Journal of the Endocrine Society

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.

The pituitary gland produces several hormones that regulate growth, metabolism, stress response, reproduction, and homeostasis. Congenital hypopituitarism is a deficiency in one or more pituitary hormones and encompasses a spectrum of clinical conditions. The pituitary has a complex embryonic origin with the oral ectoderm contributing the anterior lobe, and the neural ectoderm generating the posterior lobe. Pituitary abnormalities and growth deficiencies are associated with cleft palate however the developmental genetic connection between pituitary and orofacial cleft malformations remains to be determined. The epithelial RNA splicing regulators Esrp1 and Esrp2 are required for orofacial development in zebrafish, mice, and humans, and loss of function of these genes results in a cleft palate. Here we present a detailed developmental analysis of the genetic requirement for Esrp1/2 in pituitary morphogenesis in mouse and zebrafish. Further, we describe a patient with cleft palate and hypopituitarism that harbors a nucleotide variant in the RNA binding domain of ESRP2. The discovery of this key function for Esrp1/2 in pituitary formation has significant fundamental and clinical implications for understanding congenital hypopituitarism and craniofacial anomalies. Summary StatementEsrp1 and Esrp2 are regulators of mRNA alternative splicing that are required for both orofacial and pituitary development in vertebrates.

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.

The thyroid gland is susceptible to abnormal epithelial cell growth, often resulting in thyroid dysfunction. The serine-threonine protein kinase mechanistic target of rapamycin (mTOR) regulates cellular metabolism, proliferation, and growth through two different protein complexes, mTORC1 and mTORC2. The PI3K-Akt-mTORC1 pathways overactivity is well associated with heightened aggressiveness in thyroid cancer, but recent studies indicate the involvement of mTORC2 as well. To elucidate mTORC1s role in thyrocytes, we developed a novel mouse model with mTORC1 gain of function in thyrocytes by deleting Tuberous Sclerosis Complex 2 (TSC2), an intracellular inhibitor of mTORC1. The resulting TPO-TSC2KO mice exhibited a significant reduction in TSC2 levels, leading to a six-fold increase in mTORC1 activity. Thyroid glands of both male and female TPO-TSC2KO mice displayed rapid enlargement and continued growth throughout life, accompanied by heterogeneity among thyroid follicles, larger follicles, increased colloid and epithelium. We observed elevated thyrocyte proliferation as indicated by Ki67 staining and elevated Cyclin D3 expression in the TPO-TSC2KO mice. mTORC1 activation resulted in a progressive downregulation of key genes involved in thyroid hormone (TH) biosynthesis, including thyroglobulin, thyroid peroxidase, and sodium-iodide symporter (NIS), while TTF1, PAX8, and MCT8 mRNA levels remained unaffected. NIS protein expression was also diminished in TPO-TSC2KO mice. Treatment with the mTORC1 inhibitor rapamycin prevented thyroid mass expansion and restored the gene expression alterations in TPO-TSC2KO mice. Although T4, T3 and TSH plasma levels were normal at 2 months of age, a slight decrease in T4 and an increase in TSH levels were observed at 6 and 12 months of age while T3 remained similar in TPO-TSC2KO compared to littermate control mice. TPO-TSC2KO mice aged to 12 months or older developed aberrant thyroid conditions, including follicular hyperplasia, inflammation, and thyroid tumors. In conclusion, our thyrocyte-specific mouse model reveals that mTORC1 activation inhibits TH biosynthesis, suppresses thyrocyte gene expression, and promotes growth and proliferation. Chronic mTORC1 activation leads to thyroid tumor formation, highlighting the role of mTORC1 in thyroid dysfunction and tumorigenesis.

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.

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.

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.

IntroductionPituitary adenomas with cavernous sinus invasion represent a challenging subset of intracranial tumors. The presence of cavernous sinus invasion complicates surgical resection and increases the risk of recurrence and postoperative complications. Endoscopic endonasal surgery (EES) has emerged as a promising alternative to traditional microscopic transsphenoidal surgery, offering enhanced visualization and reduced collateral damage. This meta-analysis aims to evaluate the efficacy and safety of EES in the treatment of pituitary adenomas with cavernous sinus invasion, focusing on remission rates, gross total resection (GTR), recurrence rates, and complications. MethodsA comprehensive literature search was conducted through PubMed, Scopus, Embase, and CENTRAL databases until August 2025, following PRISMA guidelines. Studies meeting eligibility criteria, including human studies published in English and involving adult patients with pituitary adenomas and cavernous sinus invasion treated with EES, were included. Data extraction focused on patient demographics, tumor characteristics, surgical outcomes, and complications. Statistical analysis was performed using a random-effects model, and subgroup analysis was conducted based on factors such as tumor size, Knosp grade, and hormonal subtype. ResultsA total of 27 studies involving 3,591 patients were included. The pooled remission rate was 60% (95% CI: 49% to 71%), with substantial variability across studies. The pooled residual tumor rate was 15% (95% CI: 11% to 19%), and the recurrence rate was 8% (95% CI: 6% to 11%). The incidence of cerebrospinal fluid (CSF) leaks was 9% (95% CI: 3% to 14%), while the rates of ICA injury and cranial nerve injury were extremely low (0.00% and 0.01%, respectively). Subgroup analyses revealed higher remission rates in macroadenomas (68%) compared to microadenomas (33%), and GH-secreting tumors showed higher endocrinological remission rates compared to ACTH-secreting tumors. ConclusionEndoscopic endonasal surgery demonstrates moderate efficacy in the treatment of pituitary adenomas with cavernous sinus invasion, with favorable remission and resection rates. However, substantial variability across studies emphasizes the need for further standardization of surgical techniques and patient selection criteria. The procedure is generally safe, with low rates of serious complications such as ICA injury and cranial nerve damage. Further prospective studies are needed to optimize patient management and evaluate long-term outcomes, including recurrence and quality of life.

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.

During pregnancy, mammary tissue undergoes expansion and differentiation, leading to lactation, a process regulated by the hormone prolactin through the JAK2-STAT5 pathway. STAT5 activation is key to successful lactation making the mammary gland an ideal experimental system to investigate the impact of human missense mutations on mammary tissue homeostasis. Here, we investigated the effects of two human variants in the STAT5B SH2 domain, which convert tyrosine 665 to either phenylalanine (Y665F) or histidine (Y665H), both shown to activate STAT5B in cell culture. We ported these mutations into the mouse genome and found distinct and divergent functions. Homozygous Stat5bY665H mice failed to form functional mammary tissue, leading to lactation failure, with impaired alveolar development and greatly reduced expression of key differentiation genes. STAT5BY665H failed to recognize mammary enhancers and impeded STAT5A binding. In contrast, mice carrying the Stat5bY665F mutation exhibited abnormal precocious development, accompanied by an early activation of the mammary transcription program and the induction of otherwise silent genetic programs. Physiological adaptation was observed in Stat5bY665H mice as continued exposure to pregnancy hormones led to lactation. In summary, our findings highlight that human STAT5B variants can modulate their response to cytokines and thereby impact mammary homeostasis and lactation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/592736v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@25f44org.highwire.dtl.DTLVardef@1bc9daeorg.highwire.dtl.DTLVardef@141dddorg.highwire.dtl.DTLVardef@b4993b_HPS_FORMAT_FIGEXP M_FIG C_FIG

VPS28 (vacuolar protein sorting 28) is a subunit of the endosomal sorting complexes required for transport (ESCRTs), and is involved in ubiquitination. Ubiquitination is a crucial system for protein degradation in eukaryotes. Considering the recent findings on the role of ubiquitination in regulating lipid metabolism, we hypothesized that VPS28 might affect the expression of genes involved in milk fat synthesis. To test this hypothesis, we modulated VPS28 expression in the bovine mammary epithelial cell (MAC-T) line and measured the effects on triglyceride (TG) synthesis using lentivirus-mediated techniques. The results indicated that VPS28 knockdown significantly upregulated the fatty acid transporter CD36 (CD36 molecule) and the adipose differentiation-related protein (ADFP), leading to increased TG and fatty acid production, alongside elevated expression of ubiquitin (UB) protein and reduced proteasome activity. In contrast, VPS28 overexpression increased CD36 levels without significantly affecting ADFP and TG levels, showing a trend toward reduced lipid droplets and increased UB expression and proteasome activity. Furthermore, the inhibition of the ubiquitin-proteasome system and endosomal-lysosomal pathway using epoxomicin and chloroquine, respectively, resulted in a further elevation of CD36, ADFP, and TG levels, thereby enhancing cell viability. These in vitro findings were validated in vivo by a mouse model, where VPS28 knockdown enhanced CD36, ADFP, UB expression, TG content, and lipid droplets in mammary glands, without pathological changes in mammary tissue or blood TG alterations. These results confirm the pivotal role of VPS28 in regulating TG synthesis via the ubiquitination pathway, offering novel insights into the molecular mechanisms of milk fat production in a bovine in vitro cell model.

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)

AbstractIn most mammals the major site of sex hormone-binding globulin (SHBG) synthesis is the liver wherefrom it is secreted into the bloodstream and is the primary determinant of sex steroid access to target tissues. The minor site of SHBG synthesis is the testis and in lower mammals testicular SHBG has long been known to be synthesized and secreted by Sertoli cells. However, human testicular SHBG is expressed in developing germ cells from an upstream alternative promoter (altP-SHBG). Transcripts arising from this region comprise an alternative first exon (1A) with the resultant protein confined to the acrosomal compartment of the mature spermatozoa. I have dissected the regulatory components of the alternative SHBG promoter and identified motifs that are required for optimal transcriptional activity from this region. Transcriptional activity is driven by two CACCC elements that appear to be functionally redundant. The transcription factor KLF4 interacts with promoter the region spanning these elements in vivo. Knockdown of Klf4 results in decreased altP-SHBG activity, while Klf4 overexpression relieves the effects of knockdown. Based on their shared patterns of expression in vivo, I conclude that KLF4 is a transcriptional regulator of SHBG in male germ cells.

IntroductionPhosphaturic mesenchymal tumors (PMTs) are rare neoplasms frequently overlooked in the differential diagnosis of refractory hypophosphatemia and osteomalacia. Despite their clinical significance, a comprehensive synthesis of evidence on diagnostic accuracy, therapeutic outcomes, and prognostic factors remains lacking, with current literature fragmented across small case series and heterogeneous methodologies. This gap impedes the development of standardized clinical pathways for timely diagnosis and effective management. ObjectiveTo systematically evaluate and meta-analyze the best available evidence on the clinicopathological features, diagnostic performance of imaging modalities, and treatment outcomes in patients with tumor-induced osteomalacia (TIO) secondary to PMTs. MethodsA PRISMA-compliant systematic review and meta-analysis was conducted across PubMed/MEDLINE, Embase, Scopus, Web of Science, and Cochrane Library. Peer-reviewed case series ([&ge;]3 patients) published in English were included. Data extraction focused on tumor localization, biochemical response, imaging accuracy, and surgical outcomes. Random-effects models were used for pooled estimates, with heterogeneity assessed via I2 and Cochrans Q. Sensitivity and publication bias analyses ensured robustness. ResultsTen studies encompassing 1,176 patients were analyzed. Complete surgical resection yielded a high rate of biochemical remission, with consistent results across sensitivity analyses. {square}{square}Ga-DOTATATE PET/CT demonstrated superior diagnostic sensitivity compared to conventional modalities, significantly improving tumor localization. Methodological quality was moderate to high in most studies, and funnel plot symmetry indicated minimal publication bias. ConclusionThis meta-analysis confirms that early tumor localization with advanced functional imaging and complete resection are pivotal for curing TIO. A multidisciplinary approach integrating endocrinology, radiology, and surgical oncology is essential for optimal outcomes.

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.

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.

Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. Following the identification of a loss-of-function variant (p.Arg703Gln) in the PAM gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated pituitary adenomas kindreds for PAM variants. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. No germline CNVs or somatic single nucleotide variants (SNVs) were identified. We detected seven likely pathogenic heterozygous missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with GH excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or with different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, for splicing by minigene assays, and for amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs to diagnoses linked to pituitary gland hyperfunction. Identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.

ImportanceRET pathogenic variants cause Multiple Endocrine Neoplasia type 2 (MEN2), characterised by medullary thyroid cancer (MTC). With increasing incidental identification of these variants in asymptomatic individuals outside family screening, their risk of MTC and all-cause mortality without intervention remain unknown in this context. ObjectiveTo determine the risk of MTC and all-cause mortality in clinically unselected individuals and assess how the risk of MTC differ from clinically ascertained cases. Design, Setting, and ParticipantsProspective cohort study of 383,914 unrelated individuals from the clinically unselected UK population (UK Biobank) and 122,640 from the US health system (Geisinger cohort). We compared MTC risk in these cohorts to 1,078 individuals who were clinically ascertained with suspicion of MEN2 from UK routine practice. ExposuresRET pathogenic variants causing MEN2 Main Outcomes and MeasuresFrequency and the spectrum of pathogenic RET variants, Risk of clinically presented MTC, all-cause mortality without thyroidectomy. ResultsPathogenic RET variants were found in 0.04% of individuals from UK population cohort and 0.08% of individuals from US health system cohort. They were predominantly from moderate-risk category as per American Thyroid Association guideline (99.4% and 94.8% respectively). MTC risk by age 75 in variant carriers in the UK population was 2.2% (95% CI 0.7-6.8) and 19% (95% CI 5.7-30) in US health system cohort. This was significantly lower than the clinically ascertained cohort with the matched variants (95.7%, 95% CI 82.1-99.7 p<0.0001). In the UK Biobank, most variant carriers (98.2%) did not undergo thyroidectomy and their all-cause mortality by age 75 was similar to non-carriers (6.1%, 95% CI 2.7-13.8 vs 5.7%, 5.6-5.8, p=0.79), with consistent findings in the US health system cohort. Conclusions and RelevanceModerate-risk RET variants are most common in incidental cases. These variants carry substantially lower MTC risk than clinically ascertained cases. This evidence addresses a current knowledge gap, enabling more informed clinical decision-making.

BackgroundBicalutamide is a potential anti-androgen for transgender individuals with feminizing embodiment goals, but use has been limited because of hepatotoxicity in cisgender men with prostate cancer. This study compared transaminase changes in transfeminine adolescents and young adults (AYA) using low-dose bicalutamide with individuals using other methods of androgen blockade. MethodsA retrospective analysis was conducted using electronic health record data for patients starting gender affirming hormone therapy with at least 10 months of follow-up data between 2015 and 2023. Linear mixed models compared change in ALT and AST from baseline and maximum ALT and AST values in bicalutamide and comparison groups. Secondary outcomes included % individuals with ALT and AST elevation more than 1, 2, or 3 times the upper limit of normal (ULN) (Fishers exact test), standardized mean estradiol dose by group (t test), and Tanner staging of breast tissue by group (Fishers exact test). ResultsEighty-four transfeminine AYA (median age 18) taking bicalutamide were compared to 69 transfeminine AYA (median age 19) taking GnRH agonists, spironolactone or no agent in addition to estradiol. In linear mixed models adjusted for baseline age, BMI, baseline ALT or AST, and alcohol use, there was no difference in delta or maximum ALT or AST in bicalutamide and comparison groups. No individuals had an AST or ALT level > 3x ULN. Estradiol doses and Tanner stages were similar between groups in a subgroup analysis of individuals receiving pediatric care. ConclusionBicalutamide was not associated with significant change in transaminases as compared with other anti-androgen regimens over one year. Bicalutamide appears to be a safe anti-androgen for transfeminine individuals at low dose with close monitoring and deserves further study.

Individuals with Downs syndrome (DS) present increased risk for thyroid dysfunction, especially hypothyroidism, due in increased expression of the DYRK1A gene. ObjectiveThe aim of this study was to make a morphological-functional thyroid assessment in individuals with DS. Materials and MethodsThis is a descriptive cross-sectional study, consisting of 29 individuals with DS, with a mean age of 12,3 {+/-} 9,5 (0.66 - 36.00) years, 16 women (55.2%) and 13 men (44.8%), with a morphological-functional thyroid assessment being made comprising hormonal dose (Free T4, TSH), antithyroid antibody (TPOAb and TgAb) and ultrasonography of the thyroid. ResultsTwenty-three (79.3%) individuals presented normal thyroid function while 6 (20.7%) presented with thyroid dysfunction, 4 with hypothyroidism and 2 with hyperthyroidism. Autoimmune thyroiditis and goiter were present in 27.6% of the individuals. ConclusionThyroid function should be assessed periodically in individuals with DS, in view of the high prevalence of thyroid dysfunction, especially autoimmune thyroiditis with consequent hypothyroidism.