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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.

Open access

Lisa M Shepherd, Kelly Ann Schmidtke, Jonathan M Hazlehurst, Eka Melson, Janine Dretzke, Noel Hawks, Wiebeke Arlt, Abd A Tahrani, Amelia Swift, and Debbie M Carrick-Sen

Objective

The incidence of adrenal crisis (AC) remains high, particularly for people with primary adrenal insufficiency, despite the introduction of behavioural interventions. The present study aimed to identify and evaluate available evidence of interventions aiming to prevent AC in primary adrenal insufficiency.

Design

This study is a systematic review of the literature and theoretical mapping.

Methods

MEDLINE, MEDLINE in Process, EMBASE, ERIC, Cochrane CENTRAL, CINAHL, PsycINFO, the Health Management Information Consortium and trial registries were searched from inception to November 2021. Three reviewers independently selected studies and extracted data. Two reviewers appraised the studies for the risk of bias.

Results

Seven observational or mixed methods studies were identified where interventions were designed to prevent AC in adrenal insufficiency. Patient education was the focus of all interventions and utilised the same two behaviour change techniques, ‘instruction on how to perform a behaviour’ and ‘pharmacological support’. Barrier and facilitator themes aiding or hindering the intervention included knowledge, behaviour, emotions, skills, social influences and environmental context and resources. Most studies did not measure effectiveness, and assessment of knowledge varied across studies. The study quality was moderate.

Conclusion

This is an emerging field with limited studies available. Further research is required in relation to the development and assessment of different behaviour change interventions to prevent AC.

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Francisco M Acosta, Guillermo Sanchez-Delgado, Borja Martinez-Tellez, Francisco J Osuna-Prieto, Andrea Mendez-Gutierrez, Concepcion M Aguilera, Angel Gil, Jose M Llamas-Elvira, and Jonatan R Ruiz

Objectives

Brown adipose tissue (BAT) is important in the maintenance of cardiometabolic health in rodents. Recent reports appear to suggest the same in humans, although if this is true remains elusive partly because of the methodological bias that affected previous research. This cross-sectional work reports the relationships of cold-induced BAT volume, activity (peak standardized uptake, SUVpeak), and mean radiodensity (an inverse proxy of the triacylglycerols content) with the cardiometabolic and inflammatory profile of 131 young adults, and how these relationships are influenced by sex and body weight.

Design

This is a cross-sectional study.

Methods

Subjects underwent personalized cold exposure for 2 h to activate BAT, followed by static 18F-fluorodeoxyglucose PET-CT scanning to determine BAT variables. Information on cardiometabolic risk (CMR) and inflammatory markers was gathered, and a CMR score and fatty liver index (FLI) were calculated.

Results

In men, BAT volume was positively related to homocysteine and liver damage markers concentrations (independently of BMI and seasonality) and the FLI (all P ≤ 0.05). In men, BAT mean radiodensity was negatively related to the glucose and insulin concentrations, alanine aminotransferase activity, insulin resistance, total cholesterol/HDL-C, LDL-C/HDL-C, the CMR score, and the FLI (all P ≤ 0.02). In women, it was only negatively related to the FLI (P < 0.001). These associations were driven by the results for the overweight and obese subjects. No relationship was seen between BAT and inflammatory markers (P > 0.05).

Conclusions

A larger BAT volume and a lower BAT mean radiodensity are related to a higher CMR, especially in young men, which may support that BAT acts as a compensatory organ in states of metabolic disruption.

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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 Scheyer, 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.

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Tania Pilli, Cristina Dalmiglio, Gilda Dalmazio, Alfonso Sagnella, Raffaella Forleo, Lucia Brilli, Fabio Maino, Cristina Ciuoli, and Maria Grazia Castagna

Objective

Coronavirus disease-2019 (COVID-19) causes acute respiratory distress syndrome. Patients with adrenal insufficiency (AI) may develop severe complications due to this infection and should undergo COVID-19 vaccination; however, there is no consensus about the management of their replacement therapy. The aim of our study was to evaluate the tolerability and need for glucocorticoid dose adjustment related to COVID-19 mRNA vaccines in a cohort of patients with AI.

Design and methods

We prospectively administered to 88 patients (51 M/37 F; mean age: 62.3 ± 16 years), with AI (28 primary and 60 secondary AI), a questionnaire about the occurrence, severity and duration of the side effects and the need for glucocorticoid dose adjustment within 1 week after the first and the second dose of COVID-19 mRNA vaccines (Pfizer–BioNTech and Moderna).

Results

Side effects of mild to moderate severity occurred in about 70% of patients after both vaccine doses. The most common adverse events were pain at the injection site, fatigue, fever and flu-like symptoms. The occurrence and severity of the side effects were not correlated to gender, type of AI and mRNA vaccine, but their total number was higher after the second vaccine dose. Doubling the oral glucocorticoid dose was needed in up to 8% of patients, especially after the second vaccine dose, but no parenteral administration was required.

Conclusions

COVID-19 mRNA vaccines were well tolerated in patients with AI. Side effects were similar to those observed in the general population, and increasing glucocorticoid replacement therapy before vaccine administration was not needed.

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Benjamin L Green, Robert R C Grant, Christopher T Richie, Bishwanath Chatterjee, Michelly Sampaio De Melo, Frederic G Barr, Karel Pacak, Sunita K Agarwal, and Naris Nilubol

Introduction

Recurrent and metastatic pheochromocytoma (PCC) are rare advanced endocrine neoplasms with limited treatment options. Insight into the pathogenic molecular alterations in patients with advanced PCC can provide therapeutic options for precisely targeting dysregulated pathways.

Objective

We report the discovery and characterization of a novel BRAF-containing fusion transcript and its downstream molecular alterations in a patient with recurrent PCC with peritoneal seeding (pheochromocytomatosis).

Methods

We reviewed the medical record of a patient with pheochromocytomatosis. A comprehensive pan-cancer molecular profiling using next-generation sequencing (NGS) as well as confirmatory real-time-quantitative PCR were performed on surgical specimens. BRAF rearrangement and downstream molecular changes were assayed using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), respectively. Western blot was used to assess the in vitro activation of the mitogen-activated protein kinase (MAPK) signaling pathway and the EMT markers in transfected HEK-293 cells.

Results

The NGS analysis of a specimen from a 72-year-old female patient with pheochromocytomatosis showed an in-frame fusion of exon 3 of Glucocorticoid Induced 1 (GLCCI1) to exon 9 of BRAF. The upstream auto-inhibitory domain of BRAF was excluded from the GLCCI1-BRAF fusion; however, the downstream BRAF kinase domain was intact. A BRAF rearrangement was confirmed via a BRAF-specific break-apart FISH assay. Four separate tumor foci harbored GLCCI1-BRAF fusion. IHC demonstrated increased phosphorylated MEK. HEK-293 cells transfected with the GLCCI1-BRAF fusion demonstrated increased phosphorylated MEK as well as higher expression of EMT markers SNAI1 and ZEB1 in vitro.

Conclusion

We demonstrate a novel pathogenic gene fusion of GLCCI1 with the oncogenic kinase domain of BRAF, resulting in an activation of the MAPK signaling pathway and EMT markers. Thus, this patient may benefit from clinically available MEK and/or BRAF inhibitors when systemic therapy is indicated.

Summary statement

This report is the first of GLCCI1 fused to BRAF in a human neoplasm and only the second BRAF-containing fusion transcript in PCC. Detailed molecular characterization of PCC can be a valuable tool in managing patients with recurrent PCC and pheochromocytomatosis that represents a significant clinical challenge.

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Melek Yildiz, Aysel Bayram, Firdevs Bas, Volkan Karaman, Guven Toksoy, Sukran Poyrazoglu, Feryal Gun Soysal, Semen Onder, Zehra Oya Uyguner, and Feyza Darendeliler

Objective

The aim of this study was to assess the prevalence of ovarian and paraovarian adrenal rest tumors (ARTs) in gonadectomy materials of a subgroup of congenital adrenal hyperplasia (CAH) patients.

Methods

A total of 20 historical cases with clinical/molecular diagnosis of classical CAH were included in the study. All patients had 46,XX karyotype and underwent gonadectomy because of being raised as male.

Results

Median age at diagnosis of CAH was 5.7 years and was markedly delayed. All patients revealed severe virilization. Bone age was significantly advanced, and bone age/chronological age ratio was increased with a median ratio of 1.8. Median age at the time of gonadectomy was 9.2 years. Ovarian and paraovarian ARTs were detected during the pathological evaluation of gonadectomy materials in four patients (20%) (two with simple virilizing 21-hydroxylase and two with 11-beta-hydroxylase deficiency) with previously normal pelvic imaging. In three cases with ARTs, paraovarian area was composed of medium-sized polygonal cells, with round or oval monomorphic nuclei and abundant granular eosinophilic cytoplasm which is characteristic of adrenocortical tissue. The fourth case had bilateral ovarian ‘steroid cell tumors, not otherwise specified’, and the tumor was accepted as benign. Except for the ARTs, heterotopic prostate and bilateral paratubal epididymis tissue were detected in a patient.

Conclusions

Ovarian and paraovarian ARTs might be more common than previously described, especially among patients with excessive and prolonged adrenocorticotropic hormone exposure. These tumors could be detected histopathologically even if not detected by classical imaging methods.

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Julie Refardt, Tessa Brabander, Noémie S Minczeles, Richard A Feelders, Wouter W de Herder, and Johannes Hofland

Objective

Hyponatremia and hypernatremia are common electrolyte abnormalities in patients with malignancy and have been independently associated with worse survival outcomes. To date, there are no data on the impact of dysnatremia on survival outcomes in patients with neuroendocrine neoplasms (NENs).

Design

This study involves retrospective cohort analysis from a tertiary care center of NEN patients treated with peptide receptor radionuclide therapy (PRRT) with a cumulative activity of at least 3.7 GBq 177Lu-DOTATATE between the years 2000 and 2015.

Methods

Comparison of overall survival of patients with the occurrence of hyponatremia (serum sodium < 135 mmol/L) or hypernatremia (serum sodium > 145 mmol/L) before starting or during PRRT was perfomed.

Results

A total of 649 patients were included. Hyponatremia occurred in 57 patients during the observation period and was associated with a shorter median overall survival (95% CI) of 25 months (14–36) compared to 55 months (48–61) of the 512 normonatremic patients (P < 0.001), adjusted hazard ratio (HR): 1.48 (95% CI: 1.04–2.12). Overall survival time was reduced regardless of whether hyponatremia was present at baseline or during PRRT. In contrast, hypernatremia occurred in 80 patients and was associated with a longer median overall survival (95% CI) of 94 months (47–140) compared with the 512 normonatremic patients (P = 0.018), adjusted HR: 0.61 (95% CI: 0.40–0.92). This association was driven by the patients with hypernatremia during PRRT. No association between dysnatremia and progression-free survival after PRRT was observed.

Conclusions

The occurrence of hypo- or hypernatremia in PRRT-treated NET patients is associated with opposing outcomes with regard to overall survival. Sodium levels might have a prognostic role in these patients.