Multiple endocrine neoplasia type 1 (MEN1) is caused by germline mutations in the MEN1 gene, including nonsense mutations and missense variants, which result in the formation of truncated inactive menin protein and some of which cause degradation of mutant menin proteins. Here, we describe a c.1462 A > T (p.K488X) mutation in exon 10 of MEN1 as a potential pathogenic mutation in an extended Chinese family with MEN1. We observed that K488X-menin was degraded by ubiquitination modification resulting from the combined actions of carboxy-terminus of Hsc70-interacting protein (CHIP) and Heat Shock Protein Family 70 (Hsp70) in vitro. K488X-menin is a misfolded truncated protein that results in amyloid aggregation in live cells and affected tissues, which is promoted by Hsp70 and/or CHIP. Although Hsp70 can inhibit the aggregation of K488X-menin in vitro, it is not upregulated in the affected tissues in patients with MEN1, and thus cannot completely disaggregate the aggregated K488X-menin. Further, we found that K488X-menin triggers early tumourigenesis in a MEN1 mutant zebrafish model. Moreover, K488X-menin disaggregation was induced by Hsp70 activator and Hsp70 was upregulated in homozygous mutant zebrafish. Our findings provide a novel biophysical mechanism involving Hsp70 underlying MEN1 tumourigenesis in a Chinese family with MEN1.

Peptide receptor radionuclide therapy (PRRT) is recommended and approved in advanced neuroendocrine tumors (NETs). There is a lack of data on the utility of PRRT in multiple endocrine neoplasia (MEN) syndrome. This study explores the utility of PRRT in MEN syndrome patients with inoperable/metastatic NETs.

A single-center retrospective analysis of MEN syndrome patients with advanced NETs referred for PRRT was done. Upto 4 cycles of 177Lu-DOTATATE (5.5-7.4 GBq/cycle) were administered every 8-12 weeks. Treatment-related adverse events were assessed using CTCAE v5. The best response to PRRT was evaluated using RECIST 1.1. Follow-up was done to calculate the progression-free survival (PFS) and overall survival (OS).

The data of 15 patients with a median age of 36 years (IQR: 32-49) was analyzed. Fourteen patients had MEN-1 syndrome, and 1 had MEN-2 syndrome. Thirteen patients with MEN-1 syndrome had gastroenteropancreatic (GEP) NET, with the multifocal primary as the most common finding (n=7). One patient had thymic carcinoid. All patients had hyperparathyroidism, while 6 had pituitary adenoma. Fifty-three cycles of 177Lu-DOTATATE (range: 1-4) were administered with a median cumulative activity of 27.8 GBq. Twelve patients (80%) showed grade 1/2 adverse events, with leukopenia being the most common. Six patients achieved partial response (43% ORR), 6 showed stable disease (86% DCR), 2 (14%) showed disease progression during PRRT, while 1 patient was lost to follow-up. The median PFS was 32.6 months (95% CI: 14.7-not reached) with an estimated 1- and 5-year PFS rate of 86.2% (95% CI: 68-100) and 46.3% (95% CI: 13-80), and estimated 5-year OS rate of 76.2% (95% CI: 52.1-100).

177Lu-DOTATATE is a safe and effective treatment option for advanced NETs in MEN syndrome. However, large-sized multicentric prospective studies are required.

Multiple endocrine neoplasia type 1 (MEN1) is a rare disease caused by mutations in the oncosuppressor gene MEN1 and characterized by co-occurrence of tumors of the parathyroid gland, pancreas, and pituitary gland. The clinical manifestations of MEN1 are varied, and misdiagnosis is common. The life expectancy of patients with untreated MEN1 is short. Here, we report a case of a 50-year-old patient with recurrent urinary calculi for more than 10 years who had a pancreatic neuroendocrine tumor and parathyroid adenoma. The patient received a definitive diagnosis of MEN1. We analyze his clinical characteristics and describe our approach to management.

Laboratory tests showed high parathyroid hormone (PTH), high blood calcium, and low blood phosphorus levels and increased excretion of urinary calcium. Immunohistochemical analysis showed loss of menin expression in pancreatic tumor tissues. Testing of the MEN1 gene revealed a variant in exon 9 (c.1257_1268del, p.lle420_Trp423del).

The patient's clinical characteristics combined with the testing of the MEN1 gene, it implied the variant was a novel likely pathogenetic variant. For patients with recurrent urinary stones, we recommend measuring blood calcium and PTH, and if there are abnormalities, screening other endocrine glands to exclude the possibility of MEN1.

Multiple endocrine neoplasia type 1 (MEN-1) is an autosomal dominant inherited syndrome characterized by a genetic predisposition for the development of specific hormone-secreting tumors. Effective diagnosis and management of MEN-1 require genetic testing, regular surveillance, and imaging follow-up to detect and monitor tumor growth or recurrence and to plan for surgical intervention. The aim of this narrative review is to provide an overview of the current imaging modalities and their role in the diagnosis and follow-up of patients affected by MEN-1, focusing on the detection and characterization of associated neoplasms. The knowledge of the most frequent MEN-1 associated neoplasms and their imaging features is crucial for an accurate diagnosis, management, and treatment.

Surgery is the only definitive treatment for primary hyperparathyroidism (PHPT). The surgical management of PHPT has evolved over the past several decades in response to the continually growing body of evidence supporting its effectiveness in both symptomatic and asymptomatic disease. As imaging modalities for localization, operative approach, and intraoperative adjuncts, such as intraoperative parathyroid hormone testing, have been optimized, careful evaluation of the timing of parathyroidectomy in relationship to the disease's natural history has been pursued to limit the detrimental end-organ effects of untreated PHPT. Herein, we review select studies examining key aspects of PHPT management fundamental to the practicing surgical oncologist and endocrine surgeon caring for patients with PHPT.

Accurate preoperative localization is imperative for the treatment of insulinomas. Glucagon-like peptide-1 receptor (GLP-1R) imaging has demonstrated remarkable efficacy in localization of insulinomas. The aim of this study was to assess the diagnostic performance of GLP-1R PET/CT with 68Ga-exendin-4 in localization of insulinoma, and to provide evidence for clinical practice from a real-world study.

This is a retrospective analysis of our prospective cohort study of 68Ga-exendin-4 PET/CT in insulinoma (NCT02560376). Patients with endogenous hyperinsulinemic hypoglycemia and definite final diagnosis were enrolled. Results of contrast-enhanced CT (CECT) with pancreatic perfusion scan, MRI, endoscopic ultrasound, and 99mTc-HYNIC-TOC SPECT/CT were collected. The gold standard for diagnosis was histopathology (for insulinoma) or a definite clinical diagnosis of the etiology of hyperinsulinemic hypoglycemia after hospitalization in the endocrinology department (for non-insulinomatous hypoglycemia).

A total of 357 patients (including 296 insulinoma patients and 61 non-insulinoma patients) with were included. The overall sensitivity, specificity, accuracy, PPV, and NPV of 68Ga-exendin-4 PET/CT in localizing insulinoma were 94.93% (95%CI, 91.78%˜97.14%), 100.00% (95%CI, 94.13%˜100%), 95.79% (95%CI, 93.16%˜97.63%), 100.00% (95%CI, 98.32%˜100%), 80.26% (95%CI, 71.29%˜86.94%), respectively. The area under the ROC of 68Ga-exendin-4 PET/CT for diagnosing insulinoma was 0.975 (95%CI, 0.953 ˜ 0.988), which was superior to that of CECT (AUC = 0.873 [95%CI, 0.833 ˜ 0.906]), MRI (AUC = 0.825 [95%CI, 0.773 ˜ 0.869]), EUS (AUC = 0.746 [95%CI, 0.652 ˜ 0.825]) and 99mTc-HYNIC-TOC SPECT/CT (AUC = 0.618 [95%CI, 0.562 ˜ 0.672]). The lesion-based sensitivity of 68Ga-exendin-4 PET/CT in sporadic benign insulinoma was 95.47% (95%CI, 92.22%˜97.64%), and the PPV was 99.61% (95%CI 99.60%˜99.62%). In contrast, the diagnostic efficacy of 68Ga-exendin-4 PET/CT was found to be less effective in cases of sporadic malignant insulinoma or inherited syndromes, yielding a lesion-based detection rate of 66.43% and 68.04%, respectively.

68Ga-exendin-4 PET/CT is a preferred imaging modality in diagnosing insulinoma, particularly in sporadic benign insulinomas.

Background: Multiple endocrine neoplasia type 1 (MEN1)-related primary hyperparathyroidism (MPHPT) belongs to genetic PHPT that accounts for 10% of all PHPT cases, being considered the most frequent hereditary PHPT (less than 5% of all PHPT). Objective: We aimed to provide an updated clinical perspective with a double purpose: to highlight the clinical features in MPHPT, particularly, the bone health assessment, as well as the parathyroidectomy (PTx) impact. Methods: A comprehensive review of the latest 5-year, English-published, PubMed-accessed original studies. Results: The sample-based analysis (n = 17 studies) enrolled 2426 subjects (1720 with MPHPT). The study design was retrospective, except for one prospective and one case-control study. The maximum number of patients per study was of 517. Female predominance (an overall female-to-male ratio of 1.139) was confirmed (except for three studies). Age at MPHPT diagnosis (mean/median per study): 28.7 to 43.1 years; age at PTx: 32 to 43.5 years. Asymptomatic PHPT was reported in 38.3% to 67% of MPHPT. Mean total calcium varied between 1.31 and 2.88 mmol/L and highest PTH was of 317.2 pg/mL. Two studies reported similar PTH and calcaemic levels in MPHPT vs. sporadic PHPT, while another found higher values in MPHPT. Symptomatic vs. asymptomatic patients with MPHPT had similar PTH and serum calcium levels (n = 1). Osteoporosis (n = 8, N = 723 with MPHPT) was reported in 10% to 55.5% of cases, osteopenia in 5.88% to 43.9% (per study); overall fracture rate was 10% (of note, one study showed 0%). Lower bone mineral density (BMD) at DXA (n = 4) in MPHPT vs. sporadic PHPT/controls was found by some studies (n = 3, and only a single study provided third distal radius DXA-BMD assessment), but not all (n = 1). Post-PTx DXA (n = 3, N = 190 with MPHPT) showed a BMD increase (e.g., +8.5% for lumbar spine, +2.1% for total hip, +4.3% for femoral neck BMD); however, post-operatory, BMD remains lower than controls. Trabecular bone score (TBS) analysis (n = 2, N = 142 with MPHPT vs. 397 with sporadic PHPT) showed a higher prevalence of reduced TBS (n = 1) or similar (n = 1). PTx analysis in MPHPT (n = 14): rate of subtotal PTx of 39% to 66.7% (per study) or less than subtotal PTx of 46.9% (n = 1). Post-PTx complications: persistent PHPT (5.6% to 25%), recurrent PHPT (16.87% to 30%, with the highest re-operation rate of 71% in one cohort); hypoparathyroidism (12.4% to 41.7%). Genetic analysis pointed out a higher risk of post-PTx recurrence in exon 10 MEN1 pathogenic variant. Post-PTx histological exam showed a multi-glandular disease in 40% to 52.1% of MPHPT, and a parathyroid carcinoma prevalence of 1%. Conclusions: MPHPT remains a challenging ailment amid a multi-layered genetic syndrome. Current data showed a lower age at MPHPT diagnosis and surgery than found in general population, and a rate of female predominance that is lower than seen in sporadic PHPT cases, but higher than known, for instance, in MEN2. The bone involvement showed heterogeneous results, more consistent for a lower BMD, but not necessarily for a lower TBS vs. controls. PTx involves a rather high rate of recurrence, persistence and redo surgery. About one out of ten patients with MPHPT might have a prevalent fracture and PTx improves the overall bone health, but seems not to restore it to the general population level, despite the young age of the subjects. This suggests that non-parathyroid components and potentially menin protein displays negative bone effects in MEN1.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-inherited syndrome involving multiple endocrine tumors. It is characterized by multiple mutations in the tumor suppressor gene MEN1, which is located on chromosome 11q13. As main etiology of MEN1 is genetic mutations, clinical symptoms may vary. In this editorial, we comment on the article by Yuan et al. This article describes a case of (MEN1) characterized by low incidence and diagnostic complexity. MEN1 commonly presents as parathyroid, pancreatic, and pituitary tumors. Diagnosis requires a combination of serologic tests, magnetic resonance imaging, computed tomography, endoscopic ultrasonography, immunologic and pathology. The diagnosis is unique depending on the site of disease. Surgical resection is the treatment of choice for MEN1. The prognosis depends on the site of origin, but early detection and intervention is the most effective.

Primary hyperparathyroidism (PHPT) is the leading cause of hypercalcemia. It is secondary to hypersecretion of parathyroid hormone (PTH) by the parathyroid glands. Today, PHTP is asymptomatic in 80-90% of cases. Its repercussions are mainly renal (nephrolithiasis, nephrocalcinosis, decline in renal function) and skeletal (osteoporosis, fractures), and should be systematically investigated. Diagnosis is only biological, and in its classic form relies on the association of hypercalcemia, inappropriate PTH (normal or elevated) and hypercalciuria. Diagnosis of normocalcemic forms, where only PTH is elevated, requires elimination of secondary hyperparathyroidism and confirmation of elevated PTH on two consecutive samples, over a 3 to 6 months period. Imaging evaluation, which combines neck ultrasound with scintigraphy or 18F-choline PET/CT, is of interest only if surgery is indicated. Surgical management of the hyperfunctioning parathyroid gland(s) is the only curative treatment for HPTP. Medical management concerns patients for whom surgery is not indicated, who present a surgical contraindication or who refuse surgery. The diagnosis of HPTP warrants contact with an endocrinologist to ensure its management.

This study aims to investigate the clinical and genetic features and change of clinical spectrum of primary hyperparathyroidism (PHPT) in children and adolescents.

The clinical and follow-up data of 74 pediatric patients (onset age ≤ 18 years) with PHPT during 1975-2022 were retrospectively analyzed. For comparison, patients were divided into four subgroups according to their time of diagnosis. Genetic analysis was conducted in 40 patients.

Pediatric PHPT cases increased largely over time [34 cases (45.9%) in 2015-2022]. The rate of asymptomatic PHPT increased by time (14.7% in 2015-2022 vs. 0% before 2015), in accordance with routine screening of serum calcium becoming a more frequent reason for clinic visit (17.6% in 2015-2022 vs. 0% before 2015). Skeletal manifestation significantly decreased in recent years (64.7% in 2015-2022 vs. 100.0% in 1975-1994, P < 0.05). Sixty-seven patients (90.5%) of the whole cohort underwent parathyroidectomy. Atypical parathyroid adenoma and parathyroid carcinoma occurred in 13.4% and 4.5% of the surgical cases, respectively. Recurrence and persistence of PHPT were observed in 17.9% of postsurgical patients. Germline rare variations (RVs) of PHPT-related genes were found in 42.5% (17/40) of all cases with genetic testing. Compared with no-variation group, the variation group had higher incidence of multiple parathyroid lesions (42.8% vs. 4.3%, P = 0.014), and lower rate of benign lesions and higher rate of recurrence and persistence.

Milder cases of Pediatric PHPT are coming to clinical attention probably due to routine lab testing. Genetic testing is recommended for pediatric PHPT patients.

Metastatic duodenopancreatic neuroendocrine tumors (dpNETs) are the primary cause of mortality among patients with Multiple Endocrine Neoplasia Type 1 (MEN1). Emerging evidence implicates the microbiome and microbial-derived secreted factors in promoting cancer development and progression. In the current study, we report that the circulating microbial-associated uremic toxins trimethylamine N-oxide (TMAO), indoxyl sulfate (IS), cresol sulfate (CS), cresol glucuronide (CG), and phenol sulfate (PS) are elevated in MEN1 patients with metastatic dpNETs. Proteomic- and metabolomic-based analysis of resected dpNET tissues from MEN1 patients also revealed detectable levels of uremic toxins that positively correlated with peptide-based signatures corresponding to Fusobacterium nucleatum, Faecalibacterium prausnitzii, and Klebsiella pneumoniae and negatively correlated with Streptococcus pneumoniae and Streptococcus thermophilus. A microbial-associated uremic toxin panel (MUTP) was developed and, in an independent case-control validation cohort, the panel yielded an area under the receiver operating characteristic curve (AUC) of 0.94 (95 % CI: 0.85-1.00) with 67 % sensitivity at 95 % specificity for identifying MEN1 patients with metastatic dpNETS. Increases in circulating microbial-associated uremic toxins during early stages of neoplasia were also found to be associated with poor overall survival in an Men1fl/flPdx1-CreTg mouse model of MEN1 pancreatic NETs. Our findings suggest that microbial dysbiosis is associated with disease aggressiveness and that increases in circulating microbial-associated uremic toxins may be a prognostic indication for MEN1 individuals who are at risk of having metastatic dpNETs.

Bronchopulmonary Neuroendocrine Neoplasms (NEN) occur in 2-7% of patients with multiple endocrine neoplasia type 1 (MEN1). Precursor lesions have been identified for MEN1-related pancreatic, duodenal, and gastric NEN. The aim of the current study using a MEN1 mouse model was to define the precursor lesions of bronchopulmonary NEN and evaluate the potential prophylactic antitumor effects of somatostatin analogues in a transgenic MEN1 mouse model.

Fifteen mice, germline heterozygous for Men1(+/T), were treated with subcutaneous injections of lanreotide autogel (Somatuline Autogel®, IPSEN Pharma), while 15 mice were treated with subcutaneous injections of physiologic sodium chloride as the control group. Five mice from each group were euthanized after 12, 15, and 18 months, respectively. The complete lungs were resected and evaluated after hematoxylin and eosin staining and immunohistochemistry for synaptophysin and chromogranin A.

In the lungs of the 30 evaluated mice, whether treated or placebo treated, no bronchopulmonary neuroendocrine cell hyperplasia nor neuroendocrine neoplasia was detected through histopathology. However, pulmonary adenocarcinoma developed in 2 (13%) of the 15 untreated mice and in 1 (7%) of the 15 lanreotide-treated mice.

Heterozygous Men1(+/T) knockout mice do not develop bronchopulmonary NEN or precursor lesions, but pulmonary adenocarcinoma. This surprising result needs to be investigated in more detail.

This document presents the findings of the American Association of Clinical Endocrinology (AACE) on the diagnosis, management, and surveillance of patients with multiple endocrine neoplasia type 1 (MEN1) and associated tumors. The task force included a diverse group of experts in endocrinology, oncology, genetics, surgery, and patient representation. A comprehensive literature review was conducted to address key issues related to the evaluation, surveillance, and treatment of MEN1-related tumors.

The task force, comprised of 9 members with expertise in endocrinology, surgery, medical oncology, genetics, and patient advocacy, collaborated to develop guidance for the evaluation, surveillance, and management of MEN1-associated tumors. Consensus was defined as ≤1 dissenting vote and significant majority as ≥75%. Relevant studies were identified through a literature review process, and consensus statements were based on the available evidence.

The task force deliberated on the surveillance, evaluation, and management of MEN1-related tumors including parathyroid, pituitary, and gastroenteropancreatic neuroendocrine tumors and other tumors of relevance. The document also addresses the indications for MEN1 genetic testing.

This consensus statement aims to offer evidence-informed guidance for health care providers involved in the care of patients with MEN1 and associated tumors. It provides guidance on diagnostic tools, genetic testing criteria, imaging techniques, surgical interventions, and posttreatment monitoring. The practical, patient-centered approach outlined in this document is intended to improve outcomes for individuals with MEN1 and other high-risk endocrine tumors.

To describe a case of multiple endocrine neoplasia type 1 in the pediatric age group and its molecular diagnosis.

An 11-year-old boy began to present generalized tonic-clonic seizures in the presence of hypoglycemia, with high insulin dosage, leading to suspicion of insulinoma. Abdominal magnetic resonance imaging confirmed a pancreatic nodule, which was surgically resected, resulting in glycemic normalization. Low growth hormone levels and hyperprolactinemia, secondary to macroprolactinoma, were also identified. Treatment with cabergoline led to a reduction in size. Hyperparathyroidism was found asymptomatically, with parathyroid scintigraphy suggestive of adenoma, thus, the patient underwent subtotal parathyroidectomy and thymectomy with resolution of the condition. He entered puberty spontaneously at 15 years of age; however, he had decreased growth speed, short stature, and low insulin-like growth factor 1 (IGF-1) levels, indicating recombinant growth hormone. The next-generation sequencing panel for multiple endocrine neoplasia type 1 identified a probably pathogenic variant c.442A>C: p.(Thr148Pro) in heterozygosity in the MEN1 gene, without previous description in databases (ClinVar).

We highlight the pre-pubertal age of multiple endocrine neoplasia type 1 diagnosis, which is made before age 21 in only 12-17% of cases, and hypoglycemia secondary to insulinoma as the initial manifestation, differing from what is most frequently described, namely prolactinoma and parathyroid adenoma. The clinical diagnosis was made based on the occurrence of two primary endocrine tumors and confirmed through a next-generation sequencing panel, with a variant not previously described in ClinVar.

The complementary role of multi-tracer PET in deciphering 2 different pathologies in multiple endocrine neoplasia 1 (MEN-1) is illustrated in this report. A 22-year-old man, with a history of altered behavior over the past 1 year and suspected to have hyperinsulinemic hypoglycemia based on a positive 72-hour fasting test and CT abdomen revealing a lesion in the pancreas, was referred for 68Ga-Exendin-4 PET/CT. The 68Ga-Exendin PET/CT revealed focal uptake in the pancreatic lesion, and 68Ga-DOTATATE PET/CT did not show any avidity in the pancreatic lesion; however, it demonstrated somatostatin receptor (SSTR) expression in a soft tissue mass, just posterior to the thyroid. Parathyroid adenoma and hyperparathyroidism were finally proven, and genetic testing was done, which came positive for the diagnosis of MEN-1 syndrome.

Multiple endocrine neoplasia type 1 (MEN1) is a rare genetic disease with autosomal dominant transmission, which can cause various tumors, particularly endocrine, in a given patient. Primary hyperparathyroidism (PHPT) is the most common and earliest manifestation, leading to surgery before the age of 50 in most patients. Biological severity and renal and/or bone complications dictate the timing of parathyroid surgery. The objective is to correct hypercalcemia to prevent impact, while minimizing the risk of hypoparathyroidism. The most widely recommended procedure is subtotal parathyroidectomy (3 or 3.5 glands removed), with thymic horn resection via a cervical route. The development of imaging techniques, however, makes it possible to discuss partial surgery (resection of 1 or 2 glands) on a case-by-case basis depending on preoperative imaging and other elements such as patient age. Finally, hypercalcemia recurrence after initial surgery is a common feature of MEN1, and management of the remaining gland is challenging with various options: reoperation, calcimimetics and US-guided ablation or therapeutic abstention.

Multiple endocrine neoplasia type 1 (MEN1) syndrome is characterized by the presence of hyperplastic or neoplastic tumors in the parathyroid, pituitary, and gastroenteropancreatic endocrine tissues. The presence of lesions in at least two out of the three glands (pituitary, parathyroid, and pancreas) is indicative of MEN1 syndrome. Medullary thyroid carcinoma (MTC) is a type of tumor that originates from the parafollicular C cells of the thyroid gland. It is frequently found as part of MEN2 syndrome. MEN1 with MTC is a relatively uncommon occurrence. We report a rare case of MTC that later on developed parathyroid carcinoma, pituitary microadenoma, pancreatic neuroendocrine tumor (NET), and duodenal NET. The case was identified as part of MEN1 syndrome using exome sequencing and somatostatin receptor-based functional imaging 68 Ga-DOTATATE positron emission tomography/computed tomography was employed for exploring theranostic strategy in the management of the patient.

Persistent and recurrent primary hyperparathyroidism (PHPT) represent significant challenges in the management of PHPT. Persistent PHPT is defined as persistence of hypercalcemia following parathyroidectomy (PTX) or the recurrence of hypercalcemia within the first 6 months following surgery. Recurrent PHPT is defined as recurrence of hypercalcemia after 6 months following PTX and requires normalization of serum calcium prior to the recurrence. These conditions are often attributed to missed or ectopic glands, multiglandular disease, surgeon inexperience, or rare causes such as parathyromatosis and parathyroid carcinoma. Diagnosis requires a detailed biochemical evaluation, imaging studies, and exclusion of other causes of hypercalcemia as well as secondary causes of hyperparathyroidism. Preoperative imaging modalities, including neck ultrasound, SPECT-CT with 99m Tc-sestamibi scan, 4D-CT, 18F-Fluorocholine PET/CT, and PET/MRI are helpful in localizing abnormal parathyroid glands in cases requiring repeat surgery. Repeat surgery is associated with higher risk and requires an experienced surgeon. When surgery is not indicated or possible, medical management with cinacalcet and antiresorptive therapies may be considered. This review highlights the etiology, diagnostic approaches, and management strategies for persistent and recurrent PHPT, emphasizing the importance of multidisciplinary care in order to optimize outcomes.

Familial or heritable hyperparathyroidism (FHPT) is seen in approximately 10-15 % of patients with primary hyperparathyroidism (PHPT). Once the diagnosis of PHPT is established, consideration of heritable forms should be made in patients with positive family history, young onset, multi-glandular disease, and recurrent or persistent disease. FHPT encompasses both syndromic and non-syndromic forms. Syndromic forms include multiple endocrine neoplasia (MEN) types 1, 2, 3 and 4, hyperparathyroidism-jaw tumor syndrome, hereditary pheochromocytoma and paraganglioma, and the more recently reported, Birt-Hogg-Dubé (BHD) syndrome, and X-linked intellectual disability syndrome. Non-syndromic forms include familial hypocalciuric hypercalcemia (FHH)- types 1,2, and 3, neonatal severe hyperparathyroidism, GCM2-mediated hyperparathyroidism, transient neonatal hyperparathyroidism, and familial isolated hyperparathyroidism. In this review we aim to review the heritable forms of PHPT and highlight the important genetics insights and clinical implications.

The co-occurrence of primary hyperparathyroidism (PHPT) and pituitary adenomas (PAs) is often indicative of underlying genetic syndromes such as Multiple Endocrine Neoplasia type 1 (MEN1) and, less commonly, MEN4. Although both conditions can occur sporadically, their simultaneous presence warrants evaluation for genetic mutations, with MEN1 mutations being the most frequent cause. The management of concurrent PHPT and PAs, especially in MEN1 patients, presents unique challenges. Management complexities arise from the syndromic nature, involving both surgical and medical interventions tailored to each condition. PHPT often manifests earlier and more aggressively in MEN1, requiring surgical intervention. However, recurrence rates remain high due to multiglandular involvement. Pituitary adenomas in MEN1 are primarily prolactinomas, and treatment with dopamine agonists results in significant tumour control in most cases. Overall, PAs associated with MEN1 are generally responsive to medical therapy, but careful long-term monitoring is essential. The utility of genetic screening cannot be overstated, as it aids in early detection, risk stratification, and management of both the index case and affected family members by cascade screening. A multidisciplinary approach is crucial for optimizing outcomes, with ongoing surveillance to manage recurrence and associated complications. In summary, the co-occurrence of PHPT and PAs, particularly in the context of MEN1, necessitates an integrated management strategy. Genetic testing is key in confirming diagnosis and guiding treatment, while surgical and medical interventions should be tailored to the extent and nature of glandular involvement. Close monitoring for recurrence and proactive family screening are essential components of long-term care.

Multiple endocrine neoplasia 4 (MEN4) is a rare syndrome caused by germline mutations in CKDN1B, and it shares clinical manifestations with MEN1, including primary hyperparathyroidism, pituitary adenomas, and pancreatic neuroendocrine tumors (NETs). The prevalence of MEN4 is <1 per million, whereas prevalence of MEN1 is between 1/10 000 and 1/30 000.

A 51-year-old woman presented with symptomatic hypoglycemia and incidental hypercalcemia. Workup revealed a fasting plasma glucose level of 41 mg/dL (60-99 mg/dL), proinsulin level of 84.3 pmol/L (≤8.0 pmol/L), insulin level of 24 uIU/mL (3-25 uIU/mL), c-peptide level of 5.2 ng/mL (1.1-4.4 ng/mL), and β-hydroxybutyrate level of 0.34 mmol/L (0.02-0.27 mmol/L), consistent with endogenous hyperinsulinism. Computed tomography scan of the abdomen revealed a 1.5 × 1.1 × 1.0 cm pancreatic head nodule. She underwent pancreaticoduodenectomy, and pathology demonstrated a well-differentiated neuroendocrine tumor with no metastases. She became normoglycemic after surgery, and additional workup revealed primary hyperparathyroidism. Germline testing revealed a variant of unknown significance in CDKN1B (p.R93W).

Both MEN1 and MEN4 result from decreased expression of p24 and exhibit similar clinical phenotypes, but there are subtle differences in penetrance and natural history. About 10% of patients with MEN1 have insulinomas, but no insulinomas have been reported in MEN4. primary hyperparathyroidism in MEN4 exhibits a lower risk of recurrence after parathyroidectomy. This case highlights the importance of germline genetic testing when a patient presents with manifestations of MEN1.

To our knowledge, this is the first reported case of insulinoma in MEN4.

Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant disorder characterized by the occurrence of combined tumors in different glands, usually the parathyroid, pancreas and pituitary, as well as in other parts of the digestive tract. The present study describes the phenotype of a Brazilian family with MEN1 caused by a previously unreported MEN1 gene mutation.

We report the case of a 41-year-old male, the proband, who presented with angiofibromas, primary hyperparathyroidism, macroprolactinoma, and pancreatic neuroendocrine tumor. Next generation sequencing analysis of the MEN1 gene in the patient's peripheral blood DNA sample revealed a deletion of 16 base pairs (c.1366-12_1369del;p) resulting in a framing error. Additional 5 members of the family (4 brothers and a first cousin) presented with clinical features of MEN1. All brothers underwent mutation screening and tested positive for the same genetic variant. Two of them were also diagnosed with papillary thyroid carcinoma.

The c.1366-12_1369del;p mutation is located between the 10th and last exon of the MEN 1 gene and it's preceding intron, encompassing the canonical sites in the splice junction. The 10th exon of MEN1, possibly lost with this variant, encodes the last 163 amino acids that compose the Menin protein's C-terminal region, which harbors nuclear localization signals essential for its internalization into the nuclear compartment and interaction with the nuclear matrix.

Our case reports add to the literature the description of a new pathogenic variant of the MEN 1 gene.

AbstractMorning Report is a time-honored tradition where physicians-in-training present cases to their colleagues and clinical experts to collaboratively examine an interesting patient presentation. The Morning Report section seeks to carry on this tradition by presenting a patient's chief concern and story, inviting the reader to develop a differential diagnosis and discover the diagnosis alongside the authors of the case. This report examines the story of a 59-year-old man with a history of nephrolithiasis and gastroesophageal reflux who sought evaluation for fatigue and abdominal pain. Using questions, physical examination, and testing, an illness script for the presentation emerges. As the clinical course progresses, the differential is iteratively refined until a final diagnosis is made.

BACKGROUNDAmong patients with multiple endocrine neoplasia type 1 (MEN1), 80% develop duodenopancreatic neuroendocrine tumors (dpNETs), of whom 15%-25% die of metastasis. There is a need to identify biomarkers to predict aggressive disease. MEN1 genotype affords an attractive possibility as a biomarker, as it remains constant during life. Currently, patients are clinically diagnosed with MEN1 by the presence of ≥2 primary endocrine tumors (pituitary, parathyroid, and pancreas) or ≥1 primary endocrine tumor with a positive family history. From 10% to 30% of patients diagnosed clinically with MEN1 have no pathogenic germline MEN1 variants.METHODSThis was a retrospective study of 162 index patients or probands with genotype-positive and 47 with genotype-negative MEN1 enrolled from 1977 to 2022.RESULTSCompared with patients with genotype-negative disease, patients with genotype-positive disease were younger at diagnosis and had an increased frequency of recurrent parathyroid tumors, dpNETs, and angiofibromas or collagenomas. We propose a weighted scoring system to diagnose genotype-positive MEN1 based on clinical characteristics. No evidence of MEN1 mosaicism was seen in 30 tumors from 17 patients with genotype-negative MEN1. Patients with germline MEN1 variants in exons 2 and 3 had a reduced risk of distant metastases.CONCLUSIONThe clinical course of genotype-negative MEN1 is distinct from genotype-positive disease, raising uncertainty about the benefits of lifetime surveillance in patients with genotype-negative disease. MEN1 mosaicism is rare.TRIAL REGISTRATION ClinicalTrials.gov NCT04969926FUNDINGIntramural Research Program of National Institute of Diabetes and Digestive and Kidney Diseases, NIH (ZIA DK043006-46).

Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms that originate from neuroendocrine cells, characterized by their ability to secrete hormones and peptides. Once considered rare, the incidence of NETs has steadily increased due to improved diagnostic modalities. The therapeutic landscape is multifaceted, ranging from surgery for localized disease to pharmacological interventions for advanced cases. However, the absence of robust predictive biomarkers precludes patient stratification and optimization of therapy. Everolimus, an oral mTOR inhibitor, has emerged as a key therapeutic agent due to its dual role in inhibiting cell proliferation and angiogenesis. Nevertheless, challenges such as resistance mechanisms, toxicity and optimal treatment sequencing remain unresolved. This article provides a comprehensive review of the role of everolimus in the management of NETs, focusing in particular on unresolved issues, from the absence of predictive biomarkers to the unavailability of defined guidelines for determining the correct therapeutic sequence.

This review seeks to provide endocrine clinicians with a comprehensive analysis of breast cancer risk, diagnostic modalities and management strategies in women with endocrine disorders, with particular emphasis on the influence of metabolic factors such as diabetes and obesity, and the role of Menopausal Hormone Therapy (MHT).

The review examines a spectrum of endocrine disorders commonly encountered in clinical practice, including Multiple Endocrine Neoplasia Types 1 (MEN1), 2 (MEN2) and 4 (MEN4), Von Hippel-Lindau syndrome (VHL), Pheochromocytoma and Paraganglioma (PPGL), Acromegaly, Hyperprolactinaemia, Polycystic Ovary Syndrome (PCOS), Congenital Adrenal Hyperplasia (CAH), Turner Syndrome, alongside metabolic conditions such as diabetes and obesity and the effects of MHT. The review critically appraises each disorder's association with breast cancer risk, screening implications and therapeutic management.

This analysis focuses on women with the aforementioned endocrine and metabolic disorders, assessing their specific breast cancer risk profiles, informed by the latest clinical evidence and molecular insights.

The review comprehensively evaluates current evidence-based approaches to screening, diagnostic accuracy and treatment in this patient cohort. Emphasis is placed on the metabolic derangements, hormonal influences and genetic predispositions that modulate breast cancer risk, providing disorder-specific recommendations for individualised care.

The findings indicate a significantly elevated breast cancer risk in patients with MEN1, necessitating early initiation of MRI screening by age 40. In MEN2, emerging evidence suggests that combining RET inhibitors with endocrine therapy may yield clinical benefits, although further research is needed to validate this approach. The breast cancer risk associated with MEN4 and VHL syndromes, while documented, remains less well-characterised, requiring further investigation. Diabetes and obesity are confirmed as major modifiable risk factors, particularly in postmenopausal women, where hyperinsulinemia and metabolic dysfunction contribute to increased incidence and poorer outcomes, notably in triple-negative breast cancer (TNBC). The role of MHT, particularly combined oestrogen-progestogen therapy, is strongly associated with increased breast cancer risk, particularly for hormone receptor-positive malignancies, necessitating cautious use and personalised treatment planning. In contrast, oestrogen-only MHT appears to confer a reduced risk in women post-hysterectomy. For patients with PCOS, CAH and Turner Syndrome, while definitive evidence of elevated breast cancer risk is lacking, individualised screening strategies and careful hormone therapy management remain essential due to the complex interplay of hormonal and metabolic factors.

The review highlights the need for personalised breast cancer screening and management protocols in women with endocrine and metabolic disorders. For high-risk groups such as MEN1 patients, early initiation of MRI screening is warranted. In women with diabetes and obesity, targeted interventions addressing hyperinsulinemia and metabolic dysfunction are critical to mitigating their increased cancer risk. The association between MHT and breast cancer underscores the importance of individualised risk stratification in hormone therapy administration, particularly in women with predisposing genetic or endocrine conditions. Enhanced surveillance tailored to the unique risk profiles of endocrine disorder patients will facilitate early detection and improve clinical outcomes. However, further large-scale studies are necessary to refine these associations and develop robust, evidence-based guidelines.

Pancreatic neuroendocrine tumors (PNETs) are the leading cause of death related to multiple endocrine neoplasia type 1 (MEN1). Previous studies have linked certain mutations in the MEN1 gene and loss of interactions with MENIN's functional partners to the mortality or aggressiveness of PNETs. This study aimed to evaluate the genotype-phenotype correlations of MEN1-related PNETs in Korean patients and to summarize the treatment outcomes comprehensively.

We retrospectively analyzed 72 patients diagnosed with MEN1 at a tertiary care center in Korea between January 2003 and September 2022. MEN1 mutations were analyzed using direct or next-generation sequencing.

Among 40 families with MEN1, 10 had exon 2 mutations, which were the most frequently observed. Of these, 50 (69.4 %) were diagnosed with PNETs; 20 underwent pancreatic resection. Patients with truncating mutations showed a significant difference in age-related penetrance of PNET (p = 0.029). No distinct genotype was associated with malignant transformation (lymph node or distant metastasis) in MEN1-related PNETs. In the subgroup Cox model, mutations in exons 3 or 10 showed significant differences in tumor progression in the observation group (adjusted hazard ratio: 8.164,(95 % CI: 1.648-40.436), p = 0.010, HR: 8.300, (95 % CI: 1.808-38.113), p = 0.007).

PNETs in Korean patients with MEN1 exhibit a stable prognosis. An individualized follow-up strategy may be necessary, particularly for young patients with truncating mutation in the MEN1 gene. In addition, those with mutations in exons 3 or 10 may require more active surveillance to decrease the risk of progression.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-dominant disorder characterized by tumors of the pituitary, parathyroid, and endocrine-gastrointestinal tract. Pituitary neuroendocrine tumors (PitNETs) occur in about 40% of MEN1 cases, with 10% being the first manifestation. Recent studies show a slight female predominance, with microPitNETs (<1 cm) being more common than macroPitNETs (>1 cm). Functional PitNETs (FPitNETs) are more frequent than non-functional ones (36% to 48%), with prolactinomas being the most common FPitNETs. MEN1-associated PitNETs are often plurihormonal, larger, and more invasive compared to sporadic types, though patient age and FPitNET proportions are similar. MEN1 mutation-negative patients tend to have larger, symptomatic PitNETs at diagnosis. Six patients with MEN1 have been reported to have pituitary carcinomas, including a mutation- negative patient. Treatment approach between PitNETs in MEN1 and sporadic types appears to be similar. PitNETs also occur in MEN4, but their epidemiology is less understood. In patients with a MEN1-like phenotype and negative genetic testing, MEN4 should be considered.

Syndromic primary hyperparathyroidism has several features in common: younger age at diagnosis when compared with sporadic primary hyperparathyroidism, often synchronous or metachronous multi-glandular involvement, higher possibility of recurrence, association with other endocrine or extra-endocrine disorders, and suggestive family background with autosomal dominant inheritance. Hyperparathyroidism in multiple endocrine neoplasia type 1 is the most common syndromic hyperparathyroidism. It is often asymptomatic in adolescents and young adults, but may be responsible for recurrent lithiasis and/or bone loss. Hyperparathyroidism-jaw tumor syndrome is less frequent, but often immediately symptomatic, with higher blood calcium levels, and is sometimes associated with an atypic parathyroid tumor or parathyroid carcinoma. Hyperparathyroidism in multiple endocrine neoplasia type 2A is not at the forefront of the clinical picture, rarely revealing the disease, and often manifests with few symptoms. Multiple endocrine neoplasia type 4 is a more recently described entity, in which hyperparathyroidism seems to occur later and be less severe than in previous syndromes. In all cases, the indications and modalities of surgical treatment should be discussed in an expert center. The risk of recurrence after surgery, particularly high in multiple endocrine neoplasia type 1, requires long-term monitoring.

Multiple endocrine neoplasia type 1 (MEN-1) is a syndrome characterized by development of tumors including parathyroid adenomas, duodenopancreatic neuroendocrine tumors, and pituitary adenomas. We describe 1 patient with a novel and another with a rare pathogenic MEN-1 variant. Case 1 was a 61-year-old woman with recurrent hypercalcemia who ultimately required a subtotal parathyroidectomy, with a thymectomy revealing a thymoma. She then developed a gastrinoma requiring pancreatectomy and also had a biochemically nonfunctioning sellar mass. Genetic testing found a novel MEN1:c.1192delC, p.(Gln398Argfs*47) pathogenic variant. Case 2 was a 38-year-old woman with a family history of MEN-1, who had recurrent hypercalcemia and nephrolithiasis requiring a subtotal parathyroidectomy. She had a macroprolactinoma, but no pancreatic lesions. Genetic testing found a rare MEN1:c.784-9G > A pathogenic variant. MEN-1 syndrome should be considered in patients presenting with 1 or more classical MEN-1-associated tumors based on clinical suspicion.

Neuroendocrine tumors (NETs) are heterogeneous malignancies arising from enterochromaffin cells that can arise from the gastrointestinal (GI) tract and pancreas. Surgical management is the cornerstone of treatment, with the optimal approach tailored by tumor grade, size, location, and presence of metastasis. This review discusses the current strategies for the surgical management of NETs of the gastroenteropancreatic tract.

A review of the available literature was conducted to evaluate surgical approaches to NETs. Consensus guidelines were incorporated to synthesize evidence-based recommendations.

For gastric NETs, surgical approach depends on Rindi Classification, WHO grade, and tumor size, with endoscopic approaches favored for smaller and low-grade lesions. Small bowel NETs can be multifocal and thus often require a surgical approach with careful evaluation of the entire intestine. Pancreatic NETs are categorized as functional or non-functional, with enucleation or formal resection strategies based on size, location, functional status, and risk of malignancy. Colorectal NETs are primarily treated with transanal localized or formal surgical resection, depending on lesion size and depth of invasion or presence of lymph node involvement. Appendiceal NETs are either treated with appendectomy or right hemicolectomy, depending on the size, location, and invasiveness of the lesions. For metastatic NETs, cytoreduction, liver transplantation, and targeted therapies offer symptom relief and possible survival benefits.

Surgical resection provides curative potential for localized NETs and symptom control in metastatic cases. Future research is essential to refine guidelines for intermediate-risk lesions and multifocal tumors, ensuring optimal outcomes for patients with gastroenteropancreatic NETs.

Multiple endocrine neoplasia type 1 (MEN1) syndrome is an autosomal dominant disorder caused by a germline pathogenic variant in the MEN1 tumor suppressor gene. Patients with MEN1 have a high risk for primary hyperparathyroidism (PHPT) with a penetrance of nearly 100%, pituitary adenomas (PitAd) in 40% of patients, and neuroendocrine neoplasms (NEN) of the pancreas (40% of patients), duodenum, lung, and thymus. Increased MEN1-related mortality is mainly related to duodenal-pancreatic and thymic NEN. Management of PHPT differs from that of patients with sporadic disease, as the surgical approach in MEN1-related PHPT includes near-total or total parathyroidectomy because of multigland hyperplasia in most patients and the consequent high risk of recurrence. NEN management also differs from patients with sporadic disease due to multiple synchronous and metasynchronous neoplasms. In addition, the lifelong risk of developing NEN requires special considerations to avoid excessive surgeries and to minimize damage to the patient's function and well-being. This progress report will outline current insights into surveillance and management of the major clinical manifestation of MEN1 syndrome in children and adults with MEN1 diagnosis. In addition, we will discuss MEN1-like clinical presentation with negative MEN1-genetic workup and future clinical and research directions.

Lung neuroendocrine neoplasms are a group of diverse, heterogeneous tumours that range from well-differentiated, low-grade neuroendocrine tumours-such as typical and atypical carcinoids-to high-grade, poorly differentiated aggressive malignancies, such as large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC). While the incidence of SCLC has decreased, the worldwide incidence of other pulmonary neuroendocrine neoplasms has been increasing over the past decades. In addition to the standard histopathological classification of lung neuroendocrine neoplasms, the introduction of molecular and sequencing techniques has led to new advances in understanding the biology of these diseases and might influence future classifications and staging that can subsequently improve management guidelines in the adjuvant or metastatic settings. Due to the rarity of neuroendocrine neoplasms, there is a paucity of prospective studies that focus on the lungs, especially in rare, well-differentiated carcinoids and LCNECs. In contrast with the success of targeted therapies in non-small-cell lung cancer (NSCLC), high-grade neuroendocrine carcinomas of the lung often only have a few specific targetable gene alterations. Optimal therapy for LCNECs is not well defined and treatment recommendations are based on extrapolating guidelines for the management of patients with SCLC and NSCLC. This Review explores the epidemiology, diagnosis, and staging of lung neuroendocrine neoplasms to date. In addition, we focus on the evolving molecular landscape and biomarkers, ranging from tumour phenotypes to functional imaging studies and novel molecular biomarkers. We outline the various clinical outcomes, challenges, the treatment landscape, ongoing clinical trials, and future directions.

The vast majority of neuroendocrine 'neoplasms (NENs) are sporadic, although recent evidence has indicated that a subset of these cancers may also originate as a result of genetic germline mutations. To date, 10% of these cancers can be linked to an inherited genetic syndrome. Genetic diagnosis is crucial for patients with a suspected hereditary NEN syndrome, as it recognizes patients carrying germline mutations and allows for personalized clinical follow-up, considering the higher risk of developing other tumours. The potential for early genetic detection has significant implications for the treatment of patients with hereditary NEN syndrome, as it may facilitate the delivery of precision therapy that differs from that typically provided to other patients. Thus, the integration of genotypic and phenotypic diagnostic methods help clinicians to provide more informed treatment and to extend appropriate prevention to family members.

Adrenocortical tumors (ACTs) are frequently encountered in clinical practice. They vary in clinical and biological characteristics from nonfunctional to life threatening hormone excess, from benign to highly aggressive malignant tumors. Most ACTs appear to be benign and nonfunctioning. It has been controversial how these apparently benign and nonfunctioning tumors should be monitored. Over the past few decades, significant advances have been made in understanding the regulation of growth and tumorigenesis in adrenocortical cells. Defining the molecular pathomechanisms in inherited tumor syndromes led to the expansion of research to sporadic ACTs. Distinct molecular signatures have been identified in sporadic ACTs and a potential genomic classification of ACT has been proposed.

In this review, we discuss the various adrenocortical pathologies associated with hereditary syndromes with special focus on their molecular pathomechanisms, the understanding of which is important in the era of precision medicine.

Identifying the molecular pathomechanisms of the adrenocortical tumorigenesis in inherited syndromes has led to the understanding of the alterations in different signaling pathways that help explain the wide variations in the biology and behavior of ACTs.

Pancreatic neuroendocrine neoplasms (pNENs) are the second most common pancreatic malignancy. While most cases are sporadic, a small proportion is associated with genetic syndromes, such as Multiple Endocrine Neoplasia (MEN), Von Hippel-Lindau Syndrome (VHL), Neurofibromatosis Type 1 (NF1), and Tuberous Sclerosis Complex (TSC). This review aims to use pNENs as a clue to reveal the full spectrum of disease, providing a comprehensive understanding of diagnosis. It aids in promptly identifying abnormalities in other organs, recognizing familial genetic mutations, and achieving personalized treatment.

Parathyroid tumors are classified as parathyroid neuroendocrine neoplasia (NEN) by the IARC-WHO classification. These tumors can occur with NENs from other sites, which often require total-body [68Ga]-DOTA-peptides PET/CT. This study aimed to assess the utility of [68Ga]-DOTA-peptide PET/CT in imaging parathyroid NENs and to evaluate the underlying mechanisms.

Fifty patients with primary hyperparathyroidism (PHPT) and parathyroid NENs histologically confirmed as parathyroid adenomas (PAs) were included. PET/CT with [68Ga]-DOTA-peptide was performed in 16 patients with localized PAs, including 10 with MEN1 syndrome. Somatostatin receptor types 2 and 5 (SST2 and SST5) staining was performed on PAs from 48 patients. Somatostatin analogs (SSA) were prescribed in four patients with MEN 1 syndrome and 1 with persistent acromegaly, all with PAs and PHPT. The therapy effects on calcium and parathyroid hormone (iPTH) were evaluated.

[68Ga]-DOTA-peptide PET/CT detected 20 PAs with high radiopharmaceutical uptake. SST2 expression was negative on PA cell membranes in all cases and positive on endothelium in 39 (81%) PAs. Membrane SST5 expression was positive in 25 (52%) PAs and endothelial was positive in 40 (83%). Serum calcium levels decreased in patients on SSA therapy, while iPTH did not.

PET/CT with [68Ga]-DOTA-peptides can detect parathyroid NENs. The incidental detection of high [68Ga]-DOTA-peptide uptake in the parathyroid region during whole-body PET/CT may prompt biochemical evaluation for PHPT. We suggest that endothelial SST expression mediates high radiopharmaceutical uptake by PAs and that SSA treatment can reduce hypercalcemia in PHPT patients.

Primary hyperparathyroidism is characterized by elevated plasma calcium levels due to inappropriate secretion of parathyroid hormone (PTH) in most cases by an adenomatous or hyperplastic parathyroid. We present a retrospective analysis of a large cohort of patients operated on of parathyroidectomy in our center analyzing their diagnostic characteristics, intraoperative match and surgical outcomes.

We included patients with benign parathyroid disease who underwent parathyroidectomy associated or not with hemi- or total thyroidectomy at the Sant'Anna University Hospital of Ferrara between September 2003 and September 2022.

In our study 371 patients fulfilled the inclusion criteria. The most widely used preoperative imaging method was ultrasound, followed by 99mTc-sestamibi scintigraphy. In most cases, preoperative imaging correctly localized the affected parathyroid. Considering the intraoperative site of the pathologically affected parathyroid, the majority of pathological parathyroids were located in the lower districts of the neck and a smaller percentage in the upper, intermediate, and ectopic sites. Postoperative complications were infrequent.

The main challenge in parathyroid surgery lies in the difficulty in localizing the pathological parathyroid at the surgical site, which can lengthen the surgical time by increasing comorbidities. Currently, the results on pathological parathyroid localization are good. Technology needs to be developed toward greater diagnostic accuracy and minimally invasive surgical approaches.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors in multiple endocrine organs, caused by variants in the MEN1 gene. This study analyzed the clinical and genetic features of MEN1 in a Korean cohort, identifying prevalent manifestations and genetic variants, including novel variants.

This multicenter retrospective study reviewed the medical records of 117 MEN1 patients treated at three tertiary centers in Korea between January 2012 and September 2022. Patient demographics, tumor manifestations, outcomes, and MEN1 genetic testing results were collected. Variants were classified using American College of Medical Genetics and Genomics (ACMG) and French Oncogenetics Network of Neuroendocrine Tumors propositions (TENGEN) guidelines.

A total of 117 patients were enrolled, including 55 familial cases, with a mean age at diagnosis of 37.4±15.3 years. Primary hyperparathyroidism was identified as the most common presentation (84.6%). The prevalence of gastroenteropancreatic neuroendocrine tumor and pituitary neuroendocrine tumor (PitNET) was 77.8% (n=91) and 56.4% (n=66), respectively. Genetic testing revealed 61 distinct MEN1 variants in 101 patients, with 18 being novel. Four variants were reclassified according to the TENGEN guidelines. Patients with truncating variants (n=72) exhibited a higher prevalence of PitNETs compared to those with non-truncating variants (n=25) (59.7% vs. 36.0%, P=0.040).

The association between truncating variants and an increased prevalence of PitNETs in MEN1 underscores the importance of genetic characterization in guiding the clinical management of this disease. Our study sheds light on the clinical and genetic characteristics of MEN1 among the Korean population.

Neuroendocrine tumor (NET) brain metastases (BM) are rare malignancies which frequently bear a poor prognosis and have the potential to secrete hormones. The optimal treatment approach for these metastases remains unclear, with significant heterogeneity occurring both across and within primary tumor types, and outcome data are limited. Pancreatic neuroendocrine tumor (pNET) BM may be particularly aggressive. While stereotactic radiosurgery (SRS) for other NET BM has previously been described, no report has specifically investigated SRS for management of pNET BM.

A comprehensive literature search was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Search terms included ("neuroendocrine tumor" OR "neuroendocrine neoplasm" OR "neuroendocrine carcinoma" OR "NET") AND ("brain metastasis" OR "brain metastases" OR "intracranial metastases") AND ("stereotactic radiosurgery" OR "stereotactic body" OR "CyberKnife" OR "GammaKnife").

Our search strategy yielded 230 articles. After screening, a total of 16 articles with 256 patients were identified. Number of patients per study cohort ranged from 1 to 101 (mean = 16). Ten articles were single case reports. The most commonly investigated primary site was lung (5 studies), followed by skin (2 case reports), and uterine cervix (2 case reports). Median survival post-SRS ranged from 5 to 42 months. Median tumor volume ranged from 0.08 cm3 to 33.62 cm3. Local control rate was provided in 3 of 6 of the reviewed retrospective analyses. A pulmonary cohort of 101 patients reported a recurrence rate of 13.8 % at 12 months. A pulmonary case series similarly reported local progression in only 1 of 8 patients. The mixed primary cohort (33 patients) had a long-term local failure rate of 16.7 %. In addition, we describe a first reported individual case of pNET BM treated with SRS. Nearly 6-years after initial pNET diagnosis, multiple intracranial enhancing lesions were found, which were subsequently treated with SRS. Follow-up imaging demonstrated a statistically significant decrease in lesion diameter (p < 0.001), with none of the 18 BM progressing.

Given the recently increase in age-adjusted incidence of NET BM, determining an optimal treatment approach for these malignancies is of growing importance. Prognosis generally remains poor, with BM being a significant predictor of overall survival. Our review indicated large variability in outcomes both between and within primary tumor types, suggesting a need for further investigation of predictive molecular biomarkers. In addition, to the authors' knowledge, this represents the first reported case of pNET BM successfully treated with SRS.

Multiple Endocrine Neoplasia (MEN) is a group of familial cancer syndromes that encompasses several types of endocrine tumors differentiated by genetic mutations in RET, MEN1 and CDKN1B genes. Accurate diagnosis of MEN subtypes can thus be performed through genetic testing. However, MEN variants remain largely understudied in Indian populations. Additionally, few dedicated resources to understand these disorders currently exist.

Using the gold-standard ACMG/AMP guidelines, we systematically classified variants reported across the three genes in the IndiGen dataset, and established the genetic epidemiology of MEN in the Indian population. We further classified ClinVar and Mastermind variants and compiled all into a database. Finally, we designed a multiplex primer panel for rapid variant identification.

We have established the genetic prevalence of MEN as the following: 1 in 1026 individuals is likely to be afflicted with MEN linked with pathogenic RET mutations. We have further created the MAPVar database containing 3280 ACMG-classified variants freely accessible at: https://clingen.igib.res.in/MAPVar/ . Finally, our NGS primer panel covers 33 exonic regions across two pools through 38 amplicons with a total amplified region of 65 kb.

Our work establishes that MEN is a prevalent disorder in India. The rare nature of Indian variants underscores the need of genomic and functional studies to establish a more comprehensive variant landscape. Additionally, our panel offers a means of cost-effective genetic testing, and the MAPVar database a ready reference to aid in a better understanding of variant pathogenicity in clinical as well as research settings.