Multiple Endocrine Neoplasia (MEN) Syndromes

Basics

  • Multiple endocrine neoplasia (MEN) syndromes are autosomal dominant disorders that predispose individuals to the development of neoplasms, usually benign but sometimes malignant, in characteristic clusters of endocrine tissues.
  • The classic syndromes are MEN1 and MEN2A and MEN2B.
  • Also considered as closely related disorders: MEN4 (MEN1-like phenotype), von Hippel-Lindau syndrome (produces norepinephrine, not epinephrine), Cowden syndrome, Carney complex, and familial paragangliomas

Description

  • Three main subtypes:
    • MEN1: parathyroid hyperplasia or adenoma (90% penetrance at age 50 years), anterior pituitary adenomas (prolactinoma most commonly), and tumors of the endocrine pancreas (gastrinoma, insulinoma, glucagonoma, vasoactive intestinal peptide tumor [VIPoma]). A mnemonic commonly used to remember this is the 3Ps. Combinations of >20 different types of tumors are described in these patients, but the above three are considered characteristic (1)[A].
    • MEN2A: medullary thyroid carcinoma (90%), pheochromocytoma (50%), and parathyroid hyperplasia or single adenoma (20–30%) (2)[A]
    • MEN2B: medullary thyroid carcinoma (90%), pheochromocytoma, and mucosal and GI ganglioneuromatosis; marfanoid habitus (2)[A]
  • MEN4: bilateral pheochromocytomas, hyperparathyroidism/parathyroid adenoma, paraganglioma, C-cell (multifocal thyroid) hyperplasia, neuroendocrine carcinoid tumor, and hyperplasia of the endocrine pancreas. MEN4 has a variable age of onset with parathyroid and pituitary manifestations in the 4th and 3rd decades of life, respectively (3)[B].
  • Synonym(s): multiple endocrine adenomatosis (MEA); Wermer syndrome (MEN1); Sipple syndrome (MEN2); Wagenmann-Froboese syndrome

Epidemiology

  • MEN1: prevalence estimated to be 1:30,000; 10% of cases are sporadic (90% familial); male = female; clinical manifestations occur by the 5th decade in 95% of cases, with most diagnosed in early adulthood. Hyperparathyroidism is the most frequent and earliest manifestation (4).
  • MEN2: prevalence estimated at 1:30,000 individuals:
    • MEN2A: most common subtype (>80% of MEN2 cases); the typical age at onset of symptoms is 5 to 25 years (4).

Etiology and Pathophysiology

Genetics
  • Autosomal dominant
  • MEN1: results from mutation causing the loss of function of tumor suppressor gene MEN1 located on chromosome 11q13, encoding the nuclear protein menin; patients have germline mutations and develop tumors when a “second hit” occurs to the other allele. The exact action of menin not known, but it appears to be involved in the cell cycle and in DNA transcription and replication. 10% of mutations arise de novo; no mutation is identified in 10–20% of cases.
  • MEN2: results from mutation causing gain of function of proto-oncogene RET (also called MEN2 gene) located on chromosome 10q11.2, encoding the protein RET, which is a membrane tyrosine kinase receptor; 5% of MEN2A and 50% of MEN2B cases are secondary to de novo mutations; no mutation is identified in 5% of cases. There is a significant genotype–phenotype correlation.
  • MEN4: results from germline mutation causing inactivation of the cyclin-dependent kinase inhibitor 1B (CDKN1B); negative MEN1

Risk Factors

Significant family history

Commonly Associated Conditions

In addition to the defining MEN-associated tumors, other associated conditions include:

  • MEN1: adrenal cortical tumors (nonfunctioning or causing hypercortisolemia); thyroid tumors including carcinoma, adenoma, or colloid goiters; carcinoid tumors; facial angiofibromas; facial collagenomas; lipomas; meningiomas
  • MEN2A: Rare variants exist, including MEN2A with cutaneous lichen amyloidosis and with Hirschsprung disease.
  • MEN2B: developmental abnormalities including marfanoid habitus or skeletal deformities

Diagnosis

  • MEN1: Clinical diagnosis of sporadic MEN1 is made in patients with tumors in two of the three main MEN1-associated endocrine glands; familial MEN1 is diagnosed in individuals who have one of the MEN1-associated tumors in addition to having a first-degree relative with one of these three tumors (4)[B].
  • MEN2: Clinical diagnosis of sporadic MEN2 is made in patients with tumors in two of the MEN2-associated endocrine glands; familial MEN2 is diagnosed in individuals who have one of the MEN2-associated tumors in addition to having a first-degree relative with one of these three tumors (4)[B].

History

  • MEN1
    • Symptoms of hypercalcemia secondary to hyperparathyroidism, including altered mental status, constipation, nausea/vomiting, history of nephrolithiasis, history of pathologic fracture, bone pain, myalgias
    • Symptoms of increased acid production secondary to gastrinoma including abdominal pain, heartburn, vomiting, weight loss
    • Symptoms of hypoglycemia secondary to insulinoma
    • Symptoms of mass effect from a pituitary lesion, including headache or blurry vision, or visual field deficits (bitemporal hemianopsia)
    • Symptoms of hyperprolactinemia from prolactinoma, including galactorrhea, amenorrhea, infertility, or hypogonadism
    • Symptoms of acromegaly from growth hormone–secreting tumor
  • MEN2
    • Symptoms of medullary thyroid cancer, including neck mass, neck pain, or diarrhea
    • Symptoms of catecholamine excess from pheochromocytoma, including episodic headache, palpitations, nervousness, sweating, and skin flushing
    • Symptoms of hypercalcemia secondary to hyperparathyroidism, including altered mental status, constipation, nausea/vomiting, history of nephrolithiasis, history of pathologic fracture, bone pain, and myalgias
  • A positive family history is important to elucidate for diagnosis and potential screening of other family members.

Physical Exam

Findings depend on the presence of specific tumor combinations in the individual patient:

  • MEN1
    • Signs of hypercalcemia secondary to hyperparathyroidism, including hypertension and altered mental status
    • Signs of a pituitary lesion, including visual field deficit
    • Signs of hyperprolactinemia from prolactinoma, including galactorrhea, hypogonadism, and gynecomastia
    • Signs of growth hormone excess, including gigantism (children) or acromegaly (adults)
    • Signs of pancreatic tumor could include an acute abdomen.
  • MEN2
    • Presence of thyroid mass or tenderness
    • Oral or rectal lesions in mucosal ganglioneuromatosis
    • Marfanoid habitus
    • Signs of excess catecholamine from pheochromocytoma, including tachycardia and hypertension
    • Signs of hypercalcemia secondary to hyperparathyroidism, including hypertension and altered mental status

Differential Diagnosis

Isolated endocrine tumors versus MEN syndromes

Diagnostic Tests & Interpretation

Initial Tests (lab, imaging)
  • MEN1
    • Primary hyperparathyroidism: serum calcium, 24-hour urine calcium, intact parathyroid hormone level
    • Anterior pituitary tumors: prolactin, growth hormone, insulin-like growth factor 1, corticotropin, thyrotropin
    • Pancreatic and duodenal tumors: gastrin level (usually >1,000 pg/mL in patients with gastrinoma); fasting insulin and glucose; glucagon, fasting plasma VIP, fasting somatostatin
    • Consider genetic testing for MEN1 in all cases that meet the clinical criteria for MEN1, in patients <30 years of age with multiple parathyroid tumors, in patients with recurrent hyperparathyroidism, in patients with gastrinoma, and in asymptomatic relatives of patients with MEN1.
  • MEN2
    • Medullary thyroid carcinoma: calcitonin (5)[B]
    • Pheochromocytoma: plasma metanephrines, 24-hour urine catecholamines and metanephrines
    • Primary hyperparathyroidism: intact parathyroid hormone and serum calcium
  • Guidelines for radiologic screening in MEN1 carriers to be completed every 3 years:
    • Beginning at age 5 years: MRI brain
    • Beginning at age 20 years: abdominal CT scan and octreotide scan

Follow-Up Tests & Special Considerations
  • Guidelines for annual screening in MEN1 carriers:
    • Beginning at age 5 years: fasting glucose, insulin, prolactin, and insulin-like growth factor 1
    • Beginning at age 8 years: calcium, parathyroid hormone
    • Beginning at age 20 years: gastrin, chromogranin A, glucagon, proinsulin
  • Guidelines for annual screening in MEN2 carriers:
    • Screen for pheochromocytoma depending on the specific genetic mutation (plasma metanephrines and urine catecholamines and metanephrines).

Diagnostic Procedures/Other
Biopsy as indicated

Treatment

In general, treatment recommendations align with those of the specific isolated tumor.

Surgery/Other Procedures

  • Surgical management varies and depends on the specific tumor affected. For example:
    • Parathyroidectomy in hyperparathyroidism
    • Thyroidectomy in medullary thyroid carcinoma (5)[A]
    • Partial pancreatectomy for tumors such as insulinomas, glucagonomas, and VIPomas
    • Pheochromocytoma with surgical excision under α-adrenergic blockade starting 7 to 10 days prior to surgery, unilateral versus bilateral
    • Transsphenoidal pituitary surgery in some cases of pituitary tumors
  • Patients with MEN2 at a high risk of developing medullary thyroid carcinoma (MEN2B highest risk): Prophylactic total thyroidectomy with central node dissection is recommended before the age of 6 months in patients with MEN2B and before the age of 5 years in patients with MEN2A (5)[B].
  • Patients with refractory medullary thyroid carcinoma can also be treated with two agents approved by the FDA, vandetanib (Caprelsa) and cabozantinib (Cometriq).

Ongoing Care

Diet

Calcium and vitamin D should be limited in patients with hypercalcemia secondary to hyperparathyroidism until surgical intervention is complete. Patients with gastrinoma should avoid excessive acid intake.

Patient Education

  • Genetic counseling: The progeny of carriers will have a 50% chance of inheritance.
  • Importance of compliance with laboratory and radiographic screening for tumor expression

Prognosis

There is no cure. Genetic testing has improved the ability to make an earlier diagnosis and to initiate routine screening and prophylactic treatment at earlier stages. For example, in patients with certain RET mutations, the cumulative risk of a progression to medullary thyroid carcinoma is 100% by age 20 years (6)[B].

Additional Reading

  • Carney JA. Familial multiple endocrine neoplasia: the first 100 years. Am J Surg Pathol. 2005;29(2):254–274. [PMID:15644784]
  • Marini F, Falchetti A, Del Monte F, et al. Multiple endocrine neoplasia type 2. Orphanet J Rare Dis. 2006;1:45. [PMID:17105651]

See Also

Gastric Cancer ; Hyperparathyroidism ; Insulinoma ; Marfan Syndrome ; Pheochromocytoma ; Thyroid Malignant Neoplasia

Codes

ICD-10

  • E31.2 Multiple endocrine neoplasia [MEN] syndromes
  • E31.20 Multiple endocrine neoplasia [MEN] syndrome, unspecified
  • E31.21 Multiple endocrine neoplasia [MEN] type I
  • E31.22 Multiple endocrine neoplasia [MEN] type IIA
  • E31.23 Multiple endocrine neoplasia [MEN] type IIB

ICD-9

  • 258.0 Polyglandular activity in multiple endocrine adenomatosis
  • 258.01 Multiple endocrine neoplasia [MEN] type I
  • 258.02 Multiple endocrine neoplasia [MEN] type IIA
  • 258.03 Multiple endocrine neoplasia [MEN] type IIB

SNOMED

  • 30664006 multiple endocrine neoplasia, type 1 (disorder)
  • 46724008 polyglandular activity in multiple endocrine adenomatosis (disorder)
  • 61530001 multiple endocrine neoplasia, type 3 (disorder)
  • 61808009 multiple endocrine neoplasia, type 2 (disorder)

Clinical Pearls

  • Young people (<30 years of age) with hypercalcemia: Think MEN1.
  • Multiglandular involvement in hyperparathyroidism: Think MEN1.
  • Adrenal mass and tachycardia: Think pheochromocytoma.
  • A patient with a diagnosis of medullary thyroid carcinoma:
    • Test for RET.
    • Rule out pheochromocytoma to avoid complications from a catecholamine surge during thyroidectomy.
  • Red flag tumors for MEN syndromes include parathyroid carcinoma, medullary thyroid carcinoma, pheochromocytoma, and paraganglioma.
  • Pheochromocytomas in von Hippel-Lindau syndrome produce norepinephrine but not epinephrine. These tumors often have a bilateral adrenal presentation, are occasionally multifocal with abdominal or thoracic locations, and can be malignant.

Authors


Anup Sabharwal, MD, MBA, FACE

Bibliography

  1. Falchetti A. Genetics of multiple endocrine neoplasia type 1 syndrome: what’s new and what’s old. F1000Res. 2017;6:F1000 Faculty Rev-73.  [PMID:17014705]
  2. Wells SA Jr, Asa SL, Dralle H, et al; for American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567–610.  [PMID:17105651]
  3. Thakker R. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol. 2014;386(1–2):2–15.  [PMID:11739416]
  4. Rindi G, Arnold R, Bosman FT, et al. Diagnostic terms revisited: nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman TF, Carneiro F, Hruban RH, et al, eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France: International Agency for Research on Cancer; 2010:13.  [PMID:14561794]
  5. Machens A, Niccoli-Sire P, Hoegel J, et al; for European Multiple Endocrine Neoplasia (EUROMEN) Study Group. Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med. 2003;349(16):1517–1525.  [PMID:15331579]
  6. Lenders JW, Duh QY, Eisenhofer G, et al; for Endocrine Society. Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915–1942. [PMID:24893135]


© Wolters Kluwer Health Lippincott Williams & Wilkins

Multiple Endocrine Neoplasia (MEN) Syndromesis the Medicine Central Word of the day!