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 x 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. (C) 2021 by American College of Medical Genetics and Genomics. Published by Elsevier Inc.

Abstract Context Primary bilateral macronodular adrenal hyperplasia (PBMAH) with glucose-dependent insulinotropic polypeptide (GIP)-dependent Cushing's syndrome is caused by ectopic expression of GIP receptor (GIPR) in the adrenal lesions. Such ectopic expression of GIPR was also reported in other endocrine neoplasm, notably in somatotroph pituitary adenomas from acromegalic patients with paradoxical increase of GH after oral glucose load, suggesting a common molecular pathogenesis. We aimed to identify the driver event responsible for GIP-dependent PBMAH with Cushing's syndrome and ectopic GIPR expression in somatotropinomas. Methods We conducted an international, multicenter, cohort study. We collected blood and adrenal samples from patients who had undergone unilateral or bilateral adrenalectomy for GIP-dependent PBMAH with Cushing's syndrome. Adrenal samples from patients with PBMAH and Cushing's syndrome without food-dependent cortisol production were used as controls. We further collected somatotropinoma specimens from acromegaly patients followed at two expert endocrine centers in France. Results 17 patients with familial or sporadic GIP-dependent PBMAH with Cushing's syndrome were studied. We identified germline heterozygous mutations in the lysine demethylase 1A (KDM1A) gene in all 17 patients. We further identified a recurrent deletion of the short arm of chromosome 1 harboring the KDM1A locus in the adrenal lesions of affected patients. None of the 25 patients in the control group had KDM1A germline or somatic alterations. Concomitant genetic inactivation of both KDM1A alleles resulted in loss of KDM1A expression in the adrenal lesions. RNA-sequencing revealed the global impact of KDM1A loss in adrenal tissue on gene transcription and identified differentially regulated genes including those encoding for GIPR and other G-Protein-Coupled Receptors that may be involved in adrenal tumorigenesis and regulation of steroidogenesis. In vitro pharmacologic inhibition, silencing and knock-out by CRISPR-Cas9 genome editing of KDM1A led to an increase in GIPR transcripts and protein in human adrenocortical H295R cells. Somatotropinoma samples from 78 patients with acromegaly were studied. 24% of these patients presented with a paradoxical rise of GH after oral glucose load and expressed ectopically GIP-receptor in their somatotropinoma. None of the somatotropinomas harbored KDM1A pathogenic variants, but those from patients with paradoxical GH response displayed a recurrent chromosome 1p loss. Discussion We identified germline inactivating KDM1A mutations and loss of heterozygosity as a genetic predisposition to GIP-dependent PBMAH with Cushing's syndrome following a tumor suppressor gene model of tumorigenesis. We currently perform genetic screening in first-degree relatives of patients with GIP-dependent PBMAH with Cushing's syndrome and clinical examination with biochemical testing in asymptomatic KDM1A variant carriers. We did not identify somatic KDM1A mutations in somatotropinomas expressing GIPR ectopically, however their recurrent 1p chromosome loss suggests that KDM1A haploinsufficiency may contribute to GIPR expression in those tumors. Presentation: Saturday, June 11, 2022 12:15 p.m. - 12:30 p.m.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Background: GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome is caused by aberrant expression of the GIP receptor in adrenal lesions. The bilateral nature of this disease suggests germline genetic predisposition. We aimed to identify the genetic driver event responsible for GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. Methods: We conducted a multicentre, retrospective, cohort study at endocrine hospitals and university hospitals in France, Canada, Italy, Greece, Belgium, and the Netherlands. We collected blood and adrenal samples from patients who had undergone unilateral or bilateral adrenalectomy for GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. Adrenal samples from patients with primary bilateral macronodular adrenal hyperplasia who had undergone an adrenalectomy for overt or mild Cushing's syndrome without evidence of food-dependent cortisol production and those with GIP-dependent unilateral adrenocortical adenomas were used as control groups. We performed whole genome, whole exome, and targeted next generation sequencing, and copy number analyses of blood and adrenal DNA from patients with familial or sporadic disease. We performed RNA sequencing on adrenal samples and functional analyses of the identified genetic defect in the human adrenocortical cell line H295R. Findings: 17 patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome were studied. The median age of patients was 43middot3 (95% CI 38middot8-47middot8) years and most patients (15 [88%]) were women. We identified germline heterozygous pathogenic or most likely pathogenic variants in the KDM1A gene in all 17 patients. We also identified a recurrent deletion in the short p arm of chromosome 1 harboring the KDM1A locus in adrenal lesions of these patients. None of the 29 patients in the control groups had KDM1A germline or somatic alterations. Concomitant genetic inactivation of both KDM1A alleles resulted in loss of KDM1A expression in adrenal lesions. Global gene expression analysis showed GIP receptor upregulation with a log2 fold change of 7middot99 (95% CI 7middot34-8middot66; p=4middot4 x 10(-125)), and differential regulation of several other G protein-coupled receptors in GIP-dependent primary bilateral macronodular hyperplasia samples compared with control samples. In vitro pharmacological inhibition and inactivation of KDM1A by CRISPR-Cas9 genome editing resulted in an increase of GIP receptor transcripts and protein in human adrenocortical H295R cells. Interpretation: We propose that GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome results from a two-hit inactivation of KDM1A, consistent with the tumour suppressor gene model of tumorigenesis. Genetic testing and counselling should be offered to these patients and their relatives. Funding: Agence Nationale de la Recherche, Fondation du Grand defi Pierre Lavoie, and the French National Cancer Institute. Copyright (c) 2021 Elsevier Ltd. All rights reserved.

Purpose: To investigate the genetic cause of Food-dependent Cushing’s syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the GIP receptor (GIPR). Germline ARMC5 alterations have been reported in about 25 % of PBMAH index cases but are absent in patients with FDCS.Methods: A multi-omics analysis of PBMAH tissues from 36 patients treated by adrenalectomy wasperformed (RNAseq, SNP array, methylome, miRNome, exome sequencing).Results: The integrative analysis revealed three molecular groups with different clinical features: G1, PBMAH due to ARMC5 inactivating variants; G2, with GIPR ectopic expression and FDCS; and G3, with a less severe phenotype. Exome sequencing revealed germline truncating variants ofLSD1/KDM1A in the G2 group, constantly associated with a somatic loss of the LSD1/KDM1A wildtype allele on 1p, leading to a loss of LSD1/KDM1A expression both at mRNA and protein levels (p=1.2x10-12 and p<0.01, respectively). Subsequently, LSD1/KDM1A pathogenic variants were identified in 4/4 additional index cases with FDCS.Conclusion: LSD1/KDM1A inactivation explains about 90 % of FDCS PBMAH. Genetic screening for ARMC5 and LSD1/KDM1A can be offered now for the majority of PBMAH operated patients andtheir families, opening the way to earlier diagnosis and improved management.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

CONTEXT:Outcomes of congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency (21OHD) have been widely studied in children and women, but less so in men.OBJECTIVE:The objective was to analyze data from a network of metropolitan French teaching hospitals on the clinical outcome of classic 21OHD in a large sample of congenital adrenal hyperplasia/21OHD-genotyped adult men, and particularly the impact of 21OHD on the gonadotrope axis, testicular function, and fertility.METHODS:From April 2011 to June 2014, tertiary endocrinology departments provided data for 219 men with 21OHD (ages, 18-70 y; 73.6% salt wasters, 26.4% simple virilizers). Testicular sonography was performed in 164 men, and sperm analysis was performed in 71 men.RESULTS:Mean final height was 7.8 cm lower than in a reference population. Obesity was more common, and mean blood pressure was lower than in the reference population. None of the patients were diabetic, and lipid status was generally normal. Blood electrolyte status was normal in the vast majority of men, despite markedly elevated ACTH and renin levels. Serum progesterone, 17-hydroxyprogesterone, and androstenedione levels were above normal in the vast majority of cases. Hormonal profiling variously showed a normal gonadotrope-testicular axis, gonadotropin deficiency, or primary testicular insufficiency. Testicular sonography revealed testicular adrenal rest tumors (TARTs) in 34% of 164 men. Serum inhibin B and FSH levels were significantly lower and higher, respectively, in patients with TARTs. Severe oligospermia or azoospermia was found in 42% of patients and was significantly more prevalent in men with TARTs (70%) than in men with normal testes (3.6%; P < .0001). Among men living with female partners, TARTs were significantly more prevalent in those who had not fathered children.CONCLUSION:We report the spectrum of testicular/gonadotrope axis impairment in the largest cohort of 21OHD men studied to date. Our results suggest that French men with 21OHD managed in specialized centers frequently have impaired exocrine testicular function but that its reproductive implications are often overlooked.

Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity for age or final height >2 s.d. above country normal means. The median onset of rapid growth was 13 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were ≥10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final height was greater in younger onset patients, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (r=0.23, P=0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 - X-linked acrogigantism (X-LAG) - occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in >50% of cases.

Objectives. - Several cases of testicular adrenal rest tumours have been reported in men with congenital adrenal hyperplasia (CAH) due to the classical form of 21-hydroxylase deficiency but the prevalence has not been established. The aims of this report were to evaluate the frequency of testicular adrenal rest tissue in this population in a retrospective multicentre study involving eight endocrinology centres, and to determine whether treatment or genetic background had an impact on the occurrence of adrenal rest tissue. Material and methods. - Testicular adrenal rest tissue (TART) was sought clinically and with ultrasound examination in forty-five males with CAH due to the classical form of 21-hydroxylase deficiency. When the diagnosis of testicular adrenal rest tumours was sought, good observance of treatment was judged on biological concentrations of 17-hydroxyprogesterone (17OHP), delta4-androstenedione, active renin and testosterone. The results of affected and non-affected subjects were compared. Results. - TART was detected in none of the 18 subjects aged 1 to 15 years but was detected in 14 of the 27 subjects aged more than 15 years. Five patients with an abnormal echography result had no clinical signs. Therapeutic control evaluated at diagnosis of TART seemed less effective when diagnosis was made in patients with adrenal rest tissue compared to TART-free subjects. Various genotypes were observed in patients with or without TART. Conclusion. - Due to the high prevalence of TART in classical CAH and the delayed clinical diagnosis, testicular ultrasonography must be performed before puberty and thereafter regularly during adulthood even if the clinical examination is normal. (c) 2012 Elsevier Masson SAS. All rights reserved.

Objective. -To assess the effects of aerobic training on physical capacities and quality of life in men with metabolic syndrome (Mets), using field evaluation tools.Synthesis. -The physical capacities and the quality of life of eight men with Mets (59.5 +/- 4.8 years old) was assessed before and after 8 weeks of aerobic exercise training by the 6 minutes walking test and the quality of life, obesity and dietetics scale.Conclusion. -Aerobic exercise training of 8 weeks improves physical capacities and the social impact dimension of quality of life in men with Mets, without generating anthropometric modification. (C) 2011 Elsevier Masson SAS. All rights reserved.

The aim of this study was to evaluate serum and saliva adrenocortical hormones and their relationships at rest and during submaximal exercise and recovery in 9 obese diabetic middle-aged men (BMI: 35.2±1.6 kg/m2). Blood and saliva samples were taken at rest, every 10 min of a 30-min cycling exercise at 70% of maximal heart rate, and after 10 min of recovery in order to analyze cortisol, dehydroepiandrosterone sulfate (DHEA-S) and dehydroepiandrosterone (DHEA). Serum and saliva cortisol increased significantly during recovery (p<0.05), but no significant difference was observed between the rest, exercise, and recovery DHEA-S and DHEA concentrations. A strong correlation was found at rest between both serum and saliva cortisol (r=0.72, p<0.001) and DHEA-S and DHEA (r=0.93, p<0.001). Serum DHEA-S and saliva DHEA remained strongly correlated during and after the submaximal exercise (r=0.81, p<0.001), whereas a weaker but still significant relationship was observed between serum and saliva cortisol during and after the exercise (r=0.52, p<0.001). In conclusion, these results suggest that saliva adrenocortical hormones, and especially saliva DHEA, may offer a practical surrogate for serum concentrations during both rest and exercise in obese diabetic men.

CONTEXTAIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively.OBJECTIVEThe objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas.DESIGNThis study was an international, multicenter, retrospective case collection/database analysis.SETTINGThe study was conducted at 36 tertiary referral endocrine and clinical genetics departments.PATIENTSPatients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls.RESULTSThe AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy.CONCLUSIONSAIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.

J. Clin. Endocrinol. Metab. 2010 95:E373-E383 originally published online Aug 4, 2010; , doi: 10.1210/jc.2009-2556 €Lauri A. Aaltonen and Albert Beckers Gunter K. Stalla, Anna Spada, Sabina Zacharieva, Jerome Bertherat, Thierry Brue, Vincent Bours, Philippe Chanson, Anne-Paule Gimenez-Roqueplo, Fergus J. Cameron, Francoise Borson-Chazot, Ian Holdaway, Sergio P. A. Toledo,Halaby, Vinciane Corman, Marie-Therese Hagelstein, Jean-Francois Vanbellinghen, Gustavo Barcelos Barra, Saloranta, Wouter De Herder, Renato Cozzi, Mirtha Guitelman, Flavia Magri, Maria Stefania Lagonigro, GeorgesLongas, Jose Ignacio Labarta Aizpun, Marianthi Georgitsi, Ralf Paschke, Cristina Ronchi, Matti Valimaki, Carola A. Toledo, Maria Isabel Sabate, Chiara Villa, Marc Popelier, Roberto Salvatori, Juliet Jennings, Angel FerrandezAntoine Tabarin, Elisa Verrua, Eija Eloranta, Arnaud Murat, Outi Vierimaa, Pasi I. Salmela, Philippe Emy, Rodrigo Montanana, Gerald Raverot, Robert J. Weil, Timo Sane, Dominique Maiter, Sebastian Neggers, Maria Yaneva,Luciana A. Naves, Tapani Ebeling, Auli Karhu, Antti Raappana, Laure Cazabat, Ernesto De Menis, Carmen Fajardo Adrian F. Daly, Maria A. Tichomirowa, Patrick Petrossians, Elina Heliovaara, Marie-Lise Jaffrain-Rea, Anne Barlier,

Thymic neuroendocrine tumors (Th-NET) present a poor prognosis for patients with multiple endocrine neoplasia type 1 (MEN1). The purpose of this article was to study the clinical, biological, and pathological features of Th-NET in a large cohort of patients with MEN1.

Objective: The objective of this study is to investigate whether preoperative ultrasound guided insertion of a hook-needle is useful in reoperations for cervical recurrent lymph node metastases of papillary thyroid cancer.Patients and methods: 8 patients with operated papillary thyroid cancer were included in this study. They all had suspicious nonpalpable cervical lymph nodes discovered during follow-up. These lymph nodes were identified by ultrasound imaging and their metastatic nature was confirmed by fine needle aspiration cytology and measurement of in situ thyroglobulin. In all cases, surgical excision of these lymph nodes was decided. All 8 patients had a hook-needle inserted in the suspicious lymph node(s) preoperatively and under ultrasound guidance.Results and conclusion: In all 8 patients, the suspicious lymph nodes were removed and their metastatic nature was confirmed by the final pathological examination. This localization technique is very helpful for the surgeon during the excision of small and nonpalpable lymph nodes, especially in previously operated area. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

CONTEXT:An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown.OBJECTIVE:The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA).DESIGN:This was a multicenter, international, collaborative study.SETTING:The study was conducted in 34 university endocrinology and genetics departments in nine countries.PATIENTS:Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis.MAIN OUTCOME MEASURES:Presence/absence and description of AIP gene mutations were the main outcome measures.INTERVENTION:There was no intervention.RESULTS:Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations.CONCLUSIONS:AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.

Insomnia is one of the most common sleep disorders which can dramatically impair life quality and negatively affect an individual's physical and mental health. Recently, various deep learning based methods have been proposed for automatic and objective insomnia detection, owing to the great success of deep learning techniques. However, due to the scarcity of public insomnia data, a deep learning model trained on a dataset with a small number of insomnia subjects may compromise the generalization capacity of the model and eventually limit the performance of insomnia detection. Meanwhile, there have been a number of public EEG datasets collected from a large number of healthy subjects for various sleep research tasks such as sleep staging. Therefore, to utilize such abundant EEG datasets for addressing the data scarcity issue in insomnia detection, in this paper we propose a domain adaptation based model to better extract insomnia related features of the target domain by leveraging stage annotations from the source domain. For each domain, two pairs of common encoder and private encoder are firstly trained to extract sleep related features and sleep irrelevant features, respectively. In order to further discriminate source domain and target domain, a domain classifier is introduced. Then, the common encoder of the target domain will be used together with the Long Short Term Memory (LSTM) network for insomnia detection. To the best of our knowledge, this is the first deep learning based domain adaptation model using single channel raw EEG signals to detect insomnia at subject level. We use the Montreal Archive of Sleep Studies (MASS) dataset which contains only healthy subjects as source domain and two datasets which contain both healthy and insomnia subjects as target domain to validate our model's generalizability. Experimental results on the two target domain datasets (a public one and an in-house one) demonstrate that our model generalizes well on two target domain datasets with different sampling rates. In particular, our proposed method is able to improve insomnia detection performance from 50.0% to 90.9% and 66.7%–79.2% in terms of accuracy on the two target domain datasets, respectively.