Journal of the Endocrine Society

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ISSN / EISSN : 2472-1972 / 2472-1972
Current Publisher: The Endocrine Society (10.1210)
Total articles ≅ 5,169
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Kathryn Dahir, Mary Scott Roberts, Stan Krolczyk, Jill H Simmons
Journal of the Endocrine Society; doi:10.1210/jendso/bvaa151

X-linked hypophosphatemia (XLH) is a rare, hereditary, progressive musculoskeletal disease that often causes pain and short stature, as well as decreased physical function, mobility, and quality of life. Hypophosphatemia in XLH is caused by loss of function mutations in PHEX gene resulting in excess levels of the phosphate regulating hormone fibroblast growth factor23 (FGF23), which leads to renal phosphate wasting and decreased serum 1,25-dihydroxyvitamin D production. Historically, treatment options were limited to oral phosphate and active vitamin D analogues (conventional management) dosed several times daily in an attempt to improve skeletal mineralization by increasing serum phosphorus. The recent approval of burosumab, a fully human monoclonal antibody to FGF23, has provided a new, targeted treatment option for patients with XLH. This review summarizes our current understanding of XLH, the safety and efficacy of conventional management and burosumab, existing recommendations for managing patients, and unanswered questions in the field.
Lauren A Harasymiw, Scott D Grosse, Kyriakie Sarafoglou
Journal of the Endocrine Society; doi:10.1210/jendso/bvaa152

Background Little is known regarding risk for co-occurring mental health conditions among pediatric patients with congenital adrenal hyperplasia (CAH). The objective of the current study was to investigate the prevalence of medically managed attention-deficit/hyperactivity disorder (ADHD) in two large administrative samples of insured children and adolescents with and without CAH in the United States. Methods We assessed the prevalence of CAH and of medically managed ADHD using algorithms defined from diagnosis codes and filled prescriptions data using the IBM® MarketScan® Commercial and Multi-State Medicaid claims databases. We evaluated subjects who were continuously enrolled for ≥12 months with a first claim during October 2015-December 2017 when they were 5-18 years old. Results The administrative prevalence of CAH in the Commercial (N=3,685,127) and Medicaid (N=3,434,472) samples was 10.1 per 100,000 (n=372) and 7.2 per 100,000 (n=247), respectively. The prevalence of medically managed ADHD in the non-CAH population was 8.4% in the Commercial sample and 15.1% in the Medicaid sample. Among children with CAH, there was no increased prevalence of ADHD in the Commercial (9.2%, prevalence ratio (PR) = 1.1, 95% CI: 0.82-1.54, p = 0.48) or Medicaid (13.8%, PR = 0.91, 95% CI: 0.67-1.24, p = 0.55) samples compared to the general population. Conclusions Using two large samples of insured children and adolescents in the United States, we found similar prevalence of medically managed ADHD among those with CAH and the general population. Future research to assess the validity of our claims algorithm for identifying pediatric CAH cases is warranted.
Begoña Pla, Alfonso Arranz, Carolina Knott, Miguel Sampedro, Sara Jiménez, Iñigo Hernando, Monica Marazuela
Journal of the Endocrine Society; doi:10.1210/jendso/bvaa149

Aim To examine the impact of the lockdown caused by COVID-19 pandemic on both the glycemic control and the daily habits of a group of patients with type 1 diabetes mellitus (T1DM) using flash continuous glucose monitoring devices (Flash CGM). Methods Retrospective analysis based on all the information gathered in virtual consultations from a cohort of 50 adult patients with T1DM with follow-up at our site. We compared their CGM metrics during lockdown with their own previous data before the pandemic occurred, as well as the potential psychological and therapeutic changes. Results We observed a reduction of the average glucose: 160.26 ± 22.55 mg/dl vs. 150 ± 20.96 mg/dl, p=0.0009, estimated HbA1c: 7.21 ± 0.78% vs. 6.83 ± 0.71%, p=000.5, glucose management indicator (GMI) 7.15 ± 0.57 % vs. 6.88 ± 0.49 %, p=0.0003, and glycemic variability (CV): 40.74 ± 6.66 vs. 36.43 ± 6.09 p<0.0001. Time in range showed an improvement: 57.46 ± 11.85% vs a 65.76 ± 12.09%, p<0.0001, without an increase in percentage of time in hypoglycaemia. Conclusions COVID-19 lockdown was associated with an improvement in glycemic control in patients with T1DM using CGM.
Manuela G M Rocha-Braz, Monica M França, Adriana M Fernandes, Antonio M Lerario, Evelin A Zanardo, Lucas S De Santana, Leslie D Kulikowski, Regina M Martin, Berenice B Mendonca, Bruno Ferraz-De-Souza
Journal of the Endocrine Society; doi:10.1210/jendso/bvaa148

Context The genetic bases of osteoporosis (OP), a disorder with high heritability, are poorly understood at an individual level. Cases of idiopathic or familial OP have long puzzled clinicians as to whether an actionable genetic cause could be identified. Objective Genetic analysis of 28 cases of idiopathic, severe or familial osteoporosis, using targeted massively parallel sequencing (MPS). Design Targeted sequencing of 128 candidate genes using Illumina NextSeq. Variants of interest were confirmed by Sanger sequencing or SNP Array. Setting An academic tertiary hospital. Patients Thirty-seven patients (54% male, median 44 years old, 86% with fractures), corresponding to 28 sporadic or familial cases. Main Outcome Measure: Rare stop-gain, indel, splice site, copy-number or nonsynonymous variants altering protein function. Results Altogether, we identified 28 variants of interest, but only 3 were classified as pathogenic or likely pathogenic variants: COL1A2 p.(Arg708Gln), WNT1 p.(Gly169Asp) and IDUA p.(His82Gln). An association of variants in different genes was found in 21% of cases, including a young woman with severe OP bearing WNT1, PLS3 and NOTCH2 variants. Among genes of uncertain significance analyzed, a potential additional line of evidence has arisen for GWAS candidates GPR68 and NBR1, warranting further studies. Conclusions While we hope that continuing efforts to identify genetic predisposition to OP will lead to improved and personalized care in the future, the likelihood of identifying actionable pathogenic variants in intriguing cases of idiopathic or familial osteoporosis is seemingly low.
Ebenezer Nyenwe, Deirdre James, Jim Wan, Sam Dagogo-Jack
Journal of the Endocrine Society; doi:10.1210/jendso/bvaa137

Background Prediabetes, an often unrecognized precursor of type 2 diabetes (T2DM), is associated with cardiometabolic complications. Here, we investigated the utility of dexamethasone challenge in predicting incident prediabetes among normoglycemic subjects with parental T2DM enrolled in the prospective Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study. Design and Methods After documenting normoglycemic status with OGTT, participants ingested dexamethasone (2 mg) at 10:00 PM, and fasting plasma glucose (FPG-Dex) and cortisol were measured at 8:00AM the next day. Subjects were followed quarterly for 5 years, the primary outcome being incident prediabetes. Serial assessments included body composition, blood chemistry, OGTT, insulin sensitivity and secretion. Results We analyzed data from 190 participants (107 Black, 83 white; mean age 44.7±10.0 years; BMI 29.8±6.8 Kg/m 2; FPG 90.9±5.7 mg/dL). Following dexamethasone ingestion, plasma cortisol was < 5 μg/dl; FPG-dex levels displayed marked variability (81-145 mg/dl) as did delta FPG (-7 to +48 mg/dl). During 5 years of follow-up, 58 out of 190 subjects (30.5%) progressed to prediabetes. FPG-Dex (116.8±10.9 vs 106.9±10.8 mg/dL, P<0.0001) and delta FPG (23.4±10.1 vs 17.0±10.2 mg/dL, P<0.0001) were higher in progressors than nonprogressors. FPG-Dex (P=0.007) was an independent predictor of incident prediabetes in a multivariate model that included age, race, gender, BMI, waist circumference, FPG, insulin sensitivity and secretion. In further analyses, an FPG-Dex level ≥107 mg/dL predicted incident prediabetes with 88% sensitivity and 49% specificity. Conclusions The glycemic response to dexamethasone significantly predicted incident prediabetes among offspring of parents with T2DM, and may be a tool for uncovering latent risk of dysglycemia.
Celina M Caetano, Aleksandra Sliwinska, Parvathy Madhavan, James Grady, Carl D Malchoff
Journal of the Endocrine Society; doi:10.1210/jendso/bvaa145

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Tomomi Kurashige, Mika Shimamura, Yuji Nagayama
Journal of the Endocrine Society; doi:10.1210/jendso/bvaa146

Appropriate amount of iodine is critical for normal function of thyroid cells synthesizing thyroid hormones. Although normal thyroid cell lines such as rat PCCL3 and FRTL5 and human Nthy-ori 3-1 have been widely used for in vitro studies on physiological and pathophysiological effects of iodine on thyroid cells, we have recently pointed out the critical differences between FRTL5/PCCL3 cells and Nthy-ori 3-1 cells. Therefore, we here directly compared some of the cellular characteristics - iodine uptake, differentiated status, iodine-induced cytotoxicity and iodine-regulation of autophagy - between PCCL3 and Nthy-ori 3-1 cells. PCCL3 cells express mRNAs for TSH receptor and sodium/iodine symporter and incorporate iodine in a TSH-dependent manner, while Nthy-ori 3-1 cells do not either. Nevertheless, both cells were comparably resistant to iodine cytotoxicity: only far excess iodine (5 x 10 -2 M) killed 20 to 40% cells in 24 h with perchlorate exhibiting no effect, suggesting this cytotoxic effect is due to extracellular iodine. In contrast, a wide range of iodine (5 x 10 -9 to 5 x 10 -2 M) induced autophagy in PCCL3 cells, which was abolished by perchlorate, indicating intracellular iodine-induction of autophagy, but this effect was not observed in Nthy-ori 3-1 cells. In conclusion, it is critical to discriminate the effect of iodine incorporated into cells from that of extracellular iodine on thyroid cells. Iodine-uptake competent thyroid cells such as PCCL3 and FRTL5 cells, not Nthy-ori 3-1 cells, should be used for studies on iodine effect on thyroid cells.
Kate E Lines, Lisa B Nachtigall, Laura E Dichtel, Treena Cranston, Hannah Boon, Xun Zhang, Kreepa G Kooblall, Mark Stevenson, Rajesh V Thakker
Journal of the Endocrine Society; doi:10.1210/jendso/bvaa142

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by the combined occurrence of parathyroid tumors, pituitary adenomas and pancreatic neuroendocrine neoplasms (PNENs). MEN1 is caused by germline MEN1 mutations in >75% of patients, and the remaining 25% of patients may have mutations in unidentified genes or represent phenocopies with mutations in genes such as cell cycle division 73 (CDC73), the calcium sensing receptor (CASR) and cyclin dependent kinase inhibitor 1B (CDKN1B), which are associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome, familial hypocalciuric hypercalcaemia type 1 (FHH1), and MEN4, respectively. Here, we report a heterozygous c.1138C>T (p.Leu380Phe) CDC73 germline variant in a clinically diagnosed MEN1 patient, based on combined occurrence of primary hyperparathyroidism, acromegaly and a PNEN. Characterisation of the PNEN confirmed it was a neuroendocrine neoplasm as it immuno-stained positively for chromogranin and glucagon. The rare variant p.Leu380Phe occurred in a highly conserved residue, and further analysis using RNA-Scope indicated that it was associated with a significant reduction in CDC73 expression in the PNEN. Previously, CDC73 mutations have been reported to be associated with tumors of the parathyroids, kidneys, uterus and exocrine pancreas. Thus, our report of a patient with PNEN and somatotrophinoma who had a CDC73 variant, provides further evidence that CDC73 variants may result in a MEN1 phenocopy.
Yao Wang, Anu Sharma, Lissa Padnick-Silver, Megan Francis-Sedlak, Robert J Holt, Colleen Foley, Guy Massry, Raymond S Douglas
Journal of the Endocrine Society; doi:10.1210/jendso/bvaa140

Introduction Limited data exist on US referral/management patterns for moderate-to-severe thyroid eye disease (TED), a disabling condition. Methods US ophthalmologists and endocrinologists experienced in treating TED provided medical record data of moderate-to-severe TED patients and information on referral/treatment practices. Data on signs/symptoms, medical/surgical treatments, treatment response, and referral history were collected. Moderate and severe cases were stratified to interrogate treatment/practice differences. Results A total of 181 physicians provided data on 714 patients (49.4 ± 13.6 years old, 65% women, 14% severe disease). Reporting physicians diagnosed 55% of patients themselves and solely managed 37% of cases, with similar referral/co-management patterns between moderate and severe cases. Topical therapies included lubricating (79%) and glucocorticoid (39%) eye drops. Systemic therapies included oral glucocorticoids (36%), intravenous glucocorticoids (15%), and rituximab and/or tocilizumab (12%). Few patients underwent orbital radiation (4%) or surgical intervention (4%). Intravenous glucocorticoids (33% vs. 12%), biologics (26% vs. 10%), orbital radiation (11% vs. 3%), and ocular surgery (12% vs. 3%) were used more often in severe vs. moderate cases (all p < 0.001). However, severe disease was less responsive to therapy (very responsive to therapy: 28% vs. 49%, p < 0.001). Conclusions Participating physicians were primarily responsible for just over half of TED diagnoses, but solely treated <40% of patients. Severe TED was treated more often with surgery and systemic immunologic therapies than moderate disease, but was less likely to respond to treatment. These results reinforce that moderate-to-severe TED is difficult to treat with an unmet medical need in the US.
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