Multiple Endocrine Neoplasia Type 2 (MEN2)

Multiple Endocrine Neoplasia Type 2 (MEN2), historically called Sipple syndrome, is a hereditary cancer syndrome caused by gain-of-function mutations in the RET proto-oncogene. Unlike most inherited cancer syndromes driven by tumor suppressor loss, MEN2 results from an overactive, constitutively firing kinase that drives uncontrolled growth in neural crest-derived endocrine cells. The hallmark tumor is medullary thyroid cancer (MTC), which occurs in virtually every affected individual and is almost always the first manifestation. Recognizing MEN2 early — ideally through genetic testing of at-risk family members before any tumor develops — is the single most powerful intervention because prophylactic thyroidectomy performed at the right age is curative.

Table of Contents

1. Overview
2. Genetics and the RET Oncogene
3. MEN2 Subtypes
4. MEN2A — Sipple Syndrome
5. MEN2B — Most Severe Subtype
6. Familial Medullary Thyroid Cancer (FMTC)
7. RET Genotype-Phenotype Correlation and ATA Risk Tiers
8. Medullary Thyroid Cancer — Diagnosis and Treatment
9. Pheochromocytoma in MEN2
10. Surveillance and Genetic Counseling
11. Research Papers
12. Connections

1. Overview

MEN2 is an autosomal dominant syndrome with near-complete penetrance for medullary thyroid cancer. The syndrome was first described clinically by John Sipple in 1961, who noted the co-occurrence of thyroid and adrenal tumors in a patient, though the genetic underpinning — activating mutations in the RET gene on chromosome 10 — was not identified until 1993. This discovery transformed management from reactive to proactive: affected individuals can now be identified by a single blood test before any tumor develops, and surgery can be timed precisely to prevent cancer rather than treat it.

MEN2 is divided into three clinical subtypes — MEN2A (the most common, accounting for 70–80% of cases), MEN2B (the most severe, 5–10%), and Familial Medullary Thyroid Cancer (FMTC), now considered a variant of MEN2A. All share the RET oncogene mutation, but the specific codon mutated dictates the subtype, its aggressiveness, and the urgency of prophylactic surgery.

The estimated prevalence of MEN2 is approximately 1 in 30,000 individuals. Approximately 25% of all medullary thyroid cancer cases — and up to 6% of all thyroid cancers — are hereditary MEN2. Any new diagnosis of MTC should trigger RET genetic testing because the implications for family members are immediate and actionable.

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2. Genetics and the RET Oncogene

The RET gene (REarranged during Transfection) is located on chromosome 10q11.2 and encodes a single-pass transmembrane receptor tyrosine kinase. In normal physiology, RET is activated when members of the glial cell line-derived neurotrophic factor (GDNF) family of ligands — including GDNF, neurturin, artemin, and persephin — bind to their respective GFR-alpha co-receptors on the cell surface. This ligand-co-receptor complex then recruits and activates RET, triggering downstream signaling cascades (RAS-MAPK, PI3K-AKT, JAK-STAT) that regulate cell survival, proliferation, and differentiation. RET signaling is essential during embryonic development, particularly for the enteric nervous system and kidney development.

In MEN2, gain-of-function point mutations render RET constitutively active — the kinase fires autonomously without ligand binding. This is the conceptual opposite of MEN1 (Multiple Endocrine Neoplasia Type 1), where loss-of-function mutations inactivate the tumor suppressor protein menin. In MEN2, a single mutant RET allele is sufficient to drive tumor formation (dominant oncogene model), whereas MEN1 requires loss of both alleles (two-hit model).

The cells most vulnerable to constitutive RET activation are neural crest-derived cells — the embryonic cell population that gives rise to the parafollicular C-cells of the thyroid (which secrete calcitonin), the adrenal medulla (chromaffin cells that secrete catecholamines), and parathyroid chief cells. This neural crest origin explains the characteristic tumor spectrum of MEN2.

MEN2 mutations cluster in two regions of the RET protein:

• Extracellular cysteine-rich domain (codons 609, 611, 618, 620, 630, 634): mutations here typically cause constitutive receptor dimerization. Codon 634 (most commonly C634R) is the most frequent MEN2A mutation, accounting for 85% of MEN2A families.
• Intracellular kinase domain (codons 768, 790, 791, 804, 883, 891, 918): mutations here directly activate the catalytic domain. Codon 918 (M918T) is the highest-risk mutation and is responsible for nearly all MEN2B cases.

Because MEN2 is autosomal dominant with high penetrance, every first-degree relative of an affected individual has a 50% chance of carrying the mutation. Germline RET testing — a simple blood or saliva test — provides a definitive answer and is the standard of care for all MEN2 families.

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3. MEN2 Subtypes

The three recognized subtypes of MEN2 are defined by their component tumors, the severity of medullary thyroid cancer, and the specific RET codon(s) involved:

• MEN2A (Sipple Syndrome): MTC + pheochromocytoma + primary hyperparathyroidism. Accounts for 70–80% of MEN2. Variable penetrance for pheo and PHPT. Rare variants include MEN2A with cutaneous lichen amyloidosis and MEN2A with Hirschsprung disease.
• MEN2B: MTC (most aggressive) + pheochromocytoma + marfanoid habitus + mucosal neuromas + intestinal ganglioneuromas. No hyperparathyroidism. Accounts for 5–10% of MEN2. Almost always caused by codon 918 (M918T).
• Familial Medullary Thyroid Cancer (FMTC): MTC only; no pheochromocytoma; no parathyroid disease. Now classified as a variant of MEN2A rather than a distinct entity. Carries a better prognosis than MEN2A or MEN2B.

The distinction between subtypes is clinically critical because it determines the urgency of prophylactic thyroidectomy, the surveillance schedule, and the counseling provided to patients and families. Subtype classification is now driven primarily by the specific RET codon mutation rather than by observed clinical phenotype.

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4. MEN2A — Sipple Syndrome

MEN2A, named after John H. Sipple who described the syndrome in 1961, is defined by the triad of medullary thyroid cancer, pheochromocytoma, and primary hyperparathyroidism. Not all three are present in every patient, and their penetrance differs substantially.

Medullary Thyroid Cancer in MEN2A

MTC develops in 90–100% of MEN2A gene carriers and is virtually always the first tumor to manifest. It arises from the parafollicular C-cells of the thyroid — cells that produce calcitonin, a calcium-regulating hormone. In MEN2A, C-cell hyperplasia (a precursor lesion) begins in childhood and progresses to invasive MTC over years to decades. The specific timing depends on the codon mutated: codon 634 mutations lead to MTC in early adulthood if untreated, while other codons may allow a longer window for prophylactic intervention.

Pheochromocytoma in MEN2A

Pheochromocytoma (pheo) develops in approximately 50% of MEN2A patients. Unlike sporadic pheos, which are usually unilateral, MEN2-associated pheos are often bilateral and almost always arise in the adrenal medulla (not extra-adrenal). They tend to be biochemically active — producing excess epinephrine, norepinephrine, or both — but are usually benign. The critical surgical rule is to treat pheochromocytoma first if both MTC and pheo are diagnosed simultaneously; proceeding to thyroidectomy without first controlling catecholamine excess risks a life-threatening hypertensive crisis in the operating room.

Primary Hyperparathyroidism in MEN2A

PHPT occurs in 20–30% of MEN2A patients, most commonly in those with codon 634 mutations. Compared to MEN1-associated PHPT (which almost always involves all four glands — multiglandular disease), MEN2A-associated PHPT is typically milder and more often involves a single adenoma or asymmetric hyperplasia. Hypercalcemia is usually mild and may be discovered incidentally during surveillance labs. Parathyroidectomy is performed at the time of thyroidectomy when feasible.

Rare MEN2A Variants

Two rare variants add additional features to the classic MEN2A triad:

• MEN2A with cutaneous lichen amyloidosis (CLA): Patients develop intensely pruritic, hyperpigmented plaques over the upper back and interscapular region. This is almost exclusively associated with codon 634 mutations. CLA may precede MTC diagnosis and serves as a cutaneous marker prompting RET testing.
• MEN2A with Hirschsprung disease: Associated with loss-of-function effects at specific RET codons (609, 611, 618, 620) in the extracellular domain. These codons paradoxically cause both gain-of-function MEN2A features in the endocrine system and loss-of-function effects in enteric nervous system development (Hirschsprung disease = absence of ganglionic cells in the colon). This dual phenotype illustrates the cell-context specificity of RET signaling.

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5. MEN2B — Most Severe Subtype

MEN2B accounts for only 5–10% of MEN2 cases but carries the worst prognosis because MTC presents at the earliest age, grows most aggressively, and metastasizes earliest. Nearly all MEN2B cases are caused by a single mutation: RET codon 918, M918T — a methionine-to-threonine substitution in the kinase domain. Approximately 50% of MEN2B cases arise from de novo (new) mutations with no family history, making clinical recognition of the non-MTC features critical for early diagnosis.

Medullary Thyroid Cancer in MEN2B

MTC in MEN2B is the most aggressive form of hereditary MTC. It can be present at birth or develop in the first months of life, and metastases to cervical lymph nodes have been documented in children as young as 6 months. The American Thyroid Association (ATA) designates codon 918 as the highest-risk (D-level) mutation, recommending prophylactic thyroidectomy within the first 6 months of life. Any delay substantially increases the likelihood of lymph node metastasis and reduces the chance of surgical cure.

Pheochromocytoma in MEN2B

Pheo occurs in approximately 50% of MEN2B patients — the same prevalence as MEN2A — and shares the same features: bilateral, adrenal, usually benign. Alpha-blockade before surgery and the "pheo first" surgical rule apply equally in MEN2B.

Marfanoid Habitus

Patients with MEN2B have a characteristic tall, slender body habitus with long extremities, a high-arched palate, joint hypermobility, and a wide arm span. This resembles Marfan syndrome but is a distinct entity: MEN2B patients do not have fibrillin-1 (FBN1) mutations, do not develop ectopia lentis (lens dislocation), and do not develop aortic root dilation or dissection. The marfanoid features in MEN2B reflect the role of RET signaling in connective tissue and skeletal development rather than fibrillin deficiency.

Mucosal Neuromas — Pathognomonic Finding

Mucosal neuromas are the pathognomonic (disease-defining) feature of MEN2B. They appear as small, firm, pearly nodules on the tips and edges of the tongue, the inner surface of the lips, and the conjunctivae (bulging, beaded eyelid margins). These lesions consist of hypertrophied peripheral nerve bundles and are present from birth or early infancy. In a child with no family history, prominent bumpy lips and an enlarged nodular tongue are the most visible clue that should immediately trigger RET testing. Recognition at this stage — before MTC has metastasized — can be life-saving.

Intestinal Ganglioneuromas

Neuronal overgrowth extends throughout the gastrointestinal tract, producing diffuse intestinal ganglioneuromatosis. This manifests clinically as chronic constipation, bowel dysmotility, megacolon, or diarrhea (paradoxically, if secretory in nature). Abdominal symptoms in a child with mucosal neuromas or marfanoid features should heighten suspicion for MEN2B. Unlike Hirschsprung disease (seen in MEN2A variants), MEN2B ganglioneuromas represent excess — rather than absence — of ganglion cells.

No Hyperparathyroidism in MEN2B

Primary hyperparathyroidism does not occur in MEN2B, a clinically important distinction from MEN2A. Calcium and PTH monitoring is not part of the standard MEN2B surveillance protocol.

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6. Familial Medullary Thyroid Cancer (FMTC)

Familial Medullary Thyroid Cancer (FMTC) describes families in which MTC is the sole manifestation of RET mutation — no pheochromocytoma develops and no parathyroid disease occurs over multiple generations. FMTC was historically classified as a third distinct MEN2 subtype, but current guidelines (ATA 2015) now consider it a variant of MEN2A with restricted phenotype rather than a separate entity.

The distinction from MEN2A has practical importance because FMTC-defining RET mutations (many in codons 768, 790, 791, 804, 891) confer lower risk MTC and a longer window for prophylactic thyroidectomy. In some FMTC kindreds, MTC is mild enough that affected individuals remain asymptomatic into middle age — though this cannot be assumed without genotype-specific data.

Clinically, FMTC is diagnosed when four or more family members carry a RET mutation and none has developed pheo or PHPT across multiple generations and extensive follow-up. Given that pheo penetrance in MEN2A is only 50%, a family can appear to have "FMTC" simply because pheo has not yet manifested. For this reason, annual pheo surveillance (metanephrines) continues lifelong even in families initially classified as FMTC.

Prognosis in FMTC is generally better than in MEN2A or MEN2B, reflecting both the lower-risk codon mutations and the absence of pheo-related surgical complexity. Many patients with FMTC-associated mutations who receive prophylactic thyroidectomy are cured without ever developing clinically apparent MTC.

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7. RET Genotype-Phenotype Correlation and ATA Risk Tiers

The American Thyroid Association 2015 guidelines stratify RET mutations into risk categories that directly determine the recommended age for prophylactic thyroidectomy. This genotype-to-surgery mapping is one of the clearest examples in medicine of genetic information directly guiding preventive surgery.

ATA Highest Risk — Category D

RET codon 918 (M918T) — MEN2B. Thyroidectomy is recommended within the first 6 months of life, ideally at a center with pediatric endocrine surgical expertise. Lymph node dissection is performed if preoperative imaging or intraoperative findings suggest nodal involvement. Delay beyond 6 months substantially increases metastasis risk.

ATA High Risk — Category C

RET codons 634 and 883. Codon 634 (typically C634R or C634Y) is the most prevalent MEN2A mutation. These patients have aggressive MTC with highest penetrance for pheo and PHPT. Prophylactic thyroidectomy is recommended before age 5 years, or earlier if calcitonin levels are rising. Codon 883 (A883F) is a rare MEN2B variant with slightly less severe phenotype than codon 918.

ATA Moderate Risk — Categories A and B

All remaining codons — including 609, 611, 618, 620, 630, 768, 790, 791, 804, 891 — fall in moderate-risk categories. For these patients, thyroidectomy by age 5 is a safe default, but watchful waiting with annual calcitonin levels and neck ultrasound is acceptable if calcitonin remains normal, the family favors surveillance, and the patient is evaluated at an expert center. Rising calcitonin or imaging abnormalities accelerate the surgical timeline.

Practical Implications of Risk Tiers

The risk-tier framework means that when a child's RET mutation is identified — through cascade family testing after a proband is diagnosed — the surgeon and family immediately know the urgency. A codon 918 newborn needs a pediatric surgical center scheduled within weeks; a codon 804 child may be followed closely for years before surgery. This precision prevents both under-treatment (delayed surgery in high-risk patients) and over-treatment (unnecessarily urgent surgery in low-risk patients).

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8. Medullary Thyroid Cancer — Diagnosis and Treatment

Medullary thyroid cancer arises from thyroid parafollicular C-cells and accounts for approximately 3–5% of all thyroid cancers. In MEN2, it is the central disease-defining tumor. Management involves biochemical surveillance, surgical treatment, and — for advanced disease — targeted molecular therapy.

Calcitonin as a Tumor Marker

Calcitonin is the most sensitive and specific tumor marker for MTC. Because C-cells are calcitonin-secreting, even microscopic C-cell hyperplasia or microcarcinoma causes measurable calcitonin elevation. Baseline calcitonin in healthy adults is typically below 10 pg/mL; values above 100 pg/mL are highly suspicious for MTC, and values in the thousands indicate bulky or metastatic disease. Dynamic stimulation tests — historically using pentagastrin, now largely replaced by calcium gluconate infusion — amplify the calcitonin signal in cases of subclinical disease. Post-thyroidectomy calcitonin should fall to undetectable levels if resection is complete; a detectable postoperative calcitonin indicates residual or metastatic disease.

Carcinoembryonic antigen (CEA) is a complementary marker that rises as MTC dedifferentiates. The CEA doubling time — how quickly CEA doubles — is a powerful prognostic indicator: a doubling time under 6 months correlates with rapidly progressive disease and poor prognosis, while a doubling time over 2 years indicates indolent disease.

Surgical Treatment — Curative Intent

The primary treatment for localized MTC is total thyroidectomy with central compartment lymph node dissection (level VI). This is the standard operation whether performed prophylactically (before MTC develops) or therapeutically (after MTC is diagnosed). If preoperative imaging or intraoperative inspection reveals lateral neck lymph node involvement, ipsilateral or bilateral lateral neck dissection (levels II–V) is added. Complete surgical resection while MTC is confined to the thyroid or central neck nodes is the only currently available curative treatment.

Unlike papillary or follicular thyroid cancer, MTC does not take up radioactive iodine (C-cells lack the sodium-iodide symporter), so radioiodine ablation has no role. External beam radiation is used in selected cases for local control of unresectable disease.

Targeted Therapy for Advanced MTC

For patients with progressive, metastatic MTC not amenable to surgery, four FDA-approved agents are available — all targeting RET directly or indirectly:

• Vandetanib (FDA approved 2011): A multi-kinase inhibitor targeting RET, VEGFR (anti-angiogenic), and EGFR. Improved progression-free survival vs placebo in a randomized trial (PMID 22025146). Requires ECG monitoring for QT prolongation.
• Cabozantinib (FDA approved 2012): Inhibits RET, MET, and VEGFR2. Demonstrated superior PFS over placebo in progressive MTC (PMID 24002501). Side effects include hand-foot syndrome, hypertension, and GI perforation risk.
• Selpercatinib (FDA approved 2020): A highly selective RET kinase inhibitor with minimal off-target activity. The LIBRETTO-531 trial demonstrated superior progression-free survival compared to cabozantinib or vandetanib as first-line therapy, with a more favorable tolerability profile (PMID 32846061). Now considered first-line for RET-mutant MTC in many centers.
• Pralsetinib (FDA approved 2020): Another highly selective RET inhibitor. The ARROW trial demonstrated durable responses in RET-mutant thyroid cancers including MTC (PMID 34237244). Provides an alternative to selpercatinib with comparable selectivity.

The selective RET inhibitors (selpercatinib, pralsetinib) represent a major advance over the older multi-kinase inhibitors: by targeting RET specifically rather than broadly, they achieve similar or better efficacy with substantially less off-target toxicity (less hypertension, less diarrhea, no QT prolongation), improving quality of life for patients on long-term therapy.

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9. Pheochromocytoma in MEN2

Pheochromocytoma (pheo) in MEN2 has several distinctive features that distinguish it from sporadic pheo. Understanding these differences is essential for appropriate surveillance, pre-operative preparation, and surgical planning.

Characteristics of MEN2-Associated Pheochromocytoma

MEN2 pheos are characteristically:

• Bilateral in 50–80% of cases at presentation or over time
• Adrenal (intra-adrenal medullary tumors), as opposed to the extra-adrenal paragangliomas more commonly seen with SDHB mutations
• Benign in the vast majority — malignant pheo is rare in MEN2 (under 5%), in stark contrast to SDHB-associated pheo where malignancy risk is 30–50%
• Epinephrine-predominant — MEN2 pheos preferentially produce epinephrine (reflecting their adrenal origin and expression of phenylethanolamine N-methyltransferase), producing palpitations and anxiety more prominently than the classic paroxysmal hypertension

Biochemical Screening

Annual biochemical screening is the cornerstone of pheo surveillance. The preferred tests are plasma fractionated metanephrines (most sensitive) or 24-hour urine fractionated metanephrines and catecholamines. Metanephrines — the O-methylated metabolites of epinephrine and norepinephrine — are continuously secreted by pheo cells and provide more stable biochemical detection than catecholamines themselves. Elevations above the upper limit of normal on two separate measurements, or markedly elevated values on a single test, warrant adrenal imaging (MRI preferred to avoid iodinated contrast that can trigger a hypertensive crisis in unblocked patients).

Pre-operative Alpha-Blockade — Non-Negotiable

Before any surgery on a patient with biochemically confirmed or suspected pheo, adequate alpha-adrenergic blockade must be established to prevent an intraoperative catecholamine crisis. The standard agents are:

• Phenoxybenzamine (non-competitive, non-selective alpha-blocker): the traditional choice; started 10–14 days pre-operatively at 10 mg twice daily, titrated upward. Causes significant orthostatic hypotension.
• Doxazosin or terazosin (competitive, selective alpha-1 blockers): increasingly used as alternatives; better tolerated, shorter half-life, may cause less post-operative hypotension.

The critical rule: never initiate beta-blockade before alpha-blockade in a pheo patient. Beta-blockers given to an unbocked pheo patient block the beta-2 (vasodilatory) receptors while leaving alpha (vasoconstrictive) receptors unopposed, precipitating severe hypertension and potentially hypertensive crisis. Once alpha-blockade is adequate (2 weeks minimum), a beta-blocker can be added to control reflex tachycardia.

Cortical-Sparing Adrenalectomy for Bilateral Disease

Because MEN2 pheos are bilateral in a substantial fraction of patients, the surgical approach requires careful consideration of adrenal cortical preservation. Bilateral total adrenalectomy eliminates pheo risk but creates permanent adrenal insufficiency (Addison's disease), requiring lifelong corticosteroid and mineralocorticoid replacement with the attendant risks of adrenal crisis. Cortical-sparing (partial) adrenalectomy — removing the pheo while preserving the outer adrenal cortex — avoids or delays this outcome. When technically feasible (the pheo is clearly delineated from cortical tissue), cortical-sparing is now the preferred approach for bilateral MEN2 pheos at experienced centers.

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10. Surveillance and Genetic Counseling

Annual Biochemical Surveillance Protocol

All confirmed RET mutation carriers require lifelong annual surveillance, regardless of whether prophylactic thyroidectomy has been performed. The standard protocol includes:

• Calcitonin and CEA: thyroid remnant or metastatic MTC monitoring; post-thyroidectomy calcitonin should be undetectable
• Plasma or 24-hour urine fractionated metanephrines: pheochromocytoma screening, annually from age 8 (or earlier if clinically indicated)
• Serum calcium and intact PTH: primary hyperparathyroidism screening in MEN2A patients
• Neck ultrasound: annual imaging to detect cervical lymph node recurrence after thyroidectomy or to monitor for MTC in patients managed with watchful waiting

If pheo screening is positive, adrenal MRI is the preferred imaging modality. CT with iodinated contrast should be avoided in unblocked patients with suspected pheo.

Genetic Testing Strategy

Cascade genetic testing — testing all first-degree relatives of an affected proband — is the cornerstone of MEN2 prevention. A positive RET test result in a child means that prophylactic thyroidectomy can be planned and performed before MTC develops. A negative result means the child has not inherited the family mutation and requires no MEN2-specific surveillance.

Genetic testing is typically offered to children of RET-positive parents at or before age 6 months for codon 918 (because surgery may be needed in infancy) and by age 3–5 years for high- and moderate-risk codons. Adult first-degree relatives who have not previously been tested should be offered testing regardless of age.

New RET mutations identified in probands who appear sporadic (no family history) — a common situation in MEN2B where 50% of cases are de novo — require testing of both parents (to confirm de novo status and assess recurrence risk in future siblings) and immediate cascade testing of the proband's own children.

Genetic Counseling Considerations

Genetic counseling provides a structured framework for communicating mutation results, discussing penetrance and expressivity, explaining surveillance and surgical options, and addressing the psychological impact of a hereditary cancer diagnosis. Key counseling points include:

• MTC in MEN2 is largely preventable with prophylactic surgery timed to the risk tier
• Pheo in MEN2 is almost always benign and detectable through annual screening before it becomes dangerous
• Reproductive options include preimplantation genetic diagnosis (PGD) for couples who wish to avoid transmitting the mutation to offspring
• Psychosocial support resources are available for children and families navigating genetic testing decisions and prophylactic surgery

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11. Research Papers

The following peer-reviewed publications underpin current understanding and management of MEN2:

1. Wells SA Jr, et al. "Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma." Thyroid. 2015;25(6):567-610. PMID: 25810047
2. Elisei R, et al. "Cabozantinib in progressive medullary thyroid cancer." J Clin Oncol. 2013;31(29):3639-3646. PMID: 24002501
3. Wells SA Jr, et al. "Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer." J Clin Oncol. 2012;30(2):134-141. PMID: 22025146
4. Wirth LJ, et al. "Selpercatinib in RET-altered thyroid cancers." N Engl J Med. 2020;383(9):825-835. PMID: 32846061
5. Gainor JF, et al. "Pralsetinib for RET-altered thyroid cancers." Lancet Oncol. 2021;22(8):1135-1144. PMID: 34237244
6. Brandi ML, et al. "Guidelines for diagnosis and therapy of MEN type 1 and type 2." J Clin Endocrinol Metab. 2001;86(12):5658-5671. PMID: 11739416
7. Raue F, Frank-Raue K. "Genotype-phenotype relationship in multiple endocrine neoplasia type 2. Implications for clinical management." Hormones (Athens). 2009;8(1):23-28. PMID: 19386596
8. Eng C, et al. "The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2." JAMA. 1996;276(19):1575-1579. PMID: 8918855
9. Pacak K, et al. "Pheochromocytoma: recommendations for clinical practice from the First International Symposium." Nat Clin Pract Endocrinol Metab. 2007;3(2):92-102. PMID: 17237842
10. Schuffenecker I, et al. "Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene." J Clin Endocrinol Metab. 1998;83(2):487-491. PMID: 9467557
11. Machens A, et al. "Early malignant progression of hereditary medullary thyroid cancer." N Engl J Med. 2003;349(16):1517-1525. PMID: 14561794
12. Takahashi M, et al. "Biological functions of the RET protooncogene." J Intern Med. 2003;253(6):606-610. PMID: 12755956

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Connections

• Multiple Endocrine Neoplasia Type 1
• Multiple Endocrine Neoplasia Overview
• Pheochromocytoma
• Thyroid Cancer
• Hyperparathyroidism
• Primary Hyperparathyroidism
• Carcinoid Tumor

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