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Multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 () is a autosomal dominant characterized by the development of multiple tumors, primarily in the parathyroid glands, the endocrine , and the gland, leading to hormonal overproduction and associated health complications. Caused by inactivating germline mutations in the on 11q13, which encodes the protein menin essential for regulating , the condition has an estimated of 1 in 30,000 individuals and nearly complete , with over 94% of carriers manifesting symptoms by age 50. Most cases (about 90%) are inherited from an affected parent with a 50% transmission risk to offspring, while approximately 10% arise from mutations. The hallmark tumors in MEN1 are often benign but can become malignant, particularly pancreatic neuroendocrine tumors (PNETs), which occur in up to 80% of patients and include functional types like gastrinomas (causing Zollinger-Ellison syndrome with peptic ulcers) and insulinomas (leading to ). Parathyroid adenomas or hyperplasia, affecting over 95% of individuals by age 50, result in , the most common initial manifestation, characterized by elevated calcium levels, kidney stones, bone pain, and fatigue. Pituitary adenomas develop in 30-50% of cases, often prolactinomas causing menstrual irregularities, , or galactorrhea, while less frequent manifestations include thymic or bronchial carcinoids, adrenocortical tumors, and facial angiofibromas. Symptoms vary widely based on tumor functionality and location, potentially encompassing gastrointestinal issues like and ulcers, endocrine disruptions such as diabetes or , and, in advanced cases, metastatic disease reducing life expectancy. Diagnosis of MEN1 relies on clinical criteria, including the presence of tumors in two or more endocrine glands associated with the syndrome, a single tumor plus a family history of MEN1, or identification of an MEN1 mutation through , which detects abnormalities in 80-90% of cases. Screening typically begins in childhood for at-risk family members, involving biochemical tests (e.g., serum calcium, , , and levels) and imaging modalities such as MRI for pituitary tumors, for pancreatic lesions, and CT or somatostatin receptor for neuroendocrine tumors. There is no cure for MEN1, and management focuses on early detection, tumor surveillance, and individualized interventions to mitigate hormone excess and prevent malignancy. Surgical options include subtotal parathyroidectomy for hyperparathyroidism, resection of localized PNETs greater than 1 cm, and transsphenoidal surgery for symptomatic pituitary adenomas, while medical therapies such as proton pump inhibitors for gastrinomas, somatostatin analogs (e.g., octreotide) for neuroendocrine tumors, and dopamine agonists (e.g., cabergoline) for prolactinomas provide symptom control. Lifelong monitoring is essential, with guidelines recommending annual biochemical screening and periodic imaging to improve outcomes, as untreated aggressive tumors like metastatic PNETs remain the primary cause of mortality.

Overview

Definition and characteristics

Multiple endocrine neoplasia type 1 (MEN1), also known as Wermer's syndrome, is a rare autosomal dominant hereditary disorder characterized by the development of tumors in multiple endocrine glands, primarily the parathyroid glands, endocrine pancreas, and gland—collectively referred to as the "3 Ps." The syndrome was first described in 1954 by Paul Wermer, who identified it as a familial condition involving pluriglandular dysfunction transmitted in an autosomal dominant pattern. Core features of MEN1 include the formation of multifocal tumors in endocrine tissues, which are typically non-metastatic but can exhibit malignant potential, particularly in the . The disorder demonstrates near-complete , with over 95% of affected individuals developing clinical manifestations by age 50. Onset is generally in the third decade of life, though variability exists across tumor types. The tumors in MEN1 are predominantly neuroendocrine in origin and can be benign or malignant, with pancreatic lesions posing the greatest risk for aggressive behavior and contributing significantly to morbidity and mortality. While the underlying genetic basis involves mutations in the gene, leading to disrupted tumor suppression, detailed molecular mechanisms are addressed elsewhere.

Epidemiology

Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant disorder with an estimated global prevalence of 1 in 30,000 individuals. The incidence is approximately 0.1 per 100,000 person-years, though this may vary by region due to differences in diagnostic practices. In specialized referral centers, detection rates can be higher, reaching 2-3 per 100,000, reflecting improved screening in high-risk populations. The condition affects males and females equally, with no strong ethnic or racial predispositions reported across global populations. However, underdiagnosis is common in low-resource settings, where limited access to genetic testing and endocrine screening contributes to underreporting of cases. Penetrance is age-dependent, with clinical manifestations appearing in over 50% of carriers by age 20 years and nearly 95% by age 40 years; for parathyroid involvement specifically, penetrance reaches approximately 50% by age 20 and over 90% by age 50. Approximately 10% of cases arise from de novo mutations and present sporadically without a known family history, while the majority (~90%) are familial, underscoring family history as the primary risk factor. Recent data indicate a slight increase in reported cases since 2020, attributed to expanded genetic screening programs that enhance early identification.

Clinical manifestations

Parathyroid gland involvement

Parathyroid gland involvement is the most common and earliest clinical manifestation of multiple endocrine neoplasia type 1 (MEN1), affecting more than 90% of patients and typically presenting as primary hyperparathyroidism (PHPT). This condition often develops as the initial feature of MEN1, with multiglandular disease involving hyperplasia or adenomas in all four parathyroid glands, distinguishing it from the more focal involvement seen in sporadic PHPT. The age of onset is usually between 20 and 25 years, significantly earlier than the typical presentation of sporadic PHPT around age 55. The pathophysiology involves biallelic inactivation of the gene, leading to monoclonal proliferation of parathyroid cells and autonomous overproduction of (PTH), which results in elevated serum PTH levels and hypercalcemia. Unlike sporadic cases, MEN1-associated PHPT features asymmetric enlargement of multiple glands, with nodular hyperplasia progressing to adenomas over time, driven by loss of menin tumor suppressor function. Clinical signs and symptoms stem primarily from chronic hypercalcemia and , including , , and due to impaired renal concentrating ability. Nephrolithiasis occurs in approximately 50-60% of cases, often recurrent and linked to increased urinary calcium excretion. , such as and pathologic fractures, affects approximately 45% of patients, reflecting accelerated and reduced density from sustained PTH elevation. Neuropsychiatric symptoms like depression and may also arise, while is a rare but serious complication triggered by severe hypercalcemia. Untreated PHPT in MEN1 can lead to through persistent and , with studies showing a higher prevalence of renal impairment compared to sporadic PHPT. Prolonged hypercalcemia further elevates cardiovascular risks, including , vascular calcification, and increased mortality from cardiac events. Surgical management, such as subtotal , is often recommended to mitigate these effects, though recurrence remains common due to the multiglandular nature.

Pancreatic and duodenal neuroendocrine tumors

Pancreatic and duodenal neuroendocrine tumors (pNETs and dNETs) represent a major clinical feature of multiple endocrine neoplasia type 1 (), with a lifetime estimated at 60-80% in affected individuals. These tumors arise from enterochromaffin-like cells and can be multifocal, often developing in the or , with non-functional adenomas being the most prevalent subtype, accounting for approximately 50% of cases. Functional tumors, which secrete hormones leading to specific syndromes, include insulinomas (10-30% prevalence, primarily pancreatic) and gastrinomas (20-50% prevalence). Less common functional variants, such as VIPomas, glucagonomas, and somatostatinomas, occur in fewer than 5% of patients each. Insulinomas typically manifest as benign lesions but can cause severe due to excessive insulin secretion, presenting with symptoms like sweating, confusion, , and neuroglycopenic episodes such as seizures or , particularly during fasting states. Gastrinomas, the most aggressive functional subtype, lead to Zollinger-Ellison characterized by hypergastrinemia, resulting in recurrent peptic ulcers, refractory , gastroesophageal , and from hypersecretion. Rare tumors like VIPomas may produce watery , , and (WDHA ), though these are infrequent in MEN1. Non-functional tumors often remain asymptomatic until advanced, detected incidentally via imaging modalities outlined in diagnostic protocols. The malignancy risk for these neuroendocrine tumors in MEN1 is substantial, with 30-50% demonstrating metastatic potential at , particularly gastrinomas (up to 60-90% malignant) and larger non-functional lesions exceeding 2 cm. Multifocality and small tumor size (<1 cm) complicate early detection and increase the likelihood of lymph node or distant metastases, contributing significantly to MEN1-related mortality. Duodenal involvement is prominent, especially for gastrinomas, where over 80-90% originate in the proximal duodenum or periampullary region, often as multiple microadenomas, which heightens surgical challenges due to their proximity to the pancreatic head and biliary structures.

Pituitary adenomas

Pituitary adenomas occur in 15% to 55% of individuals with (MEN1), with some series reporting rates up to 42%. These tumors are frequently macroadenomas, comprising 65% to 85% of cases, though most do not cause visual field defects due to limited suprasellar extension. They tend to develop at a mean age of 38 years, often between 30 and 40 years, and are rarely bilateral or multifocal. The most common subtype is prolactinomas, accounting for 42% to 62% of pituitary adenomas in MEN1, which lead to hyperprolactinemia and associated endocrine disruptions. Somatotropinomas, or growth hormone-secreting adenomas, represent 6.5% to 25% of cases and cause acromegaly, characterized by progressive enlargement of the hands, feet, and facial features. Non-functioning adenomas comprise 15% to 42% of tumors and typically present due to mass effects rather than hormone excess. Less commonly, adrenocorticotropic hormone (ACTH)-secreting adenomas occur in 3% to 4% of cases, potentially leading to Cushing's disease, though this is rare in the MEN1 context. Clinical manifestations vary by tumor subtype but often include headaches from mass effect and hypogonadism due to pituitary compression or stalk disconnection. Prolactinomas commonly cause galactorrhea, amenorrhea, and infertility, particularly in women, while somatotropinomas may result in diabetes mellitus from insulin resistance. Growth hormone excess also predisposes to cardiovascular disease, including hypertension and cardiomyopathy, as well as arthropathy with joint pain and osteoarthritis. Diagnosis typically involves hormonal assays, such as serum prolactin or insulin-like growth factor 1 levels, alongside imaging.

Associated tumors and other features

In multiple endocrine neoplasia type 1 (MEN1), adrenal involvement primarily manifests as benign cortical adenomas or hyperplasia, occurring in 20-40% of affected individuals. These lesions are typically nonfunctional, though rare cases of cortisol-secreting adenomas leading to have been reported. In contrast to MEN2 syndromes, pheochromocytomas arising from the adrenal medulla are exceedingly rare, with an incidence of less than 1%. Carcinoid tumors, particularly foregut neuroendocrine neoplasms, represent another associated feature, though less common than the classic manifestations. Thymic carcinoids occur in 2-5% of MEN1 patients and are often aggressive, with a higher prevalence and poorer prognosis in males and smokers. Bronchial carcinoids are identified in approximately 5% of cases, while gastric carcinoids, especially type II enterochromaffin-like variants, are rarer but can arise in the context of hypergastrinemia. These tumors are generally nonfunctional and may require vigilant screening due to their metastatic potential. Non-endocrine tumors further characterize the syndrome's broader phenotype. Subcutaneous lipomas develop in up to 30% of patients, presenting as benign, soft-tissue masses often appearing in adulthood. Facial angiofibromas, resembling those in tuberous sclerosis, affect 80-85% of individuals, manifesting as multiple reddish papules on the central face. Collagenomas, firm dermal nodules composed of dense collagen, occur in about 70% of cases and are frequently multiple. Meningiomas arise in approximately 0.8% of MEN1 patients; a 2024 cohort study reported earlier onset and evidence of MEN1 gene involvement in tumorigenesis. Women with MEN1 face a 2- to 3-fold increased risk of breast cancer compared to the general population, potentially linked to MEN1 gene heterozygosity. Certain non-tumoral features also emerge, such as isolated hyperprolactinemia without a detectable pituitary adenoma, observed in a subset of patients and possibly due to subtle stalk effects or mild hyperplasia. The development of thymic and bronchial carcinoids shows a strong association with smoking history, underscoring modifiable risk factors in MEN1 management. A notable recent insight involves a 2023 case report describing metastatic adrenal liposarcoma as an initial presentation of MEN1, highlighting the syndrome's potential for rare mesenchymal tumors beyond typical endocrine pathology.

Genetics and pathogenesis

The MEN1 gene

The MEN1 gene is located on the long arm of chromosome 11 at position 11q13.1. It spans approximately 9.5 kb and consists of 10 exons, of which exons 2-10 are protein-coding, while exon 1 is untranslated. The gene encodes menin, a nuclear scaffold protein comprising 610 amino acids with a molecular weight of 67 kDa. Inactivating germline mutations in MEN1 underlie multiple endocrine neoplasia type 1, with detection rates of 80%-90% in familial cases and 65%-70% in apparently sporadic (simplex) cases. These mutations predominantly include nonsense, frameshift (via small insertions/deletions), missense, and splice-site variants, while large deletions or duplications account for 1%-4% of cases; over 1,300 distinct mutations have been identified, distributed throughout the coding region without hotspots. Although historically no clear genotype-phenotype correlations were established, recent studies as of 2025 have identified associations, including increased risk of aggressive pancreatic neuroendocrine tumors in patients with mutations affecting the JunD-interacting domain or CHES1 region. Approximately 10% of MEN1 cases arise from de novo mutations, which typically present as sporadic (simplex) cases without family history. MEN1 exhibits autosomal dominant inheritance with nearly complete penetrance by age 50. Tumorigenesis follows Knudson's two-hit hypothesis, requiring biallelic inactivation through an inherited heterozygous germline mutation plus a somatic "second hit" (e.g., loss of heterozygosity) in the wild-type allele. Post-2020 resources, such as the MEN1 entry in the Leiden Open Variation Database (LOVD), facilitate variant curation and classification, with the database last updated on November 1, 2025.

Molecular mechanisms

Menin, the protein encoded by the MEN1 gene, functions primarily as a tumor suppressor by regulating key cellular processes essential for preventing tumorigenesis. It interacts with histone methyltransferases such as mixed-lineage leukemia (MLL1 and MLL2), forming complexes that catalyze trimethylation of histone H3 at lysine 4 (H3K4me3), a mark associated with active gene transcription. This interaction enables menin to activate the expression of genes involved in cell cycle control, including cyclin-dependent kinase inhibitors like p18^Ink4c and p27^Kip1, thereby repressing cell proliferation. Additionally, menin represses transcription factors such as JunD, further inhibiting proliferative signals. Beyond transcriptional regulation, menin participates in DNA repair and genome stability through its association with death domain-associated protein (DAXX), which promotes trimethylation of histone H3 at lysine 9 (H3K9me3) to maintain heterochromatin integrity. Nuclear localization of menin is critical for these functions, mediated by three nuclear localization signals; disruptions in these signals, often caused by MEN1 mutations, impair its tumor-suppressive activity. In the context of pancreatic neuroendocrine tumors, menin suppresses insulin-like growth factor (IGF) signaling, limiting β-cell proliferation and tumor development. Tumorigenesis in MEN1 arises from biallelic inactivation of the MEN1 gene, typically involving a germline mutation and a somatic loss of heterozygosity (LOH) at chromosome 11q13, observed in more than 90% of tumors from affected tissues, including parathyroid adenomas. This loss disrupts menin's epigenetic regulatory roles, leading to altered histone modifications that derepress oncogenes and promote endocrine cell hyperplasia and neoplasia. Recent insights highlight menin's involvement in epigenetic reprogramming, where its absence reduces H3K4me3 at promoters of cell cycle inhibitors while increasing repressive H3K27me3 marks, as detailed in a 2021 review on tissue-specific drivers of MEN1 tumorigenesis. In parathyroid tumors, menin loss enhances Wnt/β-catenin signaling by stabilizing active β-catenin, driving proliferation; conversely, Wnt inhibition has shown potential to suppress tumor growth in preclinical models. Animal models, particularly heterozygous Men1 knockout mice, faithfully recapitulate the MEN1 phenotype, developing parathyroid hyperplasia by approximately 9 months, pancreatic islet tumors (insulinomas) in 28-88% of cases, and pituitary adenomas in 10-43% by 12-18 months, often with concurrent LOH. These models demonstrate that menin loss accelerates epigenetic changes, such as increased H3K4me3 at proliferative genes, underscoring its role in suppressing tumorigenesis across endocrine tissues.

Diagnosis

Clinical criteria

The clinical diagnosis of multiple endocrine neoplasia type 1 (MEN1) is suspected based on phenotypic features and family history, prompting genetic testing for confirmation. According to established criteria, suspicion arises when an individual has two or more MEN1-associated endocrine tumors, such as parathyroid adenomas, pituitary adenomas, or pancreatic neuroendocrine tumors (including or ). Alternatively, the presence of a single MEN1-associated tumor in an individual with a first-degree relative (parent, sibling, or child) affected by MEN1 or a known MEN1 mutation also warrants suspicion. Age at onset plays a key role in raising suspicion for over sporadic tumors. Parathyroid adenomas, the most common manifestation, typically occur before age 30 in patients, often multiglandular and leading to primary hyperparathyroidism with elevated parathyroid hormone () levels in the context of hypercalcemia and normal renal function. Pituitary adenomas or pancreatic neuroendocrine tumors diagnosed before age 40 similarly increase suspicion, while gastrinomas before age 40 are particularly indicative, as they present about 10 years earlier than in sporadic cases. Family history is crucial for identifying autosomal dominant inheritance patterns characteristic of MEN1. An affected first-degree relative with documented MEN1-related neoplasia or a germline MEN1 mutation supports suspicion, often identified through pedigree analysis showing vertical transmission across generations with nearly 100% penetrance by age 50. In such families, unaffected relatives may undergo screening based on these historical clues. Differential diagnosis involves excluding other hereditary syndromes and sporadic occurrences. MEN2 is distinguished by medullary thyroid carcinoma and pheochromocytoma, absent in MEN1; von Hippel-Lindau (VHL) syndrome features pheochromocytomas, hemangioblastomas, and renal cell carcinomas; and sporadic tumors typically present later in life without family history or multigland involvement. Biochemical evaluation, such as isolated PTH elevation without renal impairment, helps differentiate primary hyperparathyroidism in MEN1 from secondary causes. These clinical criteria for suspicion are outlined in international consensus guidelines, such as the 2025 American Association of Clinical Endocrinology consensus statement, which recommend genetic testing for individuals meeting these thresholds to confirm diagnosis.

Genetic testing

Genetic testing for multiple endocrine neoplasia type 1 (MEN1) primarily involves molecular analysis of the MEN1 gene, located on chromosome 11q13, which encodes the tumor suppressor protein menin. Next-generation sequencing (NGS) panels are the standard method for detecting germline mutations, including point mutations, small insertions/deletions, and splice site variants, with a sensitivity of 85-95% in identifying pathogenic variants in clinically affected individuals. For cases where sequencing is negative, multiplex ligation-dependent probe amplification (MLPA) is recommended to detect large deletions or duplications, which account for approximately 1-5% of MEN1 mutations. These tests are typically performed on blood or saliva samples in accredited laboratories, and results can confirm the diagnosis in index cases meeting clinical criteria, such as the presence of two or more endocrine tumors associated with MEN1. Indications for genetic testing include evaluation of index patients with suggestive clinical features, such as hyperparathyroidism before age 30 or multifocal neuroendocrine tumors, to establish a germline diagnosis. Cascade screening is advised for first-degree relatives of confirmed mutation carriers, involving targeted testing for the familial variant starting at age 5-10 years, with annual biochemical monitoring thereafter to enable early detection. Prenatal or preimplantation genetic testing may be offered to at-risk families, though uptake varies due to the autosomal dominant inheritance and incomplete penetrance of MEN1. In addition to genetic confirmation, diagnosis often incorporates tumor imaging to assess lesion burden. Magnetic resonance imaging (MRI) or computed tomography (CT) scans are used to evaluate pituitary adenomas and pancreatic neuroendocrine tumors, providing detailed anatomical visualization. For duodenal neuroendocrine tumors, endoscopic ultrasound (EUS) combined with endoscopy offers high-resolution detection of small lesions. Since 2020, 68Ga-DOTATATE positron emission tomography (PET) has emerged as a highly sensitive modality for localizing somatostatin receptor-positive neuroendocrine tumors throughout the body, with superior detection rates compared to conventional somatostatin receptor scintigraphy. Biochemical testing complements genetic and imaging studies by identifying functional abnormalities. Key assays include serum parathyroid hormone (PTH) and calcium for hyperparathyroidism, fasting gastrin for , chromogranin A as a general neuroendocrine marker, insulin-like growth factor 1 (IGF-1) for possible acromegaly, and prolactin for prolactinomas. An annual screening protocol is recommended for mutation carriers, starting in childhood, to monitor these markers and guide imaging as needed. Challenges in MEN1 genetic testing include the interpretation of variants of uncertain significance (VUS), which occur in up to 10-15% of sequenced cases and require multidisciplinary review, family segregation studies, or functional assays to classify pathogenicity. Additionally, the absence of a detectable mutation in some phenotypically affected individuals (up to 10-20%) may represent genotype-negative MEN1 (GN-MEN1), a distinct entity with potentially delayed onset and lower tumor burden, necessitating broader genetic panels, re-evaluation for alternative diagnoses, or clinical management based on phenotype.

Management and treatment

Surveillance and screening

Surveillance and screening protocols for (MEN1) aim to facilitate early detection of tumors in at-risk individuals and ongoing monitoring in diagnosed patients, thereby enabling timely intervention to mitigate complications such as , , and progression. For at-risk individuals, such as first-degree relatives of affected patients or those with identified MEN1 pathogenic variants, screening typically commences following genetic confirmation, with annual biochemical testing recommended starting at age 5-10, including serum (PTH), calcium, , (IGF-1), and fasting glucose to assess for parathyroid adenomas, , and potential or . Imaging complements these tests, with pituitary MRI initiated at age ≥16 years and repeated every 1-3 years if normal, while pancreatic and duodenal surveillance via MRI or endoscopic ultrasound and upper gastrointestinal endoscopy for begin at age ≥16 years, with endoscopy around age 25. In diagnosed patients with MEN1, lifelong monitoring is essential due to the high penetrance of tumors, with protocols tailored to tumor history and biochemical trends. Biennial neck ultrasound is advised for parathyroid surveillance to evaluate adenoma size and multiplicity, alongside annual biochemical assessments of PTH and calcium. For pancreatic and duodenal neuroendocrine tumors, annual fasting glucose and insulin levels help monitor for functional lesions, while 3T MRI of the abdomen is preferred every 1-3 years for higher-resolution detection of tumor progression, minimizing reliance on ionizing radiation. Pituitary monitoring continues with annual prolactin and IGF-1 testing, supplemented by MRI as needed. These strategies align with the 2025 American Association of Clinical Endocrinology (AACE) consensus statement, which integrates genetic counseling to support family screening and personalized risk assessment. Challenges in MEN1 surveillance include minimizing cumulative radiation exposure from repeated imaging, as multi-modality protocols can exceed safe thresholds (e.g., >50-100 mSv lifetime risk for secondary malignancies), prompting a shift toward non-ionizing options like MRI and where feasible. Patient adherence to intensive, lifelong protocols poses another barrier, with qualitative studies highlighting psychological burden from frequent testing starting in childhood, though quantitative compliance rates vary by center and require multidisciplinary support to optimize. Recent advances, such as 68Ga-DOTATATE for enhanced detection of small neuroendocrine tumors, improve sensitivity over conventional imaging and are increasingly incorporated into guidelines for at-risk and diagnosed individuals.

Surgical interventions

Surgical management in multiple endocrine neoplasia type 1 (MEN1) primarily addresses hyperfunctioning tumors through targeted resections, with the goal of alleviating hormone excess and preventing complications while accounting for the multifocal and recurrent nature of the disease. is the mainstay for MEN1-associated , indicated for persistent hypercalcemia lasting over one year, renal complications such as nephrolithiasis, or . The preferred techniques include subtotal parathyroidectomy (removal of 3.5 glands) or total parathyroidectomy with into the forearm muscle, often combined with transcervical to reduce the risk of occult thymic carcinoids. These approaches achieve normocalcemia in most patients initially, though recurrence rates range from 15% to 50% within 10-15 years due to supernumerary or regrowth of parathyroid tissue. For pancreatic neuroendocrine tumors (pNETs) in MEN1, is recommended for symptomatic functional lesions or nonfunctional tumors exceeding 2 cm with evidence of growth. Enucleation is suitable for solitary, small insulinomas (<2 cm), offering biochemical cure rates of approximately 90% at 10 years with low recurrence (around 6%). Duodenal gastrinomas, often multiple and proximal, typically require (Whipple procedure) for curative intent, while distal with enucleation addresses multifocal lesions in the pancreatic tail or body. Transsphenoidal resection via the endoscopic or microscopic approach is the standard for MEN1-related pituitary adenomas, indicated for macroadenomas greater than 1 cm causing compressive symptoms like defects or for functional tumors unresponsive to medical therapy. MEN1-associated adenomas are frequently larger and more invasive than sporadic cases, leading to lower rates of biochemical normalization (about 42%) compared to sporadic tumors (90%), with higher postoperative recurrence. Additional surgical interventions include prophylactic or therapeutic for thymic neuroendocrine tumors, performed during or for symptomatic/metastatic disease, and unilateral or bilateral for functional adrenal cortical adenomas causing hormone excess or tumors larger than 4 cm with suspicious features. Overall outcomes of MEN1 surgery are influenced by tumor multifocality, with morbidity including permanent in 20-30% after , pancreatic exocrine/endocrine insufficiency in up to 26% post-pNET resection, and potential recurrent laryngeal nerve injury or pituitary deficits. Long-term recurrence remains high across sites (up to 50% for ), necessitating lifelong , though early intervention improves and reduces complications.

Medical therapies

Medical therapies for multiple endocrine neoplasia type 1 (MEN1) primarily target symptom control, hormone excess, and tumor stabilization in cases where is not feasible or as adjunctive treatment. These approaches focus on specific manifestations such as , pituitary adenomas, and neuroendocrine tumors (NETs), using agents that modulate secretion or inhibit tumor growth. Pharmacological options are selected based on the affected and tumor functionality, with efficacy varying by tumor type and patient response. For , the most common feature of MEN1, —a that activates the calcium-sensing receptor on parathyroid cells—serves as an effective medical option for preoperative control of hypercalcemia or in patients unsuitable for , normalizing calcium levels in a significant proportion of cases. Bisphosphonates, such as alendronate or , are employed adjunctively to protect bone health by inhibiting activity and reducing , particularly in patients with secondary to prolonged . These agents help mitigate skeletal complications without addressing the underlying parathyroid . In MEN1-associated pituitary prolactinomas, dopamine agonists like represent first-line therapy, effectively normalizing levels and shrinking tumor volume by more than 50% in approximately 80-90% of patients, thereby alleviating symptoms such as and . Cabergoline's high affinity for D2 receptors suppresses secretion, with most patients achieving biochemical control and tumor reduction within months of initiation. For neuroendocrine tumors, particularly functioning pancreatic NETs like gastrinomas and insulinomas, somatostatin analogs such as and are key for controlling hypersecretion and stabilizing tumor growth. These agents bind to receptors on tumor cells, inhibiting or insulin release and achieving control in up to 88% of MEN1-related pancreatic NETs, with superior responses in functioning tumors. In Zollinger-Ellison syndrome caused by gastrinomas, proton pump inhibitors (PPIs) like omeprazole are essential for long-term acid suppression, preventing peptic ulcers and complications from gastric hyperacidity, with dosing titrated to maintain intragastric above 4. Acromegaly due to growth hormone-secreting pituitary adenomas in MEN1 is managed with somatostatin analogs as initial therapy to suppress and IGF-1 levels, or —a —for patients with inadequate response, effectively normalizing IGF-1 in resistant cases and improving metabolic comorbidities. Combination of somatostatin analogs and may be used for optimal control when monotherapy fails. For progressive pancreatic NETs, —an inhibitor—offers supportive therapy in advanced, unresectable disease, slowing tumor progression and extending as recommended in guidelines for well-differentiated NETs. This targeted approach is particularly relevant for non-functioning or metastatic lesions in MEN1.

Emerging treatments

Recent research into emerging treatments for multiple endocrine neoplasia type 1 () emphasizes targeted approaches that address the loss of menin function and associated epigenetic dysregulation in affected tumors. These investigational strategies, primarily in preclinical stages or early clinical trials as of 2025, aim to restore tumor suppressor activity or inhibit downstream oncogenic pathways in MEN1-associated endocrine neoplasms, such as pancreatic neuroendocrine tumors (pNETs) and parathyroid adenomas. Menin inhibitors, including small molecules like SNDX-5613 (revumenib), disrupt the interaction between menin and mixed-lineage (MLL) proteins, thereby altering epigenetic modifications such as H3K4 trimethylation. While these agents have advanced to phase I/II trials for acute s with MLL rearrangements or mutations (e.g., NCT04065399, initiated 2019 with updates through 2025 showing response rates of 30-50% in relapsed cases), their potential extension to tumors stems from shared epigenetic vulnerabilities in neuroendocrine neoplasms. Preclinical models suggest that menin-MLL disruption could suppress proliferation in menin-deficient cells by derepressing tumor-suppressive genes, though clinical adaptation for remains exploratory due to menin's tumor suppressor role in endocrine tissues. Ongoing phase I trials from 2023-2025 (e.g., NCT05731947 for revumenib in advanced solid tumors) are monitoring safety, with preliminary data indicating tolerability but no -specific efficacy reported yet. Gene therapy approaches seek to correct MEN1 mutations or restore menin expression. Preclinical studies using /Cas9 have successfully edited MEN1 mutations in patient-derived induced pluripotent stem cells (iPSCs), generating isogenic models that demonstrate reduced cellular fitness and proliferation upon menin restoration, providing a platform for testing therapeutic corrections. Additionally, viral vector-based strategies, such as adenoviral delivery of wild-type , have increased menin protein levels and decreased tumor growth by 40-60% in MEN1-knockout mouse models of pNETs, highlighting potential for gene replacement in non-resectable lesions. These efforts remain in early preclinical phases, with no active human trials for MEN1 gene editing as of 2025, though they build on broader applications in hereditary tumor syndromes. Targeted therapies modulating pathways altered by menin loss include histone deacetylase (HDAC) inhibitors and PI3K/mTOR blockers. HDAC inhibitors like SAHA (vorinostat) and LMK-235 enhance menin-mediated gene regulation by altering chromatin accessibility, reducing proliferation and inducing apoptosis in MEN1-associated pNET cell lines by up to 50% in vitro. For pancreatic NETs, expansions of mTOR inhibitors such as everolimus have shown prolonged progression-free survival (33 months vs. 12 months in sporadic cases) in MEN1 cohorts, while novel agents like sapanisertib overcome resistance in everolimus-refractory MEN1-mutant xenografts, shrinking tumors by 30-40% through selective PI3K/mTORC1/2 inhibition. These findings support ongoing phase II investigations (e.g., NCT03891832 for mTOR combinations in NETs). Immunotherapy, particularly PD-1 inhibitors, has been explored in advanced neuroendocrine tumors, including those linked to . Case reports from 2022 describe partial responses in metastatic tumors with MEN1 germline mutations treated with , achieving stable disease for 6-12 months via blockade, potentially due to high in MEN1-deficient cells. However, responses are variable, with only in MEN1 contexts, and larger trials are needed to confirm efficacy. Insights from 2021 studies on underscore epigenetic modulators as key targets, with and extra-terminal ( like reducing β-cell in mouse models by 49-55% through menin-dependent transcriptional repression. Clinical trials for these novel agents, including epigenetic combinations (e.g., NCT04830053 for in solid tumors), are recruiting as of 2025, offering hope for MEN1-specific applications.

Prognosis

The prognosis for multiple endocrine neoplasia type 1 (MEN1) has improved with early screening and specialized . Historically, the mean age at death was approximately 55 years, with a standardized mortality (SMR) of (95% CI: 1.7–2.3), indicating twice the mortality risk of the general . In contemporary cohorts undergoing regular surveillance from young adulthood, mean has risen to 70 years or more, though it remains about 10 years shorter than in the general as of 2024. MEN1-related causes account for 60–70% of deaths. The leading cause is malignant pancreatic neuroendocrine tumors (PNETs), responsible for around 42% of fatalities, followed by thymic carcinoids at approximately 10%. Other contributors include foregut carcinoids and complications from pituitary or parathyroid tumors. Twenty-year overall survival rates range from 64% to 82% across studies, with disease-related survival at 80–88%, depending on and access to care. For instance, in a prospective NIH study of 106 MEN1 patients with Zollinger-Ellison syndrome, 30-year overall survival was 82%. Adverse prognostic factors include liver or distant , PNETs larger than 3 cm, rapid tumor growth, multiple parathyroid surgeries, and thymic carcinoids (more prevalent in males). Early genetic , biochemical screening, and tumor resection significantly enhance survival by preventing and managing excess.