Oncocytic thyroid carcinoma (OCA) is a rare thyroid malignancy that has only recently been recognized as a distinct entity from follicular thyroid carcinoma. Till date, studies regarding the prognosis of OCA remain inadequate. In this retrospective study, we investigated the prognosis of OCA among 137 Japanese patients who underwent surgery at our institution. Two patients had distant metastasis before surgery (M1), and two showed distant metastasis after surgery. The 10-year and 15-year distant recurrence-free survival rates were 100%, and 92.7%, respectively. No deaths occurred owing to thyroid carcinoma. Four patients with distant metastasis/recurrence were aged ≥60 years, and their tumors were >4 cm. Further, two patients with M1 had both vascular invasion (VI) and wide capsular invasion (CI). One patient had a poorly differentiated component (approximately 30%), and one showed high cell proliferating activity (Ki-67 labeling index [LI] ≥5%). Of the two patients who developed distant metastasis after surgery, one had VI and wide CI, and although another had minimal CI and was negative for VI, the Ki-67 LI of his tumor was >5%. These findings suggest that Japanese patients with OCA generally had excellent prognosis after surgery; however, older age, large tumor size, wide CI, VI positivity, high Ki-67 LI, and the presence of a poorly differentiated component may be indicators of aggressive behavior. Further multicenter studies with larger samples and longer follow-up durations are necessary to identify clinicopathological factors accurately predicting poor prognosis in patients with OCA.

Although previous studies have described steroidogenic enzyme expression in aldosterone-producing adrenocortical carcinoma (APAC), detailed immunohistochemical evaluations of CYP11B2 at the protein level and its clinicopathological relevance remain limited. Here, we report a rare case of APAC with a comprehensive immunohistochemical analysis focusing on CYP11B2 expression. An 82-year-old woman presented with limb weakness and severe hypokalemia (serum potassium: 1.9 mmol/L). Endocrinological evaluation revealed markedly elevated plasma aldosterone levels and suppressed renin activity, indicating autonomous aldosterone secretion. Imaging identified a rapidly enlarging left adrenal mass with intratumoral hemorrhage, and adrenal venous sampling confirmed unilateral aldosterone excess. The patient underwent laparoscopic left adrenalectomy. Histopathological examination revealed a high-grade adrenocortical carcinoma with positive surgical margins. Immunohistochemical analysis demonstrated positive expression of CYP11B2, CYP11B1, and CYP17A1, whereas dehydroepiandrosterone sulfotransferase expression was absent in the tumor cells but present in the adjacent zona reticularis, suggesting disorganized steroidogenesis. Although biochemical parameters transiently improved postoperatively, the patient developed early recurrence with peritoneal dissemination and died 10 months after surgery. This case of APAC was diagnosed following severe and rapidly progressive hypokalemia, suggesting that a detailed examination of steroidogenic enzyme expression in the tumor may be valuable in elucidating the endocrine characteristics of this rare malignancy.

Brown adipose tissue (BAT) contributes to energy expenditure through cold-induced thermogenesis and is closely linked to systemic lipid metabolism. However, the dynamic changes in circulating n-3 polyunsaturated fatty acids (PUFAs) during cold exposure and their association with BAT activity remain unclear. Healthy young men underwent controlled cold exposure, and BAT activity was quantified using fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). Circulating levels of n-3 PUFAs, including α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), were measured before and after cold exposure using whole-blood lipidomics. K-means clustering based on log-transformed maximum standardized uptake value (lnSUVmax) was performed. Changes in lipid parameters were evaluated using paired t-tests and multiple regression analyses. Cold exposure significantly decreased ALA levels and the ALA/EPA ratio while increasing EPA and DPA levels and the EPA/DPA and DPA/DHA ratios. Multiple regression analyses revealed that BAT activity (lnSUVmax) was independently associated with changes in several lipid parameters. Higher SUVmax was positively associated with changes in ALA levels and the ALA/EPA ratio, whereas inverse associations were observed with changes in EPA, DPA, EPA/DPA, and DPA/DHA. Baseline lipid levels were not significant predictors of lipidomic changes. Cold-induced BAT activation is associated with dynamic remodeling of circulating n-3 fatty acids. These findings suggest that thermogenic capacity may influence systemic lipid metabolism and highlight the metabolic interplay between BAT activity and circulating n-3 PUFAs. Trial registration: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR), UMIN000029206.

In Japan, GH treatment (GHT) is used for short stature associated with small for gestational age (SGA), Noonan syndrome (NS), Turner syndrome (TS), achondroplasia (ACH), and hypochondroplasia (HCH). However, real-world data on these diagnoses and GHT use for these conditions in Japan remain limited. In this retrospective cohort study, we used the JMDC claims database (2005–2021) to extract data of children with SGA-related short stature or diagnosed with short stature diseases, namely NS, TS, ACH, or HCH, particularly in boys aged <17 years and girls aged <15 years. We reported the prevalence, comorbidities, age at diagnosis, time from diagnosis to treatment initiation, persistence to GHT, and proportion of days covered (PDC). We analyzed data from children with SGA-related short stature (n = 786), NS (n = 79), TS (n = 172), ACH (n = 107), and HCH (n = 30); the mean (standard deviation) age at initial diagnosis was 5.2 (3.5), 4.0 (4.0), 6.5 (4.2), 3.0 (4.1), and 4.5 (3.9) years, respectively. The prevalence (per 100,000) was 59.59, 5.45, 9.52, 8.31, and 2.12 for SGA-related short stature, NS, TS, ACH, and HCH, respectively. Mean PDC for SGA-related short stature, NS, TS, ACH, and HCH was 0.918, 0.984, 0.953, 0.941, and 1.000, respectively, demonstrating high persistence to GHT. This study provides insights into the current diagnosis and GHT use among children with short stature in Japan. The findings suggest that most Japanese children continue and adhere well to GHT. However, continued efforts toward early referral and diagnosis remain crucial.

Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare autosomal recessive disorder of gluconeogenesis caused by the biallelic pathogenic variants of FBP1. Recurrent episodes of hypoglycemia and lactic acidosis usually occur during childhood. Because the ketone levels during hypoglycemic attacks may vary in patients with FBPase deficiency, differentiation from fatty acid oxidation disorders can be challenging. A urinary organic acid analysis during hypoglycemic attacks, particularly the detection of glycerol and glycerol-3-phosphate, in conjunction with plasma acylcarnitine profiling, is useful for distinguishing between these disorders. Furthermore, targeted next-generation sequencing-based multigene panels for hypoglycemia and related inherited metabolic disorders have become increasingly valuable diagnostic tools in this field. At the molecular level, a useful working model is to interpret FBP1 variants along three functional dimensions: protein abundance/stability, catalytic activity, and non-canonical restraint of AKT signaling. Within this framework, many missense variants fall into two major classes: variants that preserve protein abundance, but impair the catalytic activity and variants that reduce both protein abundance and the catalytic activity through defective folding. Selected C-terminal variants additionally disrupt the AKT-regulatory scaffolding function. Emerging experimental evidence suggests that FBP1 influences hepatic lipid accumulation, fibrosis, and tumorigenesis through mechanisms beyond its canonical role in gluconeogenesis. This review summarizes the clinical features, diagnosis, genetics, and management of FBPase deficiency, with particular emphasis on the functional interpretation of FBP1 variants and the broader biological roles of FBP1.

The coronavirus disease 2019 (COVID-19) pandemic and associated lifestyle changes have affected metabolic status in individuals with diabetes. The impact of these changes on renal function in individuals with type 1 diabetes (T1D) remains unclear. We performed a post-hoc analysis of a multicenter retrospective cohort study (the IPRA-CKD study) including 190 Japanese individuals with T1D who were not receiving sodium–glucose cotransporter 2 inhibitors. Participants were recruited between June 2022 and July 2023, and longitudinal data over a consecutive 60-month period preceding enrollment were extracted at 6-month intervals and divided into periods before and during the pandemic. Annual rates of estimated glomerular filtration rate (eGFR) decline were compared between the periods before and during the COVID-19 pandemic using a linear mixed-effects model. The eGFR decline was not accelerated during the pandemic compared with before the pandemic; the estimated eGFR slopes were –1.54 ± 0.28 mL/min/1.73 m²/year before the pandemic and –1.05 ± 0.22 mL/min/1.73 m²/year during the pandemic (p = 0.27). Glycemic control was preserved during the pandemic, despite small but significant increases in body weight, blood pressure, and insulin dose. Exploratory subgroup analyses suggested a less steep eGFR decline during the pandemic among participants with body mass index ≥25 kg/m² or those receiving renin–angiotensin system inhibitors; however, these findings should be interpreted as hypothesis-generating. In this multicenter cohort of individuals with T1D, the COVID-19 pandemic was not associated with accelerated eGFR decline overall.

Clinical Trial Registry (CTR) registration: UMIN-CTR000047441

McCune-Albright syndrome (MAS) is a rare mosaic disorder caused by somatic gain-of-function variants in GNAS and frequently associated with fibrous dysplasia (FD). FD-related complications impair physical function and quality of life (QOL), yet Japanese data are lacking. We conducted a nationwide survey to characterize functional impairment and physician-perceived QOL factors in patients with MAS in Japan. Data on 43 patients were collected using a web-based questionnaire sent to council members of the Japanese Society for Pediatric Endocrinology and the Japanese Society for Bone and Mineral Research. Motor disability was assessed using the Japanese version of the modified Rankin Scale (mRS); respiratory, visual, and hearing impairments were graded using the Japanese severity criteria for designated intractable diseases. Physicians identified the single factor perceived as most affecting each patient’s QOL. Motor impairment was present in 72.1%, including moderate or severe impairment (mRS ≥3) in 30.2%; other impairments were each absent in more than 80%. The most frequent QOL-affecting factor was bone pain or fractures (37.2%), followed by facial deformity or appearance changes (18.6%) and mobility or physical activity limitation (16.3%). Physician-perceived QOL factors differed by mRS group (p < 0.001): bone pain and facial deformity predominated in patients with mRS <3, whereas mobility limitation predominated in those with mRS ≥3. These findings indicate that FD-related skeletal manifestations are a major source of disability and QOL burden in Japanese patients with MAS, supporting stratified management tailored to motor disability.

The glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide is available clinically. Although real-world studies of tirzepatide in Japanese people with type 2 diabetes (T2D) have been reported, data regarding low-dose tirzepatide and patient-reported outcomes in routine clinical practice remain limited. In this multicenter retrospective observational study, we evaluated changes in glycemic control, body mass index (BMI), metabolic parameters, patient-reported outcomes, and adverse events after initiation of low-dose tirzepatide in Japanese people with T2D. Eighty-eight subjects with T2D treated with an average dose of tirzepatide of 4.5 ± 1.0 mg/week for 24 weeks were retrospectively analyzed. The primary outcomes were changes in glycated hemoglobin (HbA1c) and BMI from baseline to 24 weeks. HbA1c levels and BMI decreased over 24 weeks after initiation of low-dose tirzepatide (HbA1c, –1.5%; BMI, –1.5 kg/m²; both p < 0.001). Additionally, serum albumin was increased, and alanine transaminase and low-density lipoprotein cholesterol were decreased significantly. In multivariable regression analysis, higher baseline HbA1c was associated with greater HbA1c reduction. In exploratory cross-sectional analyses, post-treatment Diabetes Treatment Satisfaction Questionnaire (DTSQ) scores were associated with higher baseline HbA1c, and Kanden Institute Stigma Scale (KISS) scores were associated with higher baseline BMI. Major adverse events linked with tirzepatide were gastrointestinal symptoms. In this multicenter retrospective single-arm observational study, HbA1c and BMI decreased over 24 weeks after low-dose tirzepatide initiation in Japanese people with T2D. These findings suggest that low-dose tirzepatide may be a useful treatment option in selected patients in routine clinical practice, although causal inference is limited by the observational design and lack of a control group.

Trial Registration: National University Hospital Medical Information Network (UMIN Clinical Trial Registry, UMIN000053671; approval date: March 1, 2024).

The hindbrain plays a critical role in regulating feeding, glucose metabolism, and reproductive function during malnutrition, and our previous studies suggest that hindbrain ependymal cells lining the fourth ventricle (4V) potentially contribute to the physiological responses to hindbrain glucoprivation. The present study aimed to examine the effects of 4V ependymal denudation on counterregulatory responses to hindbrain glucoprivation. Neuraminidase, an enzyme that induces ependymal denudation, was administered into the 4V of ovariectomized rats implanted with a silicone tube containing a negative feedback level of estradiol-17β (OVX + low E₂ rats) to generate an ependymal cell-disrupted model, whereas vehicle administration served as the control condition. Following 4V administration of neuraminidase or vehicle, OVX + low E₂ rats received 4V administration of 2-deoxy-D-glucose (2DG), a glucose utilization inhibitor, or xylose as an osmotic control, and food intake, blood glucose levels, and luteinizing hormone (LH) concentrations were measured. Administration of 2DG into the 4V increased food intake in control rats, whereas this response was absent in rats with ependymal denudation. In contrast, 4V administration of 2DG increased blood glucose levels and suppressed LH secretion in both control rats and rats with ependymal denudation. Taken together, these findings indicate that 4V ependymal cells may, at least in part, contribute to feeding responses during hindbrain glucoprivation.

Acquired generalized lipodystrophy (AGL) is a rare disorder characterized by progressive loss of subcutaneous and visceral adipose tissue and severe metabolic disturbances, including diabetes mellitus (DM). Although AGL is typically associated with type 2 DM, clinical experience with patients affected by both AGL and Fulminant type 1 DM (FT1DM) remains limited. We report a case of a 50-year-old man with long-standing (4-year) FT1DM who developed AGL, with histopathological and immunological evaluation and long-term follow-up after metreleptin therapy. The patient presented with rapid deterioration of glycemic control and extreme insulin resistance, requiring a marked increase in insulin dose. Imaging studies revealed generalized loss of subcutaneous and visceral adipose tissue, and skin biopsy demonstrated marked adipose tissue atrophy with infiltration of CD3⁺ (cluster of differentiation 3) and CD8⁺ T lymphocytes. Notably, soluble interleukin-2 receptor (sIL-2R) levels remained persistently elevated for more than 12 months, suggesting sustained systemic T-cell activation. Although metreleptin therapy resulted in partial improvement in glycemic control, hemoglobin A1c (HbA1c) did not return to the pre-AGL level during follow-up. This case raises the possibility that persistent immune activation may contribute to insulin resistance beyond leptin deficiency in some patients with AGL.

A woman in her thirties presented with progressive bone pain, muscle weakness, recurrent stress fractures, and delayed fracture healing. Laboratory investigations demonstrated hypophosphatemia, renal phosphate wasting, elevated fibroblast growth factor 23 (FGF23), and inappropriately low 1,25-dihydroxyvitamin D, leading to a diagnosis of FGF23-mediated tumor-induced osteomalacia (TIO) approximately one year after symptom onset. Bone scintigraphy demonstrated multiple fractures involving the ribs and pubic bones. [18F]-fluorodeoxyglucose positron emission tomography/computed tomography ([18F]-FDG PET/CT) identified mild uptake in the left femoral head/femoral neck region, and targeted magnetic resonance imaging (MRI) confirmed a well-defined 6-mm lesion with low signal intensity on T1- and T2-weighted images and high signal intensity on short tau inversion recovery images. Somatostatin receptor scintigraphy (SRS) showed no abnormal uptake. Systemic venous sampling (SVS) demonstrated elevated FGF23 levels in the left pelvic venous drainage region. CT-guided biopsy revealed a phosphaturic mesenchymal tumor (PMT) with FGF23 immunohistochemical positivity. Complete resection would likely have required hemiarthroplasty or total hip arthroplasty because of the tumor location, and the patient declined surgery. Burosumab was therefore initiated. At 24 weeks, serum phosphate increased from 1.5 to 4.1 mg/dL, alkaline phosphatase decreased from 145 to 100 U/L, generalized bone pain and gait disturbance improved markedly, pseudofracture-related uptake disappeared on bone scintigraphy, and lumbar-spine and femoral-neck bone mineral density (BMD) improved. This case shows that multimodal localization can identify micro-TIO lesions that may escape conventional strategies, and that FGF23 blockade can be clinically effective in a localized FGF23-positive 6-mm PMT when surgery is anatomically challenging or declined.

Glycogen storage disease type 1a (GSD1a) is characterized by hypoglycemia in childhood; however, cases complicated by diabetes in adulthood have increasingly been reported. The clinical phenotype of GSD1a appears heterogeneous, and insulin secretory capacity in the patients has not been fully characterized. Herein, we report the case of a 20-year-old woman with GSD1a who was initially diagnosed with type 2 diabetes in early adulthood. The patient’s glycemic control gradually deteriorated despite administration of oral antidiabetic agents. Longitudinal evaluation using 75-g oral glucose tolerance tests demonstrated a marked decline in insulin secretion within 10 months. Based on these findings, insulin therapy was initiated, resulting in stable glycemic control. This case suggests that rapid β-cell decompensation occurs during the clinical course of early-onset diabetes in young patients with GSD1a.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) carry a risk of euglycemic diabetic ketoacidosis (euDKA) during acute illness. We report an educational case of a 45-year-old man with type 1 diabetes (T1D) receiving ipragliflozin who developed severe euDKA precipitated by COVID-19. During this sick-day period, he independently discontinued basal insulin—partly because his continuous glucose monitoring (CGM) readings remained within the target range—while continuing ipragliflozin. He presented to the emergency department with worsening gastrointestinal symptoms. On arrival, although blood glucose was 246 mg/dL, venous blood gas revealed severe metabolic acidosis (pH 7.040, HCO₃^– 9.6 mmol/L) and 3+ urinary ketones. Remarkably, CGM data for the 48 hours prior to ambulance arrival showed a time in range of 71%, indicating clinically acceptable glycemic control. Quantitative analysis confirmed minimal glycemic variability (coefficient of variation 15.8%; mean amplitude of glycemic excursions 77 mg/dL). To our knowledge, this is one of the first reports to quantitatively characterize CGM data, demonstrating that favorable CGM metrics do not preclude a metabolic crisis. Although reimbursement for self-monitoring of blood ketones (SMBK) for patients with T1D receiving SGLT2i has been introduced in Japan, National Database reports reveal limited utilization and structural barriers, such as restrictions on test strip supplies. While promoting SMBK is important, the concept of euDKA remains difficult for patients to grasp. Therefore, clinicians must prioritize symptom-based sick-day rules over “normal” glucose numbers to prevent false reassurance from clinically acceptable CGM metrics. This case underscores the inherent limitations of glucose-centric monitoring and the necessity of multifaceted patient education.

Dysthyroid optic neuropathy (DON) is a severe, vision-threatening manifestation of thyroid eye disease. We conducted a retrospective descriptive case series of consecutive patients with DON treated with teprotumumab at a single center to evaluate functional, structural, magnetic resonance imaging (MRI)-based inflammatory, and safety outcomes. Six patients (10 eyes) were included. Eye-level outcomes were assessed at baseline and during follow-up using generalized estimating equations to account for within-patient correlation. The primary outcomes were best-corrected visual acuity (BCVA), expressed as logarithm of the minimum angle of resolution (logMAR) and summed cross-sectional area of the four rectus muscles (CSA). Secondary outcomes were proptosis and mean T2 signal intensity ratio (T2-SIR) of the four rectus muscles. Estimated marginal mean BCVA improved from 0.35 logMAR at baseline to 0.04 at 3 weeks, 0.05 at 12 weeks, and –0.08 at 24 weeks. Summed rectus CSA decreased from 2.11 cm² at baseline to 1.48 cm² at 12 weeks and 1.41 cm² at 24 weeks. Proptosis and mean T2-SIR also decreased during follow-up. Most non-hearing-related adverse events were mild; however, treatment was discontinued in one patient because of diarrhea and in another because of fatigue and tinnitus. American Speech-Language-Hearing Association (ASHA)-defined hearing threshold shifts were identified in at least one ear in all six patients. These findings suggest that teprotumumab was associated with early concordant improvement across functional, anatomic, and MRI-based inflammatory endpoints in patients with DON. Careful monitoring, particularly audiologic assessment, remains essential.

Maternal high fasting plasma glucose (FPG) is a well-known risk factor for large-for-gestational-age (LGA) infants. However, this association remains unclear among Japanese women with gestational diabetes mellitus (GDM). Therefore, we examined this issue in Japanese women with GDM, accounting for body mass index (BMI). This retrospective study analyzed 543 Japanese women with GDM and evaluated the associations of 1-standard deviation (SD) increments in fasting, 1-hour, and 2-hour plasma glucose and HbA1c levels with LGA. LGA was defined as birth weight above the 90th percentile for gestational age. Multivariable logistic regression was used to estimate ORs and 95% CIs for LGA per 1-SD increment in fasting, 1-hour, and 2-hour plasma glucose and HbA1c. Model 1 was adjusted for maternal age, smoking, family history of diabetes, insulin use, parity, gestational age at delivery, gestational age at diagnosis, and gestational weight gain; Model 2 was additionally adjusted for pre-pregnancy BMI. The prevalence of LGA was 9.6%. In model 1, the FPG was independently and positively associated with LGA (adjusted OR 1.44, 95% CI: 1.07–1.94). The area under the receiver operating characteristic (ROC) curve for FPG in discriminating LGA was 0.692, with an optimal cutoff of 86.0 mg/dL. After additional adjustment for pre-pregnancy BMI (model 2), FPG was no longer associated with LGA. Other glycemic parameters were not associated with low birth weight, small-for-gestational-age, or LGA. FPG at GDM diagnosis may provide limited discriminatory information for LGA. However, its association with LGA was attenuated after adjustment for pre-pregnancy BMI.

Pasireotide, a somatostatin analog with high affinity for somatostatin receptor 5 (SSTR5), is frequently used to treat residual or recurrent pituitary adenomas, but it often induces hyperglycemia by suppressing glucagon-like peptide-1 (GLP-1) secretion. Although GLP-1 receptor agonists (GLP-1RAs) have been reported to be effective for pasireotide-induced hyperglycemia, no established treatment strategy currently exists. The present report describes the first documented use of once-weekly subcutaneous tirzepatide in a patient with pasireotide-induced hyperglycemia that remained inadequately controlled despite oral GLP-1RA therapy. A 48-year-old woman without a history of glucose intolerance was diagnosed with a GH/TSH-producing pituitary adenoma/PitNET. Transsphenoidal surgery was performed, followed by initiation of pasireotide for the residual tumor. Subsequently, the patient developed progressive hyperglycemia, with the hemoglobin A1c (HbA1c) level increasing from 6.5% to 7.7%. Oral sitagliptin and semaglutide were sequentially introduced; however, glycemic control remained suboptimal. Upon switching to once-weekly subcutaneous tirzepatide, the HbA1c level decreased markedly from 7.7% to 6.3%, along with an improvement in random blood glucose levels. In conclusion, once-weekly subcutaneous tirzepatide may be a therapeutic option for selected patients with pasireotide-induced hyperglycemia. However, further studies are needed to determine whether its effects differ from those of intensified GLP-1RA therapy.

In Japan, the Corticotropin-releasing hormone (CRH) stimulation test is widely used to evaluate secondary adrenal insufficiency (SAI); however, the insulin tolerance test (ITT) is sometimes required to assess hypothalamic dysfunction. This study aimed to identify the clinical conditions in which the ITT is necessary in addition to CRH testing. We retrospectively analyzed 69 patients who underwent both tests between August 2015 and December 2024. Forty-three patients with insufficient cortisol responses during the ITT were diagnosed with SAI and the others with non-SAI. Among SAI cases, cortisol level ≥18 μg/dL during CRH testing defined hypothalamic SAI and <18 μg/dL defined pituitary SAI. Clinical profiles and ACTH responses were compared. Pituitary SAI was associated with tumors, immune-related adverse events, glucocorticoids, COVID-19, hypophysitis and empty sella. Hypothalamic SAI was mainly associated with tumors, opioids, and COVID-19. During CRH testing, ACTH responses alone poorly distinguished hypothalamic SAI from non–adrenal insufficiency among patients with normal cortisol responses to CRH; however, a specific pattern of low basal level combined with a high peak of ACTH after CRH stimulation suggested hypothalamic SAI. In addition, a peak cortisol level <12 μg/dL in the growth hormone-releasing peptide-2 (GHRP-2) stimulation test was also specific to hypothalamic SAI among patients with normal cortisol responses to CRH. In conclusion, even when cortisol responses to CRH appear adequate, the ITT remains necessary for patients with clinical or etiological features suggestive of hypothalamic dysfunction. When the ITT is contraindicated, analyzing ACTH values during the CRH stimulation test and peak cortisol levels during the GHRP-2 test would effectively support hypothalamic SAI diagnosis.

Carotid body tumors (CBTs) are rare paragangliomas in which genetic predisposition, particularly pathogenic variants in succinate dehydrogenase (SDHx) genes, plays an important role in tumorigenesis. Previous genetic studies of CBTs have primarily focused on germline SDHx variants, whereas somatic alterations remain poorly characterized. Among SDHx genes, SDHB variants are known to be associated with a higher metastatic risk, while SDHD variants are generally linked to a lower metastatic rate. We report the case of a 41-year-old man who presented with a painless right-sided neck mass. Imaging studies demonstrated a hypervascular tumor located at the carotid bifurcation with circumferential encasement of the carotid artery. During surgery, the tumor was classified as a Shamblin type III CBT, and complete surgical resection with vascular reconstruction was performed. Histopathological examination confirmed paraganglioma with metastasis to a single cervical lymph node. Germline genetic testing did not reveal any pathogenic variants. However, comprehensive tumor genomic profiling identified a somatic SDHD c.304C>G (p.His102Asp) variant accompanied by tumor-specific loss of heterozygosity (LOH) and copy-number loss at the SDHD locus, findings compatible with biallelic SDHD inactivation. The patient remained free of recurrence during follow-up. To our knowledge, this represents the first reported case of metastatic CBT harboring a somatic-only SDHD variant with tumor-specific LOH. This case suggests that reliance on germline testing alone may underestimate the molecular drivers of CBT and highlights the potential clinical value of tumor-based genomic profiling for risk stratification and prognostic assessment.

In the latter half of the 20th century, humans have produced various synthetic chemicals, several of which had serious adverse effects on ecosystems and human health. Colborn et al. noticed that some chemicals disrupt the hormonal system of living organisms. They named these chemicals endocrine-disrupting chemicals (EDCs) and published the book Our Stolen Future. In classical toxicology, toxins directly act on cellular components, such as proteins, DNA, and cell membranes; cause damage and exhibit toxicity; and demonstrate a linear dose–response relationship, thus allowing safe thresholds. EDCs transmit abnormal signals through receptors, thus causing errors in the timing, type, and quantity of gene expression, which lead to adverse effects. Through the hormonal signaling system, EDCs can exhibit hormone-disrupting effects even at low doses, thus making it difficult to establish clear thresholds. EDCs have been reported to cause adverse effects by disrupting the estrogenic, androgenic, thyroid, and other signaling systems. Therefore, EDCs affect not only the endocrine system but also the reproductive, nervous, and immune systems. Owing to the wide-ranging effects of EDCs, there is no standardized definition of EDCs, and further research is needed to scientifically clarify EDCs. However, there are accumulating reports on the health hazards to humans caused by EDCs. Considering the precautionary approach, regulations regarding EDCs need to be reevaluated at both the national and international levels. This review introduces and discusses recent research and public initiatives related to EDCs. Can “our stolen future” be regained?

This review is aimed at clarifying the background and the meaning of new terminology “pituitary neuroendocrine tumours” (PitNETs) in WHO Classification 2022. The PitNETs share the unique structures of secretory granules (SG) with other neuroendocrine tumors, the good example of which is the pancreatic NETs which are now considered to be potentially aggressive, i.e., invasive and metastatic. The PitNETs share these features of pancreatic NETs and now are considered to be potentially aggressive tumors. The PitNETs are classified according to the functions (hormones) and transcription factors, PIT1, TPIT and SF1. The PitNETs are usually slow growing tumors with generally low (<3%) Ki-67 indices. PitNETs show some morphologic features which are more closely related to aggressive growths, such as Crooke cells. The questions how those particular PitNETs are aggressive have been approached by molecular techniques such as single cell RNA seq to clarify the genomic heterogeneity and the biology of individual tumor cells. It is expected that the PitNETs will be clarified and classified with more biologically and therapeutically oriented manner.

The 45,X/46,XY mosaicism is a rare condition with a wide range of phenotypes, including a nearly normal male or female phenotype and variable degrees of gonadal differentiation. Dysgenetic gonads containing Y chromosome material carry an increased risk of developing gonadal germ cell tumors. However, to date, molecular analyses of testicular germ cell tumors (TGCTs) in patients with 45,X/46,XY mosaicism have not been reported. We encountered a 17-year-old male patient with 45,X/46,XY mosaicism who presented with undervirilized external genitalia. Ultrasound examination revealed an abnormality in the right testis, and subsequent orchiectomy confirmed the presence of gonadoblastoma, germ cell neoplasia in situ, and seminoma. Molecular analysis of the tumor tissue revealed a heterozygous pathogenic KIT mutation (c.2446G>T, p.(Asp816Tyr)) and copy number gains across nearly all chromosomes, including 12p. This is the first report of genetic analysis of a TGCT in a patient with 45,X/46,XY mosaicism, revealing molecular abnormalities similar to those in male patients without differences of sex development. Furthermore, we reviewed five cases of seminoma in patients with 45,X/46,XY mosaicism, including the present case. These observations suggest that seminoma may develop after puberty regardless of the degree of masculinization, testicular position, or initial biopsy findings, highlighting the need for careful long-term surveillance in these patients.

Iodothyronine deiodinases (DIOs) are key regulators of thyroid hormone action. Three types of DIOs, including type 1 (D1), 2 (D2), and 3 (D3), coordinate the local and systemic availability of T3. D2 primarily catalyzes the activating conversion of T4 to T3, whereas D3 mainly catalyzes the inactivating conversion of T4 to reverse T3 (rT3) and T3 to diiodothyronine (T2). D1 has a relatively low affinity for T4 and contributes less to T4 activation but preferentially catalyzes the conversion of rT3 to T2. Thyroid hormones promote D1 and D3 expression, whereas D2 activity is transcriptionally regulated via several pathways such as cAMP and post-translationally through ubiquitin-dependent proteasomal degradation. Evidence from knockout and overexpressing mouse models and human genetic variants has clarified the physiological roles of DIOs in thyroid hormone economy. Reduced D1 activity increases serum rT3 levels, D2 enhances local thyroid hormone action and contributes to circulating T3 production, and D3 decreases circulating T3 and T4 levels while increasing rT3 levels. DIO dysregulation is implicated in several clinical conditions. GH-related disorders potentially alter thyroid function via D2-mediated mechanisms. In adrenal insufficiency, thyroid function may exhibit elevated serum fT3 levels without TSH suppression. Additionally, resistance to thyroid hormone β can be associated with bezafibrate-induced consumptive hypothyroidism through increased hepatic D3 expression. This review summarizes current knowledge on the biological properties and clinical implications of DIOs and highlights their significant role in the regulation of thyroid hormone action.

This randomized controlled study aimed to clarify weight loss targets for improving obesity-related disorders in individuals with overweight or obesity. A total of 294 participants with six obesity-related conditions were assigned to either a standard or intensive treatment group, with 12-month weight loss targets of ≥3% and ≥7%, respectively. The standard group followed the Japanese Guidelines for the Management of Obesity Disease 2016. The intensive group received frequent nutritional guidance, enhanced diet and exercise therapy, and additional pharmacotherapy. The primary outcome was weight loss and improvement in at least two obesity-related disorders at 12 months. Secondary outcomes included remission of health disorders, improvement in at least one health disorder, and visceral fat reduction. At 12 months, the weight loss was –2.5% in the intensive group and –1.7% in the standard group, with no significant difference in the primary outcome. However, remission of health disorders was achieved in 16.9% of the intensive group compared with 6.2% of the standard group (adjusted odds ratio 3.079; 95% CI 1.075–8.823; p = 0.036). Visceral fat reduction was greater in the intensive group (–20.46 cm² vs. –8.9 cm²; p = 0.039). Intensive treatment significantly improved blood pressure early and increased treatment motivation scores by 10.9% (95% CI: 1.2–20.6) at 24 months (p = 0.004). In both groups, ≥60% of the participants showed improvement in at least one disorder. Despite not achieving the target weight loss, resulting in no significant difference in the primary outcome, the intensive treatment increased remission percentages, improved early blood pressure control, and enhanced long-term treatment motivation. The study was registered at UMIN Clinical Trials Registry (UMIN ID: UMIN000031862).

Immune checkpoint inhibitor (ICI)-related type 1 diabetes is a rare but potentially life-threatening immune-related adverse event, and imaging findings immediately before clinical presentation and diagnosis have rarely been documented. We report a 71-year-old woman with large cell neuroendocrine carcinoma who developed fulminant type 1 diabetes mellitus during carboplatin, nab-paclitaxel, and atezolizumab therapy. The day of clinical presentation and diagnosis was defined as Day 0. On Day –1, she developed nausea and appetite loss without abdominal pain. On Day 0, she presented with impaired consciousness and fever; laboratory evaluation showed plasma glucose 1,435 mg/dL, glycated hemoglobin (HbA1c) 6.9%, marked ketonemia, severe hyperosmolality, negative anti-glutamic acid decarboxylase (GAD) antibody, and near-complete insulin deficiency. The metabolic presentation was interpreted as diabetic ketoacidosis/hyperosmolar hyperglycemic state (DKA/HHS) overlap. Computed tomography (CT) performed on Day –2 showed radiologic enlargement of the pancreatic tail with increased peripancreatic fat attenuation, both of which had resolved on Day 0. Pancreatic volume increased from 46.0 mL at baseline to 82.5 mL on Day –2, decreased to 47.9 mL on Day 0, and further declined to 39.0 mL at 6-month follow-up. This hypothesis-generating case documents incidental transient pancreatic enlargement with peripancreatic inflammatory changes shortly before diagnosis, followed by pancreatic atrophy. This case suggests that incidental pancreatic enlargement during ICI therapy may serve as an early radiologic clue to immune-related diabetes, supporting prompt metabolic evaluation even in the absence of abdominal pain or pancreatic enzyme elevation.

Mutations in the CACNA1H and PPP2R5D genes have been associated with functional abnormalities affecting both the endocrine and nervous systems. The CACNA1H gene encodes the T-type calcium channel CaV3.2, and pathogenic variants may alter channel activation and inactivation, resulting in increased intracellular calcium influx. Elevated intracellular calcium in adrenal zona glomerulosa cells acts as a key signal for aldosterone biosynthesis, thereby promoting excessive aldosterone secretion and contributing to the development of hypertension. The PPP2R5D gene encodes a regulatory subunit of protein phosphatase 2A (PP2A). Mutations in this gene may disrupt the regulatory function of PP2A, impairing the dephosphorylation of key neuroproteins and consequently affecting neural signal transduction and brain function. Cases of early-onset hypertension accompanied by intellectual disability associated with concurrent CACNA1H and PPP2R5D mutations remain rare. We report the case of an 18-year-old female presenting with early-onset hypertension and intellectual disability. Hypertension was first diagnosed at the age of 10 years and was accompanied by recurrent dizziness and headache. Physical examination revealed central obesity and signs of hyperandrogenism. Laboratory evaluation demonstrated elevated aldosterone levels with suppressed plasma renin activity, suggesting primary aldosteronism. Genetic analysis identified heterozygous variants in CACNA1H (c.6866C>T) and PPP2R5D (c.985A>G). Based on the clinical features and genetic findings, the patient was diagnosed with familial hyperaldosteronism type IV complicated by intellectual disability. This case highlights the importance of considering genetic forms of primary aldosteronism in young patients with early-onset hypertension and atypical clinical manifestations. Genetic testing may facilitate accurate diagnosis and guide individualized management.

While preserving skeletal muscle mass (SMM) is advocated in type 2 diabetes mellitus (T2DM), mass-based assessments often overlook muscle quality. This study aimed to investigate whether the balance between cellular integrity (phase angle [PhA]) and metabolic load (body fat mass [BFM]) is more clinically relevant to glycemic control than SMM-based profiling in patients with T2DM. In this cross-sectional study of 622 patients, participants were stratified into four groups based on sex-specific medians of PhA and BFM, and similarly for SMM and BFM. Multivariate logistic regression evaluated associations with glycemic targets (HbA1c <8.0% and <7.0%), adjusting for confounders. Sensitivity analyses utilized continuous Z-scores and interaction terms. High-PhA/High-BFM and High-PhA/Low-BFM groups showed significantly higher odds of HbA1c <8.0% compared with the Low-PhA/High-BFM reference group (adjusted odds ratio [OR] 2.05, 95% confidence interval [CI] 1.22–3.44; OR 2.10, 95% CI 1.21–3.64, respectively). Conversely, SMM/BFM combinations showed no significant associations. Neither profile was significantly associated with the stricter HbA1c <7.0% target. In continuous models, the PhA × BFM interaction was significantly associated with achievement of HbA1c <8.0% (p = 0.025), whereas SMM × BFM interaction was not. In conclusion, the PhA/BFM interplay shows a clearer association with glycemic control than SMM/BFM profiling in T2DM. Higher PhA may reflect a more favorable metabolic phenotype against adiposity and is associated with a lower likelihood of severe hyperglycemia (HbA1c ≥8.0%). PhA/BFM profiling offers a novel approach to identify high-risk patients overlooked by conventional mass-based assessments.

Steatotic liver disease is a common metabolic disorder, and interleukin-1β (IL-1β) contributes to hepatic inflammation and lipid accumulation. ATP-binding cassette subfamily A member 1 (ABCA1) regulates cholesterol efflux and lipid homeostasis. This study examined whether IL-1β suppresses hepatic ABCA1 expression and explored the underlying signaling and transcriptional mechanisms. Primary mouse hepatocytes and HepG2 cells were treated with IL-1β. ABCA1 expression was assessed by Western blotting and RT-qPCR, and ABCA1 promoter activity was examined using luciferase reporter assays with inhibitors targeting phosphoinositide 3-kinase (PI3K), p38 mitogen-activated protein kinase (p38 MAPK), or an H-89-sensitive pathway. Prolactin regulatory element-binding protein (PREB) involvement was evaluated by nuclear protein analysis, PREB-binding-site mutation, and siRNA-mediated knockdown. Lipid accumulation was assessed by intracellular cholesterol measurement and Oil Red O staining. IL-1β decreased ABCA1 protein and mRNA expression in a dose- and time-dependent manner and suppressed ABCA1 promoter activity. Inhibition of p38 MAPK or treatment with H-89 attenuated IL-1β-induced suppression of promoter activity and endogenous ABCA1 expression. Representative immunoblotting showed that IL-1β enhanced p38 MAPK phosphorylation, whereas SB203580 attenuated this response. IL-1β reduced nuclear PREB expression, and p38 MAPK inhibition restored nuclear PREB expression. Mutation of the PREB-binding site or PREB knockdown abolished IL-1β-mediated suppression of ABCA1 expression. IL-1β also increased intracellular cholesterol content and Oil Red O-positive lipid accumulation. These findings suggest that IL-1β suppresses hepatic ABCA1 expression through p38 MAPK signaling and an H-89-sensitive pathway, at least partly involving PREB-associated transcriptional regulation, and that this suppression is associated with hepatocellular lipid accumulation.

Vitamin D has been linked to insulin sensitivity and glucose metabolism. However, few studies have separately examined the association between serum 25-hydroxyvitamin D₂ (25(OH)D₂) and 25-hydroxyvitamin D₃ (25(OH)D₃) levels and insulin resistance. Therefore, we investigated the associations of serum 25(OH)D₂, 25(OH)D₃, and total 25-hydroxyvitamin D (25(OH)D) levels with the metabolic score for insulin resistance (METS-IR) in a nationally representative sample of Korean adults. This cross-sectional study analyzed data from 9,297 adults aged ≥19 years who participated in the 2022–2023 Korea National Health and Nutrition Examination Survey. Linear regression was used to examine the associations of serum 25(OH)D₂, 25(OH)D₃, and total 25(OH)D levels with the METS-IR. Total 25(OH)D (β = –0.0843, 95% confidence interval [CI]: –0.0995 to –0.0691) and 25(OH)D₃ levels (β = –0.0831, 95% CI: –0.0983 to –0.0680) showed significant, linear inverse associations with the METS-IR. However, serum 25(OH)D₂ levels were not significantly associated with the METS-IR. Stratified analyses revealed that the inverse association between the 25(OH)D₃ level and METS-IR was significantly stronger in participants with obesity, diabetes mellitus, or hypercholesterolemia than in their counterparts. These findings were consistent across all the sensitivity analyses. In this nationally representative study of Korean adults, total 25(OH)D and its principal component 25(OH)D₃ were inversely associated with the METS-IR. In contrast, 25(OH)D₂ was not associated, a finding most likely attributable to its very low circulating concentrations. Because total 25(OH)D performed comparably to 25(OH)D₃, it remains a practical measure of vitamin D status in metabolic care.

Although randomized controlled trials have demonstrated the efficacy of real-time continuous glucose monitoring (rtCGM), evidence from routine clinical practice remains limited, particularly in Asian populations. This study aimed to evaluate the effectiveness and safety of rtCGM initiation in individuals with diabetes. This multicenter, single-arm, retrospective, observational study was conducted at 34 sites across Japan (Clinical trial registration: UMIN000054275). Adults ≥18 years of age with diabetes who began using the Dexcom G6 rtCGM system, had a baseline glycated hemoglobin (HbA1c) level ≥7.5%, and continued rtCGM for at least 26 weeks were included. Factors associated with changes in HbA1c levels were examined using multivariate linear regression models. Among 192 participants, the mean HbA1c levels at 26 weeks were significantly lower (8.62 ± 1.14% vs. 7.88 ± 1.16%, p < 0.001) than those at baseline, with a difference of –0.73 ± 1.03%. In the multivariate analysis, greater HbA1c reduction was independently associated with higher baseline HbA1c (β = –0.40; p < 0.001), longer CGM active time (β = –0.008; p = 0.043), and older age (β = –0.010; p = 0.012), whereas prior isCGM use was associated with smaller reductions (β = +0.28; p = 0.045). Sex was also independently associated with changes in HbA1c levels (p = 0.028). During the 26-week follow-up period, one patient (0.5%) experienced diabetic ketoacidosis and four individuals (2.1%) experienced severe hypoglycemia. rtCGM initiation was associated with significantly lower HbA1c levels after 26 weeks of rtCGM use. These findings support the efficacy and safety of the Dexcom G6 in routine clinical practice.

Hereditary adrenocortical unresponsiveness to adrenocorticotropin (HAUA) is a rare congenital disorder characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid production. HAUA encompasses familial glucocorticoid deficiency (FGD) and triple A syndrome (AAAS) and is caused by autosomal recessive defects in ACTH-signaling–related genes, including MC2R, MRAP, AAAS, NNT, TXNRD2, and MCM4. To clarify the current clinical characteristics of HAUA (including FGD and AAAS) in Japan, we conducted a nationwide questionnaire-based survey. The primary survey identified the number of affected patients, and the secondary survey collected detailed clinical information. Fifteen patients were identified from 12 institutions. Detailed clinical data were obtained from nine patients (mean age, 40.6 years). Most patients developed symptoms during childhood [3.75 (0–8) years]. Seven presented with chronic adrenal insufficiency, and two experienced life-threatening events, hypoglycemia or encephalopathy. Genetic confirmation was obtained in four cases. All patients received glucocorticoid replacement therapy (mean hydrocortisone-equivalent dose, 13.0 mg/m²/day). Notably, 50% of adult patients were obese (BMI ≥25 kg/m²), although no clear association between glucocorticoid dose and BMI was observed. Despite the limited cohort size, this study provides detailed clinical information on HAUA (including FGD and AAAS) in Japan and suggests a potential risk of obesity in long-term management.

In adults, cases of dyshormonogenetic goiter (DG) that go undiagnosed during childhood may necessitate thyroidectomy due to unexplained thyroid enlargement, often presenting diagnostic challenges. This study aimed to characterize the histopathological features of the thyroid in adult DG cases, and to evaluate the feasibility of predicting subtypes from the findings. Fifty adult patients with DG confirmed by the presence of gene variants were included. All resected thyroids showed diffuse goiter with microscopically altered thyroid follicles throughout the gland. All patients with SLC5A5 abnormality (iodide transport defect) showed lobulation accentuated by interlobular fibrosis. Follicular cells were enlarged, except in patients with SLC26A4 abnormality (Pendred syndrome). A scant colloid was observed in all patients with thyroglobulin (TG) gene abnormality. Thyroid peroxidase (TPO) gene abnormality and SLC26A4 abnormality were characterized by large follicles with Sanderson’s polsters. Multiple non-encapsulated nodular lesions were present except in two patients with SLC26A4 abnormality. These were mainly follicular thyroid adenoma-like nodules associated with TG gene abnormality, TPO gene abnormality, and SLC5A5 variant. With SLC26A4 abnormality, the nodules were follicular nodular disease-like. The proposed histological framework may be particularly valuable for adult patients undergoing thyroidectomy for unexplained diffuse enlargement or multinodularity, particularly when no prior diagnosis of DG is documented.

Dipeptidyl peptidase-4 (DPP4) is involved in immune regulation and metabolic homeostasis. Although DPP4 inhibitors are widely used in type 2 diabetes, the clinical relevance of autoantibodies against DPP4 (DPP4-Ab) remains unclear. In this study, we aimed to investigate the association between circulating DPP4-Ab levels and mortality in 274 patients with type 2 diabetes (mean age, 63 years). Serum DPP4-Ab levels were measured using amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA), and survival was assessed using Kaplan-Meier analysis and Cox proportional hazards regression analysis. During a mean follow-up of approximately 5 years, 32 deaths had occurred. Patients with elevated DPP4-Ab titers (>1,676.8 alpha counts) had a higher mortality rate than those with low titers (22.2% vs. 9.3%, p = 0.0177). In Cox proportional hazards regression analysis, DPP4-Ab titers showed a trend toward association with all-cause mortality when analyzed as a continuous variable per 100 alpha counts (a.c.) increase (hazard ratio [HR], 1.042; 95% confidence interval [CI], 0.996–1.090; p = 0.071). When patients were stratified using the predefined cutoff value of 1,676.8 a.c., the high DPP4-Ab group showed significantly higher mortality risk than the low DPP4-Ab group (HR, 2.30; 95% CI, 1.09–4.84; p = 0.028). Addition of DPP4-Ab to an age-based model only slightly improved predictive discrimination. These findings suggest that elevated DPP4-Ab titers may be associated with mortality risk; however, this association should be interpreted cautiously and warrants further investigation as a potential adjunctive immunometabolic biomarker in type 2 diabetes.

In an aging society, the establishment of safe and effective treatment strategies for older patients with type 2 diabetes is crucial. We performed a secondary analysis of the Hokkaido-TZP study (UMIN000056962), evaluating the real-world outcomes of tirzepatide in patients aged ≥65 years. Of 213 patients in the safety analysis set, 11 (5.2%) discontinued treatment because of adverse events, primarily gastrointestinal symptoms. In the effectiveness analysis set (n = 199; mean age 71.3 years, glycated hemoglobin [HbA1c] 7.79%), tirzepatide significantly reduced both HbA1c and body mass index over 6 months in the Young-old (65–74 years) and Old-old (≥75 years) groups. Notably, even among the 148 patients (74.4%) using agents associated with a risk of hypoglycemia (insulin, sulfonylureas, or glinides) at baseline, a substantial proportion (66.9%) achieved an HbA1c <7.0%. The physicians proactively adjusted these concomitant medications in 39.2% of users, but despite these preemptive reductions, this subgroup still achieved a reduction in HbA1c comparable to that of the entire cohort, and no severe hypoglycemia was reported. A significant reduction in body weight occurred, and this was more pronounced in glucagon-like peptide-1 receptor agonist-naïve patients and those taking fewer hypoglycemia-inducing agents. Furthermore, the tirzepatide dose tended to be lower in the patients who achieved greater weight loss. These findings suggest that although tirzepatide is highly effective, even in older adults, its safety must be optimized through preemptive reductions in the doses of concomitantly administered secretagogues and careful monitoring, to prevent excessive reductions in HbA1c and weight loss in this vulnerable population.

Adrenal overt Cushing syndrome (CS) is a rare disease but presents with a high risk of serious, life-threatening complications. Although florid CS is less frequently reported now, the interval between symptom onset and diagnosis still remains as long as four years. In this study, we investigated the current status of patients presenting with adrenal overt CS in the 2000s using data from the “Study of Advancing Care and Pathogenesis of Intractable Adrenal Diseases in Japan (ACPA-J study).” Based on the findings, we have established the diagnostic criteria for adrenal overt CS through the deliberation with members of the Health and Labour Sciences Research Grant “Research group on Disorders of adrenal hormones” and the public comment process conducted by the Japan Endocrine Society. We expect these diagnostic criteria to facilitate the designation of adrenal overt CS as an intractable disease and enhance standards of care.

Cushing’s disease (CD) is very rare in children. Nineteen children (≤18 years) with CD (median age at diagnosis: 13 [6–17] years; 12 females) were retrospectively analyzed using medical records (1994–2025) from Toranomon Hospital, Tokyo, Japan. Facial changes (88.9%), weight gain with decreased growth rate (88.9%), central obesity (88.9%) and hirsutism (94.4%) were frequently observed at diagnosis. Median time to diagnosis was 2.7 (0.25–5.8) years. Screening for endogenous hypercortisolism was assessed by 24-hour urinary free cortisol levels, serum cortisol levels at 23:00, and serum cortisol levels at 8:00 after a low-dose dexamethasone suppression test (DST), each with 100% sensitivity. Etiological diagnosis was evaluated by serum cortisol levels at 8:00 after a high-dose DST, plasma adrenocorticotropic hormone (ACTH) levels after a corticotropin-releasing hormone test, and plasma ACTH levels at 8:00, with sensitivities of 85.7%, 93.8%, and 83.3%, respectively. The actual tumor detection rate on magnetic resonance imaging (MRI) was 72.2%. Micro-pituitary neuroendocrine tumors were identified in 77.8% of patients. The total remission rate was 94.4% (median follow-up: 3.8 [0–10.4] years). The mean standard deviation scores (SDS) (SD) of height and body mass index (BMI) at onset and diagnosis were –0.45 (0.63) and –2.0 (1.1), and 0.61 (0.95) and 1.6 (0.75), respectively. Height and BMI SDS (SD) improved to –1.0 (0.80) and 0.091 (1.2) at the last visit (age: 11.4–17.5 years; follow-up: 1–8.6 years), respectively. This study revealed clinical characteristics of Japanese children with CD, including distinctive BMI SDS and a high tumor detection rate by MRI.

Capivasertib, an oral pan-AKT inhibitor, is a therapeutic option for hormone receptor-positive advanced breast cancer. While hyperglycemia is a recognized adverse effect of AKT inhibition, its diagnosis is often delayed in routine clinical practice. We report a case of acute-onset severe hyperglycemia with diabetic ketosis identified within 4 days of initiating capivasertib in a patient without pre-existing glucose intolerance. A 61-year-old woman developed marked hyperglycemia (random plasma glucose, 482 mg/dL) with ketosis, despite being asymptomatic. Laboratory evaluation showed markedly elevated serum insulin (591.9 μU/mL), indicating preserved pancreatic β-cell function and severe insulin resistance. Blood glucose levels improved rapidly within 2 days of admission using minimal insulin therapy and fluid replacement. Unlike previously reported cases identified after symptomatic presentation, including emergency department visits, or under intensive inpatient monitoring, this case was detected through a proactively scheduled outpatient visit on day 4—strategically timed to coincide with the end of the first dosing cycle based on the drug’s pharmacological profile. This observation highlights that severe hyperglycemia can develop very early and remain asymptomatic, underscoring the importance of proactive detection. Therefore, even in patients without pre-existing glucose intolerance or with preserved insulin secretion, proactive glucose monitoring during the first week of therapy, specifically near the end of the initial dosing cycle, is essential to prevent severe metabolic complications. Appropriate patient education and early consultation with diabetes specialists are also crucial for timely management.

We report a case of severe thyroid eye disease (TED) complicated by dysthyroid optic neuropathy (DON) in a 55-year-old woman with Graves’ disease. Despite insufficient response to high-dose intravenous steroid therapy, teprotumumab led to marked improvement in proptosis, orbital inflammation, and visual function. However, treatment was associated with progressive and persistent sensorineural hearing loss after completing eight infusions. Auditory symptoms began after the fifth infusion with intermittent aural fullness and sound reverberation, progressing to mild down-sloping sensorineural hearing loss. Nine days after the final infusion, the four-frequency pure-tone average (PTA4) was 21.25 dB hearing level (HL) in the right ear and 27.50 dB HL in the left ear. Despite initiation of oral prednisolone therapy (40 mg/day with tapering), progressive hearing loss was observed in the right ear, particularly in the low- to mid-frequency range (250–2,000 Hz), with thresholds worsening to 90 dB HL. At twenty days after the final infusion, PTA4 had increased to 75.00 dB HL in the right ear and 31.25 dB HL in the left ear. Serial audiometric assessments at 107, 128, and 198 days after the final infusion demonstrated no recovery. The patient’s history of sudden sensorineural hearing loss suggests increased susceptibility to teprotumumab-associated ototoxicity. This case underscores the importance of individualized risk assessment, careful audiologic monitoring, and shared decision-making when balancing visual recovery against the risk of potentially irreversible auditory toxicity.