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Multiple endocrine neoplasia type 2

Multiple endocrine neoplasia type 2 (MEN 2) is a rare autosomal dominant hereditary cancer syndrome characterized by the development of tumors in multiple endocrine glands, most notably medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid adenomas or hyperplasia.^[1] Caused by germline gain-of-function mutations in the RET proto-oncogene on chromosome 10, MEN 2 affects approximately 1 in 35,000 individuals and is subdivided into three main clinical variants: MEN 2A (the most common, comprising 70%-80% of cases), MEN 2B (about 5%), and familial MTC (FMTC, 10%-20%).^[1] These subtypes share a predisposition to MTC but differ in associated features, with nearly 100% lifetime risk for MTC across all forms, often presenting in early adulthood or childhood depending on the variant.^[2]^[1] In MEN 2A, affected individuals typically develop MTC, bilateral pheochromocytomas in about 50% of cases, and hyperparathyroidism due to parathyroid tumors in 20%-30%; additional features may include cutaneous lichen amyloidosis or Hirschsprung disease in rare instances.^[1] MEN 2B is distinguished by an aggressive form of MTC that often appears in infancy or early childhood, along with pheochromocytomas (50% risk) and characteristic nonendocrine manifestations such as mucosal neuromas on the lips, tongue, and eyelids, a marfanoid body habitus, and gastrointestinal ganglioneuromatosis; notably, parathyroid involvement is absent.^[2]^[1] FMTC, the mildest variant, is defined by MTC without significant pheochromocytoma or parathyroid disease (risk <1%), though it still confers a high lifetime MTC risk, with tumors often emerging later in life.^[1] The inheritance pattern is autosomal dominant, meaning each child of an affected individual has a 50% chance of inheriting the mutation; however, 5%-50% of cases may arise de novo without family history, particularly in MEN 2B.^[2]^[1] Genetic testing for RET mutations is essential for diagnosis and guides preventive strategies, such as prophylactic thyroidectomy, due to the near-universal penetrance for MTC.^[1] Symptoms vary by tumor type but commonly include neck lumps and diarrhea from MTC, episodes of hypertension and headaches from pheochromocytoma, and fatigue or kidney stones from hyperparathyroidism.^[2] Early identification through family screening is critical, as MEN 2 accounts for up to 25% of all MTC cases despite its rarity.^[1]

Overview

Definition and Subtypes

Multiple endocrine neoplasia type 2 (MEN2) is a rare autosomal dominant hereditary cancer syndrome characterized by multifocal tumors arising from neural crest-derived endocrine tissues, with medullary thyroid carcinoma (MTC) occurring in nearly 100% of affected individuals.^[3]^[4] The syndrome results from germline gain-of-function mutations in the RET proto-oncogene on chromosome 10q11.2, leading to variable penetrance and expressivity across family members.^[5]^[3] MEN2 was first described in 1961 by John H. Sipple, who reported the association between bilateral pheochromocytomas and MTC in a patient with parathyroid adenoma, highlighting the multifocal endocrine involvement.^[3] Over subsequent decades, clinical observations and genetic studies refined the classification into three main subtypes based on phenotypic variations correlated with specific RET mutations: MEN2A, MEN2B, and familial MTC (FMTC).^[5]^[3] MEN2A, the most common subtype accounting for 70-80% of cases, features MTC with nearly 100% penetrance, pheochromocytoma in 20-50% of patients, and primary hyperparathyroidism in 10-30%.^[5]^[4]^[3] MEN2B, comprising about 5% of cases, is distinguished by highly aggressive MTC with 100% penetrance often presenting in early childhood, pheochromocytoma in approximately 50% of individuals, and characteristic non-tumorous features such as marfanoid habitus and mucosal neuromas, without hyperparathyroidism.^[5]^[4] FMTC, representing 10-20% of MEN2 cases and considered a variant of MEN2A, is limited to familial occurrences of MTC with nearly 100% penetrance but lacks extrathyroidal manifestations like pheochromocytoma or hyperparathyroidism, typically showing later onset and less aggressive disease.^[5]^[3]^[4]

Epidemiology

Multiple endocrine neoplasia type 2 (MEN2) is a rare autosomal dominant syndrome with a worldwide prevalence of approximately 1 in 35,000 individuals.^[3] In the United States, the prevalence is estimated at 1 in 30,000 to 50,000, reflecting improved detection through genetic screening programs.^[3] The incidence of new cases is lower, with MEN2A reported at 8 to 28 per million live births annually and MEN2B at 1 to 3 per million, though exact figures vary due to underdiagnosis in regions without routine screening.^[6] The subtypes are distributed as MEN2A comprising 70-80%, MEN2B 5%, and FMTC 10-20% of cases (some classifications group FMTC under MEN2A, resulting in approximately 90-95% for the combined MEN2A/FMTC category).^[7] ^[8] MEN2A has an estimated prevalence of 1 in 40,000, while MEN2B ranges from 1 in 350,000 to 1 in 700,000.^[9] Demographically, MEN2 shows no significant sex bias, with equal distribution between males and females.^[1] Geographic variations are minimal in true incidence, but higher reporting occurs in Europe and North America due to established genetic screening and surveillance programs, as evidenced by national registries in countries like Denmark.^[10] The primary risk factor for MEN2 is a positive family history, with approximately 95% of cases inherited in an autosomal dominant pattern; de novo mutations account for the remaining 5%, occurring more frequently in MEN2B (up to 50% of cases) than in MEN2A (about 5%).^[1] No strong ethnic predispositions have been consistently identified across populations, though certain RET variants may show founder effects in specific groups. Diagnosis rates have increased since the 1993 discovery of RET proto-oncogene mutations as the genetic cause of MEN2, enabling proactive genetic testing and earlier identification in at-risk families.^[8] This shift has led to higher detected prevalence through screening, reducing the historical underestimation of the disease burden.^[4]

Clinical Features

Signs and Symptoms in MEN2A

Multiple endocrine neoplasia type 2A (MEN2A) primarily manifests through a classic triad of endocrine neoplasms: medullary thyroid carcinoma (MTC), pheochromocytoma, and primary hyperparathyroidism, with MTC exhibiting nearly 100% penetrance and serving as the most common initial presentation.^[1] These tumors typically emerge in early to mid-adulthood, though timelines vary by underlying RET proto-oncogene mutation, and many cases are identified asymptomatically through family screening protocols.^[11] Medullary thyroid carcinoma in MEN2A often presents as a palpable neck mass, with associated symptoms including dysphagia, hoarseness, and neck pain due to local invasion or cervical lymph node involvement.^[12] The typical age of onset is 20 to 30 years, and tumors are multifocal and bilateral in the majority of affected individuals, frequently accompanied by C-cell hyperplasia as a precursor lesion.^[1] Pheochromocytoma affects approximately 50% of patients with MEN2A and commonly causes paroxysmal hypertension, headaches, palpitations, and diaphoresis from catecholamine excess.^[11] These tumors are bilateral in about 50% of cases and usually develop in the 30s to 40s, often following the onset of MTC.^[12] Primary hyperparathyroidism occurs in 20% to 30% of individuals and results in hypercalcemia, which may lead to symptoms such as fatigue, polyuria, and kidney stones.^[1] It typically involves multiglandular hyperplasia or adenomas and arises between ages 20 and 50, though it is often mild and detected biochemically before overt symptoms emerge.^[11] Less common features in MEN2A include cutaneous lichen amyloidosis, characterized by pruritic, scaly papules on the upper back or extremities in certain families, and Hirschsprung disease, a congenital aganglionic megacolon linked to specific RET mutations such as those in codons 609, 611, 618, or 620.^[12] MTC remains the predominant initial tumor, with 10% to 20% of diagnoses occurring asymptomatically via proactive screening in mutation carriers.^[1]

Signs and Symptoms in MEN2B and FMTC

Multiple endocrine neoplasia type 2B (MEN2B) is characterized by an aggressive form of medullary thyroid carcinoma (MTC) that typically presents in early childhood, with a median age of diagnosis around 13-14 years, though metastases can occur as early as age 1 if prophylactic thyroidectomy is not performed by then.^[1] The MTC in MEN2B exhibits nearly 100% penetrance and rapid progression, often leading to lymph node and distant metastases by the time of diagnosis in untreated cases.^[3] Pheochromocytoma develops in approximately 50% of individuals with MEN2B, frequently bilateral and multicentric, with a mean age of presentation between 25-32 years but potentially as early as 8-12 years; symptoms may include episodic hypertension, headaches, palpitations, anxiety, and diaphoresis.^[3] Distinct non-endocrine features further define MEN2B, including a marfanoid habitus with tall stature, thin build, long limbs, and skeletal abnormalities such as scoliosis, kyphoscoliosis, or joint laxity, often evident from childhood.^[3] Mucosal neuromas, presenting as thickened, bumpy lesions on the lips, tongue, and eyelids, are typically visible from birth or early infancy and serve as early clinical clues.^[3] Gastrointestinal involvement manifests as ganglioneuromatosis, leading to symptoms like chronic constipation, abdominal pain, diarrhea, or megacolon due to intestinal dysmotility.^[3] Approximately 50% of MEN2B cases arise from de novo germline RET mutations, resulting in sporadic presentations without family history and often delaying recognition until symptomatic disease develops.^[1] In contrast, familial medullary thyroid carcinoma (FMTC), a subtype limited to MTC without associated pheochromocytoma or hyperparathyroidism, follows a more indolent course with later onset, typically between 20 and 50 years of age.^[13] The MTC in FMTC presents as thyroid nodules or cervical lymphadenopathy with lower aggressiveness compared to MEN2B, though it still carries high penetrance (lower than in MEN2A and MEN2B); local metastases may occur but rarely lead to mortality with appropriate management.^[1]^[3]

Pathophysiology

Genetic Basis

Multiple endocrine neoplasia type 2 (MEN2) is inherited in an autosomal dominant manner with nearly 100% penetrance for medullary thyroid carcinoma (MTC), the hallmark tumor of the syndrome. This inheritance pattern arises from germline heterozygous mutations in the RET proto-oncogene, which are transmitted from an affected parent to offspring with a 50% probability per child. De novo mutations occur in approximately 5% of MEN2A cases and up to 50% of MEN2B cases, often originating from the paternal allele.^[14]^[4] The RET gene is located on chromosome 10q11.2 and consists of 21 exons encoding a receptor tyrosine kinase that plays a crucial role in the development and differentiation of neural crest-derived cells, including those forming the thyroid C cells, adrenal medulla, and enteric nervous system. Activating mutations in RET lead to ligand-independent dimerization and constitutive signaling, promoting uncontrolled cell proliferation in affected tissues. Over 95% of MEN2 cases result from point mutations clustered in specific extracellular and kinase domains of the RET protein.^[14]^[4] Mutation hotspots are well-defined and correlate with MEN2 subtypes and disease severity. In MEN2A and familial MTC (FMTC), moderate-risk mutations typically affect codons 609, 611, 618, and 620 in exon 10, while high-risk mutations predominantly involve codon 634 in exon 11. For MEN2B, the highest-risk mutation is M918T in codon 918 of exon 16, accounting for about 95% of cases, with a rarer A883F mutation in exon 15 comprising the remainder. According to American Thyroid Association (ATA) guidelines, these are classified into moderate (ATA-MOD), high (ATA-H), and highest (ATA-HST) risk categories based on codon-specific aggressiveness, with ATA-HST mutations like M918T associated with nearly 100% MTC penetrance by early childhood and historical untreated mortality approaching 95% due to aggressive disease.^[14]^[4] Genotype-phenotype correlations are strong, enabling predictive clinical management. For instance, codon 634 mutations in MEN2A confer a high risk of pheochromocytoma (up to 50% lifetime penetrance) and primary hyperparathyroidism, alongside earlier MTC onset compared to moderate-risk codons. In contrast, exon 10 mutations may also associate with Hirschsprung disease in some families. MEN2B mutations like M918T predict a distinct phenotype with marfanoid habitus, mucosal neuromas, and rapidly progressive MTC, often leading to metastasis by age 5 if untreated. These correlations guide prophylactic thyroidectomy timing and surveillance protocols.^[14]^[4]

Molecular Mechanisms

The RET proto-oncogene encodes a single-pass transmembrane receptor tyrosine kinase essential for the development and maintenance of neural crest-derived tissues. Its structure comprises an extracellular domain with four cadherin-like motifs for ligand binding, a cysteine-rich region involved in dimerization, a single transmembrane helix, and an intracellular tyrosine kinase domain responsible for autophosphorylation and downstream signaling initiation. In physiological conditions, RET activation requires binding to glial cell line-derived neurotrophic factor (GDNF) family ligands and co-receptors (GFRα), leading to receptor dimerization and transient kinase activation.^[1]^[15] Pathogenic germline mutations in RET characteristic of MEN2 are predominantly gain-of-function alterations that result in ligand-independent dimerization and constitutive kinase activation, driving tumorigenesis. In MEN2A and familial medullary thyroid carcinoma (FMTC), missense mutations typically affect cysteine residues in the extracellular domain (e.g., codons 609, 618, 620, or 634), promoting the formation of aberrant intermolecular disulfide bonds that stabilize receptor dimers without ligand stimulation. In contrast, MEN2B mutations, such as p.Met918Thr in the kinase domain, enhance substrate affinity and autophosphorylation efficiency, often enabling activation even in monomeric forms. These mechanisms lead to persistent RET signaling, overriding normal regulatory controls and promoting uncontrolled cell growth in susceptible tissues.^[1]^[15]^[16] Constitutive RET activation in MEN2 aberrantly stimulates multiple downstream signaling pathways, particularly in thyroid C-cells and adrenal chromaffin cells. The MAPK/ERK pathway is hyperactivated, fostering cell proliferation through transcription factor modulation; the PI3K/AKT pathway enhances anti-apoptotic signals and cell survival; and the PLCγ pathway drives calcium-dependent processes that support cell migration and invasion. These disruptions collectively contribute to neoplastic transformation, with pathway emphasis varying by mutation type—for instance, kinase domain mutations in MEN2B exhibit stronger PI3K/AKT engagement, correlating with more aggressive phenotypes.^[17]^[15]^[1] The tissue-specific manifestations of MEN2 arise from RET's critical role in neural crest-derived lineages, explaining the predilection for medullary thyroid carcinoma (from C-cells) and pheochromocytoma (from adrenal chromaffin cells), where aberrant signaling disrupts developmental homeostasis. Parathyroid chief cells, though not neural crest-derived, express RET and exhibit hyperplasia or adenomas in up to 30% of MEN2A cases, potentially through similar gain-of-function effects amplified by disrupted hypercalcemia feedback loops that alter calcium-sensing dynamics. Tumor progression follows a model of multistep carcinogenesis: initial RET-driven C-cell hyperplasia precedes invasive carcinoma, often accelerated by secondary somatic events such as loss of heterozygosity or additional mutations that further enhance oncogenic signaling.^[1]^[15]^[18]

Diagnosis

Clinical Evaluation

Clinical evaluation of suspected multiple endocrine neoplasia type 2 (MEN2) begins with a detailed medical history and physical examination to identify clinical features suggestive of medullary thyroid carcinoma (MTC), pheochromocytoma, or hyperparathyroidism, particularly in the context of familial patterns. A thorough family history is essential, focusing on relatives with MTC, pheochromocytoma, or other endocrine tumors, as MEN2 exhibits autosomal dominant inheritance with high penetrance. Physical examination includes careful neck palpation to detect thyroid nodules or cervical lymphadenopathy, which may indicate MTC; up to 70% of patients with a palpable thyroid mass have lymph node metastases. Additionally, blood pressure monitoring is performed to screen for hypertension associated with pheochromocytoma.^[1]^[1] Biochemical testing plays a central role in assessing for MEN2-associated tumors prior to genetic confirmation. Serum calcitonin levels are measured as a marker for MTC or C-cell hyperplasia, with elevations greater than 100 pg/mL considered highly suspicious, particularly in the absence of other causes like renal impairment; provocative testing with intravenous calcium may be used if basal levels are equivocal. Carcinoembryonic antigen (CEA) is also evaluated, as elevated levels support MTC diagnosis and aid in disease monitoring. For pheochromocytoma, plasma free metanephrines or 24-hour urinary catecholamines and metanephrines are recommended annually starting in adolescence. In cases of suspected hyperparathyroidism, serum calcium and parathyroid hormone (PTH) levels are assessed, with hypercalcemia alongside elevated or inappropriately normal PTH indicating parathyroid involvement.^[1]^[19]^[1] Imaging studies are targeted based on clinical and biochemical findings to localize abnormalities without routine whole-body scanning. Neck ultrasound is the initial modality of choice for evaluating thyroid nodules or masses, offering high sensitivity for detecting MTC and assessing cervical lymph nodes; computed tomography (CT) may be added for better characterization if ultrasound is inconclusive. For suspected pheochromocytoma, adrenal MRI or CT is performed if biochemical tests are abnormal, providing detailed visualization of adrenal masses. These approaches prioritize cost-effectiveness and minimize unnecessary radiation exposure.^[1]^[19]^[1] Age-based screening is recommended for at-risk individuals based on clinical suspicion, with initiation guided by the American Thyroid Association (ATA) guidelines. For those with high-risk features suggestive of MEN2A or familial MTC, screening with calcitonin measurement and neck ultrasound typically begins at ages 3-5 years; for suspected MEN2B, earlier evaluation starting at 6 months is emphasized due to aggressive disease onset, with subsequent updates in the 2020s reinforcing this timeline. Annual biochemical screening for pheochromocytoma and hyperparathyroidism follows from adolescence.^[1]^[20] Differential diagnosis during clinical evaluation aims to distinguish MEN2 from sporadic MTC or other multiple endocrine neoplasia syndromes. Sporadic MTC often presents as a unifocal, later-onset tumor without C-cell hyperplasia or family history, whereas MEN2 involves multifocal disease and associated tumors. Other syndromes, such as MEN1 (characterized by parathyroid, pituitary, and pancreatic involvement) or MEN4, must be excluded through targeted history and biochemical profiles. Evaluation considers symptoms of MTC, pheochromocytoma, and hyperparathyroidism as outlined in clinical features sections.^[1]^[1]

Genetic Testing and Classification

Genetic testing for multiple endocrine neoplasia type 2 (MEN2) primarily involves molecular analysis of the RET proto-oncogene to identify germline pathogenic variants, which are causative in nearly all cases. Standard protocols recommend initial targeted sequencing of key exons, including exons 8, 10, 11, and 13 through 16, as these harbor over 95% of disease-associated variants in MEN2A and familial medullary thyroid carcinoma (FMTC), and nearly all in MEN2B.^[14] If no variant is detected in these regions, comprehensive sequencing of the entire RET coding region using next-generation sequencing (NGS) panels is advised, achieving detection rates exceeding 98% for pathogenic variants across subtypes.^[1] These methods have largely replaced biochemical screening, such as serum calcitonin measurement, for definitive diagnosis due to their superior sensitivity and specificity.^[14] Indications for RET testing include all individuals presenting with medullary thyroid carcinoma (MTC) diagnosed before age 50, even if sporadic, as well as those with a family history of MEN2, MTC, or associated features like pheochromocytoma or hyperparathyroidism.^[14] Prenatal testing and cascade screening for first-degree relatives of known mutation carriers are strongly recommended to enable early intervention, with testing ideally performed as soon as possible after birth in at-risk children.^[1] In families with a known familial variant, targeted testing for that specific mutation is sufficient and cost-effective.^[14] Interpretation of test results relies on established criteria, such as those from the American College of Medical Genetics and Genomics (ACMG). Pathogenic or likely pathogenic germline variants in RET, such as missense mutations affecting cysteine residues (e.g., p.Cys634Arg), confirm the diagnosis of MEN2 and guide clinical management.^[1] Variants of uncertain significance (VUS), which occur in a small percentage of tests, do not establish a diagnosis on their own and typically require additional evaluation, including familial segregation studies, in silico predictions, or functional assays to assess RET kinase activity and downstream signaling.^[1] Benign polymorphisms, such as p.Gly691Ser, should be distinguished from pathogenic variants to avoid unnecessary follow-up.^[14] Classification of RET variants into risk categories is based on the American Thyroid Association (ATA) guidelines, which stratify mutations by their association with MTC aggressiveness and penetrance to inform prophylactic thyroidectomy timing. Highest-risk (ATA-HST) variants, primarily p.Met918Thr in exon 16, define MEN2B and warrant thyroidectomy within the first year of life due to near-100% MTC penetrance by age 5.^[14] High-risk (ATA-H) variants, such as those at codon 634 in exon 11, are characteristic of aggressive MEN2A and recommend surgery by age 5, with over 90% MTC penetrance.^[14] Moderate-risk (ATA-MOD) variants (e.g., codons 609, 611, 618, 620 in exon 10 or p.Val804Met in exon 13) allow for individualized timing in late childhood or adulthood, guided by calcitonin levels, reflecting lower penetrance (50-80%).^[1] These categories directly influence subtype diagnosis, with codon 634 mutations exemplifying high-risk MEN2A.^[14] Post-2020 updates, including the 2022 National Comprehensive Cancer Network (NCCN) guidelines, advocate for broader multigene panels incorporating RET alongside non-RET genes (e.g., SDHB, SDHD for pheochromocytoma mimics or PRKAR1A for Carney complex) in cases of atypical presentations or negative RET results, to identify alternative hereditary syndromes.^[1] This approach enhances diagnostic yield for MEN2 mimics while maintaining RET-focused testing as the cornerstone.^[1]

Management

Surgical Interventions

Surgical interventions form the cornerstone of management for multiple endocrine neoplasia type 2 (MEN2), targeting the characteristic tumors in the thyroid, adrenal glands, and parathyroids to prevent malignancy and complications. Prophylactic surgery is emphasized, particularly for medullary thyroid carcinoma (MTC), based on RET proto-oncogene mutation risk levels classified as highest (HST), high (H), or moderate (MOD). For MTC prevention in MEN2, total thyroidectomy is the standard prophylactic procedure, often accompanied by central neck dissection if lymph node involvement is suspected. In MEN2B with the highest-risk codon 918 mutation (M918T), thyroidectomy is recommended by age 1 year or as early as possible after diagnosis to mitigate the aggressive nature of MTC. For MEN2A and familial MTC (FMTC) with highest- or high-risk mutations (e.g., codon 634), surgery is advised by age 5 years, while moderate-risk mutations allow individualized timing into late adolescence or early adulthood if basal serum calcitonin levels remain normal. Intraoperative nerve monitoring is routinely used to protect the recurrent laryngeal nerves during these procedures. Adrenal surgery addresses pheochromocytomas, which occur in up to 50% of MEN2A and nearly all MEN2B cases. For bilateral pheochromocytomas, cortical-sparing adrenalectomy is preferred to preserve adrenal function and avoid lifelong glucocorticoid replacement therapy, reducing the risk of Addisonian crisis. Unilateral adrenalectomy is performed for solitary tumors, with annual biochemical screening for contralateral involvement. Laparoscopic approaches are favored for minimal invasiveness, and pheochromocytoma resection precedes thyroidectomy if both are indicated. In MEN2A, where primary hyperparathyroidism affects 20-30% of patients, subtotal parathyroidectomy targets only enlarged glands to correct hypercalcemia while minimizing hypoparathyroidism risk. Intraoperative parathyroid hormone (PTH) monitoring guides the extent of resection, confirming adequate reduction (typically >50% drop) to predict surgical success.^[21] This procedure is often combined with thyroidectomy when hyperparathyroidism is identified preoperatively. Common complications of these surgeries include hypoparathyroidism, occurring in 10-20% of prophylactic thyroidectomies, particularly in very young patients due to challenges in identifying and preserving parathyroid glands. Transient hypocalcemia affects up to 27% postoperatively, managed with calcium and vitamin D supplementation. Recurrent laryngeal nerve injury rates range from 1-5%, mostly transient, with permanent palsy being rare in experienced centers. For adrenal surgery, cortical-sparing techniques lower the incidence of adrenal insufficiency to under 10%.

Medical Therapies

Medical therapies for multiple endocrine neoplasia type 2 (MEN2) primarily target advanced medullary thyroid carcinoma (MTC), the hallmark malignancy, while supportive treatments address associated endocrine deficiencies and comorbidities. Tyrosine kinase inhibitors (TKIs) form the cornerstone for systemic management of unresectable or metastatic MTC, inhibiting RET proto-oncogene signaling and vascular endothelial growth factor receptors to slow tumor progression.^[22] Vandetanib, a multikinase inhibitor, received FDA approval in April 2011 for symptomatic or progressive MTC in patients with unresectable locally advanced or metastatic disease. In the phase 3 ZETA trial, vandetanib demonstrated a median progression-free survival of 30.5 months compared to 19.3 months with placebo, establishing its role as a first-line option for advanced disease. Cabozantinib, another multikinase TKI, was approved by the FDA in November 2012 for progressive, metastatic MTC following the phase 3 EXAM trial, which showed a median progression-free survival of 11.2 months versus 4.0 months with placebo. Both agents require monitoring for adverse effects, including QT interval prolongation with vandetanib and hypertension with cabozantinib. More selective RET inhibitors have emerged for RET-mutant MTC, offering improved efficacy and tolerability in pretreated patients. Selpercatinib (LOXO-292), a highly potent RET inhibitor, gained FDA approval in May 2020 for advanced or metastatic RET-mutant MTC and received full FDA approval in September 2024 for adult and pediatric patients (aged 2 years and older) with advanced or metastatic RET-mutant MTC, based on the phase 1/2 LIBRETTO-001 trial reporting objective response rates of 69% in previously treated patients and 73% in treatment-naive patients, with durable responses observed through 2024 updates showing overall response rates up to 70% in expanded cohorts.^[23]^[24] Pralsetinib, another RET-specific inhibitor, was approved in December 2020 for RET-mutant MTC but voluntarily withdrawn in the US in July 2023 despite the ongoing confirmatory phase 3 AcceleRET-MTC trial (NCT04760288), with topline results expected in 2024, though it previously showed response rates of approximately 60-70% in pretreated patients.^[25]^[26] Supportive therapies are essential for managing surgical sequelae and associated features in MEN2. Post-thyroidectomy hypoparathyroidism, common in MEN2A due to parathyroid involvement, is treated with calcium supplementation and active vitamin D analogs like calcitriol to maintain normocalcemia and prevent symptoms such as tetany. For pheochromocytoma, preoperative alpha-adrenergic blockade (e.g., phenoxybenzamine) followed by beta-blockers (e.g., propranolol) is standard to control hypertension and prevent intraoperative crises prior to adrenalectomy.^[1]^[27]^[28] The 2015 American Thyroid Association guidelines, reaffirmed in subsequent updates including 2023 consensus statements, recommend TKIs such as vandetanib, cabozantinib, or selpercatinib for symptomatic or progressive metastatic MTC, with emphasis on multidisciplinary monitoring for toxicities like hypertension and QT prolongation. Emerging multikinase inhibitors and ongoing trials continue to explore options for TKI-resistant cases, building on phase 2 data from selpercatinib showing sustained objective response rates around 70% in refractory RET-mutant MTC as of 2024.^[14]^[29]

Prognosis

Outcomes by Subtype

Multiple endocrine neoplasia type 2A (MEN2A) generally carries the most favorable prognosis among the subtypes when managed with early intervention. With prophylactic thyroidectomy performed before age 5 to 8 years, the 5-year survival rate for medullary thyroid carcinoma (MTC) exceeds 95%, and the 10-year overall survival approaches 92%.^[4]^[30] Individuals who undergo routine screening and timely surgery often achieve near-normal life expectancy, with MTC recurrence rates as low as 10% post-thyroidectomy.^[4] In contrast, MEN2B is associated with the most aggressive disease course and poorest outcomes. Without early intervention, MTC leads to mortality in approximately 50% of patients by age 30, with a historical average age at death of 21 years.^[4] Historically, the 10-year survival rate was below 50%, but advancements including thyroidectomy within the first year of life and targeted therapies have improved it to around 70-74%.^[31]^[32] Familial medullary thyroid carcinoma (FMTC), the mildest subtype, exhibits excellent prognosis with MTC-specific survival rates exceeding 95%. The disease is often indolent, with later onset and high curability via thyroidectomy, resulting in minimal impact on overall survival.^[4]^[33] Key prognostic factors across subtypes include the age at thyroidectomy, with outcomes optimal when performed before age 5 years to prevent metastasis.^[4] Localized disease at diagnosis yields near-100% 5-year survival, whereas metastatic MTC reduces it to 28-40% at 10 years.^[34]^[35] Specific RET proto-oncogene mutations, such as codon 918 (M918T) in MEN2B, confer the worst prognosis, with a 10-year survival of 56% compared to 87% for non-918 variants. Recent studies from 2022 onward highlight the impact of tyrosine kinase inhibitors (TKIs) in the TKI era, particularly selective RET inhibitors like selpercatinib and pralsetinib, which have extended median progression-free survival in metastatic RET-mutant MTC from 11 months (with multikinase inhibitors) to 24-25 months, correlating with improved overall survival estimates from 2-3 years to 4-5 years in advanced cases.^[36]^[37]^[38]

Screening and Follow-up

Genetic counseling is essential for individuals and families affected by multiple endocrine neoplasia type 2 (MEN2), providing information on inheritance risks, testing implications, and management options both before and after genetic testing.^[1] Cascade screening involves one-time RET proto-oncogene testing for at-risk first-degree relatives, recommended starting in early childhood, to identify carriers early and enable preventive measures. This approach is tailored to the autosomal dominant inheritance pattern, where each child of an affected individual has a 50% risk of inheriting the pathogenic variant. For identified carriers, follow-up screening with biochemical tests is performed every 1-2 years from birth, depending on the risk level of the variant.^[4]^[19] Screening for medullary thyroid carcinoma (MTC), the most penetrant feature of MEN2, begins with annual measurement of serum calcitonin and carcinoembryonic antigen (CEA) starting at age 3-5 years for moderate-risk variants and as early as age 6 months for highest-risk cases, such as those with RET M918T mutations in MEN2B.^[1] Neck ultrasound is initiated annually from age 5 years in MEN2A and familial MTC (FMTC), or earlier in MEN2B, to detect thyroid nodules or lymph node involvement.^[19] If basal calcitonin levels are normal but clinical suspicion persists, stimulated calcitonin testing using calcium gluconate may be performed to enhance sensitivity.^[4] For pheochromocytoma, annual biochemical screening with plasma free metanephrines or 24-hour urine fractionated metanephrines and catecholamines is advised starting at age 11 years in MEN2A and FMTC, or age 8 years in MEN2B, with abdominal MRI or CT imaging if results are elevated to identify adrenal tumors.^[1] In MEN2A, hyperparathyroidism screening involves annual serum calcium and parathyroid hormone (PTH) measurements beginning at age 11 years, as parathyroid involvement occurs in up to 30% of cases and may require surgical intervention if hypercalcemia develops.^[19] Following treatment, such as prophylactic thyroidectomy, lifelong surveillance is required to monitor for MTC recurrence or metastasis, including calcitonin and CEA measurements every 6-12 months, with neck ultrasound or CT/MRI as needed based on rising levels.^[4] For patients with advanced or progressive MTC receiving tyrosine kinase inhibitors (TKIs) like selpercatinib or pralsetinib, monitoring follows National Comprehensive Cancer Network (NCCN) guidelines, emphasizing serial imaging (e.g., every 2-3 months initially) and biochemical markers to assess response and manage side effects.^[39] International variations exist, with European guidelines recommending earlier initiation of screening for high-risk pediatric MEN2 carriers, often integrating multidisciplinary care involving endocrinologists, surgeons, and geneticists from infancy to optimize outcomes.^[33] These protocols align closely with American Thyroid Association (ATA) risk classifications but emphasize family-centered approaches in pediatric settings.^[40]

References

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Multiple Endocrine Neoplasia Type 2 - GeneReviews - NCBI - NIH
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Sep 10, 2024 · Multiple endocrine neoplasia, type 2, also called MEN 2, is a rare condition. It causes tumors in the thyroid and parathyroid glands, adrenal glands, lips, ...
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Multiple Endocrine Neoplasias Type 2 - StatPearls - NCBI - NIH
Multiple endocrine neoplasia type 2 (MEN 2) is a hereditary cancer syndrome associated primarily with tumors of the adrenal gland, thyroid and parathyroid.Continuing Education Activity · Introduction · Etiology · Treatment / Management
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Feb 14, 2025 · MEN2 is caused by pathogenic variants in the RET gene. MEN2 is distinct from two similarly named syndromes, Multiple Endocrine Neoplasia Type 1 ...
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Multiple endocrine neoplasia type 2: An overview - Nature
May 5, 2011 · Multiple endocrine neoplasia type 2 is historically composed of three clinical subtypes, all of which are associated with germline mutations in the RET proto- ...
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The prevalence of MEN 2A and MEN 2B is 13–24 and 1−2 per million, respectively, while the incidence for MEN 2A and MEN 2B ranges between 8–28 and 1–3 per ...
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The total prevalence of all variants of multiple endocrine neoplasia type 2 (MEN2) is approximately 1/35,000. MEN2A, accounts for 95% of MEN2 cases. MEN2 can ...Missing: distribution | Show results with:distribution
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Nov 14, 2006 · This subtype is the most aggressive MEN2 variant. It accounts for about 5% of all cases of MEN2. MEN2B is characterized by the earlier ...
[9]
Multiple Endocrine Neoplasia Type 2 - Symptoms, Causes, Treatment
The estimated prevalence of MEN2A is about 1/40,000, while MEN2B varies between 1/350,000 to 1/700,000. MEN2A can run in families (familial cases) or can ...Missing: incidence epidemiology
[10]
Multiple Endocrine Neoplasia Type 2 - Endotext - NCBI Bookshelf
Jan 2, 2022 · A nationwide study in Denmark described higher rates with MEN2A incidence of 28 per million live births per year and a point prevalence of 24 ...Missing: demographics geographic
[11]
Multiple endocrine neoplasia 2: an overview - PMC - PubMed Central
Feb 25, 2022 · Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant familial disorder causing tumors within various endocrine glands.
[12]
Multiple Endocrine Neoplasia, Type 2A (MEN 2A) - Merck Manuals
MEN 2A is an autosomal dominant syndrome characterized by medullary carcinoma of the thyroid, pheochromocytoma, parathyroid hyperplasia or adenomas.
[13]
A Korean Family of Familial Medullary Thyroid Cancer with ...
Jan 21, 2010 · FMTC represents a less aggressive form of hereditary MTC, and it has a corresponding older age at onset, often between 20 and 40, compared to ...<|separator|>
[14]
Revised American Thyroid Association Guidelines for the ...
The ATA-HST category includes patients with MEN2B and the RET codon M918T mutation, the ATA-H category includes patients with RET codon C634 mutations and the ...
[15]
Molecular mechanisms of RET receptor-mediated oncogenesis in ...
MEN 2 is associated with point mutations of RET, predictably leading to its activation in the absence of ligands and co-receptors. Mutations are primarily amino ...
[16]
https://pubmed.ncbi.nlm.nih.gov/9681851/
[17]
Molecular genetics, therapeutics and RET inhibitor resistance for ...
Sep 28, 2024 · Due to the high risk (ca. 15–20%) of distant metastasis and limited systemic therapies, the 10-year survival rate of patients with advanced MTC ...
[18]
Molecular pathogenesis of MEN2-associated tumors | Familial Cancer
Recent data suggest that an overrepresentation of mutant RET as a 'second hit' event might trigger tumorigenesis. However, alterations in other genes might ...
[19]
2015 American Thyroid Association Management Guidelines for ...
Results: The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for ...
[20]
ATA Guidelines & Statements - American Thyroid Association
American Thyroid Association's clinical practice guidelines are the leading resources for diagnosing and treating thyroid disease and thyroid cancer.Missing: MEN2 | Show results with:MEN2
[21]
Parathyroid surgery for inherited syndromes - UpToDate
Mar 29, 2024 · ... MEN1 · - Initial parathyroidectomy · Surgical options · Choice of initial ... Intraoperative PTH monitoring · POSTOPERATIVE CARE · COMPLICATIONS ...
[22]
[PDF] 2928974 This label may not be the latest approved by FDA. For ...
Vandetanib is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic ...<|separator|>
[23]
FDA approves selpercatinib for lung and thyroid cancers with RET ...
May 11, 2020 · FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. On May 8, 2020, the Food and Drug Administration ...
[24]
Durability of Response With Selpercatinib in Patients With <i>RET</i>
Aug 2, 2024 · Selpercatinib continued to provide durable and robust responses in treatment-naïve and previously treated patients with RET-mutant MTC and RET fusion-positive ...
[25]
[PDF] GAVRETO (pralsetinib) capsule. - accessdata.fda.gov
Jul 20, 2023 · This Prior Approval sNDA provides for removal of the Advanced and Metastatic RET- mutant Medullary Thyroid Cancer (MTC) Indication, approved ...
[26]
Hypoparathyroidism - Diagnosis & treatment - Mayo Clinic
High amounts of vitamin D can help your body absorb calcium and get rid of phosphorus. Often, this vitamin D is a prescription supplement called calcitriol.
[27]
Pheochromocytoma - StatPearls - NCBI Bookshelf - NIH
Nov 7, 2024 · Apply preoperative management protocols, including alpha- and beta-adrenergic blockade, to mitigate the risk of hypertensive crises.
[28]
Systemic therapies for medullary thyroid carcinoma: state of the art
May 11, 2025 · The updated American Thyroid Association guidelines for MTC provided a clear and consistent recommendation: patients with significant tumor ...Selpercatinib · Treatment Selection And... · Neoadjuvant Therapy For...<|separator|>
[29]
Multiple Endocrine Neoplasia Type 2 (MEN2) - Medscape Reference
Apr 1, 2022 · Approximately 75% of MEN2B cases are sporadic and affected patients have de novo RET mutations, while 25% of cases occur in families with ...Missing: ethnic | Show results with:ethnic
[30]
Long-Term Survivorship in Multiple Endocrine Neoplasia Type 2B ...
Jan 1, 2018 · The overall survival rates at 5, 10, and 20 years were 85%, 74%, and 58%, respectively. After 2000 (vs before 2000), significantly more patients ...
[31]
Long-Term Survivorship in Multiple Endocrine Neoplasia Type 2B ...
Patients with MEN2B developed MTC at an early age with wide ranging aggressiveness, but the outcome was generally better after 2000 than before 2000.
[32]
Multiple Endocrine Neoplasia in Childhood: An Update on ... - MDPI
Feb 17, 2022 · The estimated prevalence of MEN2—including MEN2A, MEN2B, FMTC, and other subtypes—is 1 in 30,000 [10]. It is important to note that genetic ...
[33]
Medullary Thyroid Cancer: What It Is, Symptoms & Treatment
Jan 16, 2025 · Current research estimates that the five-year survival rate for stages 1 to 3 of medullary thyroid cancer is 93%. It's 28% for stage 4. It's ...Missing: 5- | Show results with:5-
[34]
Systemic therapies for medullary thyroid carcinoma: state of the art
May 11, 2025 · The 10-year survival rate for patients with metastatic MTC is only 21%. Over the past decade, the landscape of systemic treatment for MTC has ...
[35]
Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary ...
In the selpercatinib group, 23 patients (11.9%) had a complete response, and 111 (57.5%) had a partial response. In the control group, 4 patients (4.1%) had a ...
[36]
Medullary Thyroid Cancer: Updates and Challenges
ATA guidelines recommend a contralateral lymph node dissection when calcitonin is >200 pg/mL in an effort to achieve cure at initial operation (5); however, the ...Abstract · Pathogenesis · Surgical Management · Multikinase InhibitorsMissing: interventions | Show results with:interventions
[37]
Pralsetinib in Patients with Advanced/Metastatic Rearranged During ...
Treatment with pralsetinib demonstrated ORR between 56% and 91%, median DoR of >20 months, and median PFS of >25 months across the different patient cohorts ( ...Missing: TKIs | Show results with:TKIs
[38]
Thyroid Carcinoma - Guidelines Detail - NCCN
Thyroid Carcinoma · Guidelines · NCCN Guidelines in Practice™ · Evidence Blocks · Frameworks · Guidelines for Patients · Educational Events and Programs.Missing: MEN2 | Show results with:MEN2
[39]
2012 European Thyroid Association Guidelines for Genetic Testing ...
(e) Both parents of children below 18 years of age should sign informed consent before their child undergoes genetic testing. If for any reason one or both ...