT: A 20-year-old Ghanaian female who had been involved in a road traffic accident (RTA) was referred to the endocrine clinic after a computer tomography (CT) scan of her head revealed an incidental finding of multiple basal ganglia calcifications. Investigations revealed hypocalcaemia, hyperphosphatemia, and elevated intact PTH in the presence of normal levels of 25-hydroxyvitamin D and magnesium, and a normal kidney function. She also had phenotypic features of AHO. Findings suggested a diagnosis of PHP, however, the type could not be identified due to the unavailability of further testing. CONCLUSION: This report of a Ghanaian female with PTH resistance and features of AHO diagnosed at the age of 20 years, is expected to add to the existing literature and assist in increasing the level of awareness and facilitate the diagnosis of this disorder in our setting.

CONTEXTE ET OBJECTIF: La résistance à l'hormone parathyroïdienne (PTH), principale caractéristique biochimique d'un groupe rare de troubles connus sous le nom de pseudohypoparathyroïdie (PHP), est une cause rare d'hypocalcémie. En plus des anomalies biochimiques, certaines personnes atteintes de PHP peuvent présenter des caractéristiques d'ostéodystrophie héréditaire d'Albright (AHO). Étant un trouble rare avec un niveau significatif de variation et de chevauchement dans sa présentation clinique, le diagnostic de PHP peut être difficile dans certains contextes cliniques. Ce rapport de cas met en lumière le diagnostic de cette maladie rare. RAPPORT DE CAS: Une femme ghanéenne de 20 ans qui avait été impliquée dans un accident de la circulation routière (RTA) a été référée à la clinique endocrinienne après qu'une tomodensitométrie (TDM) de sa tête a révélé la découverte fortuite de multiples calcifications des ganglions de la base. Les examens ont révélé une hypocalcémie, une hyperphosphatémie et une PTH intacte élevée en présence de taux normaux de 25 hydroxyvitamine D et de magnésium et d'une fonction rénale normale. Elle avait également des caractéristiques phénotypiques d'AHO. La découverte a suggéré un diagnostic de PHP, mais le type n'a pas pu être identifié en raison de l'indisponibilité de tests supplémentaires. CONCLUSION: Ce rapport d'une femme ghanéenne présentant une résistance à la PTH et des caractéristiques d'AHO diagnostiquée à l'âge de 20 ans, devrait s'ajouter à la littérature existante et aider à accroître le niveau de sensibilisation et à faciliter le diagnostic de ce trouble dans notre contexte. Mots-clés: Hypocalcémie, Hormone parathyroïdienne, Ghana.