Algorithm(s)
PDF algorithm(s) available at www.arupconsult.com.
Hypercalcemia Testing Algorithm
Pheochromocytoma Testing Algorithm
Thyroid Nodules Testing Algorithm
Clinical Background
- Multiple Endocrine Neoplasia (MEN) syndromes are characterized by tumors involving multiple endocrine glands
- Subtypes are distinguished by clinical features and/or molecular testing
- MEN 1
- MEN 2 - 2A, 2B, Familial Medullary Thyroid Carcinoma (FMTC)
MEN 1 (Wermer Syndrome)
- Epidemiology
- Incidence - 1/30,000
- Age of onset - 20-45 years
- Inheritance
- Autosomal dominant - 10% of mutations are de novo
- Germline mutations in the MEN1 gene on 11q13 are causative
- Sequence analysis of MEN1 detects a germline mutation in 80-90% of familial cases and 65% of simplex patients (ie. a single occurrence of MEN 1 syndrome in a family)
- Approximately 1-3% of MEN1 mutations are large deletions
- Variable expressivity
- Genotype/phenotype associations have not been identified in MEN 1
- Penetrance for clinical features is age-related; 50% by age 20 and above 95% by age 40
- Clinical Presentation
- Parathyroid tumors
- Develop in 90-95% of patients; primary hyperparathyroidism is the first clinical manifestation in 90% of individuals
- Typically involves all four parathyroid glands (unlike sporadic disease)
- Signs - hypercalcemia, hyperparathyroidism
- Symptoms - fatigue, anorexia, polydipsia, polyuria, bone lesions, abdominal pain, kidney stones
- Gastro-entero-pancreatic (GEP) tumors
- Develop in 30-80% of patients
- Symptoms depend on specific tumor type
- Gastrinoma (Zollinger Ellison syndrome) - peptic ulcer disease, recurrent diarrhea, abdominal pain
- Insulinoma - hypoglycemia and related symptoms
- Glucagonoma - hyperglycemia, skin rash, anorexia, diarrhea
- VIPoma (Verner Morrison syndrome) - watery diarrhea, hypokalemia, achlorhydria
- Anterior pituitary tumors
- Develop in 10-60% of patients
- Symptoms depend on the pituitary hormone produced
- Amenorrhea and galactorrhea occur in females with prolactin-secreting tumors
- Reduction of libido or impotence occurs in males with prolactin-secreting tumors
- Gigantism and acromegaly occur in children and adults, respectively, with growth hormone-secreting tumors
- Hypercortisolism occurs in ACTH-secreting tumors
- Other endocrine tumors
- Adrenal cortical adenomas, 5-40% of patients
- Carcinoid tumors, 3% of patients
- Thyroid neoplasms, 8-25% of patients
- Pheochromocytoma, 0.5% of patients
- Non-endocrine tumors
- Collagenomas and facial angiofibromas, 70-85% of patients
- Lipomas, 30% of patients
- Central nervous system meningiomas or ependymomas
- Leiomyomas
- Malignant melanoma
- Treatment
- Treatment of manifestations dependant on tumor type
MEN 2
- Epidemiology
- Medullary thyroid carcinoma (MTC) accounts for approximately 5-10% of all diagnosed thyroid carcinomas; about 25% of these cases are believed to be familial
- Incidence: 1/30,000 for MEN 2 syndromes
- MEN 2A (60-90% of cases)
- MEN 2B (~5% of cases)
- FMTC (5-35% of cases)
- Inheritance
- Autosomal dominant; 5% of MEN 2A and 50% of MEN 2B mutations are de novo
- Caused by RET proto-oncogene mutations
- 95% of MEN 2A have RET mutations in exon 10 or 11
- MEN 2B is caused by a point mutation at codon 918 in exon 16 in 95% of cases and at codon 883 in exon 15 in 3-4%; rarely, the phenotype results from a mutation in other exons of the RET gene
- About 85% of FMTC is caused by a RET mutation in exon 10 or 11; although rare mutations in exons 13, 14 or 15 can be causative
- Penetrance varies by MEN 2 subtype
- Genotype/phenotype correlations can help predict risk for aggressive MTC
- Clinical Presentation
- MEN 2A
- MTC - early adulthood onset
- Pheochromocytoma - paroxysmal hypertension, palpitations, headaches
- Parathyroid tumors - hypercalcemia
- MEN 2B
- MTC - early childhood onset, aggressive
- Pheochromocytoma - paroxysmal hypertension, palpitations, headaches
- Marfanoid body type
- Megacolon
- Mucosal neuromas
- FMTC
- MTC only - middle age onset
- Prophylactic Treatment
- MEN 2A, 2B, and FMTC
- Thyroidectomy - timing depends on codon position of the identified RET mutation
See Also
Algorithm(s)
PDF algorithm(s) available at www.arupconsult.com.
Hypercalcemia Testing Algorithm
Pheochromocytoma Testing Algorithm
Thyroid Nodules Testing Algorithm
Diagnosis
Men 1 (Wermer Syndrome)
- Diagnosis
- Laboratory testing
- Goal is to identify the presence of multiple endocrine tumors using biochemical testing initially
- Parathyroid tumor - calcium and parathyroid hormone (PTH), elevated
- Gastrinoma tumor - Gastrin and gastric acid output measures, elevated
- Insulinoma and other pancreatic tumors- Chromogranin A, glucagon, serum insulin and C-peptide levels, all elevated
- Anterior pituitary tumor - prolactin and insulin-like growth factor-1 (IGF-1), elevated
- Imaging studies
- Pancreatic tumors - abdominal MRI/CT
- Anterior pituitary tumors - cranial MRI
- Indications for genetic testing
- Confirm a clinical diagnosis of MEN 1 in an individual with at least two of the three following endocrine tumors: parathyroid, pituitary, GEP
- The likelihood of detecting a germline MEN1 mutation increases in individuals with more main tumors
- Individuals with a single MEN 1 related tumor, without family history of the condition, rarely have germline MEN1 mutations
- Approximately 20-55% of families with familial isolated hyperparathyroidism (FIHP) have a germline MEN1 mutation
- Presymptomatic testing of at-risk family members when a specific MEN1 mutation has been identified in an affected relative
- Disease Monitoring
- Periodic screening for MEN 1 associated endocrine tumors beginning in early childhood and continuing for life
- Risk for malignant progression of MEN 1 associated tumors depends on tumor type
MEN 2
- Diagnosis
- MEN 2A and 2B
- Typical tumor presentation and family history
- Refer to testing algorithms for pheochromocytoma, hypercalcemia (hyperparathyroidism) and thyroid nodules
- RET mutation analysis to confirm a clinical diagnosis and allow for presymptomatic testing of family members
- FMTC
- Established by family history of MTC in multiple generations without presence of pheochromocytoma or parathyroid adenoma/hyperplasia
- RET mutation analysis to confirm a clinical diagnosis and allow for presymptomatic testing of family members
- Disease Monitoring
- Calcitonin stimulation test for residual or recurrent MTC
- PTH for parathyroid tumors and individuals who have undergone thyroidectomy with autotransplantation of parathyroids
- Chromogranin A neuroendocrine marker testing for pheochromocytoma
Algorithm(s)
PDF algorithm(s) available at www.arupconsult.com.
Hypercalcemia Testing Algorithm
Pheochromocytoma Testing Algorithm
Thyroid Nodules Testing Algorithm
| Tests |  |
Tests generally appear in the order most useful for common clinical situations
| Test name: Multiple Endocrine Neoplasia Type 2 (MEN2), RET Gene Mutations by Sequencing
|
| ARUP #: 0051390 |
| Methodology: Polymerase Chain Reaction/Sequencing
|
Use: Rule out MEN 2 for individuals with medullary thyroid carcinoma Diagnose MEN 2 |
| Limitations: Mutations in RET gene introns, regulatory regions, and exons not targeted for sequencing are not detected |
| Test name: Multiple Endocrine Neoplasia Type 2B (MEN2B), RET Gene M918T & A883F Mutations
|
| ARUP #: 0051492 |
| Methodology: Polymerase Chain Reaction/Fluorescence Monitoring
|
Use: Confirm a clinical diagnosis of MEN 2B Pre-symptomatic testing for at-risk family members when a MEN 2B mutation (M918T or A883F) has been previously identified in an affected relative |
| Limitations: Mutations other than M918T and A883F will not be detected |
| Follow-up:
Recommend that patients negative for the M918T and A883F mutations have additional sequencing of exon 10-11, 13-16 of the RET protooncogene
|
| Test name: Immunohistochemistry Stain Offering
|
| ARUP #: arup005 |
| Methodology: Immunohistochemistry
|
| Use: For fixed tissue samples, consultative services as well as immunohistochemical staining for CAM5, chromogranin A, 2 (LMW), PGP9.5, parathyroid hormone and synaptophysin are available |
| Test name: Custom PCR and Sequencing
|
| ARUP #: 0050358 |
| Methodology: Polymerase Chain Reaction*/DNA Sequencing
|
| Use: Pre-symptomatic testing of at-risk family members when a specific RET mutation has been identified in an affected relative |
| Limitations: Mutations other than the familial mutation will not be detected |
Additional Tests Available
| Test name: Calcitonin
|
| ARUP #: 0070006 |
| Methodology: Chemiluminescent Immunoassay
|
| Comments: |
| Test name: Calcium, Ionized, Serum
|
| ARUP #: 0020135 |
| Methodology: Ion-Selective Electrode/pH-Electrode
|
| Comments: |
| Test name: Calcium, Urine
|
| ARUP #: 0020472 |
| Methodology: Spectrophotometry
|
| Comments: |
| Test name: Parathyroid Hormone, Intact with Calcium
|
| ARUP #: 0070172 |
| Methodology: Electrochemiluminescent Immunoassay
|
| Comments: |
| Test name: Calcium, Ionized, Whole Blood
|
| ARUP #: 0020140 |
| Methodology: Ion-Selective Electrode/pH-Electrode
|
| Comments: |
| Test name: Calcium, Serum or Plasma
|
| ARUP #: 0020027 |
| Methodology: Spectrophotometry
|
| Comments: |
| Test name: Parathyroid Hormone, CAP
|
| ARUP #: 0095611 |
| Methodology: Immunoradiometric Assay
|
| Comments: |
| Test name: Parathyroid Hormone, Intact
|
| ARUP #: 0070346 |
| Methodology: Electrochemiluminescent Immunoassay
|
| Comments: |
| Test name: Parathyroid Hormone-Related Peptide (PTHrP)
|
| ARUP #: 0093014 |
| Methodology: Immunoradiometric Assay
|
| Comments: |
Additional Information
Refer to Multiple Endocrine Neoplasias topic at www.arupconsult.com for link to laboratories performing MEN 1 testing
Refer to MEN topic at www.arupconsult.com for the disease database of sequence variations
References
General References
Anlauf M, Perren A, Kloppel G. Endocrine precursor lesions and microadenomas of the duodenum and pancreas with and without MEN1: criteria, molecular concepts and clinical significance. Pathobiology.
2007;
74(
5):
279-284.
Blackburn M, Diamond T. Primary hyperparathyroidism and familial hyperparathyroid syndromes. Aust Fam Physician.
2007;
36(
12):
1029-1033.
Boikos SA, Stratakis CA. Molecular mechanisms of medullary thyroid carcinoma: current approaches in diagnosis and treatment. Histol Histopathol.
2008;
23(
1):
109-116.
Bordi C. Multiple endocrine neoplasia (MEN)-associated tumours. Dig Liver Dis.
2004;
36 Suppl 1:
S31-S34.
Busygina V, Bale AE. Multiple endocrine neoplasia type 1 (MEN1) as a cancer predisposition syndrome: clues into the mechanisms of MEN1-related carcinogenesis. Yale J Biol Med.
2006;
79(
3-4):
105-114.
Doherty GM. Multiple endocrine neoplasia type 1. J Surg Oncol.
2005;
89(
3):
143-150.
Duerr EM, Chung DC. Molecular genetics of neuroendocrine tumors. Best Pract Res Clin Endocrinol Metab.
2007;
21(
1):
1-14.
GeneTests: Multiple Endocrine Neoplasia. (Accessed 25 Feb 2008) Kouvaraki MA, Shapiro SE, Cote GJ, Lee JE, Yao JC, Waguespack SG, Gagel RF, Evans DB, Perrier ND. Management of pancreatic endocrine tumors in multiple endocrine neoplasia type 1. World J Surg.
2006;
30(
5):
643-653.
Lakhani VT, You YN, Wells SA. The multiple endocrine neoplasia syndromes. Annu Rev Med.
2007;
58:
253-265.
Marini F, Falchetti A, Del Monte F, Carbonell Sala S, Tognarini I, Luzi E, Brandi ML. Multiple endocrine neoplasia type 2. Orphanet J Rare Dis.
2006;
1:
45-.
Neumann HP, Vortmeyer A, Schmidt D, Werner M, Erlic Z, Cascon A, Bausch B, Januszewicz A, Eng C. Evidence of MEN-2 in the original description of classic pheochromocytoma. N Engl J Med.
2007;
357(
13):
1311-1315.
Peczkowska M, Januszewicz A. Multiple endocrine neoplasia type 2. Fam Cancer.
2005;
4(
1):
25-36.
References from the ARUP Institute for Clinical and Experimental Pathology Research®
Margraf RL, Mao R, Highsmith WE, Holtegaard LM, Wittwer CT. RET proto-oncogene genotyping using unlabeled probes, the masking technique, and amplicon high-resolution melting analysis. J Mol Diagn.
2007;
9(
2):
184-196.
Medical Reviewers
Lyon, Elaine, Ph.D. Medical Director, Molecular Genetics at ARUP Laboratories; Associate Professor, Pathology, University of Utah
Mao, Rong , M.D. Co-Medical Director, Molecular Genetics at ARUP Laboratories; Assistant Professor, Pathology, University of Utah
Meikle, A. Wayne, M.D. Medical Director, RIA and Endocrinology at ARUP Laboratories; Professor of Internal Medicine and Pathology, University of Utah
Roberts, William L. , M.D., Ph.D. Medical Director, Automated Core Laboratory at ARUP Laboratories; Professor, Pathology, University of Utah
Comprehensive Review: May 2008
Last Update: July 2008
