Multiple Endocrine Neoplasia Syndromes¶
Chapter 400 | Part 12: Endocrinology · Part 12 – Endocrinology & Metabolism · Chapter 400
Key Clinical Points¶
- MEN 1 (Wermer syndrome) is characterized by the classic triad of parathyroid adenoma, pancreatic islet cell tumors, and anterior pituitary adenomas.
- MEN 2A and 2B are caused by germline RET proto-oncogene mutations; MEN 2A includes parathyroid hyperplasia, while 2B features mucosal neuromas and marfanoid habitus.
- MEN 1-associated pancreatic NETs are typically multiple, aggressive, and have a higher risk of metastasis compared to sporadic cases.
- Zollinger-Ellison syndrome (gastrinoma) occurs in >50% of pancreatic NETs in MEN 1 patients and is a major cause of morbidity.
- Systematic screening for MEN 1 begins at specific ages: 8 for parathyroid (calcium/PTH), 5 for pituitary (prolactin/IGF-I), and 20 for gastrinoma.
- MEN 4 is caused by CDKN1B mutations; MEN 5 is caused by MAX mutations.
- MEON syndromes include HPT-JT (Parafibromin), VHL (pVHL), NF1 (Neurofibromin), and Cowden's syndrome (multiple genes).
- Pituitary tumors in MEN 1 are more frequent in women; somatotrophinomas are more common in patients >40 years.
- Surgical management of gastrinomas is controversial due of high recurrence rates; medical therapy with proton pump inhibitors (PPI) is often preferred.
- Pheochromocytoma is rare (<1%) in MEN 1 but requires screening if suspected.
1. DEFINITION & OVERVIEW¶
• Definition: Multiple endocrine neoplasia (MEN) is characterized by a predilection for tumors involving two or more endocrine glands. • Classification: ◦ Five major forms: MEN 1–5. ◦ MEONs: At least six other syndromes associated with multiple endocrine and other organ neoplasias. • Criteria for Diagnosis (MEN/MEON): 1. Clinical features: Two or more of the associated tumors in an individual. 2. Familial pattern: One of the associated tumors in a first-degree relative of a patient with a clinical diagnosis. 3. Genetic analysis: A germline mutation in the associated gene (clinically affected or asymptomatic). • MEN 1 (11q13): ◦ Parathyroid adenoma (90%). ◦ Enteropancreatic tumor (30–70%): ◦ Gastrinoma (>50%) ◦ Insulinoma (10–30%) ◦ Nonfunctioning and PPoma (20–55%) ◦ Glucagonoma (<3%) ◦ VIPoma (<1%) ◦ Pituitary adenoma (15–50%): ◦ Prolactinoma (60%) ◦ Somatotrophinoma (25%) ◦ Corticotrophinoma (<5%) ◦ Nonfunctioning (<5%) ◦ Associated tumors: Adrenal cortical tumor (20–70%), Pheochromocytoma (<1%), Bronchopulmonary NET (2%), Thymic NET (2%), Gastric NET (10%), Lipomas (>33%), Angiofibromas (85%), Collagenomas (70%), Meningiomas (8%). • MEN 2 (10q11.2): ◦ MEN 2A: MTC (90%), Pheochromocytoma (>50%), Parathyroid adenoma (10–25%). ◦ MEN 2B: MTC (>90%), Pheochromocytoma (>50%), Mucosal neuromas, Marfanoid habitus, Medullated corneal nerve fibers, Megacolon. • MEN 4 (12p13): Parathyroid adenoma, Pituitary adenoma, potentially others (e.g., reproductive organ tumors, adrenal/renal tumors). • MEN 5 (14q23.3): Pheochromocytoma, Pituitary adenoma, Parathyroid adenoma. • MEON Syndromes: ◦ HPT-JT: Parafibromin mutation (1q31.2). ◦ VHL: pVHL (elongin) mutation (3p25). ◦ NF1: Neurofibromin mutation (17q11.2). ◦ Cowden's Syndrome (CWS): PTEN, SDHB, SDHD, KLLN, PIK3CA, AKT1, SEC23B. ◦ McCune-Albright Syndrome (MAS): Gαs mutation (20q13.32).
2. EPIDEMIOLOGY¶
• MEN 1 Prevalence: ◦ General population: ~0.25%. ◦ Primary hyperparathyroidism patients: 1–18%. ◦ Pancreatic islet tumor patients: 16–38%. ◦ Pituitary tumor patients: <3%. • Clinical Course: ◦ Age of onset: 5–81 years; most develop by the fifth decade. ◦ Mortality: 50% probability of death by age 50, typically from malignant pancreatic NET or foregut carcinoid.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
• MEN 1 Genetics: ◦ Location: Chromosome 11q13. ◦ Gene: MEN1 (10 exons, 610-amino acid protein 'menin'). ◦ Mechanism: Knudson two-hit hypothesis; tumor suppressor role for menin. ◦ Mutation types: Point mutations or deletions leading to loss of heterozygosity (LOH). • MEN 2 Genetics: ◦ Gene: RET proto-oncogene. ◦ MEN 2A: Codons 634 (Cys → Arg) and 618 (missense). ◦ MEN 2B: Codon 918 (Met → Thr). • Other Genetic Drivers: ◦ MEN 4: CDKN1B mutations (p27kip1). ◦ MEN 5: MAX mutations (Myc-associated factor X). ◦ McCune-Albright: Gαs mutation (postzygotic somatic mutation). • Clinical Implications of Genetics: ◦ MEN 1 tumors are often multiple, larger, and more aggressive than sporadic cases. ◦ Difficulty in surgical cure due to multiplicity and higher rates of occult metastatic disease.
4. CLINICAL FEATURES¶
• Parathyroid Tumors: ◦ Incidence: ~90% of MEN 1 patients. ◦ Presentation: Asymptomatic hypercalcemia or symptoms (polyuria, polydipsia, constipation, malaise, dyspepsia). ◦ Comparison to sporadic cases: Earlier age of onset (20–25 vs. 55 years) and equal sex ratio (1:1 vs. 1:3). ◦ Imaging: Preoperative localization (e.g., Sestamibi) is limited as all glands may be involved. • Pancreatic Tumors: ◦ Incidence: 30–80% in MEN 1. ◦ Gastrinoma (>50%): Associated with Zollinger-Ellison syndrome; major cause of morbidity. ◦ Insulinoma (10–30%): Hypoglycemic symptoms. ◦ Glucagonoma (<3%): Potential for skin rash (necrolytic migratory erythema). ◦ VIPoma (<1%): WDHA syndrome (Watery diarrhea, hypokalemia, achlorhydria). ◦ Nonfunctioning NETs: Most common enteropancreatic NET in MEN 1; associated with worse prognosis. • Pituitary Tumors: ◦ Incidence: 15–50% of MEN 1 patients. ◦ Gender Difference: More frequent in women (often prolactinomas); somatotrophinoma more common in patients >40 years. • Other Associated Tumors: ◦ Adrenal cortical tumors: 20–70%; mostly nonfunctioning; risk of malignancy if >1 cm. ◦ Pheochromocytoma: <1% in MEN 1; requires screening. ◦ Cutaneous findings: Lipomas (>33%), Angiofibromas (85%), Collagenomas (70%). ◦ Meningiomas: 8%; often asymptomatic.
5. DIFFERENTIAL DIAGNOSIS¶
• MEN 1 Differentiation: ◦ Distinguish from sporadic primary hyperparathyroidism, sporadic pancreatic NETs, and sporadic pituitary adenomas. • MEN 2 Differentiation: ◦ Distinguish from sporadic MTC and pheochromocytoma. • MEON vs. MEN: ◦ Differentiate based on specific genetic markers (e.g., Parafibromin for HPT-JT).
6. INVESTIGATIONS & DIAGNOSIS¶
- Screening for MEN 1: • Parathyroid: Age 8 → Annual Calcium, PTH. • Pancreatic NETs (Gastrin): Age 20 → Annual Gastrin (± gastric pH). • Insulinoma: Age 5 → Annual Fasting glucose, insulin. • Other pancreatic NETs: <10 years → Annual Chromogranin A; pancreatic polypeptide, glucagon, VIP. • Anterior Pituitary: Age 5 → Annual Prolactin, IGF-I; MRI every 3 years. • Adrenal: <10 years → No annual biochemical test unless symptomatic or tumor >1 cm on imaging (MRI/CT annually). • Thymic and bronchial carcinoid: Age 15 → CT or MRI every 1–2 years.
- Screening for MEN 2 & 3: • RET Mutational Analysis: ◦ MEN 2A (Ex8, 10, 11, 13, 14, 15, 16): Test at <3–5 years. ◦ MEN 2B (Ex15, Ex16): Test ASAP and by <1 year. • First Serum Calcitonin & Neck Ultrasound: ◦ MEN 2A: Test at <3 years. ◦ MEN 2B: Test at <0.5–1 year. • Prophylactic Thyroidectomy: ◦ MEN 2A: If calcitonin high or age <5. ◦ MEN 2B: If calcitonin high or age <1. • Pheochromocytoma Screening: ◦ Must be excluded before any surgery; performed at age 11–16 for MEN 2A.
- HPT-JT Screening: • Parathyroid: Serum Ca, PTH every 6–12 months; Panoramic jaw x-ray. • Renal: Abdominal MRI every 5 years; Ultrasound and additional imaging if indicated.
7. MANAGEMENT & TREATMENT¶
- Gastrinoma Management: ◦ Medical: Proton pump inhibitors (PPI) often preferred due to high surgical recurrence rates. ◦ Surgical: Controversial; used for local control but high risk of recurrence.
- Insulinoma Management: ◦ Diagnosis: Supervised 72-h fast to confirm hypoglycemia and elevated insulin/C-peptide. ◦ Treatment: Surgical resection of the tumor.
- Pituitary Tumor Management: ◦ Monitoring: Periodic biochemical (Prolactin, IGF-1) and MRI imaging. ◦ Intervention: Based on hormone secretion and size; surgery if enlarging or causing mass effect.
- Pancreatic NET Management: ◦ Advanced Therapies: Tyrosine kinase receptor (TKR) inhibitors; mTOR signaling pathway inhibitors. ◦ Localized Treatments: PRRT (177Lu-DOTATATE), radiofrequency ablation, transarterial chemoembolization, and SIRT.
- Adrenal Tumor Management: ◦ Monitoring: Annual MRI/CT for tumors <1 cm. ◦ Surgery: Consideration for larger (>1 cm) or functional tumors.
- Carcinoid Treatment: ◦ Specific Case (ECLomas): Somatostatin analogs (SSAs) used to induce regression of gastric type II ECLomas.
8. PROGNOSIS & COMPLICATIONS¶
• MEN 1 Prognosis: ◦ High mortality risk; 50% probability of death by age 50. ◦ Primary causes: Malignant pancreatic NET or foregut carcinoid. ◦ Surgical Challenge: Multiple tumors and occult metastatic disease make surgical cure difficult. • MEN 2 Prognosis: ◦ MTC is highly aggressive; risk of metastasis depends on specific RET mutation (Table 400-4).
9. KEY PEARLS & CLINICAL TRAPS¶
• MEN 1 Rule of Thumb: Parathyroid is the most common feature (~90%); Gastrinoma is the primary driver of morbidity. • Pituitary Gender Split: Women with MEN 1 are more likely to have prolactinomas; somatotrophinoma more common in patients >40 years. • RET Mutation Risk: High-risk mutations (Ex15, Ex16) in MEN 2B require immediate intervention (<1 year). • Screening Age Gap: Note the significant difference in starting ages for various tumors in MEN 1 (e.g., Parathyroid at 8 vs. Pituitary at 5). • Non-functional Tumors: In MEN 1, nonfunctioning pancreatic NETs are common and often have a worse prognosis than functional ones.
Reference Tables¶
TABLE 399-3 Patterns of Occurrence in Inherited Pheochromocytoma and Paraganglioma–Associated Syndromes¶
Harrison's 22e, p.3079
| MUTATED GENE |
ADRENAL TUMORS |
HEAD AND NECK TUMORS |
EXTRA-ADRENAL RETROPERITONEAL OR PELVIC TUMORS |
THORACIC TUMORS |
MULTIPLE TUMORS |
BILATERAL ADRENAL TUMORS |
METASTATIC TUMORS |
FAMILY HISTORY IN PROBANDS FOR COMPONENTS OF THE GIVEN SYNDROME |
|---|---|---|---|---|---|---|---|---|
| MAX | +++++ | <x | + | <x | +++++ | ++++ | ++ | +++ |
| +++++ | <+ | + | <+ | + | ++ | + | ||
| RET | +++++ | <+ | <+ | <+ | ++++ | ++++ | <+ | + |
| ++ | ++++ | ++ | + | + | <+ | + | ||
| SDHB | ++++ | +++ | +++ | + | ++ | <+ | +++ | ++ |
| <+ | +++++ | <+ | + | + | <+ | <+ | ||
| SDHD | ++ | +++++ | + | + | ++++ | <+ | + | +++ |
| +++++ | <+ | + | + | ++++ | +++ | + | ||
| TMEM127 | +++++ | + | + | + | ++ | ++ | <+ | + |
| 400 | Multiple Endocrine Neoplasia Syndromes Rajesh V. Thakker |
TABLE 400-2 Multiple Endocrine and Other Organ Neoplasia (MEON) Syndromes DISEASE a Hyperparathyroidism-jaw tumor…¶
Harrison's 22e, p.3080
| TYPE (CHROMOSOMAL LOCATION) |
TUMORS (ESTIMATED PENETRANCE) |
GENE AND MOST FREQUENTLY MUTATED CODONS |
|---|---|---|
| MEN 1 (11q13) | Parathyroid adenoma (90%) Enteropancreatic tumor (30–70%) • Gastrinoma (>50%) • Insulinoma (10–30%) • Nonfunctioning and PPoma (20–55%) • Glucagonoma (<3%) • VIPoma (<1%) Pituitary adenoma (15–50%) • Prolactinoma (60%) • Somatotrophinoma (25%) • Corticotrophinoma (<5%) • Nonfunctioning (<5%) Associated tumors • Adrenal cortical tumor (20–70%) • Pheochromocytoma (<1%) • Bronchopulmonary NET (2%) • Thymic NET (2%) • Gastric NET (10%) • Lipomas (>33%) • Angiofibromas (85%) • Collagenomas (70%) • Meningiomas (8%) |
MEN1 83/84, 4-bp del (≈4%) 119, 3-bp del (≈3%) 209-211, 4-bp del (≈8%) 418, 3-bp del (≈4%) 514-516, del or ins (≈7%) Intron 4 ss (≈10%) |
| MTC (90%) Pheochromocytoma (>50%) Parathyroid adenoma (10–25%) MTC (100%) MTC (>90%) Pheochromocytoma (>50%) Associated abnormalities (40–50%) • Mucosal neuromas • Marfanoid habitus • Medullated corneal nerve fibers • Megacolon |
||
| MEN 4 (12p13) MEN5 (14q23.3) |
Parathyroid adenomaa Pituitary adenomaa Reproductive organ tumorsa (e.g., testicular cancer, neuroendocrine cervical carcinoma) ?Adrenal + renal tumorsa Pheochromocytomaa Pituitary adenomaa Parathyroid adenomas?a Neural crest tumors (e.g., ganglioneuroma, neuroblastoma) (other tumors? – renal cell carcinoma, renal oncocytoma, pancreatic NETs, chondrosarcoma) |
CDKN1B; no common mutations identified to date MAX; no common mutations identified to date |
TABLE 400-2 Multiple Endocrine and Other Organ Neoplasia (MEON) Syndromes
| DISEASEa | GENE PRODUCT | CHROMOSOMAL LOCATION |
|---|---|---|
| Hyperparathyroidism-jaw tumor (HPT-JT) | Parafibromin | 1q31.2 |
| PRAKAR1A ?b |
||
| von Hippel–Lindau disease (VHL) | pVHL (elongin) | 3p25 |
| Neurofibromin | ||
| Cowden’s syndrome (CWS) | ||
| CWS1 | PTEN | 10q23.31 |
| CWS2 | SDHB | 1p36.13 |
| CWS3 | SDHD | 11q23.1 |
| CWS4 | KLLN | 10q23.31 |
| CWS5 | PIK3CA | 3q26.32 |
| CWS6 | AKT1 | 14q32.33 |
| CWS7 | SEC23B | 20p11.23 |
| Gα s |
TABLE 400-3 Biochemical and Radiologic Screening in Multiple Endocrine Neoplasia Type 1 TUMOR Parathyroid Pancreatic…¶
Harrison's 22e, p.3081
| TUMOR | AGE TO BEGIN (YEARS) | BIOCHEMICAL TEST (PLASMA OR SERUM) ANNUALLY | IMAGING TEST (TIME INTERVAL) |
|---|---|---|---|
| Parathyroid | 8 | Calcium, PTH | None |
| 20 5 <10 |
Gastrin (± gastric pH) Fasting glucose, insulin Chromogranin A; pancreatic polypeptide, glucagon, vasoactive intestinal peptide |
||
| Anterior pituitary | 5 | Prolactin, IGF-I | MRI (every 3 years) |
| <10 | None unless symptoms or signs of functioning tumor and/or tumor >1 cm identified on imaging |
||
| Thymic and bronchial carcinoid | 15 | None | CT or MRI (every 1–2 years) |
TABLE 400-4 Recommendations for Tests and Surgery in MEN 2 and MEN 3 a¶
Harrison's 22e, p.3085
| RET MUTATION, EXON (EX) LOCATION, AND CODON INVOLVED |
RISKb | RECOMMENDED AGE (YEARS) FOR TEST/INTERVENTION | ||||
|---|---|---|---|---|---|---|
| RET MUTATIONAL ANALYSIS |
FIRST SERUM CALCITONIN AND NECK ULTRASOUND |
PROPHYLACTIC THYROIDECTOMY |
SCREENING FOR PHEOCHROMOCYTOMA |
SCREENING FOR PHPT |
||
| Ex8 (533)c; Ex10 (609, 611, 618, 620)c; Ex11 (630, 631, 666)c; Ex13 (768, 790)c; Ex14 (804)c; Ex15 (891)c; EX16 (912)c |
+ | <3–5 | 5 | <5d | 16e | 16 |
| ++ | <3 | <3 | <5f | 11e | ||
| Ex15 (883)g; Ex16 (918)g | +++ | ASAP and by <1 | ASAP and by <0.5–1 | ASAP and by <1 | 11e | —h |
TABLE 400-5 HPT-JT Screening Guidelines TUMOR a Parathyroid Ossifying jaw fibroma Panoramic jaw x-ray with neck Renal…¶
Harrison's 22e, p.3087
| TUMORa | TEST | FREQUENCYb |
|---|---|---|
| Parathyroid | Serum Ca, PTH | 6–12 months |
| Panoramic jaw x-ray with neck shieldingc |
||
| Renal | Abdominal MRIc,d | 5 years |
| Ultrasound (transvaginal or transabdominal) and additional imaging ± D&C if indicatede |