Journal of the Endocrine Society

IntroductionPituitary adenomas/pituitary neuroendocrine tumors (PitNETs) are common intracranial tumors, clinically affecting 1:1000 individuals and most cases remain genetically unexplained. Emerging research has highlighted the major contribution of germline pathogenic variants to tumorigenesis across many tissue types in young subjects . We investigated whether young-onset (<30 years old) pituitary macroadenomas that were negative for known genetic causes harbor pathogenic or likely pathogenic (P/LP) variants in cancer-risk genes. MethodsWe retrospectively analyzed 48 subjects (29 males; 96% GH- or PRL-secreting) with sporadic pituitary macroadenomas that were negative for known germline variants (AIP, MEN1, CDKN1B) or duplications (GPR101). Whole-exome sequencing (WES) was performed on germline DNA. Bioinformatics analysis including variant calling (for small variants and CNVs), annotation and variant prioritization were performed, using secondary analysis pipelines for WES data and AION predictor platform for tertiary analysis. Variants in established cancer-risk genes were prioritized. ResultsP/LP germline variants in cancer-risk genes were identified in 14.6% of subjects on ClinVar/ACMG criteria. This rose to 31.3% of subject with deleterious variants when additional in silico and AION predictor criteria were used. Genes included: BAP1, BRCA1, BUB1, ELAC2, FLCN, MCPH1, MSR1, MUTYH, PDE11A, POLE, POLG, PMS2, RAD51C, RECQL4, SDHA, SDHD, SEC23B, TMEM127, WRN. ConclusionsOur findings expand the spectrum of genes potentially associated with young-onset pituitary macroadenomas. The identification of a high rate of deleterious germline variants in cancer-risk genes in pituitary adenomas/PitNETs echoes similar findings in young patients across a wide range of tumors. These results may have relevance for genetic counseling and potentially could expand targeted management strategies in young patients with large pituitary tumors.

ImportanceA subset of thyroid cancers develops in a setting of a known hereditary cancerassociated syndrome. Understanding the population prevalence of thyroid cancer-associated syndromes is important to guide germline genetic testing and clinical management. ObjectiveTo estimate the prevalence of the major thyroid cancer-associated syndromes in the United States using the All of Us Research Program (AoU) data. DesignIn this cohort study, we identified pathogenic and likely pathogenic (P/LP) variants from the ClinVar database in 245,394 AoU biobank participants. We performed a logistic regression analysis of the association of ClinVar P/LP variants with thyroid cancer. P/LP variants in the genes of interest were manually curated to ensure match and pathogenicity status. We calculated the prevalence of thyroid cancer-associated syndromes defined by the presence of P/LP variants. ResultsUsing logistic regression, we found that three hereditary syndromes, multiple endocrine neoplasia type 2 (MEN2, RET gene, p = 3.23e-20), PTEN hamartoma syndrome (PHPS, PTEN gene, p = 2.59e-15), and familial adenomatous polyposis type 1 (FAP, APC gene, p = 2.73e-10) were significantly associated with thyroid cancer. All these syndromes were previously reported to increase the risk of thyroid cancer. The prevalence of thyroid cancer-associated syndromes in the AoU was 1:2,172 (113 cases), 1:8,764 (28 cases), and 1:8,461 (29 cases) for MEN2, PHPS, and FAP, respectively. Most carriers of P/LP variants were not diagnosed with the features of the syndromes, including thyroid cancer, pheochromocytoma, or primary hyperparathyroidism. Three pathogenic RET variants that cause two amino acid substitutions, V804M and V804L, constitute 65% of all MEN2 variants in the AoU, and none of these carriers were diagnosed with thyroid cancer. Conclusions and RelevanceThe prevalence of MEN2 and PHPS is [~]10-20 times higher than it is currently estimated for the general population (1:35,000 - 1,50,000 for MEN2 and 1:200,000-1:250,000 for PHTS). Most affected individuals are not diagnosed with thyroid cancer. These results further refine our understanding of the prevalence of hereditary syndromic thyroid cancers and may change the clinical approach to patients with moderate-risk RET mutations (such as V804M and V804L), potentially emphasizing active surveillance over prophylactic thyroidectomy. Key Points QuestionWhat is the prevalence of the major thyroid cancer-associated syndromes in the United States? FindingsIn this cohort study that includes 245,394 genotyped participants in the All of Us Research Program (AoU), the prevalence was 1:2,172 for multiple endocrine neoplasia type 2 (MEN2) and 1:8,764 for PTEN hamartoma syndrome (PHTS). MeaningThe prevalence of MEN2 and PHPS is [~]10-20 times higher than currently estimated for the general population.

ObjectiveMutations in several genes have been associated with familial forms of pituitary adenomas. Sporadic pituitary adenomas (i.e. with no family history or coexistent endocrine tumours) are also occasionally found to result from germline mutations in these genes, especially in young patients with larger tumours. The aim of this study was to determine the frequency of germline mutations in patients with young-onset sporadic pituitary macroadenomas. MethodsA cohort of 225 Portuguese patients with sporadic pituitary macroadenomas diagnosed before the age of 40 years was studied by whole exome sequencing (WES) followed by the analysis of a virtual panel of 29 genes that have been associated with predisposition to pituitary adenomas. ResultsPathogenic and likely pathogenic variants were identified in 16 (7.1%) of patients. The affected genes were AIP (n=4), PMS2 (n=4), MEN1 (n=2), VHL (n=2), CDH23 (n=1), MSH2 (n=1), SDHB (n=1), and TP53 (n=1). In patients diagnosed under the ages of 30 and 18 years, the frequency of mutations increased to 9.0% and 12.0%, respectively. ConclusionThis is so far the largest multigene analysis of patients with young-onset sporadic pituitary macroadenomas. We confirmed the AIP as the most frequently involved gene, but also uncovered rarer genetic causes of pituitary adenomas, including the first independent confirmation of a role of the CDH23 gene. The results may contribute to a better understanding of the genetic landscape of these tumours and help to decide which genes to include in the genetic screening of patients with young-onset pituitary macroadenomas.

BackgroundCongenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is characterized by a broad clinical spectrum, ranging from salt-wasting to nonclassical forms. Genotype-phenotype correlations based on predicted residual enzymatic activity have been widely studied, but data from Latin American populations remain scarce. Additionally, the influence of mutational burden on phenotype prediction has not been fully explored. ObjectiveTo evaluate the genotype-phenotype correlation and the impact of mutational burden on predictive accuracy in a Colombian cohort of patients with CAH. MethodsWe conducted a cross-sectional study of patients with confirmed CAH enrolled in a specialized rare disease program. Genotypic classification was based on predicted residual enzymatic activity (Null, A, B, C), and clinical phenotype was categorized as salt-wasting (SW), simple virilizing (SV), or nonclassical (NC). Genotype-phenotype concordance was defined as exact category agreement. Mutational burden was defined as the total number of pathogenic variants, dichotomized as low ([&le;]2 mutations) or high (>2). Penalized logistic regression (Firth method) was used to evaluate associations between mutational burden, sex, and concordance. ResultsAmong 48 patients with available genetic data, genotype-phenotype concordance was highest in severe genotypes: 100% in Null and 85.7% in Group A. In contrast, concordance declined in Group B (33.3%) and Group C (44.4%). Individuals with high mutational burden had significantly lower odds of concordance (OR = 0.18; 95% CI: 0.03-0.94). No significant interaction between sex and mutational burden was observed. More than one-third of Group C patients exhibited more severe phenotypes than predicted. ConclusionsOur findings support established genotype-phenotype correlations in CAH, particularly for severe genotypes. However, increased mutational burden was associated with reduced predictive accuracy, suggesting the need to consider total mutation load in clinical assessment and genetic counseling.

BackgroundNon-targeted Analysis (NTA) methods identify novel exposures; however, few chemicals have been quantified and interrogated with pregnancy complications. ObjectivesWe characterize levels of nine exogenous and endogenous chemicals in maternal and cord blood identified, selected, and confirmed in prior NTA steps including: linear and branched isomers perfluorooctane sulfonate (PFOS); perfluorohexane sulfonate (PFHxS); monoethylhexyl phthalate; 4-nitrophenol; tetraethylene glycol; tridecanedioic acid, octadecanedioic acid; and deoxycholic acid. We evaluate relationships between maternal and cord levels and the relationship gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy in a diverse pregnancy cohort in San Francisco. MethodsWe collected matched maternal and cord serum samples from 302 pregnant people at delivery from the Chemicals in Our Bodies cohort in San Francisco. Chemicals were identified via NTA and quantified using targeted approaches. We calculate distributions and Spearman correlation coefficients testing the relationship of chemicals within and between the maternal and cord blood matrices. We used logistic regression to calculate the odds of GDM and hypertensive disorders of pregnancy associated with an interquartile range increase in maternal chemical exposures. ResultsWe detected linear PFOS, PFHxS, octadecanedioic acid, and deoxycholic acid in at least 97% of maternal samples. Correlations ranged between -0.1 and 0.9. We observed strong correlations between cord and maternal levels of PFHxS (coefficient = 0.9), linear PFOS (0.8), and branched PFOS (0.8). An IQR increase in linear PFOS, branched PFOS, and octadecanedioic acid is associated with increased odds of GDM [OR (95%CI): 1.43 (0.96, 2.14), 1.56 (1.00, 2.44), and 1.26 (0.83, 1.92) respectively] and tridecanedioic acid positively associated with hypertensive disorders of pregnancy [1.28 (0.90, 1.86)]. DiscussionWe identified both exogenous and endogenous chemicals, two of which (octadecanedioic acid and tridecanedioic acid) have both endogenous and exogenous sources, and which have seldom been quantified in pregnant people or related to pregnancy complications.

ObjectiveThis study aims to investigate the increased risk in Multiple Endocrine Neoplasia type 1 patients to develop gastrinomas later in life. It focuses on the mechanisms that may come into play in duodenal enteroendocrine cells to result in gastrinoma development. By identifying key regulators involved, this study seeks to contribute towards future biomarker development and guide surveillance strategies in MEN1 patients to improve patient outcomes. Clinically, these insights may inform the development of gene expression-based surveillance tools that could be integrated into routine endoscopic or biopsy-based assessments for MEN1 patients. BackgroundGastrinomas, commonly associated with Multiple Endocrine Neoplasia type 1 (MEN1), are neuroendocrine tumors arising from duodenal enteroendocrine cells. The development and differentiation of these cells are also governed by transcription factors and signaling pathway. Loss of MEN1 disrupts this regulatory network, leading to cellular mis-specification, impaired differentiation, and increased risk of tumorigenesis. Understanding these early molecular events is clinically significant, as it may aid in identifying high-risk MEN1 patients, refining surveillance protocols, and guiding the development of targeted therapies for conditions such as Zollinger-Ellison syndrome. MethodsDatabases, including PubMed, MEDLINE, Google Scholar, and both open-access and subscription-based journals, were searched without date restrictions to investigate how the loss of MEN1 on developmental regulators (NEUROG3, ASCL1, PAX4, PAX6, ISL1, NKX2.2, INSM1, ARX, Notch, Wnt, BMP, Shh, MAPK/ERK, mTOR) of duodenal enteroendocrine cells, results in gastrinoma development. Studies meeting the criteria outlined in the methods section were systematically reviewed to address the research question. This study adheres to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. ResultsMutated MEN1 disrupts the expression of key transcription factors (NEUROG3, ASCL1, PAX4, PAX6, ISL1, NKX2.2, INSM1, ARX) and signaling pathways (Notch, Wnt, BMP, Shh, MAPK/ERK, mTOR) that govern the development and differentiation of duodenal neuroendocrine (enteroendocrine) cells. This dysregulation results in impaired cell fate specification, abnormal differentiation, and uncontrolled proliferation, events that collectively drive gastrinoma formation. These alterations may serve as early biomarkers for disease progression in MEN1 patients and offer potential targets for improved surveillance and personalized intervention strategies. ConclusionThese findings highlight the critical role of MEN1 in maintaining epithelial homeostasis and suggest that molecular profiling of dysregulated transcription factors and signaling pathways may support early detection, risk stratification, and targeted surveillance in MEN1 patients. The loss of MEN1 impairs cell fate specification and differentiation, promoting abnormal proliferation and increasing the risk of gastrinoma formation. In the future, these insights may contribute to improved diagnostic strategies and the development of personalized therapeutic approaches, ultimately enhancing clinical outcomes for patients with MEN1-associated gastrinomas.

Thyroid disorders, particularly hypothyroidism, are prevalent in the Chinese population and have been linked to specific genetic variations. This study investigates the associations between single nucleotide polymorphisms (SNPs) and thyroid disorders in a cohort of Chinese individuals. It aims to explore a novel aspect of thyroid disorders, precisely the effect of different SNPs on the prevalence of developing these disorders, autoimmune diseases, or cancer. It focuses on four SNPs: rs965513, rs179247, rs3087243, and rs231779. The analysis revealed significant associations between these SNPs and thyroid disorders, with the A allele of rs179247 showing a higher risk.

PurposeInfants and toddlers with classical congenital adrenal hyperplasia (CAH) are at high risk for adrenal crisis and associated sequelae. To better understand acute illness at this early age, we determined the frequency and severity of acute illness and hospitalizations between 0-4 years of age, both within CAH and compared to controls. We also evaluated the impact of pre-hospital stress-dose hydrocortisone on Emergency Department (ED) visits and hospitalizations. MethodsWe performed a retrospective study of 40 CAH youth and 27 age-matched controls at a tertiary center. Characteristics of acute illnesses during the first 4 years of life were recorded, including fever, vomiting, diarrhea, ED visits, hospitalizations, abnormal electrolytes, and stress-dose hydrocortisone usage. ResultsCAH youth had more frequent illnesses requiring stress-dosing when they were younger than 2 years old [4.0 (1.0-6.0)] compared to when they were 2-4 years old [3.0 (1.0-4.0), P < 0.05], with the most illnesses during their first year of life. As well, CAH infants and toddlers had more hospitalizations younger than 2 years old compared to 2-4 years old (36 vs 2). 25% (3/12) of CAH youth with abnormal electrolytes in the ED did not receive any stress-dosing (oral/IM) prior to the ED, and only 25% (3/12) had received intramuscular hydrocortisone at home. CAH youth had more frequent ED visits (7.4 times as many) and hospitalizations (38 to 0) compared to controls. ConclusionsVery young children with classical CAH are at high risk for acute illness and hospitalizations during their first 2 years of life, and do not receive adequate stress-dosing prior to the ED despite appropriate education. Our findings underscore the need for earlier recognition of acute illness in this vulnerable population and improved education regarding administration of stress-dose hydrocortisone to prevent morbidity.

Puberty is a critical developmental stage, and its early onset, termed precocious puberty, has garnered attention because of its potential health and psychosocial implications. Environmental exposure to endocrine-disrupting chemicals (EDCs), including phthalates, has been associated with alterations in pubertal timing; however, the evidence remains inconsistent. This meta-analysis investigated the association between exposure to specific phthalate metabolites and early puberty; the study focused on the effects of sex and exposure timing (prenatal vs. postnatal). We conducted a systematic search to identify studies examining phthalate exposure and early puberty, covering research published between 2014 and 2024. This search yielded 29 relevant studies, of which 13 met our inclusion criteria and were selected for analysis. A previously published meta-analysis had synthesized data from these same 13 studies, aligning with our research objectives. Due to reporting heterogeneity across the additional studies, our analysis focused on these 13 studies. Random-effects models were applied to estimate pooled relative risks (RRs), with data stratified by sex and exposure timing. Meta-regression and subgroup analyses were performed to evaluate the effects of demographic and temporal factors. The results indicated limited associations between most phthalates and early puberty risk. Postnatal exposure to mono-n-butyl phthalate was modestly associated with an increased risk of early puberty in boys (RR: 1.03; 95% confidence interval [CI]: 1.01-1.06), whereas exposure to mono-(3-carboxypropyl) phthalate was associated with a slight reduction in the risk of early puberty in girls (RR: 0.955; 95% CI: 0.917-0.995). However, these associations were not significant after adjustment for urine specific gravity, suggesting the presence of measurement variability or residual confounding. Subgroup and meta-regression analyses revealed no significant modifying effects of sex or exposure timing. Publication bias assessments indicated no substantial asymmetry. Despite these observed patterns, definitive conclusions cannot be drawn because of data limitations, small sample sizes, and methodological inconsistencies. Future research should prioritize standardized exposure and outcome reporting, larger cohorts, and investigation into the cumulative effects of phthalates with other EDCs. This study demonstrates the complexity of the effects of phthalates on pubertal timing and the need for more rigorous investigations to guide public health interventions.

Cannabis use during pregnancy continues to increase with smoking remaining the most common mode of consumption. While clinical studies highlight an association between prenatal cannabis use and adverse pregnancy outcomes, less is known about placental outcomes, even though many of the reported pregnancy outcomes are thought to be mediated via placental dysfunction. Here, we established a mouse model of gestational cannabis smoke exposure to investigate the impacts on fetal outcomes and placental structure and function. Pregnant CD1 mice were exposed daily to {Delta}9-tetrahydrocannabinol (THC)-dominant cannabis smoke (12-14% THC, 0-2% CBD) or filtered air from embryonic day (E)6.5 to E18.5 or parturition. Cannabinoid analyses in cannabis smoke-exposed, paired maternal and fetal livers revealed total THC and 11-Nor-9-carboxy-THC (THCA) concentrations of 135.95 {+/-} 13.60 ng/g and 30.84 {+/-} 4.68 ng/g, respectively. Moreover, Cyp1a1, a smoke-inducible enzyme, was induced by 4-fold in cannabis smoke-exposed placentae. No changes in offspring body weights were observed; however, there was a marked decrease in the brain-to-body weight ratio of exposed postnatal day 1 (PND1) offspring. Placentae from exposed dams were significantly reduced in size, with altered zonation marked by a significantly decreased junctional zone and increased labyrinth zone. Key trophoblast differentiation markers (Tfap2c, Tpbpa, Pcdh12) and placental endocrine regulators (Pl2, Igf1r) were significantly downregulated following cannabis smoke exposure in placentas. Furthermore, transcript levels of placental nutrient and vascularization markers, Glut1, Vegfa and Pparg were significantly decreased in cannabis smoke-exposed placentas. By employing a physiologically relevant platform of prenatal cannabis exposure in vivo we demonstrate the adverse effects of prenatal cannabis smoke exposure on placental structure and function as well as on fetal brain growth.

Significance StatementThis study identifies microhomology-mediated end joining (MMEJ) as a novel mutational mechanism underlying a pathogenic deletion in the androgen receptor gene in a patient with complete androgen insensitivity syndrome. By mapping the genomic breakpoint at the nucleotide level, we demonstrate the presence of canonical features of MMEJ, thereby expanding the known mechanisms of genomic structural variation in AR. These findings underscore the importance of incorporating copy number variation (CNV) detection and breakpoint analysis into diagnostic workflows for 46,XY differences of sex development (DSD), enabling more accurate molecular classification and improved patient management. BackgroundCopy number variations in the androgen receptor gene are an underrecognized cause of androgen insensitivity syndrome. Understanding their mutational mechanisms can improve AIS diagnosis and genotype-phenotype correlation. ObjectiveTo investigate microhomology-mediated end joining (MMEJ) as a mutational mechanism underlying a structural variant in the AR gene and to assess the contribution of AR CNVs to AIS through comparative gene burden analysis. MethodsWhole-exome sequencing, Multiplex Ligation-dependent Probe Amplification, PCR, and Sanger sequencing were used to identify and refine a hemizygous deletion affecting exons 6-8 of the AR gene in a 46,XY individual with CAIS. Breakpoint mapping and local alignment were performed using R packages Biostrings and GenomicRanges. A literature and database review identified AR CNVs in AIS cases, which were compared to CNVs in the general population to assess AR-specific CNV burden. ResultsAn accurate genomic analysis revealed an 8-bp microhomology region flanking the genomic breakpoint of the CNV event found in this CAIS patient, consistent with microhomology-mediated end joining event. Among 991 AIS cases, 49 harbored AR CNVs, significantly enriched compared to controls (OR = 4.59, P = 9.2 x 10-{superscript 1}). Exon 2 was the most frequently affected region and most strongly associated with CAIS. ConclusionThis study provides the first molecular evidence that MMEJ can mediate pathogenic deletions in the AR gene. The significant enrichment of CNVs in AIS and their non-random distribution across functional domains support their role in disease pathogenesis and highlight the value of CNV-level analysis in the diagnostic evaluation of AIS.

BackgroundIncidental adrenocortical adenomas (IA) are common. Current guidelines suggest screening for primary aldosteronism (PA) only in cases of hypertension or hypokalemia. This study aimed to evaluate the spectrum from overt PA to mild dysregulated aldosterone production with a sensitive protocol irrespective of blood pressure (BP) and potassium in patients with IA. Methods254 consecutive patients (excluding hypercortisolism) were evaluated. The spectrum of PA was defined as a suppressed renin plus the following criteria: 1)Overt PA: aldosterone-to-renin-ratio (ARR) >30 ng/dL-to-ng/mL/hr, plasma aldosterone concentration (PAC) >15ng/dL, and/or 24h urinary aldosterone >10 ug/24h; 2)Moderate PA: ARR 20-30 ng/dL-to-ng/mL/hr, PAC 10-15 ng/dL; 3)Mild dysregulated aldosterone production: ARR <20 ng/dL-to-ng/mL/hr and PAC >5-10 ng/dL. Results35% (n=89/254) met criteria for PA spectrum, 20% (34/89) were initially normotensive and 94% (84/89) normokalemic. Overt, moderate, and mild groups were 10%, 12%, and 13%. There were trends across groups of clinical severity: systolic BP (153{+/-}19, 140{+/-}14, 137{+/-}14 mmHg, p-trend<0.05), resistant hypertension (50%, 23%, 7% p-trend=<0.001), daily defined dose of antihypertensives (DDD) (3.2{+/-}1.6, 1.2{+/-}1.5, 0.4{+/-}0.6 p-trend=0.001), and lower eGFR (75.5{+/-}30.8, 97.8{+/-}38.5, 101{+/-}25.5, p-trend<0.01). At follow-up (mean 28{+/-}15 months), 87% had treatment with MR antagonists or surgery with decreased systolic BP relative to clinical severity, -31.3 {+/-}23, -12.7 {+/-}19, and -11.4 {+/-}19 mmHg, (p-trend<0.001). Similar trends were observed for DDD, with significant increase in renin. ConclusionsThere is a prevalent spectrum of clinically-relevant PA and dysregulated aldosterone production in IA, irrespective of BP or potassium, usually undetected. Aldosterone-directed treatment improved BP and normalized renin even in milder cases. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/24305640v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@1e72a4borg.highwire.dtl.DTLVardef@189d110org.highwire.dtl.DTLVardef@fc84b0org.highwire.dtl.DTLVardef@6b7de4_HPS_FORMAT_FIGEXP M_FIG C_FIG

Primary aldosteronism is characterized by renin-independent hyperaldosteronism that originates from aldosterone-producing lesions in the adrenal glands. Under physiological conditions, aldosterone synthase (CYP11B2) expression is confined to the adrenal zona glomerulosa where it catalyzes the final reaction yielding aldosterone. The regulation of CYP11B2 transcription depends on the control of cellular membrane potential and cytosolic calcium activity. In primary aldosteronism, aldosterone-producing adenomas (APAs) are characterized by disrupted regulation of CYP11B2 expression resulting in autonomous biosynthesis of aldosterone. These lesions often harbor aldosterone-driver somatic mutations in genes encoding ion transporters/channels/pumps that increase cytosolic calcium activity causing increased CYP11B2 expression and aldosterone biosynthesis. We investigated APAs devoid of known somatic mutations and detected a missense mutation and a deletion-insertion variant in MCOLN3 which encodes for mucolipin-3 (TRPML3) -- a highly conserved inwardly-rectifying, cation-permeable channel. These MCOLN3 mutations were identified in three APAs derived from male patients with primary aldosteronism: p. Y391D and p.N411_V412delinsI. Both mutations are located near the ion pore and selectivity filter of TRPML3. This is the first report of disease-causing MCOLN3 mutations in humans. Functional studies suggest MCOLN3Y391D might directly or indirectly via membrane depolarization alter calcium influx of transfected adrenocortical cells, resulting in increased CYP11B2 transcription and aldosterone production. This study implicates mutated MCOLN3 as a driver of aldosterone excess in primary aldosteronism. Significance StatementPrimary aldosteronism is a common but under-diagnosed endocrine disease that contributes to global hypertension burden and cardiovascular mortality and morbidity. Hyperaldosteronism in primary aldosteronism is mainly caused by adrenal lesions harboring somatic mutations that disrupt intracellular calcium levels and consequently aldosterone synthase expression and aldosterone production. Majority of these mutations have been identified in genes encoding ion transporters/channels/pumps. Herein, we report the first disease-causing somatic mutations in human MCOLN3 in aldosterone-producing adenomas (APAs) devoid of known mutations. In vitro investigations showed the MCOLN3 variant (p.Y391D) caused an influx of cytosolic calcium in adrenocortical cells and the subsequent increase in aldosterone synthase and aldosterone biosynthesis.

BackgroundThe weight loss medication semaglutide has recently become widely recognized for its effectiveness. Medical professionals have expressed safety concerns about semaglutide for patients who have a family background of thyroid or uterine cancers. The FDA has communicated about potential dangers requiring careful selection of patients before treatment. This study reviews existing research about semaglutide as a weight management treatment for patients with familial cancer histories while analyzing its potential advantages and dangers. ObjectiveTo examine recent studies on the use of semaglutide for weight loss in individuals with family histories of thyroid or uterine cancers, while also considering both potential risks and benefits. Primary & Secondary Outcome MeasuresSemalutides safety concerns are a concern for patients with family history of thyroid or uterine cancer. Semaglutide has potential medical advantages such as promoting weight loss and decreasing cancer risk, which is its secondary effect. InterventionSemaglutide is now a widely used treatment for weight loss, acting as an antagonist for the GLP-1 receptor. Primary & Secondary Outcome Measures: Semalutides safety concerns are a concern for patients with family history of thyroid or uterine cancer. Semaglutide has potential medical advantages such as promoting weight loss and decreasing cancer risk, which is its secondary effect. MethodsA systematic literature search was conducted to identify studies investigating the use of semaglutide in patients with a family history of thyroid or uterine cancer. The following databases were searched: PubMed, Google Scholar, and ClinicalTrials.gov. Search terms included "semaglutide," "thyroid cancer," "endometrial cancer," "GLP-1 receptor agonists," and "weight loss." Studies published between 2010 and 2024 were included. The search strategy was designed to capture both preclinical and clinical studies. Studies were included if they investigated the safety or efficacy of semaglutide in patients with a family history of thyroid or uterine cancer and provided clear data on cancer risk or weight loss outcomes. Studies lacking methodological rigor or not addressing the research question were excluded. The risk of bias in included studies was assessed using the Cochrane Risk of Bias Tool. Due to the heterogeneity of the studies, results were synthesized narratively, and a meta-analysis was not performed. ResultsA total of 4 studies involving 1,699,198 participants were included. Results showed no significant link between semaglutide use and thyroid cancer risk in human studies, although rodent studies indicated a higher risk of thyroid C-cell tumors. Preclinical data suggested potential benefits of semaglutide in reducing endometrial cancer risk, but definitive human research is needed. Article SummaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSThis review utilizes a systematic and comprehensive search strategy across multiple databases, focusing on high-risk populations and applying clear inclusion criteria for both preclinical and clinical data. However, the studies included are heterogeneous, human data on cancer risk is limited, long-term safety information is lacking, potential publication bias may be present, and the findings cannot be generalized. ConclusionIt is recommended that healthcare providers carefully review patient records and exercise caution when prescribing semaglutide to those with a history of thyroid or uterine cancers in their family.

Background68Ga-Pentixafor positron emission tomography/computed tomography (PET/CT) is an emerging method for the classifying primary aldosteronism (PA). How to use this method for PA classification is still controversial. MethodsA retrospective study was conducted in patients with PA who underwent PET/CT. These patients had a classification diagnosis of unilateral PA (UPA) or bilateral PA (BPA) based on adrenal venous sampling or post-surgical outcomes. Area under the receiver operating characteristic curve (AUC), specificity and sensitivity were used to analyze the accuracy of the lateralization index (LI) based on adrenal maximum standardized uptake value (SUVmax), dominant side SUVmax adjusted by liver, dominant side of SUVmax and visual analysis. ResultsA total of 208 PA patients were included, with 128 UPA and 80 BPA. The AUC for diagnosing UPA using LI and visual analysis were 0.82 [95% CI, 0{middle dot}77-0{middle dot}87] and 0.82 (95% CI, 0{middle dot}76-0{middle dot}87), respectively, higher than the dominant side of SUVmax [0.72, (95%CI, 0{middle dot}65-0{middle dot}78)] and dominant side SUVmax adjusted by liver [0.71,(95%CI, 0{middle dot}64-0{middle dot}77)]. Visual analysis showed a sensitivity of 0.73 (95%CI,0.65-0.81) and a specificity of 0.88(95%CI,0.80-0.95). The LI cutoff of 1.50 resulted the highest Youden Index of 0.59, with a sensitivity of 0.68 (95%CI,0.59-0.76) and a specificity of 0.91 (95%CI,0.83-0.96). When the LI cutoff was increased to 1.65, the sensitivity reduced to 0.61 (95%CI,0.53-0.70), while the specificity increased to 0.96 (95%CI,0.89-1.00). ConclusionBoth LI and visual analysis of PET/CT could be used in the classification diagnosis of PA. Nevertheless, visual analysis is more sensitive, and LI is more advantageous in specificity.

PurposeTo evaluate the clinical, laboratory, radiological, therapeutic, and prognostic characteristics of patients with acromegaly according to the size of the growth hormone (GH)-secreting pituitary adenoma at diagnosis. Patients and MethodsObservational, retrospective, single-center study of patients with acromegaly followed at a tertiary center. Data from medical records were evaluated regarding age, symptoms, presence of arterial hypertension, type 2 diabetes mellitus, hypopituitarism, size of the initial lesion, invasiveness (cavernous sinus invasion), T2-weighted magnetic resonance imaging signal intensity, GH and insulin-like growth factor type 1 (IGF-1) levels, treatment performed [surgery, use of somatostatin receptor ligands (SRL), pegvisomant, cabergoline and bromocriptine and radiotherapy] and response to surgical or adjuvant treatment (normal levels of GH and/or IGF-1 after each treatment instituted).Patients were divided into groups according to the size of the adenoma at diagnosis (group I = [&le;] 10 mm, II = 10-19 mm, III = 20-29 mm, IV = 30-39 mm and V = [&ge;] 40 mm), and comparisons were made between the 5 groups and two-by-two comparisons. Results117 patients were studied (59 women, age at diagnosis 43 {+/-} 13 years). Group I consisted of 11 patients (9%), group II of 54 (46%), group III of 34 (29%), group IV of 10 (9%) and group V of 8 patients (7%). The prevalence of hypertension, diabetes mellitus and hypopituitarism were 49%, 25% and 28%, respectively. Hypopituitarism, invasiveness, and the use of SRL had their prevalence increased according to the size of the adenoma, as well as GH levels. Age, on the other hand, showed a negative correlation with tumor size, and group I was older when compared to the group with macroadenoma. The ROC curves showed that in relation to the size of the adenoma at diagnosis, most of the outcomes evaluated (hypopituitarism, invasiveness, radiotherapy, use of SRL, use of medications other than SRL, disease control after surgery) occurred with a tumor diameter of around 20 mm. ConclusionOur study demonstrated that microadenomas and macroadenomas < 20 mm are associated with lower morbidity and better therapeutic response in acromegaly. From a tumor diameter of 20 mm, there was no significant difference in the clinical, therapeutic and prognostic behavior of GH-secreting pituitary adenomas. Trial Registration number (Plataforma Brasil)CAAE 30066220.2.0000.0096 (April 02, 2020)

BackgroundHeterozygous c.283+1G>A and c.283G>A variants in the THRB gene, encoding for thyroid hormone receptor (TR){beta}1 and {beta}2, lead to autosomal dominant macular dystrophy (ADMD). We report the detailed clinical characterization of two first-degree relatives with ADMD, heterozygous for THRB c.283+1G>A, and an unrelated ADMD patient with a novel variant, c.283G>C. The genomic and molecular consequences of both variants were studied. MethodsgDNA and mRNA were obtained from leukocytes. Clinical characterization included biochemistry, bone density and body composition, ECG, echocardiography, ultrasound, audiometry and color-vision. In vitro assays investigated TR function and DNA binding. ResultsThe patients manifested no resistance to thyroid hormone beta (RTH{beta}) and had normal FT4 and TSH. Detailed studies in two patients showed no goiter, tachycardia, hypercholesterinemia or hepatic steatosis. Hearing was not impaired. Both had impaired color vision and reduced bone density. RT-PCR from all three patients revealed skipping of exon 4 exclusive to TR{beta}1, producing a deletion of 87 amino acids in the N-terminal domain (TR{beta}1{Delta}NTD). In vitro, DNA-binding affinity of TR{beta}1{Delta}NTD to DR4-TRE with or without RXR was comparable to TR{beta}1WT. Surprisingly, TR{beta}1{Delta}NTD was transcriptionally twice more active than TR{beta}1WT with a similar EC50 for T3, demonstrating gain-of-function of TR{beta}1{Delta}NTD. THRA expression in leukocytes was increased by 3-fold compared to unrelated controls and different from RTH{beta} patients. ConclusionThese THRB splice site variants produce TR{beta}1 exon 4 skipping, resulting in a gain-of-function mutant, TR{beta}1{Delta}NTD. This explains the dominant ADMD phenotype devoid of RTH{beta} and suggests a TR{beta}1 gain-of-function syndrome.

ContextAdrenocortical carcinoma (ACC) is a rare and aggressive malignancy. Current treatment algorithms are associated with diagnostic limitations, high recurrence rates and poor prognosis. Identifying specific biomarkers that facilitate accurate diagnosis and provide prognostic insights could significantly enhance the patient outcomes in ACC. ObjectiveTo investigate whether microRNA machinery, specifically argonaute 2 (AGO2), a key enzyme in the miRNA pathway, has the potential to be a diagnostic and prognostic biomarker for adrenocortical carcinoma (ACC). DesignThis study analyzed mRNA expression of genes involved in the miRNA biogenesis pathway using RNASeq data from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) dataset, followed by target protein quantification in tissue samples using commercial ELISA kits. SettingPublicly available mRNASeq datasets (TCGA-GTEX) and frozen tissue samples from the tumour bank of the Kolling Institute of Medical Research. ParticipantsWe analyzed data for 79 ACC and 190 normal adrenal cortex (NAC) samples from the TCGA and GTEx datasets, as well as for 31 other cancer types from the TCGA. We then performed protein quantification in 15 NAC, 15 benign adrenal adenoma (AA), and 15 ACC tissue homogenates. Intervention(s)None. Main Outcome MeasuresAGO2 mRNA and protein expression in ACC and its prognostic correlation. ResultsAGO2 was significantly overexpressed in ACC, compared to NAC and AA (p<0.001). Kaplan- Meier survival analysis revealed that higher expression of AGO2 was associated with significantly worse overall survival in ACC (HR 7.07, p<0.001). Among all 32 cancer types in TCGA, AGO2s prognostic utility was most significant in ACC. ConclusionsAGO2 holds potential as a diagnostic and distinct prognostic biomarker in ACC.

BackgroundRadioiodine is commonly prescribed as a permanent treatment for thyrotoxicosis. At ADHB, Auckland, New Zealand, radioiodine dose is individualised by the prescribing physician according to patient characteristics. AimsWe investigated the outcomes of this approach. MethodsWe identified all patients receiving radioiodine for thyrotoxicosis at ADHB in 2015 and retrieved relevant clinical details. Results222 patients were prescribed radioiodine: 147 (66%) for Graves disease, 58 (26%) for toxic nodular goitre, and 17 (8%) for solitary toxic nodule. For Graves disease, 80% had one radioiodine dose (first dose median 550 MBq, range 200-1000 MBq; total dose 200-2400 MBq), 92% had the thyrotoxicosis cured, and 83% required thyroxine post-radioiodine. For toxic nodular goitre, 93% had one dose (median 550 MBq, range 400-1000 MBq, total dose 400-1800 MBq), 93% were cured and 22% required thyroxine. For solitary toxic nodule, all had one dose (median 550 MBq, range 500-550 MBq), all were cured and 35% required thyroxine. In 69/222 (31%) patients (35% of individuals with Graves disease, 17% with toxic nodular goitre, and 47% with solitary toxic nodule), the most recent TSH (mean 3.2 years post-radioiodine) was elevated (30% TSH >10 mu/L, 70% TSH 4-10 mu/L). ConclusionsFollowing radioiodine treatment, >90% of individuals have the thyrotoxicosis cured, but hypothyroidism is usual in Graves disease and occurs in 22-35% in toxic nodular goitre or solitary toxic nodule. Many individuals taking thyroxine after radioiodine have suboptimally controlled hypothyroidism.

ContextA comprehensive evaluation of thyroid disease and health through multimodal assessment is warranted. ObjectiveTo clarify the epidemiology and clinical significance of abnormal findings on thyroid examinations in a medical checkup setting. DesignProspective cohort study conducted between April 1, 2016, and December 31, 2021. SettingJapanese adults undergoing self-paid medical checkups at the Preemptive Medicine and Lifestyle Disease Research Center, Kyoto University Hospital Main Outcome MeasuresAll subjects underwent thyroid function tests, ultrasonography, and 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET); anti-thyroperoxidase antibody (TPOAb) titers were measured in a subset of subjects. ResultsIn the original cohort of 4,407 subjects (2,643 males and 1,764 females), the prevalence of thyroid dysfunction, increased blood flow on ultrasonography, diffuse thyroid FDG uptake, and thyroid nodules was 5.81%, 2.45%, 3.43%, and 39.71%, respectively; all were more frequent in females. Among 2,420 subjects with TPOAb measurements, TPOAb positivity was 7.19% and was significantly associated with thyroid dysfunction only at titers [&ge;] 128 IU/mL. Multivariate analyses identified age, sex, and thyroid volume as major determinants of thyroid function. Using data from 1,840 subjects without any thyroid abnormalities, we established sex-specific reference ranges for thyroid dimensions and found their correlations with age and body size. ConclusionsThis cohort provides epidemiological and physiological insights into thyroid health by integrating findings from thyroid function tests, ultrasonography, FDG-PET, and TPOAb measurements. Furthermore, the present study highlights the associations across abnormal findings, relationships within thyroid physiology, and the clinical relevance of high-titer TPOAb.