Primary aldosteronism is the most common form of secondary hypertension, and aldosterone-producing adenoma (APA) is the most prevalent surgically curable subtype of primary aldosteronism. Over the past decade, the identification of recurrent somatic mutations, most notably in KCNJ5, has transformed the molecular understanding of APA and has revealed substantial heterogeneity across tumors. In parallel, advances in transcriptomic, epigenomic, and metabolomic profiling have further expanded insights into genotype-dependent differences in steroidogenic activity, cellular morphology, and clinical presentation. More recently, the application of single-cell, single-nucleus, and spatial transcriptomics technologies has revealed an additional layer of complexity, demonstrating marked heterogeneity within individual APA tissues. These studies show that APAs are composed of transcriptionally and functionally diverse cell populations with variable steroidogenic capacities, extending beyond what can be explained by the somatic mutation status alone. This review summarizes the current evidence for both intertumoral and intratumoral heterogeneity in APA, integrating findings from genomic, epigenomic, metabolomic, and single-cell–based studies. By highlighting how mutation-driven differences intersect with cell-state diversity and differentiation processes, this review aimed to provide a comprehensive framework for understanding the pathophysiology of APA and discuss the potential implications for disease classification, biomarker development, and future therapeutic strategies.

Social jetlag (SJL), the misalignment between biological and social time, has been linked to adverse metabolic outcomes. However, the effect of body mass index (BMI) on this association remains unclear, particularly in Asian populations. This cross-sectional study utilized data from the Taiwan Biobank, including 65,832 adults with complete information on sleep timing and metabolic parameters. SJL was calculated as the difference in mid-sleep time between workdays and free days and categorized as <2 or ≥2 h. Metabolic syndrome (MetS) was defined using standard clinical criteria. Multivariable logistic regression models were used to examine the association between SJL and MetS, with stepwise adjustment for sociodemographic, lifestyle, and clinical factors. Additional analyses stratified participants into BMI categories (<24, 24–26.9, ≥27 kg/m²). After full adjustment including BMI, SJL ≥2 h was not significantly associated with MetS (adjusted odds ratio = 1.05, 95% confidence interval: 0.98–1.12; p = 0.180). In BMI-stratified analyses, a significant association was observed only in the overweight group (BMI 24–26.9 kg/m²; adjusted odds ratio = 1.12, 95% confidence interval: 1.01–1.24; p = 0.035), but not in normal-weight or obese groups. An association between SJL and MetS was observed only in the overweight group, suggesting a BMI-dependent association between SJL and MetS. These findings highlight the importance of considering BMI when evaluating the association between SJL and MetS and indicate that the relationship between circadian misalignment and metabolic risk may vary across BMI categories.

Endothelial dysfunction is an early feature of diabetic vascular injury. Stress-induced activation of the hypothalamic–pituitary–adrenal (HPA) axis, together with autonomic imbalance, may contribute to endothelial dysfunction. However, its clinical relevance in diabetes remains to be fully elucidated. We retrospectively analyzed 60 patients with diabetes who underwent both flow-mediated dilation (FMD) of the brachial artery and the coefficient of variation of the R–R interval (CVRR) measurements. The primary objective was to examine the association between FMD and stress-related hormones, including adrenocorticotropic hormone (ACTH) and cortisol. The secondary objective was to evaluate the association with autonomic function (CVRR) and other clinical variables. Mean FMD was 5.10 ± 2.32%. FMD correlated inversely with ACTH (r = –0.41, p = 0.0015) and cortisol (r = –0.39, p = 0.0024), and positively with CVRR (r = 0.49, p < 0.001). These relationships were stronger in patients with BMI ≥27 kg/m², among whom the correlation between FMD and ACTH was particularly pronounced (r = –0.68, p = 0.0007). No significant associations were found between FMD and hemoglobin A1c or other lipid parameters. Given the cross-sectional design, these findings indicated associations rather than causality. Our results suggest that the HPA axis activity and autonomic function may be associated with endothelial dysfunction in diabetes, particularly in individuals with a higher BMI. This study was registered in the UMIN Clinical Trials Registry (UMIN-CTR; UMIN000060540).

Pheochromocytoma and paraganglioma (PPGL) require sensitive biochemical screening to prevent delayed or missed diagnoses. In Japan, plasma-free metanephrines (pMN/pNMN) measured using enzyme immunoassay have been covered by national insurance since 2019; however, the real-world diagnostic performance of the currently applied cutoff values has not been evaluated. We retrospectively identified consecutive adults who underwent pMN/pNMN testing in routine practice at five endocrinology departments between 2019 and 2025, of whom 817 were included in the final analysis. Patients were classified post hoc as having PPGL (n = 107) or serving as controls (n = 710) based on pathological findings, functional imaging, and clinical follow-up. Diagnostic performance at the current cutoff values (pMN >130 pg/mL or pNMN >506 pg/mL) was evaluated by sensitivity and specificity, compared with spot and 24-hour urinary metanephrine measurements using receiver operating characteristic (ROC) analyses, and optimized cutoff combinations were determined using the Youden index. The current cutoff values showed high specificity (99.9%) but limited sensitivity (82.2%), particularly in patients with abdominal paraganglioma (76.0%). Plasma and urinary metanephrine measurements demonstrated comparable performance in the ROC analyses. False-negative cases based on the current cutoff values had significantly smaller tumors than true-positive cases (p = 0.016). Urinary biochemistry and functional imaging offered crucial complementary diagnostic value. Our optimized thresholds (pMN >120 pg/mL or pNMN >290 pg/mL) significantly enhanced sensitivity (92.5%) while maintaining high specificity (99.2%), consistent with postoperative biochemical remission. These findings suggest that current pMN/pNMN cutoff values may limit diagnostic sensitivity, necessitating optimized thresholds and a multimodal approach in accordance with the PPGL guidelines. Registration Number: UMIN000060658.

Follicular thyroid carcinoma (FTC) is known to occasionally show distant recurrence (DR); however, no prognostic scoring system has been established. Furthermore, although prognostic factors have been identified, their weights as predictors of poor prognosis remain unclear. In this study, we aimed to establish a weighted scoring system for predicting DR in FTC using conventional prognostic factors and Ki-67 labeling index (LI). We analyzed data of 597 patients with FTC without distant metastasis at initial surgery. Tumor size >4 cm, male sex, age ≥60 years, Ki-67 LI >5%, and vascular invasion (VI) ≥4 (V2) significantly and VI 0–4 (V1) marginally affected DR. Wide capsular invasion was not significantly associated with DR. Stepwise model selection using the Akaike Information Criterion identified age ≥60 years, Ki-67 LI >5%, V1, V2, and tumor size >4 cm as suitable components of the score. According to the beta coefficient value, we assigned a score of 2 to age ≥60 years, Ki-67 LI >5%, and V2, and a score of 1 to tumor size >4 cm and V1, with the sum representing the final score. We categorized patients into three categories according to the DR rates: low-risk (score 0–2; n = 388, 65.0%), intermediate-risk (score 3–4; n = 156, 26.1%), and high-risk (score 5–7; n = 53, 8.9%). The 10-year DR-free survival rates declined from the low- to the high-risk categories (96.0% vs. 90.3% vs. 54.9%). These findings indicate that high-risk patients identified using this prognostic scoring model should be carefully monitored for DR following completion thyroidectomy.

Recurrent Cushing’s disease is most commonly caused by residual or newly developed pituitary neuroendocrine tumor (PitNET) tissue within the sellar region. Extrasellar recurrence due to postoperative tumor cell seeding is exceedingly rare. We report the unique case of a 30-year-old woman who achieved endocrine remission after gross total resection of an ACTH-secreting PitNET but later developed biochemical and clinical recurrence without radiological evidence of a sellar lesion. Despite long-term medical therapy including cabergoline, metyrapone, and pasireotide, the hypercortisolism gradually progressed. Nearly 10 years after the initial surgery, a reoperation was performed to explore the occult tumor. Intraoperatively, a small soft tumor attached to the posterior surface of the anterior wall of the sphenoid sinus was discovered. Histopathological examination confirmed the presence of a recurrent corticotrophic PitNET. A retrospective review of CT, MRI, and octreotide scintigraphy revealed a subtle lesion that had previously been overlooked. Complete resection resulted in an immediate endocrine remission. This case demonstrates that recurrent Cushing’s disease may, although rarely, arise from the implantation of tumor cells that drop into the sphenoid sinus during transsphenoidal surgery. Awareness of this mechanism is crucial for evaluating MRI-negative recurrences. Careful inspection of the sphenoid sinus and meticulous irrigation during surgery may help prevent iatrogenic seeding and improve long-term outcomes.

Oculo-facio-cardio-dental (OFCD) syndrome is a rare X-linked dominant disorder caused by pathogenic variants in the BCOR gene and is characterized by distinctive craniofacial, ocular, cardiac, and dental abnormalities. Although OFCD syndrome is a well-defined developmental disorder, its association with endocrine tumors has not been clearly established. We report a female patient with genetically confirmed OFCD syndrome harboring a novel heterozygous deletion in BCOR who developed metachronous multiple insulinomas. The patient presented with recurrent hypoglycemic episodes, and pancreatic neuroendocrine tumors were detected at different time points, necessitating repeated surgical interventions. Histopathological examination confirmed insulinoma in each resected lesion. Comprehensive clinical and pathological evaluations revealed no features suggestive of other known hereditary insulinoma-associated syndromes, including multiple endocrine neoplasia type 1. Previous reports have described either recurrent insulinoma without genetic confirmation of OFCD syndrome or multiple insulinomas without documented recurrence in genetically confirmed cases. In contrast, the present case uniquely demonstrates metachronous development of multiple insulinomas in association with a novel BCOR deletion. Given the role of BCOR in transcriptional repression and developmental regulation, this case suggests a potential contribution of BCOR dysfunction to pancreatic neuroendocrine tumorigenesis. Our findings expand the phenotypic and genotypic spectrum of OFCD syndrome and underscore the importance of long-term surveillance and further accumulation of cases to clarify tumor predisposition in this rare disorder.