European Journal of Endocrinology最新文献

{"title":"Plasma proteomic profiling identifies APOA4 as a downregulated biomarker of adrenocortical carcinoma: a multi-platform discovery and validation study.","authors":"Seung Shin Park, Hoseok Seo, Sun Joon Moon, Han Na Jang, Seung Hun Lee, Su Jin Kim, Kyu Eun Lee, Dohyun Han, Jung Hee Kim","doi":"10.1093/ejendo/lvag079","DOIUrl":"https://doi.org/10.1093/ejendo/lvag079","url":null,"abstract":"<p><strong>Objectives: </strong>Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy associated with heterogeneous prognosis. Preoperative differentiation from adrenocortical adenoma (ACA) remains challenging, and no serum tumor marker has been established. We aimed to identify circulating protein biomarkers that distinguish ACC from ACA using a stepwise, multi-platform proteomics strategy.</p><p><strong>Methods: </strong>We assembled discovery (ACC=10, ACA=67) and verification (ACC=7, ACA=11) cohorts from a tertiary center and profiled fasting plasma using LC-MS/MS with data-independent acquisition. Differentially expressed proteins (DEPs) were defined by t-tests with P<0.05 and |fold-change|>1.2; DEPs common to both cohorts were prioritized. Targeted validation by parallel reaction monitoring (PRM) used an expanded, two-center cohort including additional cases from Asan Medical Center (ACC=31; ACA=78). Orthogonal validation employed the Olink Explore 384 Inflammation II panel in an independent set (ACC=15; ACA=24).</p><p><strong>Results: </strong>The discovery cohort yielded 67 DEPs (22 up-regulated and 45 down-regulated in ACC), and the verification cohort identified 17 DEPs. Three proteins; CD44, PRG4, and APOA4 were common to both analyses and were under-expressed in ACC compared to ACA. In PRM, CD44 and APOA4 showed directionally concordant, significant decreases in ACC, prioritizing these markers for further evaluation. In the Olink analysis, 40 proteins differed between ACC and ACA after FDR correction; APOA4 remained significantly lower in ACC.</p><p><strong>Conclusion: </strong>Across discovery, targeted, and orthogonal platforms, APOA4 consistently exhibited lower circulating levels in ACC, supporting its potential as a serum biomarker for the preoperative differentiation of ACC from ACA. External, multi-ethnic validation and clinically deployable assays, alone or within multi-marker panels are warranted.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First Clinical Demonstration of Sustained IGF-1 Elevation via Oral SSTR5 Antagonism: A Phase 1 Trial of SCO-240.","authors":"Harunobu Nishizaki, Jun Sugama, Hideki Hirose, Ryokichi Koyama, Masanori Watanabe, Yusuke Moritoh","doi":"10.1093/ejendo/lvag081","DOIUrl":"https://doi.org/10.1093/ejendo/lvag081","url":null,"abstract":"<p><strong>Objective: </strong>Somatostatin receptor 5 (SSTR5) negatively regulates growth hormone (GH) secretion in the human pituitary. Current therapy for GH deficiency (GHD) relies on exogenous recombinant GH injections, posing a significant treatment burden. SCO-240 is a novel, oral selective SSTR5 antagonist designed to stimulate the GH/insulin-like growth factor 1 (IGF-1) axis by \"releasing the brake\" on endogenous GH secretion. We evaluated whether sustained SSTR5 antagonism could induce a durable IGF-1 response while maintaining endocrine selectivity and metabolic neutrality.</p><p><strong>Design and methods: </strong>In this randomized, double-blind, placebo-controlled Phase 1 study, 32 healthy Japanese men received once-daily oral SCO-240 (3, 10, 20, or 80 mg) or placebo for 7 days. Safety, pharmacokinetics, the GH-IGF-1 axis, metabolic parameters, and anterior pituitary hormones were assessed.</p><p><strong>Results: </strong>SCO-240 was safe and well-tolerated; all treatment-emergent adverse events were mild and resolved spontaneously. Steady-state plasma concentrations of SCO-240 were achieved by Day 2. SCO-240 induced a robust, sustained increase in serum IGF-1 across all dose levels, which remained elevated above placebo from Day 2 through Day 8. This response was driven by enhanced GH secretion, characterized by persistent basal tone and enhanced pulsatility. Notably, SCO-240 exhibited a metabolically neutral profile, with no alterations in other pituitary axes, fasting glucose, or fasting/post-prandial insulin levels.</p><p><strong>Conclusions: </strong>Multiple oral doses of SCO-240 elicited selective, sustained, and physiologically regulated activation of the GH-IGF-1 axis without detrimental metabolic effects. These findings highlight SSTR5 as a druggable target and support SCO-240 as a potential first-in-class oral therapy for some forms of GHD.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Magnesium as an Endocrine Modulator: Physiological Roles, Clinical Evidence, and Therapeutic Perspectives.","authors":"Andrea Palermo, Anda Mihaela Naciu, Guido Zavatta, Eleonora Sargentini, Ciro Menale, Maria P Yavropoulou, Cristiana Cipriani, Gaia Tabacco, Athanasios D Anastasilakis","doi":"10.1093/ejendo/lvag076","DOIUrl":"https://doi.org/10.1093/ejendo/lvag076","url":null,"abstract":"<p><strong>Context: </strong>Magnesium deficiency is prevalent and increasingly recognized as an endocrine-relevant condition due to its involvement in hormone secretion, metabolic homeostasis, and cellular signaling.</p><p><strong>Objective: </strong>To review current evidence on the role of magnesium in key endocrine systems and evaluate its clinical and therapeutic implications.</p><p><strong>Evidence synthesis: </strong>Magnesium influences glucose metabolism, bone health, thyroid function, reproduction, cardiometabolic regulation, and HPA-axis activity. Clinical evidence shows strong associations between magnesium status and several endocrine diseases.</p><p><strong>Conclusion: </strong>Magnesium plays a multifaceted endocrine role with clinically significant implications. Improved diagnostic approaches and further interventional studies are warranted.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TPD52 inhibits aldosterone synthesis through suppression of CAMKK2 signaling.","authors":"Ling Xie, Linqiang Ma, Bing Kang, Zhihao Chen, Shuangxin Qi, Manman Du, Jiayu Li, Junlong Li, Yifan He, Yong Xu, Wei Huang, Rufei Gao, Jinbo Hu, Shumin Yang, Qifu Li, Chuan Peng","doi":"10.1093/ejendo/lvag073","DOIUrl":"10.1093/ejendo/lvag073","url":null,"abstract":"<p><strong>Background: </strong>Aldosterone-producing adenomas (APA) are a major cause of primary aldosteronism. While gene mutations in APA trigger aldosterone overproduction via calcium signaling, their precise regulatory mechanisms remain unclear. Our prior proteomic analysis identified significant upregulation of tumor protein D52 (TPD52), an oncogene protein implicated in cancer progression, in APA. This study investigates the role of TPD52 in regulating aldosterone synthesis and its molecular mechanism.</p><p><strong>Methods: </strong>TPD52 expression was validated in APA specimens. Gain- and loss-of-function studies in NCI-H295R cells were performed to assess its role in aldosterone synthesis. Mechanistic insights were obtained through transcriptomics and Co-immunoprecipitation-mass spectrometry (Co-IP-MS), with key results validated in NCI-H295R and HEK-293T cells. Finally, we overexpressed TPD52 in primary APA cells to assess its regulation of aldosterone.</p><p><strong>Results: </strong>TPD52 was upregulated in APA tissues. Functionally, TPD52 overexpression suppressed aldosterone synthesis in NCI-H295R cells, whereas its knockdown enhanced aldosterone production. Transcriptomic analysis confirmed that TPD52 knockdown promoted CYP11B2 (aldosterone synthase) expression and aldosterone synthesis. Co-IP-MS identified calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) as a novel TPD52-interacting protein. This interaction suppressed phosphorylation of calmodulin-dependent protein kinase 4 (CAMK4) and CREB. Importantly, CAMKK2 overexpression rescued the TPD52-mediated suppression of CYP11B2 expression and aldosterone synthesis. Overexpression of TPD52 in primary APA cells also reduced CYP11B2 expression and aldosterone production.</p><p><strong>Conclusions: </strong>TPD52 acts as a negative regulator of aldosterone synthesis by inhibiting the CAMKK2-CAMK4-CREB signaling axis.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":" ","pages":"590-602"},"PeriodicalIF":5.2,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence and incidence of dysnatremia in European community-dwelling older adults-a secondary analysis of the DO-HEALTH trial.","authors":"Laura Potasso, Maud Wieczorek, Sophie Monnerat, Julia Beck, Endel John Orav, Mirjam Christ-Crain, Heike A Bischoff-Ferrari","doi":"10.1093/ejendo/lvag054","DOIUrl":"https://doi.org/10.1093/ejendo/lvag054","url":null,"abstract":"<p><strong>Objective: </strong>Dysnatremia is the most common electrolyte abnormality detected during hospitalizations and outpatient visits and is associated with adverse outcomes in older adults. However, data on its prevalence and incidence in community-dwelling older individuals remain limited. This study aimed to estimate the prevalence and incidence of dysnatremia in this population across 5 European countries (Austria, France, Germany, Portugal, and Switzerland).</p><p><strong>Design: </strong>Observational analysis of DO-HEALTH, a 3-year multicenter clinical trial including 2157 community-dwelling, generally healthy adults aged 70 years and older.</p><p><strong>Methods: </strong>Sodium blood levels were collected at baseline, 12, 24, and 36 months. Dysnatremia was defined as sodium levels <135 mmol/L (hyponatremia) or >145 mmol/L (hypernatremia). Baseline prevalence and 3-year incidence were estimated overall and by predefined subgroups based on sex, age, country of residence, body mass index, prevalent chronic conditions, polypharmacy, and use of thiazide-like diuretics.</p><p><strong>Results: </strong>At baseline, 2141 participants (99.3%) had available sodium data. The prevalence of dysnatremia was 3.4% (2.4% hyponatremia; 1.0% hypernatremia), with higher prevalence in participants aged ≥75 years (4.8%) and those using thiazide or thiazide-like diuretics (5.4%). Over 3 years, 150 participants (7.0%) experienced at least 1 episode of dysnatremia (3.8% hyponatremia; 3.2% hypernatremia). Higher incidence of dysnatremia was observed among participants living in Switzerland, using thiazide or thiazide-like diuretics, and with prevalent dysnatremia at baseline.</p><p><strong>Conclusions: </strong>Dysnatremia, previously linked to adverse outcomes in older adults, was observed in a non-negligible proportion of generally healthy, community-dwelling older individuals. These findings provide valuable epidemiologic data and identify subgroups that may warrant closer clinical attention.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":"194 5","pages":"567-577"},"PeriodicalIF":5.2,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioimpedance spectroscopy uncovers extracellular fluid excess in primary aldosteronism.","authors":"Marianna Viukari, Antero Ylänen, Eeva Kokko, Lauri Suojanen, Eeva Moilanen, Niina Matikainen, Pasi I Nevalainen, Esa Hämäläinen, Ilkka Pörsti","doi":"10.1093/ejendo/lvag070","DOIUrl":"10.1093/ejendo/lvag070","url":null,"abstract":"<p><strong>Objective: </strong>Primary aldosteronism is a common but underdiagnosed cause of secondary hypertension, characterized by volume overload. Bioimpedance spectroscopy is widely used to assess fluid status in dialysis patients. We examined whether this method can distinguish primary aldosteronism from essential hypertension (EH).</p><p><strong>Design: </strong>Patients with confirmed primary aldosteronism (n = 77), EH (n = 90), and normotensive controls (n = 79) were prospectively recruited for a cross-sectional comparison.</p><p><strong>Methods: </strong>Total body water, extracellular and intracellular water, and overhydration were measured using bioimpedance spectroscopy. Analyses were adjusted for sex, age, body surface area, estimated glomerular filtration rate, diuretic or spironolactone use, and comorbid diabetes or heart failure. Routine laboratory and hormonal tests were performed.</p><p><strong>Results: </strong>Extracellular water (ECW) volume was 0.69 ± 1.04 and 0.88 ± 1.04 L/m2 higher, and overhydration 0.76 ± 1.4 and 0.92 ± 1.4 L greater, in primary aldosteronism than in EH and normotensive controls, respectively (P < .001 for all). Total body water did not differ significantly among groups (21.3 ± 2.2, 21.0 ± 2.8, and 21.6 ± 2.4 L/m2, respectively; P = .083). Plasma N-terminal pro-atrial natriuretic peptide concentration was highest in primary aldosteronism. Primary aldosteronism severity correlated positively with ECW volume (rS = 0.31), overhydration (rS = 0.43), and extracellular-to-intracellular water ratio (rS = 0.36; P < .01 for all).</p><p><strong>Conclusion: </strong>ECW overload in primary aldosteronism can be assessed using bioimpedance spectroscopy. Further research should determine whether addition of this method to current approaches can improve diagnostic accuracy for primary aldosteronism.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":" ","pages":"578-589"},"PeriodicalIF":5.2,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipodystrophy look-alikes: navigating diagnostic overlap with endocrine diseases.","authors":"Giovanni Ceccarini, Donatella Gilio, Silvia Magno, Lavinia Palladino, Ferruccio Santini","doi":"10.1093/ejendo/lvag067","DOIUrl":"10.1093/ejendo/lvag067","url":null,"abstract":"<p><p>Lipodystrophy syndromes are rare and heterogeneous disorders characterized by partial or generalized absence of subcutaneous adipose tissue. These conditions are associated with severe metabolic complications, including insulin resistance, diabetes, dyslipidemia, and hepatic steatosis. Because of their rarity and clinical variability, lipodystrophies are often under-recognized and may be mistaken for more common endocrine disorders, leading to misdiagnosis and delayed treatment. Several endocrine diseases share overlapping clinical manifestations with lipodystrophy, such as abnormal fat distribution, hyperandrogenism, growth disturbances, or metabolic dysfunction. Such overlap poses significant diagnostic challenges, especially for nonspecialist clinicians. A precise differential diagnosis is crucial as management strategies differ substantially between lipodystrophies and other endocrine conditions. This review explores the main diagnostic pitfalls encountered when assessing patients with suspected lipodystrophy and offers practical guidance on the clinical, biochemical, and imaging features useful for distinguishing these conditions from other endocrinological disorders. Recognizing lipodystrophy early is crucial to prevent severe complications and initiate targeted treatments, including lifestyle interventions, insulin-sensitizing drugs, lipid-lowering therapies, and, when appropriate, recombinant leptin (metreleptin) therapy. By outlining key clinical clues and common areas of overlap, this review aims to help clinicians avoid misdiagnoses and ensure timely, accurate identification of lipodystrophy syndromes.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":" ","pages":"R1-R16"},"PeriodicalIF":5.2,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of diagnosis and targeted interventions on the quality of life and neuropsychiatric outcomes of patients with adrenal tumours: a systematic review.","authors":"Barbara Ruggiero, Giuliana Zhu, Liam Swan, Onnicha Suntornlohanakul, Mengjie Xu, Cristina L Ronchi, Yasir S Elhassan, Derick Yates, Alessandro Prete","doi":"10.1093/ejendo/lvag072","DOIUrl":"10.1093/ejendo/lvag072","url":null,"abstract":"<p><strong>Objective: </strong>To systematically evaluate the impact of adrenal tumour diagnosis and targeted interventions on health-related quality of life (HRQoL) and neuropsychiatric outcomes across tumour subtypes.</p><p><strong>Design: </strong>Systematic review.</p><p><strong>Methods: </strong>A literature search of MEDLINE, Embase, Cochrane Library, and CINAHL (January 1990-March 2026) identified studies reporting HRQoL and neuropsychiatric outcomes in adults with adrenal tumours, including non-functioning adrenal tumours (NFAT), mild autonomous cortisol secretion (MACS), adrenal Cushing's syndrome (CS), primary aldosteronism (PA), phaeochromocytoma/paraganglioma (PPGL), and adrenocortical carcinoma (ACC). Study quality was assessed using CONSORT-PRO and Newcastle-Ottawa criteria. Due to methodological heterogeneity, findings were synthesized narratively.</p><p><strong>Results: </strong>A total of 117 studies involving 35 361 patients were included. CONSORT-PRO quality was good but heterogeneous, whereas observational study quality was mostly moderate or low. Across tumour subtypes, adrenal tumours were consistently associated with impaired HRQoL and neuropsychiatric outcomes. A gradient of burden was evident, with mild impairment in NFAT, intermediate impairment in MACS and PA, and the most pronounced and persistent deficits in adrenal CS, PPGL, and ACC. Targeted interventions were often associated with improved patient-reported outcomes, though the magnitude and consistency of benefit varied across tumour subtypes and study design. Recovery was frequently incomplete. Most studies relied on generic HRQoL instruments, and no disease-specific neuropsychiatric tools were identified.</p><p><strong>Conclusions: </strong>Adrenal tumours are associated with substantial and often persistent impairment in patient well-being across tumour subtypes. Although treatment generally improves outcomes, residual symptoms are common, underscoring the need for long-term, patient-centred care and for the development of adrenal tumour-specific patient-reported outcome measures.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":" ","pages":"S41-S55"},"PeriodicalIF":5.2,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147728844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular imaging in pituitary neuroendocrine tumors: a narrative review of advances, challenges, and future perspectives.","authors":"Romy van der Groef, Ilanah Pruis, Amber Audhoe, Julie Refardt, Sophie Veldhuijzen van Zanten, Sebastian Neggers","doi":"10.1093/ejendo/lvag071","DOIUrl":"10.1093/ejendo/lvag071","url":null,"abstract":"<p><p>Molecular imaging has emerged as a promising adjunct for the evaluation of pituitary neuroendocrine tumors (PitNETs), as magnetic resonance imaging (MRI), despite being the primary imaging modality, remains inconclusive in a substantial proportion of patients. Molecular imaging techniques, including single photon emission computed tomography (SPECT) and positron emission tomography (PET), can complement anatomical MR imaging by enabling in vivo visualization of tumor metabolism, receptor expression, and amino acid transport. This narrative review summarizes current evidence on the clinical utility of molecular imaging across corticotroph, somatotroph, lactotroph, and nonfunctioning PitNETs, with a focus on diagnostic performance and impact on patient management. Among available tracers, amino acid PET shows the most consistent added diagnostic value in patients with inconclusive MRI findings, particularly when integrated into hybrid or coregistered PET-MRI protocols. Emerging data indicate that this approach improves tumor localization and supports clinical decision-making, including surgical planning and management of persistent or recurrent disease. Defining the precise role of molecular imaging within endocrine diagnostic pathways will require larger-scale prospective clinical trials using standardized acquisition and interpretation protocols. Broader clinical implementation is further supported by emerging European interdisciplinary collaborations between experts in endocrinology, nuclear medicine, radiology, neurosurgery, and radiotherapy, with a shared focus on advancing individualized PitNET care.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":" ","pages":"R83-R97"},"PeriodicalIF":5.2,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147697873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence of germline variants in USP8, USP48, CABLES1 and PAM in patients with pituitary adenomas.","authors":"Idoia Martinez de Lapiscina, Candela Baquero, Alicia Santos, Ana Rosa Molina, Maria Dolores Moure, Maite Aramburu, Rodrigo Bancalari, Mauro Boronat, Gloria Bueno, Paula Casano-Sancho, Concepcion Fernandez-Ramos, Emilio Garcia-Garcia, Amparo Gonzalez, Natividad Gonzalez-Rivera, Julio Guerrero-Fernandez, Maria Isabel Hernandez, Miguel Paja, Nancy Portillo, Itxaso Rica, Alfonso Soto-Moreno, Larisa Suarez-Ortega, Amaia Vela, Luis Castaño, Nuria Valdes","doi":"10.1093/ejendo/lvag074","DOIUrl":"10.1093/ejendo/lvag074","url":null,"abstract":"<p><strong>Objective: </strong>Approximately 5% of pituitary adenomas (PA) are familial, linked to germline variants in AIP, or syndrome-related genes like MEN1. While somatic GNAS and USP8 variants predominate in specific subtypes, PAM and CABLES1 genes are emerging.</p><p><strong>Design: </strong>To investigate the prevalence and clinical significance of germline variants in CABLES1, USP8, USP48, and PAM in patients with PA without established predisposition gene variants.</p><p><strong>Methods: </strong>We analyzed germline DNA from 346 unrelated patients (mostly diagnosed <35 years) with isolated familial or sporadic PA, using a panel targeting CABLES1, USP8, USP48, and PAM. After excluding 20 with variants in known predisposition genes (MEN1, AIP, CDKN1B, PRKAR1A, SDHB, SDHC, SDHD, GNAS, DICER1), 326 patients remained for analysis. Variant interpretation followed American College of Medical Genetics and Genomics criteria with population frequencies, in silico prediction and segregation analysis. We analyzed tumor DNA from 2 cases to assess loss of heterozygosity (LOH).</p><p><strong>Results: </strong>Uncommon heterozygous germline variants were identified in 30 patients (9.2%), all clinically sporadic. Most variants were classified as benign or of uncertain significance (VUS). Several variants, including USP8 c.104+3A>G, USP48 p.(Pro361Thr), p.(Tyr927Cys) and c.2884 3C>T, and CABLES1 p.(Glu178Lys), were enriched compared with gnomAD frequencies. CABLES1 variants were predominant in macroprolactinomas, USP48 in nonfunctioning PA, and USP8 in prolactinomas and somatotropinomas. No significant genotype-phenotype associations emerged. Familial testing revealed unaffected carriers and LOH was not detected.</p><p><strong>Conclusions: </strong>No (likely) pathogenic germline variants were identified. While most were benign or VUS, specific variants-most notably in USP48-showed nominal enrichment compared to gnomAD frequencies, which might suggest a potential low-penetrance susceptibility or modifier effect that will require further validation. This work primarily focused on PAM, CABLES1, USP8, and USP48, but other germline or somatic variants may also contribute. Clinical management and genetic counseling should not be guided by benign variants or VUS.</p>","PeriodicalId":11884,"journal":{"name":"European Journal of Endocrinology","volume":" ","pages":"603-614"},"PeriodicalIF":5.2,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}