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The Turkish Journal of Pediatrics 2023Familial hypocalciuric hypercalcemia (FHH) is one of the conditions that should be considered in the differential diagnosis of hypercalcemia and normo-hypophosphatemia... (Review)
Review
Cinacalcet therapy in a child with novel homozygous CASR p.Glu353Lys mutation causing familial hypocalciuric hypercalcemia type 1: case report and review of the literature.
BACKGROUND
Familial hypocalciuric hypercalcemia (FHH) is one of the conditions that should be considered in the differential diagnosis of hypercalcemia and normo-hypophosphatemia in childhood. Heterozygous Calcium-sensing receptor (CASR) gene mutations cause FHH, and homozygous CASR gene mutations cause neonatal severe primary hyperparathyroidism (NSHPT). Cinacalcet is an allosteric modulator of Calciumsensing receptor (CaSR), and has been used in the treatment of these clinical entities in recent years.
CASE
A 26-month-old boy was examined for a recurrent rash. During the evaluation, hypercalcemia (13.3 mg/ dL), hypophosphatemia (2.3 mg/dL) and inappropriately normal PTH level (67 pg/mL) were observed. Neck and renal ultrasonography were normal. The parathyroid scintigraphy was unremarkable. The patient`s family members were also evaluated, and hypocalciuria (fractional excretion of calcium were 0.01%, 0.04% on two separate tests) was detected concurrently with the patient`s hypercalcemia. The mother`s serum calcium was 10.2 mg/dL, the father`s was 10.6 mg/dL, and the brother`s was 12.8 mg/dL. CASR gene sequencing showed a novel homozygous mutation in exon 4 (c.1057G > A), which had generated a substitution of the amino acid glutamate to lysine at codon 353 (p.Glu353Lys). This mutation was homozygous in the children and heterozygous in the parents. Fluid hydration, furosemide, oral phosphorus, prednisolone, pamidronate and cinacalcet treatments were used in the management of hypercalcemia of the proband. A longer and more effective control was achieved with cinacalcet treatment.
CONCLUSIONS
FHH can be seen in heterozygous as well as homozygous CASR gene mutations. Different clinical findings may occur in different individuals from the same family. Cinacalcet therapy can be used successfully in the treatment of individuals with FHH.
Topics: Humans; Male; Calcium; Cinacalcet; Hypercalcemia; Hypophosphatemia; Mutation; Receptors, Calcium-Sensing; Child, Preschool
PubMed: 37853976
DOI: 10.24953/turkjped.2022.1040 -
Cureus Aug 2023Hypercalcemia of malignancy (HCM) is an important cancer-related medical emergency. It is a sign of advanced disease with a poor prognosis. We report a case of a...
Hypercalcemia of malignancy (HCM) is an important cancer-related medical emergency. It is a sign of advanced disease with a poor prognosis. We report a case of a 55-year-old man who presented with decreased sensorium, constipation for 4 days, dysphonia, and weight loss for the past three months. The physical examination showed a petrous nodular lesion of the neck in relation to the right sternocleidomastoid muscle. The digital rectal examination showed an enlarged prostate with a nodule of hard consistency. The blood revealed a hypercalcemia of 18.9 mg/dl and a prostate-specific antigen of 319.18 ng/ml. After further investigation, we discovered a squamous cell carcinoma of the larynx with multiple osteolytic bone lesions and a prostate adenocarcinoma. The hypercalcemia was treated with sodium pamidronate with good results. Such severe hypercalcemia demanded further research which revealed that not only the osteolytic lesions contributed to the elevation of calcium serum levels but also the tumor secretion of parathyroid hormone-related protein. This case highlights the importance of not only having a high suspicion for malignancy in patients presenting with hypercalcemia but also being aware of possible additional diagnoses in a patient with an already identified primary pathology.
PubMed: 37772252
DOI: 10.7759/cureus.44272 -
Frontiers in Immunology 2023Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure...
Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include "shock and kill" strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells. The modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy. Aminobisphosphonates (N-BPs) that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies. Here, we show the use of N-BPs as a novel class of LRA: we found in assays using primary cells from ART-suppressed people living with HIV-1 that N-BPs induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin (PHA). RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further evidence of alendronate-mediated latency reversal and activation of immune effector cells. Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of N-BPs to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination.
Topics: Humans; HIV Infections; HIV-1; Virus Activation; Virus Latency; Alendronate; HIV Seropositivity
PubMed: 37744358
DOI: 10.3389/fimmu.2023.1219250 -
Journal of Bone and Mineral Research :... Nov 2023Bisphosphonates are first-line treatments for several bone and mineral disorders. Studies have reported an increased incidence of serious atrial fibrillation in patients... (Meta-Analysis)
Meta-Analysis
Bisphosphonates are first-line treatments for several bone and mineral disorders. Studies have reported an increased incidence of serious atrial fibrillation in patients receiving bisphosphonates; however, uncertainty remains as to whether electrical disturbances are precipitated by bisphosphonates. We aimed to review the literature for studies reporting electrocardiogram (ECG) findings in patients receiving intravenous bisphosphonates for any indication. We searched MEDLINE and EMBASE from inception until January 14, 2023, for studies reporting ECG parameters after intravenous bisphosphonate infusion. We excluded studies that only reported atrial fibrillation. Study quality was assessed using the Newcastle-Ottawa scale. Continuous data were meta-analyzed if reported in at least two studies. Random-effects models were fitted and reported as standardized mean difference (SMD) with 95% confidence intervals (95% CIs). We found 1083 unique records, of which 11 met our inclusion and exclusion criteria. Studies had a low to low/moderate risk of bias. Six prospective cohort studies were included in the meta-analysis. Five studies used zoledronic acid, whereas one study used pamidronate. Most studies (n = 4) were conducted in postmenopausal women with osteoporosis, one study was conducted in patients with bone metastases, and one study in children with osteoporosis secondary to cerebral palsy. Study populations ranged from n = 15 to n = 116. Heart rate-corrected QT (QTc) was significantly longer post-infusion (SMD = 0.46 ms [95% CI 0.80 to 0.11]; n = 67 patients, k = 2 studies, τ = 0). There were no differences in heart rate, P wave (maximum), P wave (minimum), P wave dispersion, PR interval, QRS duration, QTc, QTc (maximum), QTc (minimum), and QTc dispersion. The correlation between pre- and post-infusion QTc was not significant (p = 0.93). Overall, there is a weak association between intravenous bisphosphonate infusion and a QTc interval prolongation. However, there is insufficient evidence to support an association between intravenous bisphosphonate and any ECG variable changes, which may precipitate atrial fibrillation. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Child; Humans; Female; Diphosphonates; Bone Density Conservation Agents; Atrial Fibrillation; Prospective Studies; Osteoporosis; Electrocardiography; Minerals
PubMed: 37681243
DOI: 10.1002/jbmr.4911 -
Cureus Aug 2023Significant hypercalcaemia can occur in intensive care unit (ICU) patients. Immobilisation hypercalcaemia has been infrequently reported after ICU admission. Patients,...
Significant hypercalcaemia can occur in intensive care unit (ICU) patients. Immobilisation hypercalcaemia has been infrequently reported after ICU admission. Patients, therefore, usually require extensive workup to rule out other common causes of hypercalcaemia, such as hyperparathyroidism. A case series of five patients who were diagnosed with hypercalcaemia due to immobilisation and received treatment with pamidronate between 2019 and 2023 were reported. The majority of cases were assessed as having hypercalcaemia due to immobilisation in the setting of low to normal parathyroid hormone levels, no suspicion of malignancy, and absence of other possible causative factors. Treatment with pamidronate started 10 to 60 days after hypercalcaemia was identified, and one or two doses of 30 mg of pamidronate were successful in resolving it. Immobilisation hypercalcaemia following ICU admission was uncommon but treatable with pamidronate.
PubMed: 37680410
DOI: 10.7759/cureus.43070 -
Cureus Aug 2023The parathyroid gland is responsible for the synthesis and secretion of parathyroid hormone, which is synthesized and released at an inverse relationship to the level of...
The parathyroid gland is responsible for the synthesis and secretion of parathyroid hormone, which is synthesized and released at an inverse relationship to the level of ionized calcium in the blood. Primary hyperparathyroidism affects women more than men. There are various causes for hyperparathyroidism-induced hypercalcemia and the most common cause is parathyroid adenoma. A less common cause of vitamin D-mediated parathyroid hormone-independent hypercalcemia is the loss of function mutation of the gene. The gene encodes the vitamin D 24-hydroxylase enzyme, responsible for hydroxylating the active form of vitamin D into an inactive form, and mutations in the gene can lead to elevated active vitamin D metabolite levels. It can result in hypercalcemia and hypercalciuria-related complications. We present a case of a 72-year-old male patient referred to the endocrine clinic, who had repeated treatments for hypercalcemia and recurrent renal calculi. He underwent ultrasound, computerized tomography, and sestamibi scans, all reported as normal. Following this, the patient underwent a positron emission tomography (PET) scan, which was also normal. He then finally underwent genetic testing and tested positive for the gene. He was started on fluconazole 50mg once a day and cinacalcet 30mg twice with normalization of calcium level. Three of his family members also tested positive for the condition.
PubMed: 37664318
DOI: 10.7759/cureus.42811 -
Indian Journal of Endocrinology and... 2023Osteogenesis imperfecta (OI) is a genetic disorder of the extracellular matrix of bone characterized by low bone mass manifesting as frequent fractures, delayed motor...
CONTEXT
Osteogenesis imperfecta (OI) is a genetic disorder of the extracellular matrix of bone characterized by low bone mass manifesting as frequent fractures, delayed motor development, pain, and impaired quality of life. The intravenous bisphosphonate, pamidronate is an established treatment for OI. Recently, zoledronic acid (ZA) has been used for the management of OI.
AIM
To assess the efficacy and safety of ZA in children below five years of age with OI.
SETTINGS AND DESIGN
A hospital-based prospective observational study.
METHODS AND MATERIAL
Patients with OI aged less than five years attending our centre were treated with intravenous ZA at a dose of 0.05 mg/kg every six months. Subjects were closely monitored for clinical and biochemical variables, adverse events, and new-onset fractures. The response to therapy was assessed by monitoring clinical variables including the degree of bony pains, number of fractures, height/length standard deviation score (SDS), and motor developmental milestones. All patients were analysed at baseline and at the end of two years for biochemical parameters and clinical severity score (CSS) as proposed by Aglan . with modifications.
RESULTS
After two years of treatment, OI patients showed a significant decline in the rate of fractures ( < 0.001), improvement in ambulation ( = 0.005), alleviation of pain ( < 0.001), and improvement in height SDS ( < 0.05). There was a significant improvement in CSS after two years of therapy. Apart from mild flu-like symptoms and mild asymptomatic hypocalcaemia immediately post-infusion, no other adverse effect was noted.
CONCLUSION
ZA therapy in infants and children below five years of age with OI was effective and safe and a more convenient alternative to pamidronate.
PubMed: 37583407
DOI: 10.4103/ijem.ijem_268_22 -
Orphanet Journal of Rare Diseases Jul 2023Chronic nonbacterial osteomyelitis (CNO) is a rare, and impactful auto-inflammatory bone disease occurring in children and adults. Clinical care for CNO is challenging,...
BACKGROUND
Chronic nonbacterial osteomyelitis (CNO) is a rare, and impactful auto-inflammatory bone disease occurring in children and adults. Clinical care for CNO is challenging, as the condition lacks validated classification criteria and evidence-based therapies. This study aimed to map the current diagnostic and therapeutic practices for CNO in adults, as a first step towards a standardized disease definition and future consensus treatment plans.
METHODS
A primary survey was spread among global rheumatological/bone networks and 57 experts as identified from literature (May 2022), covering terminology, diagnostic tools (clinical, radiological, biochemical) and treatment steps. A secondary survey (sent to primary survey responders in August 2022) further queried key diagnostic features, treatment motivations, disease activity and treatment response monitoring.
RESULTS
36 and 23 physicians completed the primary and secondary survey respectively. Diagnosis was mainly based on individual physician assessment, in which the combination of chronic relapsing-remitting bone pain with radiologically-proven osteitis/osteomyelitis, sclerosis, hyperostosis and increased isotope uptake on bone scintigraphy were reported indicative of CNO. Physicians appeared more likely to refer to the condition as synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome in the presence of joint and skin pathology. MRI was most frequently performed, and the preferred diagnostic test for 47%. X-rays were second-most frequently used, although considered least informative of all available tools. Typical imaging features reported were hyperostosis, osteitis, osteosclerosis, bone marrow edema, while degeneration, soft tissue calcification, and ankylosis were not regarded characteristic. Inflammation markers and bone markers were generally regarded unhelpful for diagnostic and monitoring purposes and physicians infrequently performed bone biopsies. Management strategies diverged, including indications for treatment, response monitoring and declaration of remission. Step-1 treatment consisted of non-steroidal anti-inflammatory drugs/COX-2 inhibitors (83%). Common step 2-3 treatments were pamidronate, methotrexate, and TNF-a-inhibition (anti-TNFα), the latter two regarded especially convenient to co-target extra-skeletal inflammation in SAPHO syndrome. Overall pamidronate and anti-TNFα and were considered the most effective treatments.
CONCLUSIONS
Following from our survey data, adult CNO is a broad and insufficiently characterized disease spectrum, including extra-osseous features. MRI is the favoured imaging diagnostic, and management strategies vary significantly. Overall, pamidronate and anti-TNFα are regarded most successful. The results lay out current practices for adult CNO, which may serve as backbone for a future consensus clinical guideline.
Topics: Child; Adult; Humans; Osteitis; Pamidronate; Osteomyelitis; Acquired Hyperostosis Syndrome; Hyperostosis; Inflammation
PubMed: 37480122
DOI: 10.1186/s13023-023-02831-1 -
Bone Reports Jun 2023gene variants lead to a severe type of osteogenesis imperfecta (OI) attributed to defects in the matrix mineralization. We present 18 patients with gene variants...
gene variants lead to a severe type of osteogenesis imperfecta (OI) attributed to defects in the matrix mineralization. We present 18 patients with gene variants leading to severe progressive deforming OI, the largest series in the world to date. These patients were normal at birth and had the first fracture between 2 months to 9 years; progression of deformities was seen in 12 adolescents who became nonambulatory. Radiologically, compression fractures with kyphoscoliosis, protrusio acetabuli, and lytic lesions in the metaphysis and pelvis were seen in older children with classical popcorn appearance in the distal femoral metaphysis in three. By exome sequencing and targeted sequencing, we identified ten variants. One was unreported and novel; three other novel variants in this series were reported earlier. The recurrent deletion inframe mutation p.phe277del was found in 5 patients from three families. Alkaline phosphatase was elevated in all children on the first visit. Bone mineral density was low in all patients and showed improvement at two years in seven children on regular pamidronate therapy. For others, the 2 year BMD data were not available. The Z scores for four of the seven children showed worsening at the 2-year follow-up.
PubMed: 37425194
DOI: 10.1016/j.bonr.2023.101690 -
Scientific Reports Jul 2023Atypical femur fracture (AFF) is a rare but catastrophic adverse event first reported in the long-term use of alendronate, one of the most commonly used drugs for...
Atypical femur fracture (AFF) is a rare but catastrophic adverse event first reported in the long-term use of alendronate, one of the most commonly used drugs for osteoporosis currently. However, further evidence is needed to learn more regarding other common anti-osteoporosis drugs and the risk for AFF. In this study, reports of AFF were identified from Food and Drug Administration Adverse Event Reporting System database. Disproportionality analyses were performed to examine the reporting odds ratio (ROR), information component (IC) and adjusted ROR (adj. ROR) signals for AFF for common anti-osteoporosis drugs. A total of 1692 unique AFF reports were identified. The disproportionality signals (the lower bound of 95% confidence interval > 1 for ROR and adjusted ROR, and > 0 for IC) were detected for alendronate, denosumab, pamidronate, risedronate, zoledronate, ibandronate, and teriparatide while no signal was detected for raloxifene, abaloparatide, and romosozumab. When restricted in patients with osteoporosis, the disproportionality signals were still detected for alendronate, pamidronate, risedronate, denosumab, and ibandronate. Our results suggest that alendronate has the largest risk signal, while the risks varied among different bisphosphonates. In addition, denosumab was found statistically associated with AFF in both the entire database and patients with osteoporosis.
Topics: Humans; Alendronate; Bone Density Conservation Agents; Risedronic Acid; Denosumab; Ibandronic Acid; Pharmaceutical Preparations; Pamidronate; Osteoporosis; Diphosphonates; Femur
PubMed: 37407650
DOI: 10.1038/s41598-023-37944-x