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Purpose: Primary bilateral macronodular adrenal hyperplasia (PBMAH), the most common cause of Cushing's syndrome due to bilateral nodules, is a heterogeneous disease at the clinical, hormonal and morphological levels. ARMC5 inactivating pathogenic variants are causative of PBMAH and rare variants of PDE11A have been associated with PBMAH., Methods: Leukocyte DNA of 354 PBMAH index cases was sequenced for ARMC5 and PDE11A genes by Next generation sequencing (NGS). Phenotypic characteristics of 334 of these patients were analysed to study the genotype/phenotype correlations., Results: Seven out of 16 PDE11A variants were considered damaging according to in silico predictions: six missense variants (p.Tyr727Cys, p.Met623Arg, p.Tyr658Cys, p.Ag867Trp, p.Asn298Ser, p.Glu840Lys) and one stop-gain variant (p.Arg307Ter). In the cohort, 11.4% of patients had one of these variants and 19.2% had ARMC5 pathogenic variants. There was no significant difference in the distribution of PDE11A damaging variants according to ARMC5 status (p=0.83; OR=0.79, 95%CI [0.26-2.03]), neither in the distribution of ARMC5 pathogenic variants according to PDE11A status (p=0.83; OR=0.81, 95%CI [0.27-2.04]). Patients with PDE11A damaging variants had lower urinary free cortisol (UFC) (0.7 vs 1.25ULN, p=0.0002), midnight plasma cortisol (157.81 vs 222.19nmol/L, p=0.016) and number of adrenal nodules (3.46 vs 4.74, p=0.048) compared to PDE11A wild-type patients. Patients with ARMC5 pathogenic variants had a more severe phenotype with more frequent comorbidities and were more often treated by adrenalectomy (60%)., Conclusions: PDE11A appears to be a modulator of PBMAH phenotype, damaging variants being associated with an attenuated form. This may contribute to the heterogeneity of PBMAH and could impact patients' management., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Adrenal Cushing represents 20% of cases of endogenous hypercorticism. Unilateral cortisol-producing adenoma (CPA), a benign tumor, and adrenocortical carcinoma (ACC), a malignant tumor, are more frequent than bilateral adrenal nodular diseases (primary bilateral macronodular adrenal hyperplasia (PBMAH) and primary pigmented nodular adrenal disease (PPNAD)).In cortisol-producing adrenal tumors, the signaling pathways mainly altered are the protein kinase A and Wnt/β-catenin pathways. Studying components of these pathways and exploring syndromic and familial cases of these tumors has historically enabled identification of many of the predisposing genes. More recently, pangenomic sequencing revealed alterations in sporadic tumors.In ACC, mainly due to TP53 alterations causing Li-Fraumeni syndrome, germline predisposition is frequent in children, while it is rare in adults. Pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, MSH6, and PMS2, which cause Lynch syndrome or alterations of IGF2 and CDKN1C (11p15 locus) in Beckwith-Wiedemann syndrome, can also cause ACC. Rarely, ACC is described in other hereditary tumor syndromes due to germline pathogenic variants in MEN1 or APC and, in very rare cases, NF1, SDH, PRKAR1A, or BRCA2. Concerning ACC somatic alterations, TP53 and genetic or epigenetic alterations at the 11p15 locus are also frequently described, as well as CTNNB1 and ZNRF3 pathogenic variants.CPAs mainly harbor somatic pathogenic variants in PRKACA and CTNNB1 and, less frequently, PRKAR1A, PRKACB, or GNAS1 pathogenic variants. Isolated PBMAH is due to ARMC5 inactivating pathogenic variants in 20 to 25% of cases and to KDM1A pathogenic variants in food-dependent Cushing. Syndromic PBMAH may be due to germline pathogenic variants in MEN1, APC, or FH, causing type 1 multiple endocrine neoplasia, familial adenomatous polyposis, or hereditary leiomyomatosis-kidney cancer syndrome, respectively. PRKAR1A germline pathogenic variants are the main alteration causing PPNAD (isolated or part of Carney complex)., (© 2024. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

Bilateral macronodular adrenocortical disease (BMAD) is an uncommon cause of Cushing's syndrome leading to bilateral macronodules. Isolated BMAD has been classified into three molecular groups: patients with ARMC5 alteration, KDM1A alteration, and patients without known genetic cause. The aim of this study was to identify by NGS, in a cohort of 26 patients with BMAD, the somatic alterations acquired in different nodules after macrodissection from patients with germline ARMC5 or KDM1A alterations and to analyze potential somatic alterations in a panel of five other genes involved in adrenal pathology (GNAS, PDE8B, PDE11A, PRKAR1A, and PRKACA). Twenty-three patients (7 ARMC5, 3 KDM1A, and 13 BMAD with unknown genetic cause) were analyzable. Somatic ARMC5 or KDM1A events were exclusively observed in patients with germline ARMC5 and KDM1A alterations, respectively. Six out of 7 ARMC5 patients have a high heterogeneity in identified somatic events, whereas one ARMC5 and all KDM1A patients show a loss of heterozygosity (LOH) in all nodules. Except for passenger alterations of GNAS, no genetic alteration susceptible to causing the disease was detected in the BMAD with unknown genetic cause. Our study reinforces our knowledge of the somatic genetic heterogeneity of ARMC5 and the somatic homogeneity of KDM1A. It reveals the absence of purely somatic events in these two genes and provides a new tool for detecting KDM1A alterations by FISH 1p36/1q25., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: Whether F18-choline (FCH) positron emission tomographic (PET)/computed tomographic (CT) scan can replace Tc99m-sestaMIBI (MIBI) single-photon emission (SPE)CT/CT as a first-line imaging technique for preoperative localization of parathyroid adenomas (PTA) in patients with primary hyperparathyroidism (PHPT) is unclear., Objective: To compare first-line FCH PET/CT vs MIBI SPECT/CT for optimal care in patients with PHPT needing parathyroidectomy and to compare the proportions of patients in whom the first-line imaging method resulted in successful minimally invasive parathyroidectomy (MIP) and normalization of calcemia 1 month after surgery., Design, Setting, and Participants: A French multicenter randomized open diagnostic intervention phase 3 trial was conducted. Patients were enrolled from November 2019 to May 2022 and participated up to 6 months after surgery. The study included adults with PHPT and an indication for surgical treatment. Patients with previous parathyroid surgery or multiple endocrine neoplasia type 1 (MEN1) were ineligible., Interventions: Patients were assigned in a 1:1 ratio to receive first-line FCH PET/CT (FCH1) or MIBI SPECT/CT (MIBI1). In the event of negative or inconclusive first-line imaging, they received second-line FCH PET/CT (FCH2) after MIBI1 or MIBI SPECT/CT (MIBI2) after FCH1. All patients underwent surgery under general anesthesia within 12 weeks following the last imaging. Clinical and biologic (serum calcemia and parathyroid hormone levels) assessments were performed 1 and 6 months after surgery., Main Outcomes and Measures: The primary outcome was a true-positive first-line imaging-guided MIP combined with uncorrected serum calcium levels of 2.55 mmol/l or less 1 month after surgery, corresponding to the local upper limit of normality., Results: Overall, 57 patients received FCH1 (n = 29) or MIBI1 (n = 28). The mean (SD) age of patients was 62.8 (12.5) years with 15 male (26%) and 42 female (74%) patients. Baseline patient characteristics were similar between groups. Normocalcemia at 1 month after positive first-line imaging-guided MIP was observed in 23 of 27 patients (85%) in the FCH1 group and 14 of 25 patients (56%) in the MIBI1 group. Sensitivity was 82% (95% CI, 62%-93%) and 63% (95% CI, 42%-80%) for FCH1 and MIBI1, respectively. Follow-up at 6 months with biochemical measures was available in 43 patients, confirming that all patients with normocalcemia at 1 month after surgery still had it at 6 months. No adverse events related to imaging and 4 adverse events related to surgery were reported., Conclusions: This randomized clinical trial found that first-line FCH PET/CT is a suitable and safe replacement for MIBI SPECT/CT. FCH PET/CT leads more patients with PHPT to correct imaging-guided MIP and normocalcemia than MIBI SPECT/CT thanks to its superior sensitivity., Trial Registration: ClinicalTrials.gov Identifier: NCT04040946.

Background & Aims: Insufficient screening and management of malnutrition leads to increase morbidity and mortality., Aims: to evaluate the characteristics and clinical outcomes of malnourished patients referred to a specialized outpatient clinic for the management of malnutrition (primary); to compare the latter according to malnutrition severity; to determine the factors associated with severe malnutrition and mortality; to compare the consistency of the decided medical nutrition therapy with the European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines (secondary)., Methods: This retrospective, observational study included malnourished adults referred for the first time to the specialized nutrition consultation of a teaching University Hospital during 50 months. Malnutrition was diagnosed according to the Global Leadership Initiative on Malnutrition criteria, including body composition assessment by bioimpedance analysis., Statistics: Chi2 or Fisher, Student or Wilcoxon rank-sum tests; multivariable logistic regression to assess the factors associated with severe malnutrition and mortality., Results: 108 malnourished adults were included: 74% had severe malnutrition. The main secondary diagnosis was digestive cancer (48.2%). During the follow-up (median = 70 days) after the first nutritional consultation, 11% of patients were admitted at hospital, 19% had infections and 23.1% died, without any difference according to malnutrition severity. Severely malnourished patients had lower body mass index, a smaller fat mass index (FMI) (4.6 ± 1.8 vs 6.0 ± 2.5 kg/m 2 ; p = 0.01), and a higher level of total body water (64.7 ± 7.1 vs 60.6 ± 5.4%; p = 0.02), compared to moderately malnourished individuals. A low FMI (odds ratio = 0.72 [0.54-0.96]) was the only factor significantly associated with severe malnutrition. We did not find any factor associated with mortality. There was a moderate consistency (47.1%) between the decided medical nutrition therapy and the ESPEN guidelines of nutritional care., Conclusions: Adults referred for the first time to a specialized nutritional consultation present mostly with severe malnutrition and are at risk for significant complications, leading to a high mortality rate. In this population, a low FMI is associated with severe malnutrition. An earlier diagnosis and care of malnutrition and an earlier referral to clinical nutrition units would improve outcomes., Competing Interests: Declaration of competing interest Patricia Vaduva has received a grant from IPSEN for fundamental scientific work and personal honoraria for lectures and/or meeting attendance from Lilly, Sanofi and Urgo, outside the field of this article. Maxime Esvan declared no conflict of interest. Ronan Thibault received consulting and conference fees from Aguettant, Baxter, BBraun, Fresenius-Kabi, Nestlé Health Science, Nutricia, Roche; and conference fees from Astra-Zeneca, Homeperf, Lactalis, Shire, and Theradial. Ronan Thibault designed and received royalties for the Simple Evaluation of Food Intake® (SEFI®) (Knoë-Groupe Get, le Kremlin Bicêtre, France)., (Copyright © 2024 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Objective: Carney complex (CNC) is a rare genetic syndrome, mostly due to germline loss-of-function pathogenic variants in PRKAR1A. Carney complex includes pigmented skin lesions, cardiac myxomas, primary pigmented nodular adrenocortical dysplasia, and various breast benign tumors., Design: The present study was designed to describe the characteristics of breast lesions in CNC patients and their association with other manifestations of CNC and PRKAR1A genotype., Methods: A 3-year follow-up multicenter French prospective study of CNC patients included 50 women who were analyzed for CNC manifestations and particularly breast lesions, with breast imaging, genotyping, and hormonal settings., Results: Among the 38 women with breast imaging, 14 (39%) had breast lesions, half of them bilateral. Ten women (26%) presented with benign lesions and six with breast carcinomas (16%): one had ductal carcinoma in situ at 54, and five had invasive cancer before 50 years old, whom one with contralateral breast cancer during follow-up. The occurrence of breast cancer was more frequent in women with PRKAR1A pathogenic variant odds ratio = 6.34 (1.63-17.91) than in general population of same age. The mean age at breast cancer diagnosis was 44.7 years old: 17 years younger than in the general population. Breast cancer patients had good prognosis factors. All breast carcinomas occurred in individuals with familial CNC and PRKAR1A pathogenic variants. Loss of heterozygosity at the PRKAR1A locus in the 2 invasive breast carcinomas analyzed suggested a driver role of this tumor suppressor gene., Conclusions: As CNC could predispose to breast carcinoma, an adequate screening strategy and follow-up should be discussed in affected women., Clinical Trial Registration: ClinicalTrial.gov NCT00668291., Competing Interests: Conflict of interest: The authors have no conflict of interest to declare. Co-authors G.R. and G.A. are on the editorial board of EJE. They were not involved in the review or editorial process for this paper, on which they are listed as authors., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Several studies suggest an association between endometriosis and the risk of cardio-metabolic diseases. This study aimed to prospectively evaluate the association between history of endometriosis and incident type 2 diabetes., Study Design: E3N is a prospective cohort of 98,995 French women aged 40-65 years at inclusion. Multivariable Cox regression models were used to estimate hazard ratios and 95 % confidence intervals for the association between endometriosis and incident type 2 diabetes. We evaluated effect modification by age, body mass index, infertility treatment, adherence to the Mediterranean diet, and menopausal status., Results: Age at inclusion was 51 ± 6 years and there were 2672 incident cases of type 2 diabetes. A total of 4606 women reported surgically-confirmed endometriosis among 83,582 women with no history of diabetes at inclusion. Endometriosis was not associated with type 2 diabetes risk in a model adjusted for age, BMI, physical activity, smoking, education, age at menarche and oral contraceptive use (hazard ratio [HR] = 1.09; 95 % confidence interval [CI] = 0.92-1.29), neither after further adjustment for family history of diabetes, hypertension and menopausal status (HR = 0.97;95%CI = 0.80-1.16). The relationship did not differ by age at inclusion, BMI, infertility treatment, diet or menopausal status (p > 0.05)., Conclusions: Surgically-confirmed endometriosis was not associated with the risk of type 2 diabetes in this large cohort, confirming that endometriosis is not a risk marker for type 2 diabetes., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Thyrotoxic periodic paralysis (TPP) is a rare and most often acquired subtype of hypokalemic periodic paralysis. The association of varying degrees of muscle weakness, hyperthyroidism and hypokalemia characterizes it. The treatment requires potassium supplementation, control of hyperthyroidism and prevention measures. It is a frequent disease in Asian men, but much rare in Caucasian or African populations. This is the first report of TPP associated with lactic metabolic acidosis in an African man., Case Presentation: A 23 year-old African man, native from Morocco, with recurrent episodes of tetraparesis for eleven months, and abdominal pain, was referred for evaluation. Biochemical investigations showed severe hypokalemia associated with hyperthyroidism and lactic metabolic acidosis. His EKG showed signs of hypokalemia such as sinus tachycardia and U waves. After potassium supplementation, neurological recuperation was quick and complete. Thyroid ultrasound identified a hypoechogenic and hypervascularized goiter, associated with high levels of thyroid antibodies, in favor of Grave's disease. With antithyroid drugs and life-style changes, the patient did not have any other attack., Review of Literature: In addition to the case report, this article presents an extended review of literature, from the first large study reporting the diagnosis and incidence of TPP in 1957 to nowadays. Are reported here the latest information concerning epidemiology, clinical manifestations, complementary examinations, management and genetic finding. The lactic acidosis observed initially is exceptional, never described in TPP. TPP is a diagnostic and therapeutic emergency, requiring careful potassium supplementation, in order to avoid the risk of the onset of rebound hyperkalemia, to be maintained until the etiological treatment is effective. Paraclinical assessment with emergency EKG and electromyogram are essential to assess the impact., Discussion: It is essential in the face of any hypokalaemic periodic paralysis, including in non-Asian subjects, to search hyperthyroidism., Conclusions: This report demonstrates the importance of thyroid testing in case of acute muscle weakness, even in non-Asian patients in order to diagnose TPP. This is a rare but possible etiology, to be distinguished from the familial form of hypokalemic periodic paralysis. It also questions on the impact of TPP on energetic metabolism, in particular on lactic metabolism., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

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.

Purpose: This study aimed to investigate the genetic cause of food-dependent Cushing syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the glucose-dependent insulinotropic polypeptide receptor. Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS., Methods: A multiomics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNA sequencing, single-nucleotide variant array, methylome, miRNome, exome sequencing)., Results: The integrative analysis revealed 3 molecular groups with different clinical features, namely G1, comprising 16 patients with ARMC5 inactivating variants; G2, comprising 6 patients with FDCS with glucose-dependent insulinotropic polypeptide receptor ectopic expression; and G3, comprising 14 patients with a less severe phenotype. Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels (P = 1.2 × 10 -12 and P < .01, respectively). Subsequently, KDM1A pathogenic variants were identified in 4 of 4 additional index cases with FDCS., Conclusion: KDM1A inactivation explains about 90% of FDCS PBMAH. Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. All rights reserved.)

This review reports the main molecular alterations leading to development of benign cortisol- and/or aldosterone-secreting adrenal tumors. Causes of adrenal Cushing syndrome can be divided in 2 groups: multiple bilateral tumors or adenomas secreting cortisol. Bilateral causes are mainly primary pigmented nodular adrenocortical disease, most of the time due to PRKAR1A germline-inactivating mutations, and primary bilateral macronodular adrenal hyperplasia that can be caused in some rare syndromic cases by germline-inactivating mutations of MEN1 , APC , and FH and of ARMC5 in isolated forms. PRKACA somatic-activating mutations are the main alterations in unilateral cortisol-producing adenomas. In primary hyperaldosteronism (PA), familial forms were identified in 1% to 5% of cases: familial hyperaldosteronism type I (FH-I) due to a chimeric CYP11B1/CYP11B2 hybrid gene, FH-II due to CLCN-2 germline mutations, FH-III due to KCNJ5 germline mutations, FH-IV due to CACNA1H germline mutations and PA, and seizures and neurological abnormalities syndrome due to CACNA1D germline mutations. Several somatic mutations have been found in aldosterone-producing adenomas in KCNJ5 , ATP1A1 , ATP2B3 , CACNA1D , and CTNNB1 genes. In addition to these genetic alterations, genome-wide approaches identified several new alterations in transcriptome, methylome, and miRnome studies, highlighting new pathways involved in steroid dysregulation., (© Endocrine Society 2020.)