Search Results (59)

A 31-year-old female patient with a 4-year history of multiple endocrine neoplasia type 1 (MEN1) presented with abdominal pain and weight loss that she had been experiencing over the past 6 months. Somatostatin receptor (SSTR) scintigraphy using 99mTc-HYNIC-TOC revealed increased uptake in the known pancreatic neuroendocrine tumor as well as diffuse increased uptake in bilateral lactating breasts. This case highlights physiological upregulation of somatostatin receptor expression in a lactating breast. Full article

Menin, the product of the Multiple Endocrine Neoplasia type 1 (MEN1) gene, is a scaffold protein, the lack of which leads to the development of a tumor syndrome primarily affecting endocrine organs. Although it is classified as an oncosuppressor, menin is a ubiquitous protein whose expression is also abundant in non-endocrine tissues such as the central nervous system, where knowledge of menin’s role still remains limited. In this article, we aim to draw attention to an underestimated clinical aspect of MEN1 syndrome, i.e., the psychological/psychiatric manifestations, in which menin deficiency could have an important function. Our aim is to highlight that a multidisciplinary team caring for patients with MEN1 throughout their lives should include professionals such as psychologists and psychiatrists in order to better manage any mental illness associated with the syndrome and to further improve the patient’s quality of life. Full article

Background: Pituitary neuroendocrine tumors (PitNETs) are a core manifestation of multiple endocrine neoplasia type 1 (MEN1), yet their true prevalence, biological behavior, and optimal management remain debated. Earlier reports suggested increased aggressiveness compared with sporadic PitNETs, while more recent surveillance-based studies indicate a predominantly indolent phenotype. Methods: We conducted a retrospective single-center study including all patients with clinical, familial, or genetic MEN1 referred to the Endocrinology Unit of the University of Naples “Federico II”, ENETS Center of Excellence, between January 2004 and June 2025. Demographic, clinical, radiological, hormonal, and therapeutic data were systematically collected. PitNETs were classified by size and hormonal activity. Results: Among 103 MEN1 patients (61 women), 50 (48.5%) were diagnosed with PitNETs at a mean age of 35.1 years. Microadenomas predominated (60%), and tumors were equally distributed between functioning and non-functioning lesions. Prolactin-secreting PitNETs were the most common functioning subtype (42%), followed by rare GH-, ACTH-, or mixed-secreting PitNETs. Dopamine agonists, mainly cabergoline, were prescribed in 38% of cases, while neurosurgical intervention was required in 14%, exclusively for macroadenomas. During follow-up, recurrence occurred in 8% of patients. No significant sex-related differences were observed in prevalence, tumor size, functional status, treatment approach, or outcomes. Conclusions: In our MEN1 cohort, PitNETs were frequent but largely indolent, with a predominance of microadenomas and limited need for surgery. Our findings support individualized, subtype-driven surveillance strategies, with conservative management for clinically non-functioning microadenomas and closer monitoring of prolactin-secreting PitNETs due to variable medical responsiveness. Full article

Background/Objectives: The RET (Rearranged during Transfection) gene encodes a receptor tyrosine kinase. RET plays a critical role in embryonic development and postnatal physiology. This review provides a comprehensive overview of RET-associated disorders, focusing on the molecular mechanisms of RET activation, associated clinical phenotypes and therapeutic implications. In addition, we present an updated RET mutation database. Methods: RET mutation database is built through the integration and curation of data from two major RET mutation repositories: the Leiden Open Variation Database (LOVD) and the Cancer Knowledge Base (CKB) as well as information derived from the ClinVar database. Results: To date, 78 pathogenic RET mutations have been identified, among these, 71 (91.0%) are single nucleotide substitutions (missense variants), 2 (2.6%) are deletions, 1 (1.3%) are indels, 2 (2.6%) are nonsense mutations and 1 (1.3%) mutation affecting the introns. A pronounced clustering was observed in exons 10–11, accounting for ~60% of cases, suggesting a potential mutational hotspot with structural or functional relevance. Conclusions: Aberrant RET activation, resulting from activating missense variants, gene fusions, or overexpression, underlies a wide spectrum of human diseases. These include multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid carcinoma (MTC), Hirschsprung disease, and pheochromocytoma. The existence and use of a database classifying variants in the RET gene plays a fundamental role in molecular diagnostics and personalized medicine. Full article

Background and Clinical Significance: Ganglioneuromatosis is a benign proliferation of mature ganglion cells, Schwann cells, and nerve fibers within the enteric or autonomic nervous system. According to the WHO classification, it encompasses a spectrum range from solitary ganglioneuroma to ganglioneuromatous polyposis and diffuse mural involvement. It is most commonly encountered in the colon and small bowel and is strongly associated with hereditary syndromes such as neurofibromatosis type 1 (NF1), multiple endocrine neoplasia type 2B (MEN2B), and Cowden syndrome. The involvement of the gallbladder is exceptional and only isolated cases have been documented. Case Presentation: We present the case of 64-year-old man admitted with longstanding right hypochondrium and epigastric pain, accompanied by intermittent nausea and occasional bilious vomiting. A cholecystectomy was performed and the histology result showed hypertrophic nerve fibers with interspersed mature ganglion cells within the fibromuscular layer. Immunohistochemistry supported neural origin and glial differentiations, consistent with ganglioneuromatosis of the gallbladder. The patient has no clinical evidence of NF1, MEN2B, or Cowden syndrome, adding a non-syndromic adult case to the very limited literature on this entity. Conclusions: This is a rare, non-syndromic adult case of gallbladder ganglioneuromatosis, contributing to the very limited literature on this entity. Full article

A 66-year-old female underwent a colonoscopy for persistent left lower abdominal discomfort and mucous stool passage. Endoscopic examination revealed a 3 mm sessile polyp in the ascending colon. Histopathological examination of the polyp showed preserved crypt architecture with a monomorphic spindle-cell proliferation within the lamina propria. Scattered ganglion cells were present and demonstrated immunoreactivity for Calretinin and S100. The lesion was diagnosed as a colonic ganglioneuroma. Ganglioneuromas are rarely localised to the gastrointestinal tract and often detected incidentally during colonoscopic screening. While solitary lesions are typically sporadic; diffuse or multiple ganglioneuromas may be associated with hereditary syndromes such as neurofibromatosis type 1, multiple endocrine neoplasia type 2B, and juvenile polyposis, the latter belonging to the PTEN-hamartoma tumour syndrome spectrum. Clinically, most colonic ganglioneuromas are asymptomatic, although some may present with nonspecific gastrointestinal symptoms. Despite their benign nature, rare cases of malignant transformation and association with adenocarcinoma have been reported. Full article

Multiple Endocrine Neoplasia Type 1 (MEN1) is an autosomal dominant disorder commonly associated with tumor development in the parathyroid glands, pancreas, and pituitary gland. While pituitary adenomas are frequently observed in MEN1 patients, the presence of additional tumors within the pituitary gland is unusual. Moreover, the co-occurrence of a pituitary adenoma with an atypical teratoid/rhabdoid tumor (ATRT) has not been previously documented. ATRT is a rare, aggressive neoplasm predominantly affecting young children and is typically associated with inactivating mutations in the SMARCB1 or SMARCA4 tumor suppressor genes. These mutations result in uncontrolled cellular proliferation, which underlies the malignancy’s rapid progression. In adults, ATRT is exceedingly rare, making this case particularly noteworthy for its uniqueness in both tumor type and patient demographics. ATRTs are now classified into three molecular subgroups—MYC, SHH, and TYR—each with distinct epigenetic and clinical features, further refining diagnostic and prognostic assessments. In this case report, we describe a case of a female patient with MEN1 who experienced several recurrences of pituitary adenoma, ultimately necessitating surgical resection. Detailed pathological evaluation of the resected tissue revealed two distinct neoplasms within the pituitary gland: one typical of a pituitary adenoma, and the other confirmed as ATRT. The diagnosis of ATRT was established through extensive workup including immunohistochemical analysis, next-generation sequencing and methylation profiling, which served as essential tools in distinguishing ATRT from other potential differential diagnoses. This case illustrates the complex diagnostic journey and challenges encountered in identifying ATRT in the context of MEN1, underscoring the importance of using advanced molecular and immunohistochemical techniques in atypical presentations. Furthermore, it expands the understanding of potential tumor associations within MEN1, providing insight for pathologists and clinicians into the rare possibility of concurrent tumors in addition to pituitary adenoma in MEN1 patients. Raising awareness of such co-occurrences could prompt earlier diagnostic considerations by refining the differential diagnosis in patients with MEN1 presenting with unusual tumor types. Full article

Background and Clinical Significance: Multiple Endocrine Neoplasia type 1 (MEN1) is a rare autosomal dominant disorder caused by mutations in the MEN1 gene. Although primarily characterized by endocrine tumors, renal manifestations remain underreported. Case Presentation: We report a three-generation family carrying a pathogenic MEN1 mutation (c.1351-3_1359del) with a co-occurring Claudin 16 (CLDN16) variant (c.324+13C>G). Genetic testing included MLPA and whole-exome sequencing (WES), with bioinformatics analysis validating variant pathogenicity. All three patients exhibited primary hyperparathyroidism, hypercalcemia, hypercalciuria, early nephrocalcinosis, and renal hypomagnesemia. The CLDN16 variant, previously considered benign, co-segregated with hypomagnesemia and renal involvement, suggesting a potential modifying role. Conclusions: These findings support the need for comprehensive genetic screening in MEN1 patients with atypical renal presentations. Concomitant genetic variations can alter the principal phenotype. Full article

Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary tumor syndrome caused by inactivating mutations of the MEN1 gene and characterized by the occurrence of multiple endocrine tumors within a single patient (i.e., parathyroid, pituitary, and pancreatic neuroendocrine tumors (NETs)). However, the lack of a genotype–phenotype correlation does not allow individual disease evolution to be foreseen. Epigenetic factors, such as microRNAs, are suspected to contribute to MEN1 tumorigenesis, presumably explaining the lack of genotype–phenotype association. Our previous studies indicated miR-24-3p, miR-1301-3p, miR-664a-3p, and miR-4258 as potentially involved in MEN1 parathyroid tumorigenesis. In this study, we examined the expression of two circulating microRNAs (c-miRNAs), miR-24-3p and miR-1301-3p, in the serum of MEN1 patients. c-miRNAs were evaluated by RT-qPCR in serum collected from 25 MEN1 patients and 25 age- and gender-matched healthy volunteers (HCs). Receiver operating characteristic (ROC) curves were constructed to determine miRNA sensitivity and specificity. RT-PCR analysis revealed that expression levels of circulating miR-1301-3p were significantly downregulated, while those of miR-24-3p were significantly upregulated in the serum of MEN1 patients compared to HCs. Additionally, ROC analysis exhibited a good diagnostic power for both miRNAs (area under the ROC curve (AUC) values: 0.7356 and 0.7928 for miR-1301-3p and miR-24-3p, respectively) in distinguishing MEN1 patients from matched HCs. These preliminary data suggest circulating miR-1301-3p and miR-24-3p as potential non-invasive diagnostic biomarkers for MEN1 syndrome, regardless of different clinical phenotypes and MEN1 mutation types. Full article

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. Full article

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. Full article

Introduction: 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. Methods: 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. Results: 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. Conclusions: 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. Full article

Worldwide, nearly 40% of adults are overweight and 13% are obese. Health consequences of excess weight include cardiovascular diseases, type 2 diabetes, dyslipidemia, and increased mortality. Treating obesity is challenging and calorie restriction often leads to rebound weight gain. Treatments such as bariatric surgery create hesitancy among patients due to their invasiveness. GLP-1 medications have revolutionized weight loss and can reduce body weight in obese patients by between 15% and 25% on average after about 1 year. Their mode of action is to mimic the endogenous GLP-1, an intestinal hormone that regulates glucose metabolism and satiety. However, GLP-1 drugs carry known risks and, since their use for weight loss is recent, may carry unforeseen risks as well. They carry a boxed warning for people with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. Gastrointestinal adverse events (nausea, vomiting, diarrhea) are fairly common while pancreatitis and intestinal obstruction are rarer. There may be a loss of lean body mass as well as premature facial aging. A significant disadvantage of using these medications is the high rate of weight regain when they are discontinued. Achieving success with pharmacologic treatment and then weaning to avoid future negative effects would be ideal. Full article

Background: Multiple endocrine neoplasia type 2A (MEN 2A) is a rare hereditary cancer syndrome caused by pathogenic variants in the rearranged during transfection (RET) gene and is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), primary hyperparathyroidism (PHPT), cutaneous lichen amyloidosis (CLA), and Hirschsprung’s disease. Phenotypic data on the RET C611Y variant remain sparse. Consequently, we aimed to establish a clinical risk profile. Methods: We conducted a nationwide study of all cases (n = 128) born after 1 January 1930 and recognized as carrying the RET C611Y variant in Denmark before 1 April 2021. Results: The median follow-up after birth was 47 years (range, 3–92). Age-related penetrance at age 70 years for MTC was 98% (CI, 91–100), for PHEO 24% (CI, 16–37), and for PHPT 10% (CI, 5–20). None had CLA or Hirschsprung’s disease. The age-related progression of MTC was significant (p < 0.001). The mean age at T0N0M0 was 16 years (CI, 12–20), at T1-4N0M0 38 years (CI, 34–42), at TxN1M0 45 years (CI, 38–53) and at TxNxM1 49 years (CI, 36–61). At the last follow-up, 56% of thyroidectomized cases (n = 103) were biochemically cured. Overall survival at 70 years was 74% (CI, 59–84). Conclusions: RET C611Y is associated with a very high penetrance of MTC and a low penetrance of PHEO and PHPT. CLA and Hirschsprung’s disease almost never occur. MTC seems moderately aggressive, but large variability can be seen. Overall survival may be comparable to that of the general population. Full article

Germline mutations in the MEN1 gene encoding menin protein cause multiple endocrine neoplasia type 1 (MEN1) syndrome. Recent evidence suggests that inhibiting the interaction of menin with its crucial oncogenic protein partners represents a promising therapeutic strategy to AML. Menin plays a critical role in lysine methyltransferase 2A (KMT2A)-gene-rearranged and NPM1-m acute leukemias, both associated with adverse outcomes with current standard therapies, especially in the relapsed/refractory setting. Disrupting the menin–KMT2A interaction affects the proleukemogenic HOX/MEIS transcription program. This disruption leads to the differentiation of KMT2Ar and NPM1-m AML cells. Small molecular inhibitors of the menin–KMT2A interaction target the central cavity of MEN1 to inhibit the MEN1-KMT2A interaction and could target a similar transcriptional dependency in other leukemia subsets, broadening their therapeutic potential. These agents, both as monotherapies and in combination with synergistic drugs, are undergoing preclinical and clinical evaluation with promising early results. With the growing literature around menin inhibitors in AML, we discussed the biology of menin, its mechanism of action, its interacting partners in leukemia, possible inhibitors, their implications, synergistic drugs, and future therapeutic strategies in this review. Full article