Multiple Endocrine Neoplasia- Causes, Symptoms, Diagnosis, Treatment and Ongoing care

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 multiple endocrine glands.The classic syndromes are MEN1 and MEN2, but we also consider MEN4 (MEN1-like phenotype), Von Hippel–Lindau syndrome, Cowden syndrome, Carney complex, and familial paragangliomas as part of the spectrum of disease.

Description

3 main subtypes: MEN1: Parathyroid hyperplasia or adenoma (90% penetrance at age 40), anterior pituitary adenomas (prolactinoma most commonly), and tumors of the endocrine pancreas (gastrinoma, insulinoma, glucagonoma, vasoactive intestinal peptide tumor [VIPoma]). Combinations of over 20 different types of tumors are described in these patients, but the above 3 are considered characteristic.MEN2A: Medullary thyroid carcinoma (90%), pheochromocytoma (50%), and parathyroid hyperplasia or single adenoma (20–30%).MEN2B: Medullary thyroid carcinoma (90%), pheochromocytoma, and mucosal and gastrointestinal ganglioneuromatosis; marfanoid habitusMEN4: Bilateral pheochromocytomas, hyperparathyroidism/parathyroid adenoma, paraganglioma, C cell (multifocal thyroid) hyperplasia, neuroendocrine carcinoid tumor, and hyperplasia of the endocrine pancreasSynonym(s): Multiple endocrine adenomatosis (MEA); Wermer syndrome (MEN1); Sipple syndrome (MEN2); Wagenmann-Froboese syndrome

Epidemiology

MEN1: Prevalence estimated to be 1 in 30,000; 10% of cases are sporadic (90% familial); Male:Female is 1:1; 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.MEN2: Prevalence estimated at 1 in 30,000 individuals: MEN2A: Most common subtype (>80% of MEN2 cases); the typical age at onset of symptoms is 5 to 25 years

Risk Factors

Significant family history

Genetics

Autosomal dominantMEN1: Results from mutation causing 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” to the other allele occurs. The exact action of menin is unknown, but it appears to be involved in the cell cycle and DNA transcription and replication. 10% of mutations arise de novo; no mutation identified in 10–20% of cases.MEN2: Results from mutation causing gain of function of protooncogene 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 identified in 5% of cases. Significant genotype-phenotype correlation.MEN4: Results from germline mutation causing inactivation of the cyclin-dependent kinase inhibitor 1B (CDKN1B); negative MEN1

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, meningiomasMEN2A: Rare variants exist including MEN2A with cutaneous lichen amyloidosis and with Hirschsprung’s disease.MEN2B: Developmental abnormalities including marfanoid habitus or skeletal deformities

Diagnosis

MEN1: Clinical diagnosis of sporadic MEN1 is made in patients with tumors in 2 of the 3 main MEN1-associated endocrine glands; familial MEN1 is diagnosed in individuals who have 1 of the MEN1-associated tumors in addition to having a 1st-degree relative with 1 of these 3 tumors (1).MEN2: Clinical diagnosis of sporadic MEN2 is made in patients with tumors in 2 of the MEN2-associated endocrine glands; familial MEN2 is diagnosed in individuals who have 1 of the MEN2-associated tumors in addition to having a 1st-degree relative with 1 of these 3 tumors (2).

History

Complaints relate to the mechanism of action of the specific secretory product of the patient’s tumor/s: 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 pituitary lesion including headache or blurry vision; 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, myalgias.Positive family history is important to elucidate.

Physical Exam

Physical exam findings depend upon the presence of specific tumor combinations in the individual patient:

MEN1: Signs of hypercalcemia secondary to hyperparathyroidism include hypertension and altered mental status; signs of pituitary lesion including visual field deficit; signs of hyperprolactinemia from prolactinoma including galactorrhea, hypogonadism, gynecomastia; signs of growth hormone excess including gigantism (children) or acromegaly (adults); signs of pancreatic tumor could include acute abdomenMEN2: Presence of thyroid mass or tenderness; signs of excess catecholamine from pheochromocytoma including tachycardia and hypertension; signs of hypercalcemia secondary to hyperparathyroidism include hypertension and altered mental status; oral or rectal lesions in mucosal ganglioneuromatosis; marfanoid habitus

Diagnostic Tests & Interpretation

Lab

Initial lab tests

MEN1: Primary hyperparathyroidism: Serum calcium, 24-hour urine calcium, intact parathyroid hormone levelAnterior pituitary tumors: Prolactin, growth hormone, insulinlike growth factor-1, corticotropinPancreatic and duodenal tumors: Gastrin level (usually higher than 1,000 pg/mL in patients with gastrinoma); fasting insulin and glucose; glucagon, fasting plasma VIP, fasting somatostatinConsider genetic testing for MEN1 in all cases that meet clinical criteria for MEN1, in patients under 30 years of age with multiple parathyroid tumors, in patients with recurrent hyperparathyroidism, in patients with gastrinoma, and in asymptomatic relatives of patients with MEN1MEN2: Medullary thyroid carcinoma: CalcitoninPheochromocytoma: Plasma metanephrines, 24-hour urine catecholamines and metanephrinesPrimary hyperparathyroidism: Intact parathyroid hormone and serum calcium

Follow-Up & Special Considerations

Guidelines for annual screening in MEN1 carriers (1): Beginning at age 5: Fasting glucose, insulin, prolactin, and insulinlike growth factor 1Beginning at age 8: Calcium, parathyroid hormoneBeginning at age 20: Gastrin, chromogranin-A, glucagon, proinsulinGuidelines for annual screening in MEN2 carriers: Screen for pheochromocytoma depending upon the specific genetic mutation (plasma metanephrines and urine catecholamines and metanephrines)

Imaging

Guidelines for radiologic screening in MEN1 carriers to be completed every 3 years (1):

Beginning at age 5: MRI brainBeginning at age 20: Abdominal CT scan and octreotide scan

Diagnostic Procedures/Surgery

Biopsy as indicated

Differential Diagnosis

Isolated tumors vs MEN syndromes

Treatment

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

Additional Treatment

Issues for Referral

Referral to endocrinologist is recommended for assistance with management.

Surgery/Other Procedures

Surgical management varies and depends upon the specific tumor affected. For example: Parathyroidectomy in hyperparathyroidismThyroidectomy in medullary thyroid carcinomaPartial pancreatectomy for tumors such as insulinomas, glucagonomas, VIPomasPheochromocytoma with surgical excision under a-adrenergic blockade starting 7–10 days prior to surgery, unilateral vs bilateralTrans-sphenoidal pituitary surgery in some cases of pituitary tumorsPatients with MEN2 at a high risk of developing medullary thyroid carcinoma (MEN2B highest risk). Prophylactic total thyroidectomy with central node dissection recommended before the age of 6 months in patients with MEN2B and before the age of 5 years in patients with MEN2A (1).

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: Progeny of carriers will have 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 progression to medullary thyroid carcinoma is 100% by age 20 (3).

References

1. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001;86:5658–71.

2. Marini F, Falchetti A, Del Monte F, et al. Multiple endocrine neoplasia type 2. Orphanet journal of rare diseases. 2006;1:45.

3. Machens A, Niccoli-Sire P, Hoegel J, et al. Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med. 2003;349:1517–25.

Additional Reading

Carney JA. Familial multiple endocrine neoplasia: the first 100 years. Am J Surg Pathol. 2005;29:254–74.

Marini F, Falchetti A, Del Monte F, Carbonell Sala S, Gozzini A, Luzi E, Brandi ML et al. Multiple endocrine neoplasia type 1. Orphanet journal of rare diseases. 2006;1:38.

Santoro M, Melillo RM, Carlomagno F, Vecchio G, Fusco A et al. Minireview: RET: normal and abnormal functions. Endocrinology. 2004;145:5448–51.

See Also (Topic, Algorithm, Electronic Media Element)

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

Codes

ICD9

258.01 Multiple endocrine neoplasia [MEN] type I258.02 Multiple endocrine neoplasia [MEN] type IIA258.03 Multiple endocrine neoplasia [MEN] type IIBV84.81 Genetic susceptibility to multiple endocrine neoplasia [MEN]

Snomed

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

Clinical Pearls

Young people (<30 years old) with hypercalcemia: Think MEN 1.Multiglandular involvement in hyperparathyroidism: Think MEN 1.Adrenal mass and tachycardia: Think pheochromocytoma.Patient with diagnosis of MTC: Test for RET.Rule out pheochromocytoma to avoid complications from catecholamine surge during thyroidectomy.Red-flag tumors for MEN syndromes include parathyroid carcinoma, medullary thyroid carcinoma, pheochromocytoma, and paraganglioma.