A retrospective review of the short Synacthen test in Queensland hospitals.

BACKGROUND: The short Synacthen test (SST) is widely used to investigate adrenal insufficiency, but it can be time-consuming, costly and labour-intensive to perform and is not without risk of adverse events. AIM: To review SST requesting patterns and practices across public hospitals in Queensland. METHODS: The electronic medical records of patients who underwent a SST with Pathology Queensland between January 2020 and December 2020 were reviewed to collect data regarding the indication for the test, the requesting speciality, SST results and any adverse events. RESULTS: Six hundred and fifty-two SSTs were identified, of which 363 individual patients were included in the analysis. The majority of the tests (n = 198, 54.5%) were performed in the inpatient setting. Endocrinology most commonly ordered SSTs (n = 188, 51.8%). The suspected aetiology of adrenal insufficiency was unclear in a large proportion of requests (n = 167, 46.0%). Static testing of morning cortisol prior to SST was performed in only 249 (68.6%) patients. Of 140 inpatients data, 17.9% (n = 25) showed a robust static cortisol of ≥400 nmol/L and were treated as having normal adrenal function, suggesting SST was unnecessary in these patients. Twenty-two (6.1%) patients had a documented adverse event occurring during or after the SST. CONCLUSIONS: There was wide variability in requesting patterns and practices for SSTs across Queensland. More than one in six SSTs could have been avoided if a static morning cortisol had been performed prior. Clinician education and the adoption of a structured referral form may improve testing practices.

Tumor-Induced Osteomalacia in a Patient with Crohn's Disease: A Case Report and Approach to Investigating Hypophosphatemia.

Introduction: Hypophosphatemia occurs commonly in inflammatory bowel disease (IBD) patients and can cause considerable morbidity. The differential diagnoses in IBD include nutritional causes and hypophosphatemia induced by some formulations of intravenous iron infusions. Case Presentation: We present the case of a 37-year-old man with active Crohn's disease, presenting with difficulty walking and fractures of the vertebrae and calcaneus. He had long-standing hypophosphatemia. Nutritional causes for hypophosphatemia were considered in the first instance given the presence of chronic diarrhea and vitamin D deficiency; however, there was minimal response to appropriate supplementation with oral phosphorous and vitamin D. Iron infusion-induced hypophosphatemia was then considered, but the nadir phosphate level preceded any iron infusion. Therefore, work-up was undertaken for less common causes. He was ultimately diagnosed with tumor-induced osteomalacia, caused by excess fibroblast growth factor 23 (FGF23) secretion from a phosphaturic mesenchymal tumor about the knee. He had complete resolution of symptoms and biochemical abnormalities following successful resection of the tumor. Conclusion: This case illustrates the approach to investigation of hypophosphatemia in IBD patients. If the time course and response to phosphate supplementation are not as expected for nutritional or iron infusion-induced hypophosphatemia, less common causes should be considered.

Reducing the off-target endocrinologic adverse effects of azole antifungals-can it be done?

Azoles are among the most effective and widely used class of antifungals for prophylaxis as well as empirical and directed therapy against yeast and mould infections. Their use appears to be increasing worldwide. All triazoles cause hepatotoxicity, drug-drug interactions, and QTc prolongation (except isavuconazole); however, there are growing concerns following increasing reports of off-target endocrinologic adverse events. Skeletal fluorosis, pseudohyperaldosteronism, adrenal insufficiency, hyponatraemia and hypogonadism have all been documented in relation to azole use, causing considerable morbidity. The following review provides new insights into the clinical incidence and underlying pathophysiology of azole-associated endocrinopathies. Routine clinical and biochemical monitoring (including therapeutic drug monitoring) of endocrinologic adverse events may play a role in their prevention and progression. Novel azoles in preclinical and clinical stages of development may offer therapeutic advantages due to their greater selectivity of binding to fungal CYP51. The integration of pharmacogenomics into routine clinical practice holds future promise in guiding antifungal drug and dose selection to reduce the risk of off-target phenomena, including endocrinologic adverse events.

Voriconazole-Associated Periostitis: New Insights into Pathophysiology and Management.

Voriconazole-associated periostitis (VAP) is an underrecognized and unpredictable side effect of long-term voriconazole therapy. We report two cases of VAP occurring in the post-transplant setting: a 68-year-old lung transplant recipient who required ongoing voriconazole therapy, in whom urinary alkalinization was used to promote fluoride excretion and minimize voriconazole-related skeletal toxicity, and a 68-year-old stem-cell transplant recipient with a high voriconazole dose requirement, identified on pharmacogenomic testing to be a CYP2C19 ultrarapid metabolizer, the dominant enzyme in voriconazole metabolism. This is the first reported case of pharmacogenomic profiling in VAP and may explain the variability in individual susceptibility to this uncommon adverse effect. Our findings provide new insights into both the management and underlying pathophysiology of VAP. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

A family with partially penetrant multicentric carpotarsal osteolysis due to gonadal mosaicism: First reported case.

Multicentric carpotarsal osteolysis (MCTO) is an autosomal dominant condition characterized by carpal-tarsal abnormalities; over half of affected individuals also develop renal disease. MCTO is caused by mutations of MAFB; however, there is no clear phenotype-genotype correlation. We describe the first reported family of variable MCTO phenotype due to mosaicism: the proband had classical skeletal features and renal involvement due to focal segmental glomerulosclerosis (FSGS), and the father had profound renal impairment due to FSGS, necessitating kidney transplantation. Mosaicism was first suspected in this family due to unequal allele ratios in the sequencing chromatograph of the initial blood sample of proband's father and confirmed by sequencing DNA extracted from the father's hair, collected from different bodily parts. This case highlights the need for a high index of clinical suspicion to detect low-level parental mosaicism, as well as a potential role for MAFB mutation screening in individuals with isolated FSGS.

Characterization of Normal Murine Carpal Bone Development Prompts Re-Evaluation of Pathologic Osteolysis as the Cause of Human Carpal-Tarsal Osteolysis Disorders.

Multicentric carpal-tarsal osteolysis; multicentric osteolysis, nodulosis, and arthropathy; and Winchester syndromes, skeletal dysplasias characterized by carpal/tarsal and epiphyseal abnormalities, are caused by mutations in v-maf musculoaponeurotic fibrosarcoma oncogene ortholog B (MAFB), matrix metalloproteinase (MMP) 2, and MMP14, respectively; however, the underlying pathophysiology is unclear. Osteoclast-mediated osteolysis has been regarded as the main mechanism, but does not explain the skeletal distribution. We hypothesized that MAFB, MMP-2, and MMP-14 have integral roles in carpal/tarsal and epiphyseal bone development. Normal neonatal mouse forepaws were imaged by micro-computed tomography and examined histologically. Murine forepaw ossification occurred sequentially. Subarticular regions of endochondral ossification showed morphologic and calcification patterns that were distinct from archetypical physeal endochondral ossification. This suggests that two different forms of endochondral ossification occur. The skeletal sites showing the greatest abnormality in the carpal-tarsal osteolysis syndromes are regions of subarticular ossification. Thus, abnormal bone formation in areas of subarticular ossification may explain the site-specific distribution of the carpal-tarsal osteolysis phenotype. MafB, Mmp-2, and Mmp-14 were expressed widely, and tartrate-resistant acid phosphatase staining notably was absent in the subarticular regions of the cartilage anlagen and entheses at a time point most relevant to the human osteolysis syndromes. Thus, abnormal peri-articular skeletal development and modeling, rather than excessive bone resorption, may be the underlying pathophysiology of these skeletal syndromes.

The IFITM5 mutation c.-14C > T results in an elongated transcript expressed in human bone; and causes varying phenotypic severity of osteogenesis imperfecta type V.

BACKGROUND: The genetic mutation resulting in osteogenesis imperfecta (OI) type V was recently characterised as a single point mutation (c.-14C > T) in the 5' untranslated region (UTR) of IFITM5, a gene encoding a transmembrane protein with expression restricted to skeletal tissue. This mutation creates an alternative start codon and has been shown in a eukaryotic cell line to result in a longer variant of IFITM5, but its expression has not previously been demonstrated in bone from a patient with OI type V. METHODS: Sanger sequencing of the IFITM5 5' UTR was performed in our cohort of subjects with a clinical diagnosis of OI type V. Clinical data was collated from referring clinicians. RNA was extracted from a bone sample from one patient and Sanger sequenced to determine expression of wild-type and mutant IFITM5. RESULTS: All nine subjects with OI type V were heterozygous for the c.-14C > T IFITM5 mutation. Clinically, there was heterogeneity in phenotype, particularly in the manifestation of bone fragility amongst subjects. Both wild-type and mutant IFITM5 mRNA transcripts were present in bone. CONCLUSIONS: The c.-14C > T IFITM5 mutation does not result in an RNA-null allele but is expressed in bone. Individuals with identical mutations in IFITM5 have highly variable phenotypic expression, even within the same family.

A novel mutation of the primary protein kinase C phosphorylation site in the calcium-sensing receptor causes autosomal dominant hypocalcemia.

OBJECTIVE: The calcium-sensing receptor (CASR) is a key controller of calcium homeostasis by regulating parathyroid hormone (PTH) secretion and renal calcium reabsorption. CASR(T888) is a protein kinase C (PKC) phosphorylation site in the receptor's intracellular domain that has previously been identified as a critical negative regulator of CASR downstream signaling in vitro, but whose importance in vivo is unknown. CASE REPORT: The proband presented with mild symptomatic hypocalcemia following treatment for nephrotic syndrome due to minimal change glomerulonephropathy. Laboratory tests revealed inappropriately normal PTH concentrations and relative hypercalciuria typical of autosomal dominant hypocalcemia. His asymptomatic father had similar laboratory test results. DESIGN AND METHODS: The CASR gene was sequenced. To investigate the molecular consequences of CASR(T888M) mutation, site-directed mutagenesis was used to modify the wild-type (wt)-CASR gene, with the resulting mutant being transfected transiently into HEK-293 cells. RESULTS: A novel CASR missense mutation, T888M, was identified in both cases. The CASR(T888M) mutant exhibited enhanced sensitivity to extracellular calcium concentration, both for intracellular calcium (Ca(2+)(i)) mobilization and for ERK phosphorylation, despite having unaltered levels of cell surface expression. Furthermore, CASR(T888M) elicited sustained Ca(2+)(i) mobilization rather than high frequency Ca(2+)(i) oscillations, and, unlike the wt-CASR, the response was resistant to acute inhibition by the PKC activator, phorbol 12-myristate 13-acetate. CONCLUSIONS: The clinical and functional data provide the first genotype-phenotype correlation for a mutation at T888, indicating its critical physiological importance in CASR signaling. Thus, CASR(T888) represents a functionally important, inhibitory phosphorylation site that contributes to the control of PTH secretion.