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Craniopharyngiomas are rare hypothalamic-pituitary tumors found in young children, adolescents and adults, and their multidisciplinary management required, calls for consistent practices for practicioners, patients and families. The French Endocrine Society and French Society for Pediatric Endocrinology & Diabetes enlisted and coordinated adult and paediatric endocrinologists, neurosurgeons, pathologists, radiotherapists as well as psychologists, dieticians and a patient association, to draft a reference document on this severe disease. The management of craniopharyngiomas remains complex due to their aggressive nature, invasive behavior, and propensity for recurrence, requiring a sequential and measured therapeutic approach and follow-up in expert centers. Although patient survival rates are high, the consequences of both the tumor and its treatment can lead to serious comorbidities and impaired quality of life, particularly in those patients with lesional hypothalamic syndrome. Recent advances have allowed the two described tumor types - papillary and adamantinomatous - to be associated with distinct molecular signatures, specific pathophysiological mechanisms and ipso facto, distinct therapeutic approaches, including innovative medications for hyperphagia, that will continue to evolve. This consensus statement covers all stages in the management of patients with craniopharyngioma, from diagnosis to therapeutic strategies including the long-term follow-up., (Copyright © 2024. Published by Elsevier Masson SAS.)

Cushing's syndrome is due to overproduction of cortisol, leading to abnormal and prolonged exposure to cortisol. The most common etiology is Cushing disease, while adrenal causes are rarer. Knowledge of the genetics of Cushing's syndrome, and particularly the adrenal causes, has improved considerably over the last 10 years, thanks in particular to technical advances in high-throughput sequencing. The present study, by a group of experts from the French Society of Endocrinology and the French Society of Pediatric Endocrinology and Diabetology, reviewed the literature on germline genetic alterations leading to a predisposition to develop Cushing's syndrome. The review led to a consensus statement on genetic screening for Cushing disease and adrenal Cushing's syndrome., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Context: Germline CDKN1B variants predispose patients to multiple endocrine neoplasia type 4 (MEN4), a rare MEN1-like syndrome, with <100 reported cases since its discovery in 2006. Although CDKN1B mutations are frequently suggested to explain cases of genetically negative MEN1, the prevalence and phenotype of MEN4 patients is poorly known, and genetic counseling is unclear., Objective: To evaluate the prevalence of MEN4 in MEN1-suspected patients and characterize the phenotype of MEN4 patients., Design: Retrospective observational nationwide study. Narrative review of literature and variant class reassessment., Patients: We included all adult patients with class 3/4/5 CDKN1B variants identified by the laboratories from the French Oncogenetic Network on Neuroendocrine Tumors network between 2015 and 2022 through germline genetic testing for MEN1 suspicion. After class reassessment, we compared the phenotype of symptomatic patients with class 4/5 CDKN1B variants (ie, with genetically confirmed MEN4 diagnosis) in our series and in literature with 66 matched MEN1 patients from the UMD-MEN1 database., Results: From 5600 MEN1-suspected patients analyzed, 4 with class 4/5 CDKN1B variant were found (0.07%). They presented with multiple duodenal NET, primary hyperparathyroidism (PHPT) and adrenal nodule, isolated PHPT, PHPT, and pancreatic neuroendocrine tumor. We listed 29 patients with CDKN1B class 4/5 variants from the literature. Compared with matched MEN1 patients, MEN4 patients presented lower NET incidence and older age at PHPT diagnosis., Conclusion: The prevalence of MEN4 is low. PHPT and pituitary adenoma represent the main associated lesions, NETs are rare. Our results suggest a milder and later phenotype than in MEN1. Our observations will help to improve genetic counseling and management of MEN4 families., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Lipomatoses are benign proliferation of adipose tissue. Lipomas (benign fat tumors) are the most common component of lipomatosis. They may be unique or multiple, encapsulated or not, subcutaneous or sometimes visceral. In some cases, they form large areas of non-encapsulated fat hypertrophy, with a variable degree of fibrosis. They can develop despite the absence of obesity. They may be familial or acquired. At difference with lipodystrophy syndromes, they are not associated with lipoatrophy areas, except in some rare cases such as type 2 familial partial lipodystrophy syndromes (FPLD2). Their metabolic impact is variable in part depending on associated obesity. They may have functional or aesthetic consequences. Lipomatosis may be isolated, be part of a syndrome, or may be visceral. Isolated lipomatoses include multiple symmetrical lipomatosis (Madelung disease or Launois-Bensaude syndrome), familial multiple lipomatosis, the painful Dercum's disease also called Adiposis Dolorosa or Ander syndrome, mesosomatic lipomatosis also called Roch-Leri lipomatosis, familial angiolipomatosis, lipedema and hibernomas. Syndromic lipomatoses include PIK3CA-related disorders, Cowden/PTEN hamartomas-tumor syndrome, some lipodystrophy syndromes, and mitochondrial diseases, especially MERRF, multiple endocrine neoplasia type 1, neurofibromatosis type 1, Wilson disease, Pai or Haberland syndromes. Finally, visceral lipomatoses have been reported in numerous organs and sites: pancreatic, adrenal, abdominal, epidural, mediastinal, epicardial… The aim of this review is to present the main types of lipomatosis and their physiopathological component, when it is known., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: A high prevalence of increased DHEAS (dehydroepiandrosterone sulfate) levels (about a third of cases) has been reported in women with polycystic ovary syndrome (PCOS). This excess of adrenal androgens remains a mystery in this ovarian pathology. It is well known that DHEAS production correlates negatively with age, and study populations of women with PCOS are generally young. To avoid this bias, a study was carried out on a large population of women with PCOS and control women, using normal DHEAS values for each age group, to better assess prevalence and better understand the link between PCOS and DHEAS., Methods: A retrospective cross-sectional study was conducted at the Lille University Hospital. A total of 1223 patients with PCOS according to the Rotterdam criteria and 517 control women were included. DHEAS elevation was diagnosed according to the standards of the Lille University Hospital Institute of Biochemistry and Molecular Biology, based on patient age. The prevalence of increased serum DHEAS levels was calculated in each population and according to PCOS phenotype. Correlations were assessed between serum DHEAS levels and clinical, hormonal, and metabolic markers, with adjustment for age., Results: Prevalence of increased DHEAS was significantly higher in the PCOS group than in the control group (8.1 vs. 4.3%; OR=1.98 (95%CI: 1.23-3.19), P=0.005, and OR=1.07 (95%CI: 1.05-1.09), P=0.014 without and with adjustment for BMI respectively), and in phenotypes A and C than in controls (OR=2.88 (95%CI: 1.76 to 4.72), P<0.001 and OR=2.81 (95%CI: 1.39 to 5.67), P=0.004 respectively), but not in phenotype D. A correlation was found between DHEAS level and total testosteronemia (r=0.34, P<0.001), androstenedione (r=0.24, P<0.001), 17 hydroxyprogesteronemia (r=0.22, P<0.001) and age (r=0.25, P<0.001). No correlations were found with AMH, LH or FSH, and a very weak positive correlation was found with BMI (r=0.15; P<0.001)., Conclusion: Using age-dependent norms, DHEAS elevation was found in only 8.1% of women with PCOS (11% in the case of phenotypes A and C) versus 4.3% in controls and women with phenotype D. DHEAS levels correlated only with other androgens, and not (or only minimally) with other ovarian, pituitary or metabolic markers. DHEAS assay therefore appears to be of no interest for positive diagnosis or understanding of the pathophysiology of PCOS, except in case of very high testosterone levels., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

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

Context: In patients with neurofibromatosis type 1 (NF1), guidelines suggest screening for pheochromocytoma by metanephrine measurement and abdominal imaging, which may lead to the discovery of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and their differential diagnosis, gastrointestinal stromal tumors (GISTs). Other endocrine manifestations such as follicular thyroid carcinoma and primary hyperparathyroidism have also been reported in a few cases., Objective: This study aimed to describe prevalence and clinical presentation of these manifestations through systematic screening in a large cohort of patients., Methods: In this monocentric retrospective study, 108 patients with NF1 were included and screened for endocrine manifestations and GISTs. Clinical, laboratory, molecular profile, pathology, and morphologic (abdominal computed tomography scan and/or magnetic resonance imaging) and functional imaging were collected., Results: Twenty-four patients (22.2% of the cohort, 16 female, mean age 42.6 years) presented with pheochromocytomas that were unilateral in 65.5%, benign in 89.7%, and with a ganglioneural component in 20.7%. Three female patients (2.8% of the cohort, aged 42-63 years) presented with well-differentiated GEP-NETs, and 4 (3.7%) with GISTs. One patient had primary hyperparathyroidism, 1 patient had medullary microcarcinoma, and 16 patients had goiter, multinodular in 10 cases. There was no correlation between pheochromocytoma and other NF1 tumoral manifestations, nor correlations between pheochromocytoma and NF1 genotype, despite a familial clustering in one-third of patients., Conclusion: The pheochromocytoma prevalence in this NF1 cohort was higher (>20%) than previously described, confirming the interest of systematic screening, especially in young women. The prevalence of GEP-NETs and GISTs was about 3%, respectively. No phenotype-genotype correlation was observed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

In order to explore pituitary adenoma (PA), magnetic resonance imaging (MRI) remains the cornerstone. However, there are some limitations and MRI can be non-conclusive. The development of additional imaging modalities like nuclear medicine explorations may help to confirm PA diagnosis, guide management and follow up. Nuclear medicine uses radiopharmaceuticals for imaging with single photon emission computed tomography (SPECT), or positron emission tomography (PET), coupled to CT scan. Radiopharmaceuticals products target specific cellular elements which allow to explore several biological pathways. Nuclear medicine may also be used for therapeutic purposes and recent developments of approach based on Peptide Receptor Radionuclide Therapy (PRRT) for treatment of aggressive PA and pituitary carcinoma will be reviewed. Several radiotracers have been studied in the context of PA, and the aim of this paper is to discuss their respective performances and clinical interest., Competing Interests: Conflicts of Interest BC, AJ, SE, EM, AB, GL, MCV, DH, CCR, CB; none., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Objective: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a heterogeneous disease characterized by adrenal macronodules and variable levels of cortisol excess, with not clearly established clinical diagnostic criteria. It can be caused by ARMC5 germline pathogenic variants. In this study, we aimed to identify predictive criteria for ARMC5 variants., Methods: We included 352 consecutive index patients from 12 European centers, sequenced for germline ARMC5 alteration. Clinical, biological and imaging data were collected retrospectively., Results: 52 patients (14.8%) carried ARMC5 germline pathogenic variants and showed a more distinct phenotype than non-mutated patients for cortisol excess (24-h urinary free cortisol 2.32 vs 1.11-fold ULN, respectively, P < 0.001) and adrenal morphology (maximal adrenal diameter 104 vs 83 mm, respectively, P < 0.001) and were more often surgically or medically treated (67.9 vs 36.8%, respectively, P < 0.001). ARMC5-mutated patients showed a constant, bilateral adrenal involvement and at least a possible autonomous cortisol secretion (defined by a plasma cortisol after 1 mg dexamethasone suppression above 50 nmol/L), while these criteria were not systematic in WT patients (78.3%). The association of these two criteria holds a 100% sensitivity and a 100% negative predictive value for ARMC5 pathogenic variant., Conclusion: We report the largest series of index patients investigated for ARMC5 and confirm that ARMC5 pathogenic variants are associated with a more severe phenotype in most cases. To minimize negative ARMC5 screening, genotyping should be limited to clear bilateral adrenal involvement and autonomous cortisol secretion, with an optimum sensitivity for routine clinical practice. These findings will also help to better define PBMAH diagnostic criteria.

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

Lipomas are the most common soft tissue tumors and are malignant in only 1% of cases. Lipomatosis is defined as the presence of multiple benign lipomas on the body, without lipoatrophy. Their impact on quality of life is significant. Different entities have been described such as symmetrical multiple lipomatosis (MSL), also called Madelung's disease and familial multiple lipomatosis (FML). MSL occurs preferentially in men (but also women) who are alcohol abuser. There are different subtypes of the disease, the most classic of which affects the upper body and the nuchal region with a buffalo hump appearance. A metabolic component with obesity is frequent. In contrast to Dercum's disease, there is no pain. SAOS, complications of the metabolic syndrome and of alcohol abuse including cancers, may be associated and should be screened. FML has been little described in the literature since Brodie's first report in 1846. FML occurs preferentially in the third decade but equally in women and men. Its autosomal dominant component is classically accepted with variable penetrance within the same family. Association with naevi, angiomas, polyneuropathies and with gastrointestinal comorbidities has been reported. Interestingly, and in contrast with most lipodystrophy disorders, the patients show an insulin sensitivity profile. A better understanding of the underlying pathophysiological mechanisms would open up avenues on therapeutic research, since treatments are only symptomatic to date., Competing Interests: Disclosure of Competing Interest The authors declare that they have no competing interest., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Lipodystrophy syndromes (LS) constitute a group of rare diseases of the adipose tissue, characterized by a complete or selective deficiency of the fat mass. These disorders are associated with important insulin resistance, cardiovascular and metabolic comorbidities that impact patient's survival and quality of life. Management is challenging and includes diet, physical activity, and specific pharmacological treatment of LS-associated comorbidities. Because of a common pathophysiology involving decreased concentration of the adipokine leptin, efforts have been made to develop therapeutic strategies with leptin replacement therapy. Metreleptin, a recombinant human leptin analogue, has been proposed in hypoleptinemic patients since the beginning of 2000's. The treatment leads to an improvement in metabolic parameters, more important in generalized than in partial LS forms. In this review, the current knowledge about the development of the drug, its outcomes in the treatment of lipodystrophic patients as well as the peculiarities of its use will be presented., Competing Interests: Declaration of Competing Interest BC, ML, AJ, KLM, LL, CD, SE: None. MCV: Yes., (Copyright © 2021. Published by Elsevier Masson SAS.)

Bilateral adrenal hyperplasia is a rare cause of Cushing's syndrome. Micronodular adrenal hyperplasia, including the primary pigmented micronodular adrenal dysplasia (PPNAD) and the isolated micronodular adrenal hyperplasia (iMAD), can be distinguished from the primary bilateral macronodular adrenal hyperplasia (PBMAH) according to the size of the nodules. They both lead to overt or subclinical CS. In the latter case, PPNAD is usually diagnosed after a systematic screening in patients presenting with Carney complex, while for PBMAH, the diagnosis is often incidental on imaging. Identification of causal genes and genetic counseling also help in the diagnoses. This review discusses the last decades' findings on genetic and molecular causes of bilateral adrenal hyperplasia, including the several mechanisms altering the PKA pathway, the recent discovery of ARMC5 , and the role of the adrenal paracrine regulation. Finally, the treatment of bilateral adrenal hyperplasia will be discussed, focusing on current data on unilateral adrenalectomy.