Publications by authors named "Jérôme Bertherat"

301 Publications

Primary bilateral macronodular adrenal hyperplasia: definitely a genetic disease.

Nat Rev Endocrinol 2022 Aug 3. Epub 2022 Aug 3.

Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France.

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is an adrenal cause of Cushing syndrome. Nowadays, a PBMAH diagnosis is more frequent than previously, as a result of progress in the diagnostic methods for adrenal incidentalomas, which are widely available. Although some rare syndromic forms of PBMAH are known to be of genetic origin, non-syndromic forms of PBMAH have only been recognized as a genetic disease in the past 10 years. Genomics studies have highlighted the molecular heterogeneity of PBMAH and identified molecular subgroups, allowing improved understanding of the clinical heterogeneity of this disease. Furthermore, the generation of these subgroups permitted the identification of new genes responsible for PBMAH. Constitutive inactivating variants in ARMC5 and KDM1A are responsible for the development of distinct forms of PBMAH. To date, pathogenic variants of ARMC5 are responsible for 20-25% of PBMAH, whereas germline KDM1A alterations have been identified in >90% of PBMAH causing food-dependent Cushing syndrome. The identification of pathogenic variants in ARMC5 and KDM1A demonstrated that PBMAH, despite mostly being diagnosed in adults aged 45-60 years, is a genetic disorder. This Review summarizes the important progress made in the past 10 years in understanding the genetics of PBMAH, which have led to a better understanding of the pathophysiology, opening new clinical perspectives.
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http://dx.doi.org/10.1038/s41574-022-00718-yDOI Listing
August 2022

Cushing's disease: role of bilateral adrenalectomy.

Pituitary 2022 Jul 26. Epub 2022 Jul 26.

Endocrinology Department, Center for Rare Adrenal Diseases, Cochin Hospital, AP-HP, Université Paris Cité, 75014, Paris, France.

Introduction: Laparoscopic bilateral adrenalectomy (BAD) is one of the treatments of Cushing's Disease (CD), but its indications and outcome is debated.

Methods: The literature on BAD was reviewed as part of a work performed for the Cushing's disease guideline.

Results: The surgical morbidity of BAD is reported between 10 and 18% and no mortality has been reported in the largest series. Because of the endocrine sacrifice it will be mostly performed after a multidisciplinary team discussion in selected cases of refractory CD (mostly after failure of pituitary surgery and/or medical treatment). It is also frequently discussed in female patients desiring pregnancy. Corticotroph tumor progression occurs in 40% of the patients but is in most patients manageable when detected early by a careful long term monitoring with pituitary MRI and ACTH assays after BAD.

Conclusion: BAD is a safe and effective treatment of CD used in specific situations and requiring long term monitoring.
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http://dx.doi.org/10.1007/s11102-022-01260-wDOI Listing
July 2022

Sperm cryopreservation in young males with congenital adrenal hyperplasia (CAH).

Clin Endocrinol (Oxf) 2022 Jun 23. Epub 2022 Jun 23.

Assistance publique, Hôpitaux de Paris (AP-HP) Centre, Université de Paris, Cochin, Service de Biologie de la Reproduction, CECOS, Paris, France.

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http://dx.doi.org/10.1111/cen.14792DOI Listing
June 2022

Decreased steroidogenic enzyme activity in benign adrenocortical tumors is more pronounced in bilateral lesions as determined by steroid profiling in LC-MS/MS during ACTH stimulation test.

Endocr Connect 2022 Aug 19;11(8). Epub 2022 Jul 19.

Université Paris Cité, Paris, France.

Objective: Large response of steroid precursors, including 17-hydroxyprogesterone, to adrenocorticotropic hormone (ACTH) has been described in adrenocortical tumors, suggesting the existence of intra-tumoral enzymatic deficiencies. This study aimed to compare steroidogenesis enzymes activity in unilateral and bilateral benign tumors using serum steroid profiling in liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) in the basal state and after ACTH 1-24 stimulation.

Design And Methods: A serum profile of seven consecutive adrenal steroids was determined in LC-MS/MS in the basal state (T0) and after ACTH 1-24 stimulation (T60) in 35 patients with bilateral adrenocortical tumors (BL), 38 patients with unilateral tumors (UL) and 37 control subjects (CT). Response amplitude of each individual steroid was evaluated by T60/T0 ratio, whereas enzymatic activity was assessed by the downstream/upstream steroid ratio. Adrenal volume was quantified by a semi-automatic segmentation method.

Results: For the seven steroids assayed, the amplitude of response to ACTH was higher in BL than in UL and in CT. The difference between BL and UL persisted even after matching patients on adrenal volume. On glucocorticoids pathway, enzymatic activity of CYP11B1 was significantly decreased in BL (78.3 (43.1-199.4)) in comparison to both UL (122.7 (13.8-228.4), P = 0.0002) and CT (186.8 (42.1-1236.3), P < 0.0001). On mineralocorticoids and androgens pathways, the enzymatic activity of CYP11B2 and CYP17A1-17,20 lyase was also lower in BL than UL and CT.

Conclusions: Decreased activity of distal steroidogenesis enzymes CYP11B1, CYP11B2 and CYP17A1-17,20 lyase, responsible for an explosive response to ACTH of upstream precursors in bilateral tumors, limits the synthesis of bioactive steroids, in particular cortisol, despite the increase in adrenal mass.

Significance Statement: Activity of distal steroidogenesis enzymes (CYP11B1, CYP11B2 and CYP17A1 on glucocorticoids, mineralocorticoids and androgens pathways, respectively) is decreased in adrenocortical benign tumors. This decrease is more pronounced in bilateral lesions and seems to depend more on the nature of the lesion than on the increase in adrenal volume. It is responsible for the explosive response to ACTH of steroid precursors located upstream of these enzymes. It probably allows bioactive steroids, particularly cortisol, to stay in the normal range for a long time despite the increase in adrenal mass.
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http://dx.doi.org/10.1530/EC-22-0063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9346343PMC
August 2022

Differences in the spectrum of steroidogenic enzyme inhibition between Osilodrostat and Metyrapone in ACTH-dependent Cushing syndrome patients.

Eur J Endocrinol 2022 Aug 4;187(2):315-322. Epub 2022 Jul 4.

Institut Cochin, Inserm U1016-CNRS UMR8104-Université de Paris, Paris, France.

Introduction: Osilodrostat is a new 11β-hydroxylase inhibitor with a mode of action analogous to Metyrapone. The objective of this study was to compare steroidogenic profiles in patients treated with either Osilodrostat or Metyrapone for adrenocorticotrophic hormone (ACTH)-dependent Cushing's syndrome (CS).

Methods: Patients followed up at Cochin hospital Endocrinology department between March 2019 and December 2021 for an ACTH-dependent CS, controlled by either Osilodrostat or Metyrapone, were included. A serum profile of five steroids (cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, androstenedione and testosterone) was determined using UPLC- tandem mass spectrometry (UPLC-MS/MS).

Results: Nineteen patients treated with Osilodrostat, eight patients treated with Metyrapone and six patients treated with consecutive Metyrapone then Osilodrostat were included. Hypocortisolism (basal cortisol <100 nmol/L) was found in 48% of patients treated with Osilodrostat and 7% of patients treated with Metyrapone. 11-deoxycortisol and androstenedione levels were higher in patients treated with Metyrapone (80.9 (2.2-688.4) and 14.9 (2.5-54.3) nmol/L, respectively) than in patients treated with Osilodrostat (10.3 (0.5-71.9) and 4.0 (0.3-13.3) nmol/L) (P = 0.0009 and P = 0.0005). Testosterone level in women was also higher in Metyrapone group (3.3 (0.93-4.82) nmol/L vs 1.31(0.13-5.09) nmol/L, P = 0.0146). CYP11B1 activity (11-deoxycortisol/cortisol) was not significantly different between the two groups. CYP21A2 activity (17OHprogesterone/11-deoxycortisol) and CYP17A1 activity (17OHprogesterone/androstenedione) were significantly decreased in Osilodrostat group (P < 0.0001).

Conclusion: In patients with ACTH-dependent CS, the use of CYP11B1 inhibitors in routine care suggests that Osilodrostat has a less specific effect on the inhibition of steroidogenic enzymes than Metyrapone. This might explain a smaller increase in 11-deoxycortisol and androgen levels in patients treated with Osilodrostat.
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http://dx.doi.org/10.1530/EJE-22-0208DOI Listing
August 2022

Perioperative outcomes of pheochromocytoma/paraganglioma surgery preceded by Takotsubo-like cardiomyopathy.

Surgery 2022 May 16. Epub 2022 May 16.

Department of Digestive, Hepato-biliary and Endocrine Surgery, Referral Center for Rare Adrenal Diseases, Cochin Hospital, APHP, Paris, France; Department of Hepato-Biliary and Pancreatic Surgery and Liver Transplantation, AP-HP Pitié-Salpêtrière Hospital, Paris, France; Department of General, Visceral, and Endocrine Surgery, Pitié-Salpêtrière Hospital, AP-HP, Paris, France; Sorbonne University, Paris, France. Electronic address:

Background: Pheochromocytomas and paragangliomas can induce severe cardiovascular manifestations such as Takotsubo-like cardiomyopathy. What the perioperative outcomes are of patients presenting with pheochromocytomas/paragangliomas preceded by Takotsubo-like cardiomyopathy remains an unresolved question.

Methods: From 2006 to 2019, all patients who underwent surgery for pheochromocytomas/paragangliomas preceded by Takotsubo-like cardiomyopathy were included from 3 high-volume centers, with specific attention to perioperative hemodynamic instability and postoperative outcomes.

Results: Overall, 37 patients were included, with a median age of 45 years. Patients were operated on 2 months (1-4) after a Takotsubo-like cardiomyopathy episode; 33 (89%) had a laparoscopic approach. All those who underwent surgery presented in a hemodynamically stable situation. All except 1 of the pheochromocytomas/paragangliomas patients had at least 1 antihypertensive treatment at the time of surgery. The median preoperative systolic blood pressure in the Takotsubo-like cardiomyopathy group was 120 mm Hg (95-132). Overall, 27/34 (79%) of patients required vasoactive drugs during surgery with nicardipine (n = 22), esmolol (n = 12), and/or norepinephrine (n = 8). No patient presented a catecholamine-induced life-threatening complication such as hypertensive crisis, cardiac arrhythmias, pulmonary edema, cardiac ischemia, or Takotsubo-like cardiomyopathy in the perioperative period. Severe morbi-mortality was nil. The systematic review identified 5 studies including 38 pheochromocytomas/paragangliomas patients with at least 1 episode of acute heart failure considered as Takotsubo-like cardiomyopathy before surgery, of which 28 patients had delayed surgery with 1 postoperative death.

Conclusion: Hemodynamically stabilized patients with pheochromocytomas/paragangliomas preceded by Takotsubo-like cardiomyopathy can be safely scheduled for an elective pheochromocytomas/paragangliomas surgery, with similar intra and postoperative outcomes as those without Takotsubo-like cardiomyopathy.
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http://dx.doi.org/10.1016/j.surg.2022.04.004DOI Listing
May 2022

Identification of predictive criteria for pathogenic variants of primary bilateral macronodular adrenal hyperplasia (PBMAH) gene ARMC5 in 352 unselected patients.

Eur J Endocrinol 2022 May 24;187(1):123-134. Epub 2022 May 24.

Department of Endocrinology, Diabetology, Metabolism and Nutrition, CHU Lille, Inserm U1190, Lille, France.

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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http://dx.doi.org/10.1530/EJE-21-1032DOI Listing
May 2022

Clinical Biology of the Pituitary Adenoma.

Endocr Rev 2022 Apr 8. Epub 2022 Apr 8.

The Garvan Institute of Medical Research and St. Vincents Hospital, Sydney, Australia.

All endocrine glands are susceptible to neoplastic growth, yet the health consequences of these neoplasms differ between endocrine tissues. Pituitary neoplasms are highly prevalent and overwhelmingly benign, exhibiting a spectrum of diverse behaviors and impact on health. To understand the clinical biology of these common yet often innocuous neoplasms, we review pituitary physiology, and adenoma epidemiology, pathophysiology, behavior, and clinical consequences. The anterior pituitary develops in response to a range of complex brain signals integrating with intrinsic ectodermal cell transcriptional events that together determine gland growth, cell type differentiation, and hormonal production, in turn maintaining optimal endocrine health. Pituitary adenomas occur in ten percent of the population; however, the overwhelming majority remain harmless during life. Triggered by somatic or germline mutations, disease-causing adenomas manifest pathogenic mechanisms that disrupt intra-pituitary signaling to promote benign cell proliferation associated with chromosomal instability. Cellular senescence acts as a mechanistic buffer protecting against malignant transformation, an extremely rare event. It is estimated that fewer than one thousandth of all pituitary adenomas cause clinically significant disease. Adenomas variably and adversely affect morbidity and mortality depending on cell type, hormone secretory activity, and growth behavior. For most clinically apparent adenomas, multimodal therapy controlling hormone secretion and adenoma growth lead to improved quality of life and normalized mortality. The clinical biology of pituitary adenomas and particularly their benign nature stands in marked contrast to other tumors of the endocrine system such as thyroid and neuroendocrine tumors.
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http://dx.doi.org/10.1210/endrev/bnac010DOI Listing
April 2022

The role of adrenal venous sampling (AVS) in primary bilateral macronodular adrenocortical hyperplasia (PBMAH): a study of 16 patients.

Endocrine 2022 05 10;76(2):434-445. Epub 2022 Mar 10.

Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München, Germany.

Objective: Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a rare cause of ACTH-independent Cushing's syndrome. Current guidelines recommend bilateral adrenalectomy for PBMAH, but several studies showed clinical effectiveness of unilateral adrenalectomy despite bilateral disease in selected patients. Our aim was to evaluate the gain of information which can be obtained through adrenal venous sampling (AVS) based cortisol lateralization ratios for guidance of unilateral adrenalectomy.

Design: We performed a retrospective analysis of 16 patients with PBMAH and clinical overt cortisol secretion in three centers METHODS: Selectivity of adrenal vein sampling during AVS was defined as a gradient of cortisol or a reference adrenal hormone ≥2.0 between adrenal and peripheral vein. Lateralization was assumed if the dominant to non-dominant ratio of cortisol to reference hormone was ≥4.0.

Results: AVS was technically successful in all patients based on absolute cortisol levels and in 13 of 16 patients (81%) based on reference hormone levels. Lateralization was documented in 8 of 16 patients. In patients with lateralization, in 5 of 8 cases this occurred toward morphologically larger adrenals, while in 3 patients lateralization was present in bilaterally identical adrenals. The combined volume of adrenals correlated positively with urinary free cortisol, suggesting that adrenal size is the dominant determinant of cortisol secretion.

Conclusions: In this study the gain of information through AVS for unilateral adrenalectomy was limited in patients with PBMAH and marked adrenal asymmetry.
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http://dx.doi.org/10.1007/s12020-022-03020-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9068666PMC
May 2022

Transcriptome in paraffin samples for the diagnosis and prognosis of adrenocortical carcinoma.

Eur J Endocrinol 2022 Apr 21;186(6):607-617. Epub 2022 Apr 21.

Université de Paris, Institut Cochin, INSERM U-1016, CNRS UMR-8104, Paris, France.

Design: Molecular classification is important for the diagnosis and prognosis of adrenocortical tumors (ACT). Transcriptome profiles separate adrenocortical adenomas 'C2' from carcinomas, and identify two groups of carcinomas 'C1A' and 'C1B', of poor and better prognosis respectively. However, many ACT cannot be profiled because of improper or absent freezing procedures, a mandatory requirement so far. The main aim was to determine transcriptome profiles on formalin-fixed paraffin-embedded (FFPE) samples, using the new 3'-end RNA-sequencing technology. A secondary aim was to demonstrate the ability of this technique to explore large FFPE archives, by focusing on the rare oncocytic ACT variants.

Methods: We included 131 ACT: a training cohort from Cochin hospital and an independent validation cohort from Wuerzburg hospital. The 3' transcriptome was generated from FFPE samples using QuantSeq (Lexogen, Vienna, Austria) and NextSeq500 (Illumina, San Diego, CA, USA).

Results: In the training cohort, unsupervised clustering identified three groups: 'C1A' aggressive carcinomas (n = 28, 29%), 'C1B' more indolent carcinomas (n = 28, 29%), and 'C2' adenomas (n = 39, 41%). The prognostic value of FFPE transcriptome was confirmed in the validation cohort (5-year OS: 26% in 'C1A' (n = 26) and 100% in 'C1B' (n = 10), P = 0.003). FFPE transcriptome was an independent prognostic factor in a multivariable model including tumor stage and Ki-67 (OS HR: 7.5, P = 0.01). Oncocytic ACT (n = 19) did not form any specific cluster. Oncocytic carcinomas (n = 6) and oncocytic ACT of uncertain malignant potential (n = 4) were all in 'C1B'.

Conclusions: The 3' RNA-sequencing represents a convenient solution for determining ACT molecular class from FFPE samples. This technique should facilitate routine use and large retrospective studies.
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http://dx.doi.org/10.1530/EJE-21-1228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9066577PMC
April 2022

Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe.

Eur J Endocrinol 2022 Mar 23;186(5):K17-K24. Epub 2022 Mar 23.

Laboratoire de Biochimie et Biologie Moléculaire, Hospices Civils de Lyon, Centre National de Référence 'Développement Génital: du fœtus à l'adulte DEV-GEN' Université Lyon I, Lyon, France.

Objective: To assess the current medical practice in Europe regarding prenatal dexamethasone (Pdex) treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency.

Design And Methods: A questionnaire was designed and distributed, including 17 questions collecting quantitative and qualitative data. Thirty-six medical centres from 14 European countries responded and 30 out of 36 centres were reference centres of the European Reference Network on Rare Endocrine Conditions, EndoERN.

Results: Pdex treatment is currently provided by 36% of the surveyed centres. The treatment is initiated by different specialties, that is paediatricians, endocrinologists, gynaecologists or geneticists. Regarding the starting point of Pdex, 23% stated to initiate therapy at 4-5 weeks postconception (wpc), 31% at 6 wpc and 46 % as early as pregnancy is confirmed and before 7 wpc at the latest. A dose of 20 µg/kg/day is used. Dose distribution among the centres varies from once to thrice daily. Prenatal diagnostics for treated cases are conducted in 72% of the responding centres. Cases treated per country and year vary between 0.5 and 8.25. Registries for long-term follow-up are only available at 46% of the centres that are using Pdex treatment. National registries are only available in Sweden and France.

Conclusions: This study reveals a high international variability and discrepancy in the use of Pdex treatment across Europe. It highlights the importance of a European cooperation initiative for a joint international prospective trial to establish evidence-based guidelines on prenatal diagnostics, treatment and follow-up of pregnancies at risk for CAH.
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http://dx.doi.org/10.1530/EJE-21-0554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010809PMC
March 2022

Consensus statement by the French Society of Endocrinology (SFE) and French Society of Pediatric Endocrinology & Diabetology (SFEDP) on diagnosis of Cushing's syndrome.

Ann Endocrinol (Paris) 2022 Apr 19;83(2):119-141. Epub 2022 Feb 19.

Service d'Endocrinologie Nutrition, Hôpital Ambroise-Paré, GHU Paris-Saclay, AP-HP Boulogne, EA4340, Université de Versailles-Saint-Quentin, Paris, France.

Cushing's syndrome is defined by prolonged exposure to glucocorticoids, leading to excess morbidity and mortality. Diagnosis of this rare pathology is difficult due to the low specificity of the clinical signs, the variable severity of the clinical presentation, and the difficulties of interpretation associated with the diagnostic methods. The present consensus paper by 38 experts of the French Society of Endocrinology and the French Society of Pediatric Endocrinology and Diabetology aimed firstly to detail the circumstances suggesting diagnosis and the biologic diagnosis tools and their interpretation for positive diagnosis and for etiologic diagnosis according to ACTH-independent and -dependent mechanisms. Secondly, situations making diagnosis complex (pregnancy, intense hypercortisolism, fluctuating Cushing's syndrome, pediatric forms and genetically determined forms) were detailed. Lastly, methods of surveillance and diagnosis of recurrence were dealt with in the final section.
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http://dx.doi.org/10.1016/j.ando.2022.02.001DOI Listing
April 2022

ENDO-ERN ON RARE ENDOCRINE CONDITIONS: Endo-ERN in its fifth year: a pinch of care, science, curiosity and new horizons.

Endocr Connect 2022 Mar 24;11(3). Epub 2022 Mar 24.

Adult Chair and Coordinator of Endo-ERN, Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.

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http://dx.doi.org/10.1530/EC-22-0082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010804PMC
March 2022

Adrenal Mass Characterization in the Era of Quantitative Imaging: State of the Art.

Cancers (Basel) 2022 Jan 23;14(3). Epub 2022 Jan 23.

Department of Radiology, Cochin Teaching Hospital, AP-HP, Université de Paris, 75014 Paris, France.

Detection and characterization of adrenal lesions have evolved during the past two decades. Although the role of imaging in adrenal lesions associated with hormonal secretion is usually straightforward, characterization of non-functioning adrenal lesions may be challenging to confidently identify those that need to be resected. Although many adrenal lesions can be readily diagnosed when they display typical imaging features, the diagnosis may be challenging for atypical lesions. Computed tomography (CT) remains the cornerstone of adrenal imaging, but other morphological or functional modalities can be used in combination to reach a diagnosis and avoid useless biopsy or surgery. Early- and delayed-phase contrast-enhanced CT images are essential for diagnosing lipid-poor adenoma. Ongoing studies are evaluating the capabilities of dual-energy CT to provide valid virtual non-contrast attenuation and iodine density measurements from contrast-enhanced examinations. Adrenal lesions with attenuation values between 10 and 30 Hounsfield units (HU) on unenhanced CT can be characterized by MRI when iodinated contrast material injection cannot be performed. F-FDG PET/CT helps differentiate between atypical benign and malignant adrenal lesions, with the adrenal-to-liver maximum standardized uptake value ratio being the most discriminative variable. Recent studies evaluating the capabilities of radiomics and artificial intelligence have shown encouraging results.
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http://dx.doi.org/10.3390/cancers14030569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8833697PMC
January 2022

Identification of glucocorticoid-related molecular signature by whole blood methylome analysis.

Eur J Endocrinol 2022 Jan 13;186(2):297-308. Epub 2022 Jan 13.

Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.

Objective: Cushing's syndrome represents a state of excessive glucocorticoids related to glucocorticoid treatments or to endogenous hypercortisolism. Cushing's syndrome is associated with high morbidity, with significant inter-individual variability. Likewise, adrenal insufficiency is a life-threatening condition of cortisol deprivation. Currently, hormone assays contribute to identify Cushing's syndrome or adrenal insufficiency. However, no biomarker directly quantifies the biological glucocorticoid action. The aim of this study was to identify such markers.

Design: We evaluated whole blood DNA methylome in 94 samples obtained from patients with different glucocorticoid states (Cushing's syndrome, eucortisolism, adrenal insufficiency). We used an independent cohort of 91 samples for validation.

Methods: Leukocyte DNA was obtained from whole blood samples. Methylome was determined using the Illumina methylation chip array (~850 000 CpG sites). Both unsupervised (principal component analysis) and supervised (Limma) methods were used to explore methylome profiles. A Lasso-penalized regression was used to select optimal discriminating features.

Results: Whole blood methylation profile was able to discriminate samples by their glucocorticoid status: glucocorticoid excess was associated with DNA hypomethylation, recovering within months after Cushing's syndrome correction. In Cushing's syndrome, an enrichment in hypomethylated CpG sites was observed in the region of FKBP5 gene locus. A methylation predictor of glucocorticoid excess was built on a training cohort and validated on two independent cohorts. Potential CpG sites associated with the risk for specific complications, such as glucocorticoid-related hypertension or osteoporosis, were identified, needing now to be confirmed on independent cohorts.

Conclusions: Whole blood DNA methylome is dynamically impacted by glucocorticoids. This biomarker could contribute to better assessment of glucocorticoid action beyond hormone assays.
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http://dx.doi.org/10.1530/EJE-21-0907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8789024PMC
January 2022

KDM1A inactivation causes hereditary food-dependent Cushing syndrome.

Genet Med 2022 02 30;24(2):374-383. Epub 2021 Nov 30.

Institut Cochin, Inserm U1016, CNRS UMR8104, Université de Paris, Paris, France.

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 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.
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http://dx.doi.org/10.1016/j.gim.2021.09.018DOI Listing
February 2022

Consensus on diagnosis and management of Cushing's disease: a guideline update.

Lancet Diabetes Endocrinol 2021 12 20;9(12):847-875. Epub 2021 Oct 20.

San Raffaele Vita-Salute University, Milan, Italy.

Cushing's disease requires accurate diagnosis, careful treatment selection, and long-term management to optimise patient outcomes. The Pituitary Society convened a consensus workshop comprising more than 50 academic researchers and clinical experts to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, data from 2015 to present about screening and diagnosis; surgery, medical, and radiation therapy; and disease-related and treatment-related complications of Cushing's disease summarised in recorded lectures were reviewed by all participants. During the meeting, concise summaries of the recorded lectures were presented, followed by small group breakout discussions. Consensus opinions from each group were collated into a draft document, which was reviewed and approved by all participants. Recommendations regarding use of laboratory tests, imaging, and treatment options are presented, along with algorithms for diagnosis of Cushing's syndrome and management of Cushing's disease. Topics considered most important to address in future research are also identified.
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http://dx.doi.org/10.1016/S2213-8587(21)00235-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743006PMC
December 2021

Pituitary surgery as alternative to dopamine agonists treatment for microprolactinomas: a cohort study.

Eur J Endocrinol 2021 Oct 21;185(6):783-791. Epub 2021 Oct 21.

Department of Neurosurgery, Foch Hospital, Suresnes, France.

Objective: Microprolactinomas are currently treated with dopamine agonists. Outcome information on microprolactinoma patients treated by surgery is limited. This study reports the first large series of consecutive non-invasive microprolactinoma patients treated by pituitary surgery and evaluates the efficiency and safety of this treatment.

Design: Follow-up of a cohort of consecutive patients treated by surgery.

Methods: Between January 2008 and October 2020, 114 adult patients with pure microprolactinomas were operated on in a single tertiary expert neurosurgical department, using an endoscopic endonasal transsphenoidal approach. Eligible patients presented with a microprolactinoma with no obvious cavernous invasion on MRI. Prolactin was assayed before and after surgery. Disease-free survival was modeled using Kaplan-Meier representation. A cox regression model was used to predict remission.

Results: Median follow-up was 18.2 months (range: 2.8-155). In this cohort, 14/114 (12%) patients were not cured by surgery, including ten early surgical failures and four late relapses occurring 37.4 months (33-41.8) after surgery. From Kaplan-Meier estimates, 1-year and 5-year disease free survival was 90.9% (95% CI: 85.6-96.4%) and 81% (95% CI: 71.2-92.1%) respectively. The preoperative prolactinemia was the only significant preoperative predictive factor for remission (P < 0.05). No severe complication was reported, with no anterior pituitary deficiency after surgery, one diabetes insipidus, and one postoperative cerebrospinal fluid leakage properly treated by muscle plasty.

Conclusions: In well-selected microprolactinoma patients, pituitary surgery performed by an expert neurosurgical team is a valid first-line alternative treatment to dopamine agonists.
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http://dx.doi.org/10.1530/EJE-21-0293DOI Listing
October 2021

Adrenal ganglioneuromas: a retrospective multicentric study of 104 cases from the COMETE network.

Eur J Endocrinol 2021 Aug 27;185(4):463-474. Epub 2021 Aug 27.

Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Centre de Référence des Maladies Rares de la Surrénale, Unité Fonctionnelle d 'Hypertension Artérielle, Université de Paris, Paris, France.

Objective: Adrenal ganglioneuromas are rare, differentiated, neuroblastic tumors that originate from the peripheral sympathetic nervous system. Because of their rarity, information is limited, derived from small cases series. Our objective was to characterize this tumor and provide help for its management.

Methods: A retrospective multicenter analysis of adrenal ganglioneuromas from 20 French centers belonging to the COMETE network and one Belgian center.

Results: Among the 104 cases identified, 59.6% were women (n = 62/104), median age at diagnosis was 29 years, with 24 pediatric cases. 60.6% (n = 63/104) were incidentalomas. Ganglioneuromas were non-secreting tumors in 90.8% of cases (n = 89/98), whereas the preoperative hormonal evaluation was indeterminate for 9.2% of patients (n = 9/98). CT imaging, performed on 96 patients, revealed large tumors (median diameter of 50 mm) with a non-contrast density > 10 Hounsfield units in 98.1% (n = 52/53) and calcifications in 64.6% of cases (n = 31/48). Increased uptake on 123I-MIBG scintigraphy and 18F-FDG-PET/CT was observed in 26.7% (n = 8/30) and 42.2% (n = 19/45) of the tumors, respectively. All 104 patients underwent surgery. No recurrence was observed among the 42 patients who had an imaging follow-up (mean 29.6 months, median 18 months (4-156)).

Conclusion: Adrenal ganglioneuromas are large tumors, mostly nonfunctioning, without benign imaging features. Although the duration of follow-up was limited in our series, no recurrence was identified. A review of the literature confirms the absence of postoperative recurrence. Based on all available data, in the absence of special circumstances (genetic form, uncertain histological diagnosis), long-term follow-up is not necessary after complete surgery for patients with an adrenal ganglioneuroma.
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http://dx.doi.org/10.1530/EJE-20-1049DOI Listing
August 2021

Prognostic transcriptome classes of duodenopancreatic neuroendocrine tumors.

Endocr Relat Cancer 2021 06 21;28(8):563-571. Epub 2021 Jun 21.

Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France.

Duodenopancreatic neuroendocrine tumors (DPNETs) aggressiveness is heterogeneous. Tumor grade and extension are commonly used for prognostic determination. Yet, grade classes are empirically defined, with regular updates changing the definition of classes. Genomic screening may provide more objective classes and reflect tumor biology. The aim of this study was to provide a transcriptome classification of DPNETs. We included 66 DPNETs, covering the entire clinical spectrum of the disease in terms of secretion, grade, and stage. Three distinct molecular groups were identified, associated with distinct outcomes (log-rank P < 0.01): (i) better-outcome DPNETs with pancreatic beta-cell signature. This group was mainly composed of well-differentiated, grade 1 insulinomas; (ii) poor-outcome DPNETs with pancreatic alpha-cell and hepatic signature. This group included all neuroendocrine carcinomas and grade 3 DPNETs, but also some grade 1 and grade 2 DPNETs and (iii) intermediate-outcome DPNETs with pancreatic exocrine and progenitor signature. This group included grade 1 and grade 2 DPNETs, with some insulinomas. Fibrinogen gene FGA expression was one of the topmost expressed liver genes. FGA expression was associated with disease-free survival (HR = 1.13, P = 0.005) and could be validated on two independent cohorts. This original pathophysiologic insight provides new prognostic classification perspectives.
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http://dx.doi.org/10.1530/ERC-21-0051DOI Listing
June 2021

Surgical management of insulinoma over three decades.

HPB (Oxford) 2021 12 27;23(12):1799-1806. Epub 2021 Apr 27.

Department of Digestive, Hepato-biliary and Endocrine Surgery, Cochin Hospital, APHP, 75014 Paris, France; Université de Paris, 75006 Paris, France. Electronic address:

Background: This paper reports our experience of the perioperative management of patients with sporadic, non-malignant, pancreatic insulinoma.

Methods: A retrospective monocentric cohort study was performed from January 1989 to July 2019, including all the patients who had been operated on for pancreatic insulinoma. The preoperative work-up, surgical management, and postoperative outcome were analyzed.

Results: Eighty patients underwent surgery for sporadic pancreatic insulinoma, 50 of which were female (62%), with a median age of 50 (36-70) years. Preoperatively, the tumors were localized in 76 patients (95%). Computed tomography (CT) and magnetic resonance imaging allowed exact preoperative tumor localization in 76% of the patients (64-85 and 58-88 patients, respectively), increasing to 96% when endoscopic ultrasonography was performed. Forty-one parenchyma-sparing pancreatectomies (PSP) (including enucleation, caudal pancreatectomy, and uncinate process resection) and 39 pancreatic resections were performed. The mortality rate was 6% (n = 5), with a morbidity rate of 72%, including 24 severe complications (30%) and 35 pancreatic fistulas (44%). No differences were found between formal pancreatectomy and PSP in terms of postoperative outcome procedures. The surgery was curative in all the patients.

Conclusion: CT used in combination with endoscopic ultrasonography allows accurate localization of insulinomas in almost all patients. When possible, a parenchyma-sparing pancreatectomy should be proposed as the first-line surgical strategy.
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http://dx.doi.org/10.1016/j.hpb.2021.04.013DOI Listing
December 2021

Preoperative Detection of Liver Involvement by Right-Sided Adrenocortical Carcinoma Using CT and MRI.

Cancers (Basel) 2021 Mar 31;13(7). Epub 2021 Mar 31.

Department of Diagnostic and Interventional Imaging, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.

The major prognosis factor of adrenocortical carcinoma (ACC) is the completeness of surgery. The aim of our study was to identify preoperative imaging features associated with direct liver involvement (DLI) by right-sided ACC. Two radiologists, blinded to the outcome, independently reviewed preoperative CT and MRI examinations for eight signs of DLI, in patients operated for right-sided ACC and retrospectively included from November 2007 to January 2020. DLI was confirmed using surgical and histopathological findings. Kappa values were calculated. Univariable and multivariable analyses were performed by using a logistic regression model. Receiver operating characteristic (ROC) curves were built for CT and MRI. Twenty-nine patients were included. Seven patients had DLI requiring resection. At multivariable analysis, focal ACC bulge was the single independent sign associated with DLI on CT (OR: 60.00; 95% CI: 4.60-782.40; < 0.001), and ACC contour disruption was the single independent sign associated with DLI on MRI (OR: 126.00; 95% CI: 6.82-2328.21; < 0.001). Both signs were highly reproducible, with respective kappa values of 0.85 and 0.91. The areas under ROC curves of MRI and CT models were not different ( = 0.838). Focal ACC bulge on CT and ACC contour disruption on MRI are independent and highly reproducible signs, strongly associated with DLI by right-sided ACC on preoperative imaging. MRI does not improve the preoperative assessment of DLI by comparison with CT.
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http://dx.doi.org/10.3390/cancers13071603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036813PMC
March 2021

Rapid control of severe ectopic Cushing's syndrome by oral osilodrostat monotherapy.

Eur J Endocrinol 2021 May;184(5):L13-L15

Department of Endocrinology, Polyclinic of Saint Côme, Compiegne, France.

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http://dx.doi.org/10.1530/EJE-21-0147DOI Listing
May 2021

Update on primary bilateral macronodular adrenal hyperplasia (PBMAH).

Endocrine 2021 03 15;71(3):595-603. Epub 2021 Feb 15.

Institut Cochin, Université de Paris, Inserm U1016, CNRS UMR8104, 24 rue du Faubourg Saint-Jacques, 75014, Paris, France.

Primary bilateral macronodular adrenal hyperplasia (PBMAH), characterized by bilateral benign adrenal macronodules (>1 cm) potentially responsible for variable levels of cortisol excess, is a rare and heterogeneous disease. However, its frequency increases due to incidentally diagnosed cases on abdominal imaging carried out for reasons other than suspected adrenal disease. Mostly isolated, it can also be associated with dominantly inherited genetic conditions in rare cases. Considering the bilateral nature of adrenal involvement and the description of familial cases, the search of a genetic predisposition has led to the identification of germline heterozygous inactivating mutations of the putative tumor suppressor gene ARMC5, causing around 25% of the apparent sporadic cases. Rigorous biochemical and imaging assessment are key elements in the management of this challenging disease in terms of diagnosis. Treatment is reserved for symptomatic patients with overt or subclinical Cushing syndrome, and was historically based on bilateral adrenalectomy, which nowadays tends to be replaced by unilateral adrenalectomy or lifelong treatment with cortisol synthesis inhibitors.
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http://dx.doi.org/10.1007/s12020-021-02645-wDOI Listing
March 2021

What Did We Learn from the Molecular Biology of Adrenal Cortical Neoplasia? From Histopathology to Translational Genomics.

Endocr Pathol 2021 Mar 3;32(1):102-133. Epub 2021 Feb 3.

Department of Pathology, University Health Network, Toronto, ON, Canada.

Approximately one-tenth of the general population exhibit adrenal cortical nodules, and the incidence has increased. Afflicted patients display a multifaceted symptomatology-sometimes with rather spectacular features. Given the general infrequency as well as the specific clinical, histological, and molecular considerations characterizing these lesions, adrenal cortical tumors should be investigated by endocrine pathologists in high-volume tertiary centers. Even so, to distinguish specific forms of benign adrenal cortical lesions as well as to pinpoint malignant cases with the highest risk of poor outcome is often challenging using conventional histology alone, and molecular genetics and translational biomarkers are therefore gaining increased attention as a possible discriminator in this context. In general, our understanding of adrenal cortical tumorigenesis has increased tremendously the last decade, not least due to the development of next-generation sequencing techniques. Comprehensive analyses have helped establish the link between benign aldosterone-producing adrenal cortical proliferations and ion channel mutations, as well as mutations in the protein kinase A (PKA) signaling pathway coupled to cortisol-producing adrenal cortical lesions. Moreover, molecular classifications of adrenal cortical tumors have facilitated the distinction of benign from malignant forms, as well as the prognostication of the individual patients with verified adrenal cortical carcinoma, enabling high-resolution diagnostics that is not entirely possible by histology alone. Therefore, combinations of histology, immunohistochemistry, and next-generation multi-omic analyses are all needed in an integrated fashion to properly distinguish malignancy in some cases. Despite significant progress made in the field, current clinical and pathological challenges include the preoperative distinction of non-metastatic low-grade adrenal cortical carcinoma confined to the adrenal gland, adoption of individualized therapeutic algorithms aligned with molecular and histopathologic risk stratification tools, and histological confirmation of functional adrenal cortical disease in the context of multifocal adrenal cortical proliferations. We herein review the histological, genetic, and epigenetic landscapes of benign and malignant adrenal cortical neoplasia from a modern surgical endocrine pathology perspective and highlight key mechanisms of value for diagnostic and prognostic purposes.
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http://dx.doi.org/10.1007/s12022-021-09667-0DOI Listing
March 2021

MANAGEMENT OF ENDOCRINE DISEASE: Carney complex: clinical and genetic update 20 years after the identification of the CNC1 (PRKAR1A) gene.

Eur J Endocrinol 2021 Mar;184(3):R99-R109

Université de Paris, Institut Cochin, Inserm U1016, Paris, France.

Described for the first time in 1985, Carney complex (CNC) is a rare dominantly inherited multiple neoplasia syndrome with almost full penetrance and characterized by both endocrine - primary pigmented nodular adrenocortical disease with Cushing's syndrome, acromegaly and thyroid tumors - and non-endocrine manifestations such as cardiac, cutaneous and mucosal myxomas, pigmented cutaneous lesions, psammomatous melanotic schwannoma, osteochondromyxoma and a wide range of other tumours with potential malignancy. The pathophysiology of CNC is a model of dysregulation of the cAMP/PKA signalling in human diseases. As described 20 years ago, inactivating heterozygous mutations of PRKAR1A formerly known as CNC1, encoding the regulatory subunit 1α of protein kinase A, are identified in more than 70% of the index cases, while inactivating mutations of genes encoding phosphodiesterases are found in rare and particular forms of the complex. There is at present no medical specific treatment for CNC, every confirmed or suspected CNC patient should be managed by a multi-disciplinary team according to each manifestation of the disease and offered a long-term follow-up and genetic counselling. The better knowledge that we have now of this fascinating rare disease and its genetics will help to improve patients outcome.
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http://dx.doi.org/10.1530/EJE-20-1120DOI Listing
March 2021

CRH-Receptor Molecular Imaging Reveals the Intimacy of Corticotroph Adenomas.

J Clin Endocrinol Metab 2021 03;106(4):e1902-e1904

Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, Paris, France.

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http://dx.doi.org/10.1210/clinem/dgaa883DOI Listing
March 2021

The EuRRECa Project as a Model for Data Access and Governance Policies for Rare Disease Registries That Collect Clinical Outcomes.

Int J Environ Res Public Health 2020 11 25;17(23). Epub 2020 Nov 25.

Developmental Endocrinology Research Group, Royal Hospital for Children, University of Glasgow, Glasgow G51 4TF, UK.

Rare disease (RD) registries are important platforms that facilitate communication between health care professionals, patients and other members of the multidisciplinary team. RD registries enable data sharing and promotion of research and audits, often in an international setting, with the overall aim of improving patient care. RD registries also have a fundamental role in supporting the work of clinical networks such as the European Reference Networks (ERNs) for rare diseases. With the recent expansion of RD registries, it has become even more essential to outline standards of good practice in relation to governance, infrastructure, documentation, training, audits and adopting the Findable, Accessible, Interoperable and Reusable (FAIR) data principles to maintain registries of high quality. For the purpose of this paper, we highlight vital aspects of data access and data governance policies for RD registries, using the European Registries for Rare Endocrine Conditions (EuRRECa) as an example of a project that aims to promote good standards of practice for improving the quality of utilization of RD registries.
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http://dx.doi.org/10.3390/ijerph17238743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727867PMC
November 2020

Screening of a Large Cohort of Asymptomatic SDHx Mutation Carriers in Routine Practice.

J Clin Endocrinol Metab 2021 03;106(3):e1301-e1315

Department of Nuclear Medicine, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.

Context: When an SDHx mutation is identified in a patient with a pheochromocytoma (PCC) or a paraganglioma (PGL), predictive genetic testing can detect mutation carriers that would benefit from screening protocols.

Objective: To define the tumor detection rate in a large cohort of asymptomatic SDHX mutation carriers.

Design And Setting: Retrospective multicentric study in 6 referral centers.

Patients: Between 2005 and 2019, 249 asymptomatic SDHx (171 SDHB, 31 SDHC, 47 SDHD) mutation carriers, with at least 1 imaging work-up were enrolled.

Results: Initial work-up, including anatomical (98% of subjects [97-100% according to center]) and/or functional imaging (67% [14-90%]) detected 48 tumors in 40 patients. After a negative initial work-up, 124 patients benefited from 1 to 9 subsequent follow-up assessments (mean: 1.9 per patient), with a median follow-up time of 5 (1-13) years. Anatomical (86% [49-100 %]) and/or functional imaging (36% [7-60 %]) identified 10 new tumors (mean size: 16 mm [4-50]) in 10 patients. Altogether, 58 tumors (55 paraganglioma [PGL], including 45 head and neck PGL, 2 pheochromocytoma [PCC], 1 gastrointestinal stromal tumor [GIST]), were detected in 50 patients (22 [13%] SDHB, 1 [3.2%] SDHC, and 27 [57%] SDHD), with a median age of 41 years old [11-86], 76% without catecholamine secretion and 80% during initial imaging work-up.

Conclusions: Imaging screening enabled detection of tumors in 20% of asymptomatic SDHx mutation carriers, with a higher detection rate in SDHD (57%) than in SDHB (13%) and SDHC (3%) mutation carriers, arguing for a gene-by-gene approach. Prospective studies using well-defined protocols are needed to obtain strong and useful data.
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http://dx.doi.org/10.1210/clinem/dgaa888DOI Listing
March 2021
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