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Junichi Ishigami, Yasuyuki Honda, Amy B Karger, Josef Coresh, Elizabeth Selvin, Pamela L Lutsey, and Kunihiro Matsushita

Objective

Fibroblast growth factor 23 (FGF23) concentration increases in response to declining kidney function to preserve normal phosphate concentrations. However, the etiological association of change in FGF23 concentration with mortality has not been examined in the general population.

Design and methods

We analyzed 5458 participants of the Atherosclerosis Risk in Communities Study who had intact FGF23 and estimated glomerular filtration rate (eGFR) assessed during midlife (visit 3, 1993–1995, mean age: 58 years) and late life (visit 5, 2011–2013, 76 years) to examine the association of FGF23 change over 18 years from mid-life to late life with the subsequent risk of mortality in late life using Cox regression models.

Results

The median 18-year change in intact FGF23 was +17.3 pg/mL. During a median follow-up of 7.2 years following visit 5, 1176 participants died. In multivariable Cox models, elevated mortality was seen in the highest quartile of FGF23 change (ΔFGF23: ≥31.3 pg/mL) (adjusted hazard ratio (aHR): 1.61 (95%CI: 1.36–1.90), or 1.37 (1.15–1.64) after additionally adjusting for eGFR change, compared with the lowest quartile (≤6.4 pg/mL)). When both FGF23 change and FGF23 in late life were simultaneously entered into the Cox model, FGF23 in late life, but not FGF23 change, was an independent predictor of mortality; however, we observed a high correlation between FGF23 change from midlife to late life and FGF23 in late life (r = 0.77).

Conclusions

Serum intact FGF23 change from midlife to late life was associated with subsequent risk of mortality independent of decline in kidney function. Our findings further support the implications of FGF23 beyond its association with kidney function.

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Chao Ling, Xiafei Hong, Mengyue Xu, Yutong Wang, Xiaosen Ma, Yunying Cui, Rui Jiang, Dingyan Cao, Huanwen Wu, Anli Tong, Yupei Zhao, and Wenming Wu

Objectives

The pancreatic neuroendocrine tumors (PanNETs) are a group of clinically heterogeneous neoplasms. Although previous studies illustrated the somatic mutation pattern for PanNETs, the germline mutation pattern is still unclear. Here, we comprehensively screened the underlying germline mutations in a cohort of multiple endocrine neoplasia type 1 (MEN1)-related and sporadic PanNETs to reveal the characteristics of germline mutation in PanNET patients.

Methods

Patients diagnosed with PanNETs by biopsy or surgical pathology were enrolled in this study. Peripheral blood samples were used for genomic DNA purification and subsequent sequencing. The following sequencing techniques were used and compared for validation: (1) targeted gene capture with a customized panel; (2) whole exome sequencing data from previous study.

Results

A total of 184 PanNET patients were enrolled, including 20 MEN1-related and 164 sporadic cases. In this study, MEN1 mutation rate in MEN1-related PanNETs was 60% (12/20), of which 50% were novel mutation sites. For sporadic PanNETs, the overall germline mutation rate was very low. Besides the rare MEN1 mutation, previously unreported germline variant in DAXX was found in one non-functional PanNET.

Conclusions

This study revealed distinctive germline mutation rates between MEN1-related and sporadic PanNETs. The novel MEN1 mutations contribute to revealing the spectrum of MEN1 mutations in PanNETs. The newly discovered germline variant of DAXX in sporadic PanNET implies a tendency of convergence between germline and somatic mutation genes.

Open access

Rasmus Juul Kildemoes, Christian Hollensen, Beverly M K Biller, Gudmundur Johannsson, Yutaka Takahashi, and Michael Højby Rasmussen

Objective

Growth hormone (GH) replacement therapy in patients with adult growth hormone deficiency (AGHD) is individually titrated due to variable dose–responses among patients. The aim of this study was to provide clinical guidance on dosing and titration of the novel long-acting GH derivative somapacitan based on analyses of somapacitan dose–insulin-like growth factor I (IGF-I) responses in AGHD patients.

Design

Analyses of dosing information, 4364 somapacitan concentration samples and 4880 IGF-I samples from 330 AGHD patients treated with somapacitan in three phase 3 trials.

Methods

Pharmacokinetic/pharmacodynamic modelling was used to evaluate starting dose groups by age and oral oestrogen therapy, characterise the dose–IGF-I response in the overall AGHD population and patient subgroups, predict the IGF-I response to dose changes and simulate missed dosing.

Results

The analyses supported the clinical recommendations of higher starting doses for younger patients and women on oral oestrogen replacement therapy. For patients switching from daily GH treatment, the mean maintenance dose ratio between somapacitan (mg/week) and somatropin (mg/day) was predicted to be 8.2 (observed interquartile range of 6.7–9.1). Simulations of IGF-I SDS profiles confirmed the appropriate time for IGF-I sampling to be 3–4 days after somapacitan dosing and supported somapacitan administration with up to 3 days delay in case of missed dosing. Subgroup analyses characterised the dose–exposure–IGF-I response in patient subgroups and indicated that dose requirements are mainly influenced by sex and oral oestrogen treatment.

Conclusions

This study extends the knowledge of the somapacitan dose–IGF-I response and provides information on clinical dosing of once-weekly somapacitan in patients with AGHD.

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Chantal A Lebbink, Lisa H de Vries, Inne H M Borel Rinkes, Arthur J A T Braat, Rachel S van Leeuwaarde, Lutske Lodewijk, Mark J C van Treijen, Menno R Vriens, Gerlof D Valk, Hanneke M van Santen, and Bart de Keizer

Objective

To evaluate the usefulness of [18F]fluorodeoxyglucose (FDG) positron emissive tomography (PET)/CT in patients with low detectable thyroglobulin levels suspicious for persistent or recurrent differentiated thyroid cancer (DTC).

Methods

A retrospective case series study evaluating FDG PET/CT in patients with detectable thyroglobulin (Tg) levels (≥0.20 and <10.00 ng/mL) after initial treatment with total thyroidectomy and I-131 thyroid remnant ablation for pT1-3aN0-1bM0 DTC. Sensitivity, specificity, positive (PPV) and negative predictive value (NPV) of FDG PET/CT were calculated.

Results

Twenty-seven patients underwent FDG PET/CT. Median Tg level at FDG PET/CT was 2.00 ng/mL (range 0.30–9.00). FDG PET/CT was positive in 14 patients (51.9%): lesions suspicious for lymph node metastases were depicted in 12 patients, and lung metastases in 2. DTC was confirmed in 13/14 FDG PET/CT-positive patients. In 9/13 patients with a negative FDG PET/CT, DTC was confirmed ≤3 months after FDG PET/CT. The sensitivity, PPV, specificity and NPV were 59.1, 92.9, 80.0 and 30.8%, respectively.

Conclusions

This case series shows that FDG PET/CT might be useful to detect persistent or recurrent DTC in patients with low detectable Tg. However, when FDG PET/CT is negative, this does not rule out DTC and further investigations are necessary.

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Cihan Atila, Odile Gaisl, Deborah R Vogt, Laura Werlen, Gabor Szinnai, and Mirjam Christ-Crain

Background

The differential diagnosis of diabetes insipidus is challenging. The most reliable approaches are copeptin measurements after hypertonic saline infusion or arginine, which is a known growth hormone secretagogue but has recently also been shown to stimulate the neurohypophysis. Similar to arginine, glucagon stimulates growth hormone release, but its effect on the neurohypophysis is poorly studied.

Design

Double-blind, randomized, placebo-controlled trial including 22 healthy participants, 10 patients with central diabetes insipidus, and 10 patients with primary polydipsia at the University Hospital Basel, Switzerland.

Methods

Each participant underwent the glucagon test (s.c. injection of 1 mg glucagon) and placebo test. The primary objective was to determine whether glucagon stimulates copeptin and to explore whether the copeptin response differentiates between diabetes insipidus and primary polydipsia. Copeptin levels were measured at baseline, 30, 60, 90, 120, 150, and 180 min after injection.

Results

In healthy participants, glucagon stimulated copeptin with a median increase of 7.56 (2.38; 28.03) pmol/L, while placebo had no effect (0.10 pmol/L (−0.70; 0.68); P < 0.001). In patients with diabetes insipidus, copeptin showed no relevant increase upon glucagon, with an increase of 0.55 (0.21; 1.65) pmol/L, whereas copeptin was stimulated in patients with primary polydipsia with an increase of 15.70 (5.99; 24.39) pmol/L. Using a copeptin cut-off level of 4.6pmol/L had a sensitivity of 100% (95% CI: 100–100) and a specificity of 90% (95% CI: 70–100) to discriminate between diabetes insipidus and primary polydipsia.

Conclusion

Glucagon stimulates the neurohypophysis, and glucagon-stimulated copeptin has the potential for a safe, novel, and precise test in the differential diagnosis of diabetes insipidus.

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Christina Blagojevic, Tracy Heung, Sarah Malecki, Shengjie Ying, Sabrina Cancelliere, Robert A Hegele, and Anne S Bassett

Objective

Mild to moderate hypertriglyceridemia is a condition often associated with obesity and diabetes, with as yet incomplete knowledge of underlying genetic architecture. The 22q11.2 microdeletion is associated with multimorbidity, including increased risk of obesity and diabetes. In this study, we sought to investigate whether the 22q11.2 microdeletion was associated with mild to moderate hypertriglyceridemia (1.7–10 mmol/L).

Design

This was a cohort study comparing 6793 population-based adults and 267 with a 22q11.2 microdeletion aged 17–69 years, excluding those with diabetes or on statins.

Methods

We used binomial logistic regression modeling to identify predictors of hypertriglyceridemia, accounting for the 22q11.2 microdeletion, male sex, BMI, ethnicity, age, and antipsychotic medications.

Results

The 22q11.2 microdeletion was a significant independent predictor of mild to moderate hypertriglyceridemia (odds ratio (OR): 2.35, 95% CI: 1.70–3.26). All other factors examined were also significant predictors (OR: 1.23–2.10), except for antipsychotic medication use. Within the 22q11.2 microdeletion subgroup, only male sex (OR: 3.10, 95% CI: 1.77–5.44) and BMI (OR: 1.63, 95% CI: 1.14–1.98) were significant predictors of hypertriglyceridemia, evident at mean age 31.2 years.

Conclusions

The 22q11.2 microdeletion is associated with hypertriglyceridemia even when accounting for other known risk factors for elevated triglycerides. This effect is seen in young adulthood (76.6% were <40 years), in the absence of diabetes, and irrespective of antipsychotics, suggesting that the 22q11.2 microdeletion may represent an unrecognized genetic risk factor for hypertriglyceridemia, providing novel opportunities for animal and cellular models. Early dyslipidemia screening and management strategies would appear prudent for individuals with 22q11.2 microdeletions.

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Lucas Bouys, Anna Vaczlavik, Anne Jouinot, Patricia Vaduva, Stéphanie Espiard, Guillaume Assié, Rossella Libé, Karine Perlemoine, Bruno Ragazzon, Laurence Guignat, Lionel Groussin, Léopoldine Bricaire, Isadora Pontes Cavalcante, Fidéline Bonnet-Serrano, Hervé Lefebvre, Marie-Laure Raffin-Sanson, Nicolas Chevalier, Philippe Touraine, Christel Jublanc, Camille Vatier, Gérald Raverot, Magalie Haissaguerre, Luigi Maione, Matthias Kroiss, Martin Fassnacht, Sophie Christin-Maitre, Eric Pasmant, Françoise Borson-Chazot, Antoine Tabarin, Marie-Christine Vantyghem, Martin Reincke, Peter Kamenicky, Marie-Odile North, Jérôme Bertherat, and the COMETE and ENSAT networks groups and collaborators

Objective

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a heterogeneous disease characterized by adrenal macronodules and variable levels of cortisol excess, with not clearly established clinical diagnostic criteria. It can be caused by ARMC5 germline pathogenic variants. In this study, we aimed to identify predictive criteria for ARMC5 variants.

Methods

We included 352 consecutive index patients from 12 European centers, sequenced for germline ARMC5 alteration. Clinical, biological and imaging data were collected retrospectively.

Results

52 patients (14.8%) carried ARMC5 germline pathogenic variants and showed a more distinct phenotype than non-mutated patients for cortisol excess (24-h urinary free cortisol 2.32 vs 1.11-fold ULN, respectively, P  < 0.001) and adrenal morphology (maximal adrenal diameter 104 vs 83 mm, respectively, P  < 0.001) and were more often surgically or medically treated (67.9 vs 36.8%, respectively, P  < 0.001). ARMC5-mutated patients showed a constant, bilateral adrenal involvement and at least a possible autonomous cortisol secretion (defined by a plasma cortisol after 1 mg dexamethasone suppression above 50 nmol/L), while these criteria were not systematic in WT patients (78.3%). The association of these two criteria holds a 100% sensitivity and a 100% negative predictive value for ARMC5 pathogenic variant.

Conclusion

We report the largest series of index patients investigated for ARMC5 and confirm that ARMC5 pathogenic variants are associated with a more severe phenotype in most cases. To minimize negative ARMC5 screening, genotyping should be limited to clear bilateral adrenal involvement and autonomous cortisol secretion, with an optimum sensitivity for routine clinical practice. These findings will also help to better define PBMAH diagnostic criteria.

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Jeffrey M McManus, Navin Sabharwal, Peter Bazeley, and Nima Sharifi

Context

A sex discordance in COVID exists, with males disproportionately affected. Although sex steroids may play a role in this discordance, no definitive genetic data exist to support androgen-mediated immune suppression neither for viral susceptibility nor for adrenally produced androgens.

Objective

The common adrenal-permissive missense-encoding variant HSD3B1(1245C) that enables androgen synthesis from adrenal precursors and that has been linked to suppression of inflammation in severe asthma was investigated in COVID susceptibility and outcomes reported in the UK Biobank.

Methods

The UK Biobank is a long-term study with detailed medical information and health outcomes for over 500 000 genotyped individuals. We obtained COVID test results, inpatient hospital records, and death records and tested for associations between COVID susceptibility or outcomes and HSD3B1(1245A/C) genotype. Primary analyses were performed on the UK Biobank Caucasian cohort. The outcomes were identification as a COVID case among all subjects, COVID positivity among COVID-tested subjects, and mortality among subjects identified as COVID cases.

Results

Adrenal-permissive HSD3B1(1245C) genotype was associated with identification as a COVID case (odds ratio (OR): 1.11 per C allele, 95% CI: 1.04–1.18, P  = 0.0013) and COVID-test positivity (OR: 1.09, 95% CI: 1.02–1.17, P  = 0.011) in older (≥70 years of age) women. In women identified as COVID cases, there was a positive linear relationship between age and 1245C allele frequency (P  < 0.0001). No associations were found between genotype and mortality or between genotype and circulating sex hormone levels.

Conclusion

Our study suggests that a common androgen synthesis variant regulates immune susceptibility to COVID infection in women, with increasingly strong effects as women age.

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Lucie Coppin, Sophie Giraud, Eric Pasmant, Arnaud Lagarde, Marie-Odile North, Lauriane Le-Collen, Valérie Aubert, Grégory Mougel, Miriam Ladsous, Alyzée Louboutin, Hedia Brixi, Magalie Haissaguerre, Nicolas Schreyer, Marc Klein, Antoine Tabarin, Brigitte Delemer, Anne Barlier, Marie-Françoise Odou, and Pauline Romanet

MEN1 is an autosomal dominant hereditary syndrome characterized by several endocrine tumors, in most cases affecting the parathyroid glands, pancreas, and anterior pituitary. It is the result of inactivating mutations in the tumor suppressor gene MEN1. More than 1300 different mutations have been identified in this gene. Mosaic MEN1 mutations have been previously described in only a few patients in the literature. In this paper, we provide a review of six cases of MEN1 mosaicism reported in the literature supplemented with six additional cases described by the French TENgen network of laboratories. This review highlights that (i) MEN1 mosaicism is not associated with a mild phenotype and results in the same natural history as heterozygous MEN1 mutation and (ii) that more systematic detection of MEN1 mosaic mutation enables improvements in both patient monitoring and genetic counseling.