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Free access

Luigi Maione, Thierry Brue, Albert Beckers, Brigitte Delemer, Patrick Petrossians, Françoise Borson-Chazot, Olivier Chabre, Patrick François, Jérôme Bertherat, Christine Cortet-Rudelli, Philippe Chanson, and for the French Acromegaly Registry Group

Context

Acromegaly is a rare disease associated with chronic multisystem complications. National registries have been created in several countries.

Design

The French Registry contains data on acromegaly epidemiology, management and comorbidities recorded over more than three decades, retrospectively until 1999 and prospectively from 1999 to 2012.

Results

Data could be analyzed for 999 of the 1034 patients included in the registry (46% males). Disease control, defined as IGF-I normalization (adjusted for age and sex), was achieved in 75% of patients at the last follow-up visit. Half the patients with uncontrolled disease had IGF-I levels below 1.5 times the upper limit of normal (ULN). The proportion of patients with surgically cured disease did not change markedly over time, whereas the proportion of patients with uncontrolled disease fell and the proportion of patients with medically controlled disease rose. Cardiovascular, metabolic, respiratory and rheumatologic comorbidities and their outcomes were recorded for most patients, and no noteworthy overall deterioration was noted over time. Cancer occurred in 10% of patients, for a standardized incidence ratio of 1.34 (95% CI: 0.94–1.87) in men and 1.24 (0.77–1.73) in women. Forty-one patients died during follow-up, for a standardized mortality ratio of 1.05 (0.70–1.42). Most deaths were due to cancer.

Conclusions

The majority of patients with acromegaly now have successful disease control thanks to the multistep management. The incidence of comorbidities following diagnosis of acromegaly is very low. Life expectancy is now close to that of the general population, probably owing to better management of the GH/IGF-I excess and comorbidities.

Free access

Laura Bessiène, Fidéline Bonnet, Florence Tenenbaum, Mathieu Jozwiak, Anthony Corchia, Jérôme Bertherat, and Lionel Groussin

Free access

Luis G Pérez-Rivas, Marily Theodoropoulou, Troy H Puar, Julia Fazel, Mareike R Stieg, Francesco Ferraù, Guillaume Assié, Monica R Gadelha, Timo Deutschbein, Maria C Fragoso, Benno Kusters, Wolfgang Saeger, Jürgen Honegger, Michael Buchfelder, Márta Korbonits, Jérôme Bertherat, Günter K Stalla, Ad R Hermus, Felix Beuschlein, and Martin Reincke

Objective

Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene are frequent in corticotroph tumors causing Cushing’s disease (CD). Corticotroph tumor progression, the so-called Nelson’s syndrome (NS), is a potentially life-threatening complication of bilateral adrenalectomy in patients with refractory CD that is caused by the development of an ACTH-secreting tumor of the pituitary gland. Whether USP8 alterations are also present in progressive Nelson’s tumors has not been studied in detail so far.

Design and Methods

Retrospective, multicenter study involving tumors from 33 patients with progressive corticotroph tumors (29 females) and screening for somatic mutations on the mutational hotspot of the USP8 gene in the exon 14 with Sanger sequencing.

Results

Fifteen out of 33 tumors (45%) presented with a mutation in the exon 14 of USP8, with c.2159C>A (p.Pro720Gln) being the most frequent (9/33), followed by c.2155_2157delTCC (p.Ser718del, 4/33) and c.2152T>C (p.Ser718Pro, 2/33). This prevalence is similar to that previously reported for CD. Mutations were found exclusively in females. Other variables, such as age at diagnosis with NS, body mass index, hyperpigmentation, visual field defects, adenoma size or mortality, did not significantly differ between patients with wild-type and mutant tumors. Patients with USP8 mutant tumors exhibited higher levels of plasma ACTH after surgery (median: 640 vs 112 pg/mL, P = 0.03). No differences were observed in ACTH normalization (<50 pg/mL) and tumor control after surgery for Nelson’s tumor.

Conclusion

Somatic mutations in USP8 are common in Nelson’s tumors, indicating that they do not drive the corticotroph tumor progression that leads to NS, and may be associated with a less favorable biochemical outcome after surgery for Nelson’s tumor.

Restricted access

Bertrand Baussart, Chiara Villa, Anne Jouinot, Marie-Laure Raffin-Sanson, Luc Foubert, Laure Cazabat, Michèle Bernier, Fideline Bonnet, Anthony Dohan, Jerome Bertherat, Guillaume Assié, and Stephan Gaillard

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.

Free access

Lucie Allard, Frédérique Albarel, Jérôme Bertherat, Philippe Jean Caron, Christine Cortet, Carine Courtillot, Brigitte Delemer, Christel Jublanc, Dominique Maiter, Marie Laure Nunes, Gerald Raverot, Julie Sarfati, Sylvie Salenave, Emmanuelle Corruble, Walid Choucha, and Philippe Chanson

Context

In patients treated with antipsychotics, the rare occurrence of a macroprolactinoma represents a therapeutic challenge.

Objective

Our aim was to evaluate the efficacy and psychiatric safety of dopamine agonists (DAs) prescribed for large macroprolactinomas in patients with psychosis treated with antipsychotics.

Design

This was a multicenter (France and Belgium) retrospective study.

Patients

Eighteen patients treated with antipsychotics were included.

Results

Under DA, median PRL levels decreased from 1247 (117–81 132) to 42 (4–573) ng/mL (P = 0.008), from 3850 (449–38 000) to 141 (60–6000) ng/mL (P = 0.037) and from 1664 (94–9400) to 1215 (48–5640) ng/mL (P = 0.56) when given alone (n = 8), before surgery (n = 7), or after surgery (n = 6), respectively. The prolactinoma median largest diameter decreased by 28% (0–57) in patients under DAs alone (P = 0.02) but did not change when given after surgery. Optic chiasm decompression was achieved in 82% of patients. Five patients (28%) were admitted for psychotic relapse while receiving DAs (but three of them had stopped antipsychotic treatment at that time). A more severe underlying psychosis, rather than the DA treatment itself, may explain such psychiatric admissions.

Conclusion

Even if the DA efficacy on PRL levels and tumor volume in patients with macroprolactinoma under antipsychotic drugs is less impressive than that typically observed, it may be considered satisfactory for half of our patients, particularly in cases of optic chiasm compression. Psychotic exacerbation was unusual in these patients, occurring mostly in those with the most severe psychotic forms. DAs may therefore be used as antitumor treatment for macroprolactinoma in patients with visual involvement, severe headaches or invasion into the skull base who receive antipsychotics.

Restricted access

Elisa Deflorenne, Michel Peuchmaur, Delphine Vezzosi, Christiane Ajzenberg, Laurent Brunaud, Nicolas Chevalier, Sophie Christin-Maitre, Bénédicte Decoudier, Natacha Driessens, Delphine D Drui, Olivier Gilly, Pierre Goudet, Frédéric Illouz, Christel Jublanc, Hervé Lefebvre, Antoine-Guy Lopez, Charlotte Lussey, Aurelien Morini, Marie-Laure Raffin-Sanson, Isabelle Raingeard, Peggy Renoult-Pierre, Caroline Storey, Antoine Tabarin, Marie Christine Vantyghem, Emmanuelle Vidal-Petiot, Eric Baudin, Jerome Bertherat, and Laurence Amar

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.

Open access

Roberta Armignacco, Anne Jouinot, Lucas Bouys, Amandine Septier, Thomas Lartigue, Mario Neou, Cassandra Gaspar, Karine Perlemoine, Leah Braun, Anna Riester, Fidéline Bonnet-Serrano, Anne Blanchard, Laurence Amar, Carla Scaroni, Filippo Ceccato, Gian Paolo Rossi, Tracy Ann Williams, Casper K Larsen, Stéphanie Allassonnière, Maria-Christina Zennaro, Felix Beuschlein, Martin Reincke, Jérôme Bertherat, and Guillaume Assié

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.

Open access

Anne Jouinot, Juliane Lippert, Mathilde Sibony, Florian Violon, Lindsay Jeanpierre, Daniel De Murat, Roberta Armignacco, Amandine Septier, Karine Perlemoine, Franck Letourneur, Brigitte Izac, Bruno Ragazzon, Karen Leroy, Eric Pasmant, Marie-Odile North, Sébastien Gaujoux, Bertrand Dousset, Lionel Groussin, Rossella Libe, Benoit Terris, Martin Fassnacht, Cristina L Ronchi, Jérôme Bertherat, and Guillaume Assie

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.

Restricted access

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

Objective

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

Methods

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

Results

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

Conclusion

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

Open access

Hanna Nowotny, Uta Neumann, Véronique Tardy-Guidollet, S Faisal Ahmed, Federico Baronio, Tadej Battelino, Jérôme Bertherat, Oliver Blankenstein, Marco Bonomi, Claire Bouvattier, Aude Brac de la Perrière, Sara Brucker, Marco Cappa, Philippe Chanson, Hedi L Claahsen-van der Grinten, Annamaria Colao, Martine Cools, Justin H Davies, Helmut-Günther Dörr, Wiebke K Fenske, Ezio Ghigo, Roberta Giordano, Claus H Gravholt, Angela Huebner, Eystein Sverre Husebye, Rebecca Igbokwe, Anders Juul, Florian W Kiefer, Juliane Léger, Rita Menassa, Gesine Meyer, Vassos Neocleous, Leonidas A Phylactou, Julia Rohayem, Gianni Russo, Carla Scaroni, Philippe Touraine, Nicole Unger, Jarmila Vojtková, Diego Yeste, Svetlana Lajic, and Nicole Reisch

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.