Multiple Endocrine Neoplasias

Indications for Testing

• MEN1
  • Diagnostic testing for patients with clinical or biochemical evidence of MEN1
  • Presymptomatic genetic testing of at-risk family members (advised when a specific MEN1 gene variant has been identified in an affected relative)
• MEN2A or MEN2B
  • Presence of two or more characteristic tumors (medullary thyroid carcinoma [MTC] and/or pheochromocytoma; parathyroid adenoma or hyperplasia in MEN2A) in individual or close relatives 
  • Additional clinical features suggestive of MEN2B include distinctive facies with large lips, mucosal neuromas on the lips/tongue, gastrointestinal tract ganglioneuromatosis, and marfanoid habitus.
• FMTC (variant of MEN2A)
  • Family history of FMTC in multiple relatives without the presence of pheochromocytoma or parathyroid adenoma/hyperplasia
• MEN4
  • Parathyroid tumors
  • Pituitary adenomas
  • Other MEN1-related tumors are possible (e.g., pancreatic neuroendocrine tumors [PanNETs])

Laboratory Testing

Initial Testing and Surveillance

Multiple Endocrine Neoplasia Type 1

In certain clinical scenarios, biochemical testing may identify the presence of tumors that characterize MEN1. For carcinoid tumors, 24-hour urine or plasma 5-hydroxyindoleacetic acid (5-HIAA) testing may be indicated ; additional testing (i.e., adrenocorticotropic hormone [ACTH], gastrin, insulin, somatostatin, pancreatic polypeptide, serotonin, histamine, or tachykinins concentrations) depends on the tumor location. 

In cases of parathyroid multiglandular involvement, calcium and parathyroid hormone (PTH) measurement should be considered in individuals 5 years or older following an initial diagnosis of MEN1. ^,  In cases of insulinoma and other pancreatic tumors, levels of chromogranin A, glucagon, serum insulin, and C-peptide may suggest disease.  Vasoactive intestinal peptide (VIP) testing is useful for identifying vasoactive intestinal polypeptide-secreting tumors (VIPomas).  Prolactin and insulin-like growth factor-1 (IGF-1) can be indicated biochemical screening tests for anterior pituitary tumors; additional testing is available based on symptoms, although importantly, magnetic resonance imaging (MRI) is the most sensitive approach for identifying these tumors.  Gastrin and gastric output measures may show irregularities that suggest gastrinoma, usually in patients older than 20 years.  In MEN2, measurement of metanephrines can be suggestive of pheochromocytoma. 

Refer to the ARUP Consult Neuroendocrine Tumors topic for more information about biochemical screening for carcinoid tumors and NETs (i.e., gastrinomas, insulinomas, glucagonomas, VIPomas, somatostatinomas, pheochromocytomas) of relevance and significance in MEN1.

Periodic screening for MEN1-associated endocrine tumors should begin in early childhood and continue for life. ^, ,  Refer to the MEN1 Biochemical Surveillance Recommendations table for more information.

For individuals with a 50% risk of developing MEN1 (i.e., those with an affected parent), surveillance should consist of measurement of serum prolactin concentrations annually beginning at 5 years of age, calcium and PTH concentrations annually beginning at 10 years of age, and serum gastrin concentrations when fasting if diarrhea or reflux are present, beginning at 20 years of age. 

Multiple Endocrine Neoplasia Types 2A and 2B

Elevated plasma calcitonin concentrations can suggest MTC or C-cell hyperplasia (CCH), a precursor to MTC.  Plasma calcitonin concentrations should be measured before intravenous calcium administration, with subsequent measurements 2 minutes and 5 minutes after initial measurement.  In individuals with MEN2A, MEN2B, or FMTC, plasma-free metanephrines or 24-hour urine for fractionated metanephrines should be measured before any surgery to evaluate for functioning pheochromocytoma. Fractionated urinary or plasma metanephrines have been suggested by some to differentiate false-positive results, which can occur.  Biochemical evidence of parathyroid abnormalities includes elevated PTH concurrent with elevated serum calcium levels. 

Periodic screening for MEN2-associated manifestations should begin early in life. ^,  Refer to the MEN2 Biochemical Surveillance Recommendations table for more information.

Multiple Endocrine Neoplasia Type 4

Biochemical surveillance should start at 25 years of age for individuals at risk for MEN4.  In alternate years, screening should include serum gastrin and calcium testing, and every 3-5 years, screening should include prolactin and IGF-1 measurement.  Screening should also include imaging as recommended in guidelines. 

Diagnosis

Multiple Endocrine Neoplasia Type 1

Genetic testing is the definitive diagnostic test for MEN1, and detecting a pathogenic/likely pathogenic (P/LP) variant in the MEN1 gene confirms the diagnosis. The likelihood of detecting a germline MEN1 variant increases in proportion to the number of characteristic tumors identified in the patient.  MEN1 P/LP variants are seldom detected in patients with a single MEN1-associated tumor and negative family history. Up to half of families with familial isolated hyperparathyroidism (FIHP) have germline MEN1 pathogenic variants. 

Guidelines recommend ordering genetic testing for any individual with a clinical diagnosis of MEN1, individuals with clinical findings or features of MEN1, including two or more MEN1-associated tumors or other manifestations that are suspicious for the diagnosis (such as primary hyperparathyroidism [PHPT] before 30 years of age), and individuals with close family member(s) with a MEN1 P/LP variant.  In sporadic cases that fail to meet current guidelines-based criteria, consideration may be given to performing MEN1 germline genetic testing when there is a NET of the stomach, lungs, or thymus in an individual younger than 40 years, there is presence of a pancreatic NET, or a MEN1 P/LP variant is identified by somatic tumor testing. 

For cases of familial MEN1, genetic testing should occur before biochemical testing and/or imaging to reduce testing and costs that may be unnecessary.  Because evidence of disease can manifest early in life, genetic testing is recommended in at-risk individuals at age 5-10 years.  If a pathogenic MEN1 variant has been identified in a family member, genetic testing in at-risk individuals should specifically target the familial variant. Because there are overlapping conditions with similar tumors and features, MEN1 genetic testing can be performed as part of a multigene panel.  For NETs, an appropriate gene testing panel may include AP2S1, CASR, CDC73, CDKN1B (for MEN4), GCM2, GNA11, MAX (for MEN5), MEN1, and RET. 

Comprehensive genomic sequencing (i.e., exome sequencing or whole genome sequencing) may be appropriate when phenotypic overlap exists with other tumor-predisposing conditions that make selection of single gene or targeted gene panel testing difficult. 

Multiple Endocrine Neoplasia Types 2A and 2B

The diagnosis of MEN2 can be made using clinical criteria. Genetic testing for RET P/LP variants is recommended as a confirmatory diagnostic test. Surveillance and treatment recommendations are specific to the genetic variant(s) identified; as such, genetic testing is recommended for all at-risk individuals.  Identifying the causative variant(s) also enables testing of family members to identify additional individuals who should receive surveillance.  Genetic testing may use a targeted gene test or multigene panel. When MEN2B is suspected, RET pathogenic variants p.Met918Thr and p.Ala883Phe can be specifically tested for, as disease-causing alterations in these genes explain virtually all cases. 

FMTC is now considered to be a variant of MEN2A. In cases of suspected FMTC, RET variant analysis can be performed to confirm a clinical diagnosis and allow for presymptomatic testing of family members. Refer to the MEN2 Biochemical Surveillance Recommendations table for more information.

• For additional information, refer to the ARUP Consult Pheochromocytoma - Paraganglioma Biochemical Testing Algorithm and Thyroid Nodules Testing Algorithm.
• For an in-depth summary of guidelines-based laboratory testing recommendations for pheochromocytoma and its association with MEN2, refer to the ARUP Consult Pheochromocytoma - Paraganglioma topic.

Multiple Endocrine Neoplasia Type 4

The approach for definitive diagnosis of MEN4 is molecular genetic testing targeting the CDKN1B gene. A confirmed P/LP variant in the gene is diagnostic of MEN4.