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NCI/PDQ^® Health professionals: Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)

National Cancer Institute
Last Modified: December 13, 2012

TABLE OF CONTENTS

• Introduction

• Multiple Endocrine Neoplasia Type 1
  • Clinical Description
  • Parathyroid Tumors and PHPT
  • PNETs
  • Pituitary Tumors
  • Other MEN1-Associated Tumors
  • Making the Diagnosis of MEN1
  • Molecular Genetics of MEN1
  • Genetic Testing and Differential Diagnosis
  • Surveillance
  • Interventions
    • Parathyroid tumors

• Multiple Endocrine Neoplasia Type 2
  • Clinical Description
  • MTC and C-Cell Hyperplasia
    • Natural history of MTC
    • Hereditary MTC
  • Pheochromocytoma
  • Primary Hyperparathyroidism (PHPT)
  • Clinical Diagnosis of MEN2 Subtypes
    • MEN2A
    • Familial medullary thyroid carcinoma (FMTC)
    • MEN2B
  • Genetically Related Disorder
    • Hirschsprung disease (HSCR)
  • Molecular Genetics of MEN2
    • Genetic testing
  • Genotype-Phenotype Correlations and Risk Stratification
  • Interventions
    • Risk-reducing thyroidectomy
    • Screening of at-risk individuals for pheochromocytoma
    • Screening of at-risk individuals for hyperparathyroidism
    • Screening of at-risk individuals in kindreds without an identifiable
    • Treatment for those with MTC
    • Treatment for those with pheochromocytoma
    • Treatment for those with hyperparathyroidism
  • Genetic Counseling
    • Mode of inheritance
    • Psychosocial issues

• Changes to This Summary (12/13/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
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Introduction

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[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]

There are several hereditary syndromes that involve endocrine or neuroendocrine glands, such as multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2 (MEN2), pheochromocytoma, paraganglioma, and von Hippel-Lindau syndrome. This summary currently focuses on MEN1 and MEN2. Additional sections are in progress.

The term multiple endocrine neoplasia is used to describe a group of heritable tumors of endocrine tissues that may be benign or malignant. They are typicially classified into two main categories: MEN1 and MEN2. The tumors usually manifest themselves by overproduction of hormones, tumor growth, or both.

Comprising varying combinations of more than 20 endocrine and nonendocrine tumors, MEN1 may be a difficult syndrome to define clinically. In general, however, MEN1 is characterized by tumors of the parathyroids, pancreas, and pituitary gland. This syndrome may also include carcinoid tumors, adrenocortical tumors, and nonendocrine tumors, such as facial angiofibromas, collagenomas, lipomas, meningiomas, ependymomas, and leiomyomas.

MEN1 syndrome, also known as Wermer syndrome, results from a mutation in the MEN1 gene. It has a prevalence of about 1 in 30,000 individuals. 1

MEN2 is caused by a mutation in the RET proto-oncogene. Historically, MEN2 has been further stratified into the following three subtypes based on the presence or absence of certain endocrine tumors in the individual or family:

• MEN2A (OMIM).
• Familial medullary thyroid carcinoma (FMTC) (OMIM).
• MEN2B (OMIM).

All three subtypes of MEN2 (MEN2A, FMTC, and MEN2B) impart a high risk of developing medullary thyroid cancer (MTC). MEN2A has an increased risk of pheochromocytoma and parathyroid adenoma and/or hyperplasia. MEN2B has an increased risk of pheochromocytoma and includes additional clinical features, such as mucosal neuromas of the lips and tongue, distinctive faces with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and an asthenic Marfanoid body habitus. FMTC has been defined as the presence of at least four individuals with MTC without any other signs or symptoms of pheochromocytoma or hyperparathyroidism in the proband or other family members. 2

Some families previously classified as having FMTC will go on to develop one or more of the MEN2A-related tumors, suggesting that FMTC is simply a milder variant of MEN2A. Offspring of affected individuals have a 50% chance of inheriting the RET gene mutation.

The age at onset of MTC is different for each subtype of MEN2. MTC typically occurs during early childhood in patients with MEN2B, predominantly during early adulthood in patients with MEN2A, and during middle-age in patients with FMTC.

Germline DNA-based testing of the RET gene (chromosomal region 10q11.2) identifies disease-causing mutations in more than 95% of individuals with MEN2A and MEN2B and in about 88% of individuals with FMTC. 3

The prevalence of MEN2 has been estimated to be between 1 in 30,000 4 5 and 1 in 35,000 individuals. 6 The vast majority of MEN2 cases are MEN2A. In the United States, an estimated 423 cases of MEN2-related MTC are diagnosed per year. 7

References:

1. Agarwal SK, Ozawa A, Mateo CM, et al.: The MEN1 gene and pituitary tumours. Horm Res 71 (Suppl 2): 131-8, 2009. [PUBMED Abstract]
2. Eng C: Seminars in medicine of the Beth Israel Hospital, Boston. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung's disease. N Engl J Med 335 (13): 943-51, 1996. [PUBMED Abstract]
3. Brandi ML, Gagel RF, Angeli A, et al.: Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86 (12): 5658-71, 2001. [PUBMED Abstract]
4. Mulligan LM, Kwok JB, Healey CS, et al.: Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363 (6428): 458-60, 1993. [PUBMED Abstract]
5. Donis-Keller H, Dou S, Chi D, et al.: Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 2 (7): 851-6, 1993. [PUBMED Abstract]
6. DeLellis RA, Lloyd RV, Heitz PU, et al., eds.: Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC Press, 2004. World Health Organization classification of tumours, vol. 8. [PUBMED Abstract]
7. American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online [PUBMED Abstract]

Multiple Endocrine Neoplasia Type 1

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Clinical Description

Multiple endocrine neoplasia type 1 (MEN1) (OMIM) is an autosomal dominant syndrome with an estimated incidence in the general population of 1 to 2 per 100,000. 1 The major endocrine features of MEN1 include the following:

• Parathyroid tumors and primary hyperparathyroidism (PHPT).
• Pancreatic neuroendocrine tumors (PNETs) of the duodenum.
• Pituitary tumors.

A diagnosis of MEN1 is made when an individual has two of these three major endocrine tumors. Familial MEN1 is defined as at least one MEN1 case plus at least one first-degree relative with one of these three tumors. 2 3 4 The age-related penetrance of MEN1 is 45% at age 30 years, 82% at age 50 years, and 96% at age 70 years. 2 5

Parathyroid Tumors and PHPT

The most common features and often the first presenting signs of MEN1 are parathyroid tumors, which result in PHPT. These tumors occur in 80% to 100% of patients by age 50 years. 2 6 7 8 Unlike the solitary adenoma seen in sporadic cases, MEN1-associated parathyroid tumors are typically multiglandular and often hyperplastic. 1 The average age at onset of PHPT in MEN1 is 20 to 25 years, in contrast to that in the general population, which is typically age 50 to 59 years. Parathyroid carcinoma in MEN1 is rare but has been described. 9 10 11 12

Individuals with MEN1-associated PHPT will have elevated parathyroid hormone (PTH) and calcium levels in the blood. The clinical manifestations of PHPT are mainly the result of hypercalcemia. Mild hypercalcemia may go undetected and have few or no symptoms. More severe hypercalcemia can result in the following:

• Constipation.
• Nausea and vomiting.
• Dehydration
• Decreased appetite and abdominal pain.
• Anorexia.
• Diuresis.
• Kidney stones.
• Increased bone resorption with resultant increased risk of bone fracture.
• Lethargy.
• Depression.
• Confusion.
• Hypertension.
• Shortened QT interval.

Since MEN1-associated hypercalcemia is directly related to the presence of parathyroid tumors, surgical removal of these tumors may result in normalization of calcium and PTH levels and relief of symptoms; however, high recurrence rates following surgery have been reported in some series. 13 14 15 (Refer to the Interventions section of this summary for more information.)

PNETs

PNETs of the duodenum, the second most common endocrine manifestation in MEN1, occur in 30% to 80% of patients by age 40 years. 2 8 Gastrinomas represent 50% of the gastrointestinal neuroendocrine tumors in MEN1 and are the major cause of morbidity and mortality in MEN1 patients. 2 13 Gastrinomas are usually multicentric, with small (<0.5 cm) foci throughout the duodenum. 16 Most result in peptic ulcer disease (Zollinger-Ellison syndrome), and half are malignant at the time of diagnosis. 13 16 17

Other functioning PNETs seen in MEN1 include the following:

• Insulinomas (10%20% penetrance).
• Vasoactive intestinal peptide tumors (~1% penetrance).
• Glucagonomas (1%5% penetrance).
• Somatistatinomas (~1% penetrance).

Nonfunctioning PNETs were originally thought to be relatively uncommon tumors in individuals with MEN1, with early penetrance estimates of 20%. 18 19 With the advent of genetic testing and improved imaging techniques, however, their prevalence in MEN1 has increased, with one study showing a frequency as high as 55% by age 39 years in MEN1 mutation carriers undergoing prospective endoscopic ultrasound of the pancreas. 20 21 These tumors can be metastatic. One study of 108 MEN1 mutation carriers with nonfunctioning PNETs showed a positive correlation between tumor size and rate of metastasis and death, with tumors larger than 2 cm having significantly higher rates of metastasis than those smaller than 2 cm. 22 (Refer to the Molecular Genetics of MEN1 section for more information about MEN1 gene mutations.)

Pituitary Tumors

Approximately 15% to 50% of MEN1 patients will develop a pituitary tumor. 2 8 Two-thirds are microadenomas (<1.0 cm in diameter), and the majority are prolactin-secreting. 23 Other functioning pituitary tumors can include somatotropinomas and corticotropinomas.

Other MEN1-Associated Tumors

Other manifestations of MEN1 include carcinoids of the foregut (5%10% of MEN1 patients). These are typically bronchial or thymic and are sometimes gastric. Skin lesions are also common and can include facial angiofibromas (up to 80% of MEN1 patients) and collagenomas (~75% of MEN1 patients). 24 Lipomas (~30% of MEN1 patients) and adrenal cortical lesions (up to 50% of MEN1 patients), including cortical adenomas, diffuse or nodular hyperplasia, or rarely, carcinoma are also common. 25 26 27 The following manifestations have also been reported: 28 29 30

• Thyroid adenomas.
• Pheochromocytoma.
• Spinal ependymoma.
• Meningioma.
• Leiomyoma (e.g., esophageal, lung, and uterine).

Making the Diagnosis of MEN1

MEN1 is often difficult to diagnose in the absence of a significant family history or a positive genetic test for a mutation in the MEN1 gene. One study of 560 individuals with MEN1 showed a significant delay between the time of the first presenting symptom and the diagnosis of MEN1. 31 This may be because some presenting symptoms of MEN1-associated tumors, such as amenorrhea, peptic ulcers, hypoglycemia, and nephrolithiasis, are not specific to MEN1.

Furthermore, identification of an MEN1-associated tumor is not sufficient to make the clinical diagnosis of MEN1 and may not trigger a referral to an endocrinologist. Other studies have shown similar findings, with median time between first presenting symptom and diagnosis of MEN1 ranging from 7.6 years to 12 years. 5 26 Genetic testing alleviates some of this delay. Several studies have shown statistically significant differences in the age at MEN1 diagnosis between probands and their family members. In one study, clinically symptomatic probands were diagnosed with MEN1 at a mean age of 47.5 years (standard deviation [SD] +/- 13.5 years), while family members were diagnosed at a mean age of 38.5 years (SD +/- 15.4 years; P < .001). 31 In another study of 154 individuals with MEN1, probands were diagnosed at a mean age of 39.5 years (range: 1874 years), compared with a mean age 27 years (range: 1456 years; P < .05) in family members diagnosed by predictive genetic testing. 32 These findings underscore the importance of increased awareness of the signs and symptoms of MEN1-related tumors and the constellation of findings necessary to suspect the diagnosis. It also highlights the importance of genetic counseling and testing and communication among family members once a diagnosis of MEN1 is made.

Since many of the tumors in MEN1 are underdianosed or misdiagnosed, identifying an MEN1 gene mutation in the proband early in the disease process can allow for early detection and treatment of tumors and earlier identification of at-risk family members. Many studies have been performed to determine the prevalence of MEN1 gene mutations among patients with apparently sporadic MEN1-related tumors. For example, approximately one-third of patients with Zollinger-Ellison syndrome will carry an MEN1 mutation. 33 34 In individuals with apparently isolated PHPT or pituitary adenomas, the mutation prevalence is lower, on the order of 2% to 5%, 23 35 36 but the prevalence is higher in individuals diagnosed with these tumors before age 30 years. Some authors suggest genetic testing for mutations in MEN1 if one of the following conditions is present: 37 38

• Gastrinoma at any age.
• Multifocal pancreatic islet cell tumors at any age.
• Parathyroid hyperplasia/adenomas before age 30 or 40 years.
• Multiglandular parathyroid adenomas/hyperplasia or recurrent PHPT.
• Presence of one of the three main MEN1 tumors plus one of the less common tumors/findings.
• Presence of two or more features (e.g., adrenal adenomas and carcinoid tumor).

Molecular Genetics of MEN1

The MEN1 gene is located on chromosome 11q13 and encodes the protein menin. 3 39 40 Over 1,300 mutations have been identified in the MEN1 gene to date, and these are scattered across the entire coding region. 41 The majority (~65%) of these are nonsense or frameshift mutations. The remainder are missense mutations (20%), which lead to expression of an altered protein, splice-site mutations (9%), or partial- or whole-gene deletions (1%4%). There is currently no evidence of genotype-phenotype correlations, and inter- and intra-familial variability is common. 42 43

Genetic Testing and Differential Diagnosis

Genetic testing for MEN1 mutations is recommended for individuals meeting clinical diagnostic criteria and may be considered in a subset of the less common tumors. (Refer to the bulleted list in the Making the diagnosis of MEN1 section of this summary for more information.) For individuals meeting diagnostic criteria, the mutation detection rate is approximately 75% to 90% 42 44 but may be lower in simplex cases. 45. Individuals with isolated parathyroid and/or pituitary tumors are less likely to have an identifiable mutation than those with pancreatic tumors. 45. The majority of commercial laboratories currently offering MEN1 testing use DNA sequencing as their primary method. 46 Several offer additional analysis for partial- or whole-gene deletion and/or duplication, although such mutations are rare and deletion/duplication testing is often reserved for individuals or families in which there is a very high clinical suspicion.

Genetic testing for MEN1 mutations can be used to distinguish between MEN1 and other forms of hereditary hyperparathyroidism, such as familial isolated hyperparathyroidism (FIHP) (OMIM), hyperparathyroidism-jaw tumor syndrome (HPT-JT), and familial hypocalciuric hypercalcemia (FHH). [Note: The hyperparathyroidism in FHH is not primary hyperparathyroidism, which is seen in MEN1, HPT-JT and FIHP.] HPT-JT, which is caused by germline mutations in the HRPT2 gene, is associated with primary HPT, ossifying lesions of the maxilla and mandible, and renal lesions, usually bilateral renal cysts, hamartomas, and in some cases, Wilms tumor. 47 48 Unlike MEN1, HPT-JT is associated with an increased risk of parathyroid carcinoma. 49 FIHP, as its name suggests, is characterized by isolated primary HPT with no additional endocrine features; in some families, FIHP is the initial diagnosis of what later develops into MEN1, HPT-JT, or FHH. 50 51 52 Approximately 20% of families with a clinical diagnosis of FIHP carry germline MEN1 mutations. 51 53 54 Mutations in the calcium-sensing receptor gene (CaSR) cause FHH, which can closely mimic the HPT in MEN1. Distinguishing between MEN1 and FHH can be critical in terms of management, as removal of the parathyroid glands in FHH does not correct the patient's HPT and results in unnecessary surgery without relief of symptoms. 55 Given the differential risks and management of these conditions and the increased risk of parathyroid carcinoma in HPT-JT, genetic diagnosis in a patient presenting with early-onset HPT may play an important role in the management of these patients and their families.

Surveillance

Screening and surveillance for MEN1 may employ a combination of biochemical tests and imaging. Available recommendations are summarized in Table 1. 4 37

Table 1. Practice Guidelines for Surveillance of Multiple Endocrine Neoplasia Type 1 (MEN1)^a

^aAdapted from Brandi et al. and Thakker et al. .^bThe recommendations for abdominal imaging differ between two published guidelines for the diagnosis and management of MEN1. There is weak evidence at this time to support annual imaging before age 10 years. Imaging before age 10 years does identify disease in a high proportion of patients, but it is not clear whether this impacts prognosis.

Biochemical Test or Procedure	Condition Screened For	Age Screening Initiated (y)	Frequency
Serum prolactin and/or insulin-like growth factor 1	Pituitary tumors	5	Every 1 y
Fasting total serum calcium and/or ionized calcium and PTH	Parathyroid tumors and PHPT	8	Every 1 y
Fasting serum gastrin	PNETs	20	Every 1 y
Chromogranin A, pancreatic polypeptide, glucagon, and vasointestinal polypeptide	PNETs	<10	Every 1 y
Fasting glucose and insulin	PNETs	5	Every 1 y
Brain MRI	Pituitary tumors	5	Every 35 y based on biochemical results
Abdominal CT or MRIb	PNETs	20	Every 35 y based on biochemical results
Abdominal CT, MRI, or endoscopic USb	PNETs	<10	Every 1 y
CT = computed tomography; MRI = magnetic resonance imaging; PHPT = primary hyperparathyroidism; PNETs = pancreatic neuroendocrine tumors; PTH = parathyroid hormone; US = ultrasound.
4 37
4 37 20 56

Interventions

Surgical management of MEN1 is complex and controversial, given the multifocal and multiglandular nature of the disease and the high risk of tumor recurrence even after surgery. Establishing the diagnosis of MEN1 prior to making surgical decisions and referring affected individuals to a surgeon with experience in treating MEN1 can be critical in preventing unnecessary surgeries or inappropriate surgical approaches.

Parathyroid tumors

Once evidence of parathyroid disease is established biochemically, the recommended course of action is surgical removal of the parathyroids. The timing and the extent of surgery, however, remain controversial. 57 Some groups reserve surgical intervention for symptomatic patients, with continued annual biochemical screening for those who are asymptomatic. Once surgery is necessary, subtotal parathyroidectomy (removal of 33.5 glands) is often suggested as the initial treatment. However, the rate of recurrence is quite high (55%66%), and reoperation is often necessary. 13 14 15 Another study has shown that bilaterial thymectomy reduces the likelihood of recurrence. 58 Total parathyroidectomy with autotransplantation of parathyroid tissue to the forearm is also an option. A benefit of this approach is the easier removal of recurrent disease from the forearm than from the neck. Although the likelihood of recurrence is lowered by more extensive surgery, this must be weighed against the risk of rendering the patient hypoparathyroid. 58 Management of persistent hypoparathyroidism with oral calcitriol is necessary.

References:

1. Chandrasekharappa SC, Teh BT: Clinical and molecular aspects of multiple endocrine neoplasia type 1. Front Horm Res 28: 50-80, 2001. [PUBMED Abstract]
2. Trump D, Farren B, Wooding C, et al.: Clinical studies of multiple endocrine neoplasia type 1 (MEN1) QJM 89 (9): 653-69, 1996. [PUBMED Abstract]
3. Chandrasekharappa SC, Guru SC, Manickam P, et al.: Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276 (5311): 404-7, 1997. [PUBMED Abstract]
4. Brandi ML, Gagel RF, Angeli A, et al.: Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86 (12): 5658-71, 2001. [PUBMED Abstract]
5. Carty SE, Helm AK, Amico JA, et al.: The variable penetrance and spectrum of manifestations of multiple endocrine neoplasia type 1. Surgery 124 (6): 1106-13; discussion 1113-4, 1998. [PUBMED Abstract]
6. Benson L, Ljunghall S, Akerstrím G, et al.: Hyperparathyroidism presenting as the first lesion in multiple endocrine neoplasia type 1. Am J Med 82 (4): 731-7, 1987. [PUBMED Abstract]
7. Brandi ML, Marx SJ, Aurbach GD, et al.: Familial multiple endocrine neoplasia type I: a new look at pathophysiology. Endocr Rev 8 (4): 391-405, 1987. [PUBMED Abstract]
8. Thakker RV: Multiple endocrine neoplasia type 1. In: DeGroot LJ, Besser M, Burger HG, eds.: Endocrinology. Volume 3. 3rd ed. Philadelphia, Pa: WB Saunders Co, 1995, pp 2815-31. [PUBMED Abstract]
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13. Norton JA, Venzon DJ, Berna MJ, et al.: Prospective study of surgery for primary hyperparathyroidism (HPT) in multiple endocrine neoplasia-type 1 and Zollinger-Ellison syndrome: long-term outcome of a more virulent form of HPT. Ann Surg 247 (3): 501-10, 2008. [PUBMED Abstract]
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39. Larsson C, Skogseid B, Oberg K, et al.: Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature 332 (6159): 85-7, 1988. [PUBMED Abstract]
40. Bassett JH, Forbes SA, Pannett AA, et al.: Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet 62 (2): 232-44, 1998. [PUBMED Abstract]
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42. Giraud S, Zhang CX, Serova-Sinilnikova O, et al.: Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. Am J Hum Genet 63 (2): 455-67, 1998. [PUBMED Abstract]
43. Wautot V, Vercherat C, Lespinasse J, et al.: Germline mutation profile of MEN1 in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein. Hum Mutat 20 (1): 35-47, 2002. [PUBMED Abstract]
44. Agarwal SK, Kester MB, Debelenko LV, et al.: Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum Mol Genet 6 (7): 1169-75, 1997. [PUBMED Abstract]
45. Klein RD, Salih S, Bessoni J, et al.: Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med 7 (2): 131-8, 2005. [PUBMED Abstract]
46. GeneTests: Medical Genetics Information Resource [Database]. Seattle, WA: University of Washington, 2010. Available online. [PUBMED Abstract]
47. Teh BT, Farnebo F, Kristoffersson U, et al.: Autosomal dominant primary hyperparathyroidism and jaw tumor syndrome associated with renal hamartomas and cystic kidney disease: linkage to 1q21-q32 and loss of the wild type allele in renal hamartomas. J Clin Endocrinol Metab 81 (12): 4204-11, 1996. [PUBMED Abstract]
48. Carpten JD, Robbins CM, Villablanca A, et al.: HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet 32 (4): 676-80, 2002. [PUBMED Abstract]
49. Marx SJ: Multiple endocrine neoplasia type 1. In: Vogelstein B, Kinzler KW, eds.: The Genetic Basis of Human Cancer. New York, NY: McGraw-Hill, 1998, pp 489-506. [PUBMED Abstract]
50. Warner J, Epstein M, Sweet A, et al.: Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications. J Med Genet 41 (3): 155-60, 2004. [PUBMED Abstract]
51. Mizusawa N, Uchino S, Iwata T, et al.: Genetic analyses in patients with familial isolated hyperparathyroidism and hyperparathyroidism-jaw tumour syndrome. Clin Endocrinol (Oxf) 65 (1): 9-16, 2006. [PUBMED Abstract]
52. Cetani F, Pardi E, Borsari S, et al.: Molecular pathogenesis of primary hyperparathyroidism. J Endocrinol Invest 34 (7 Suppl): 35-9, 2011. [PUBMED Abstract]
53. Miedlich S, Lohmann T, Schneyer U, et al.: Familial isolated primary hyperparathyroidism--a multiple endocrine neoplasia type 1 variant? Eur J Endocrinol 145 (2): 155-60, 2001. [PUBMED Abstract]
54. Cetani F, Pardi E, Ambrogini E, et al.: Genetic analyses in familial isolated hyperparathyroidism: implication for clinical assessment and surgical management. Clin Endocrinol (Oxf) 64 (2): 146-52, 2006. [PUBMED Abstract]
55. Raue F, Frank-Raue K: Primary hyperparathyroidism--what the nephrologist should know--an update. Nephrol Dial Transplant 22 (3): 696-9, 2007. [PUBMED Abstract]
56. Langer P, Kann PH, Fendrich V, et al.: Prospective evaluation of imaging procedures for the detection of pancreaticoduodenal endocrine tumors in patients with multiple endocrine neoplasia type 1. World J Surg 28 (12): 1317-22, 2004. [PUBMED Abstract]
57. Hubbard JG, Sebag F, Maweja S, et al.: Primary hyperparathyroidism in MEN 1--how radical should surgery be? Langenbecks Arch Surg 386 (8): 553-7, 2002. [PUBMED Abstract]
58. Pieterman CR, van Hulsteijn LT, den Heijer M, et al.: Primary hyperparathyroidism in MEN1 patients: a cohort study with longterm follow-up on preferred surgical procedure and the relation with genotype. Ann Surg 255 (6): 1171-8, 2012. [PUBMED Abstract]

Multiple Endocrine Neoplasia Type 2

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Clinical Description

The endocrine disorders observed in multiple endocrine neoplasia type 2 (MEN2) are medullary thyroid cancer (MTC); its precursor, C-cell hyperplasia (CCH); pheochromocytoma; and parathyroid adenomas and/or hyperplasia. MEN2-associated MTC is often bilateral and/or multifocal and arises in the background of CCH. In contrast, sporadic MTC is typically unilateral and/or unifocal. Since approximately 75% to 80% of sporadic cases also have associated CCH, this histopathologic feature cannot be used as a predictor of familial disease. 1 Metastatic spread of MTC to regional lymph nodes (i.e., parathyroid, paratracheal, jugular chain, and upper mediastinum) or to distant sites, such as the liver, is common in patients who present with a palpable thyroid mass or diarrhea. 2 3 Although pheochromocytomas rarely metastasize, they can be clinically significant in cases of intractable hypertension or anesthesia-induced hypertensive crises. Parathyroid abnormalities in MEN2 can range from benign parathyroid adenomas or multigland hyperplasia to clinically evident hyperparathyroidism with hypercalcemia and renal stones.

Historically, individuals and families with MEN2 were classified into one of the following three clinical subtypes based on the presence or absence of certain endocrine tumors in the individual or family:

1. MEN2A (OMIM).
2. Familial medullary thyroid carcinoma (FMTC) (OMIM).
3. MEN2B (OMIM).

Current stratification is moving away from a solely phenotype-based classification and more toward one that is based on genotype (i.e., the mutation) and phenotype. 4

Clinical findings in the three MEN2 subtypes are summarized in Table 2. All three subtypes confer a high risk of MTC; MEN2A and MEN2B confer an increased risk of pheochromocytoma, and MEN2A has an increased risk of parathyroid hyperplasia and/or adenoma. Classifying a patient or family by MEN2 subtype is useful in determining prognosis and management.

Table 2. Percentage of Patients with Clinical Features of MEN2 by Subtype

^aPercentages based on observations in referral populations.

Subtype	Medullary Thyroid Carcinoma (%)a	Pheochromocytoma (%)a	Parathyroid Disease (%)a
MEN2A	95	50	1530
FMTC	~100	0	0
MEN2B	100	50	Uncommon
FMTC = familial medullary thyroid carcinoma; MEN2 = multiple endocrine neoplasia type 2.
5 6 7 8 9

MTC and C-Cell Hyperplasia

MTC originates in calcitonin-producing cells (C-cells) of the thyroid gland. MTC is diagnosed when nests of C-cells extend beyond the basement membrane and infiltrate and destroy thyroid follicles. CCH is diagnosed histologically by the presence of an increased number of diffusely scattered or clustered C-cells. 10 11 Individuals with RET (REarranged during Transfection) mutations and CCH are at substantially increased risk of progressing to MTC, although such progression is not universal. 12 13 MTC and CCH are suspected in the presence of an elevated plasma calcitonin concentration.

A study of 10,864 patients with nodular thyroid disease found 44 (1 of every 250) cases of MTC after stimulation with calcitonin, none of which were clinically suspected. Consequently, half of these patients had no evidence of MTC on fine-needle biopsy and thus might not have undergone surgery without the positive calcitonin stimulation test. 14 CCH associated with a positive calcitonin stimulation test occurs in about 5% of the general population; therefore, the plasma calcitonin responses to stimulation do not always distinguish CCH from small MTC and cannot always distinguish between carriers and noncarriers in an MEN2 family. 12 13 15

MTC accounts for 2% to 3% of new cases of thyroid cancer diagnosed annually in the United States, 16 although this figure may be an underrepresentation of true incidence because of changes in diagnostic techniques. The total number of new cases of MTC diagnosed annually in the United States is between 1,000 and 1,200, about 75% of which are sporadic (i.e., they occur in the absence of a family history of either MTC or other endocrine abnormalities seen in MEN2). The peak incidence of the sporadic form is in the fifth and sixth decades of life. 2 17 A study in the United Kingdom estimated the incidence of MTC at 20 to 25 new cases per year among a population of 55 million. 7

In the absence of a positive family history, MEN2 may be suspected when MTC occurs at an early age or is bilateral or multifocal. While small series of apparently sporadic MTC cases have suggested a higher prevalence of germline RET mutations, 18 19 larger series indicate a prevalence range of 1% to 7%. 20 21 Based on these data, it is widely recommended that RET gene mutation testing be performed for all cases of MTC. 22 23 24 25

Level of evidence (Screening): 3

Natural history of MTC

Thyroid cancer represents approximately 3% of new malignancies occurring annually in the United States, with an estimated 56,460 cancer diagnoses and 1,780 cancer deaths per year. 26 Of these cancer diagnoses, 2% to 3% are MTC. 16 27

MTC arises from the parafollicular calcitonin-secreting cells of the thyroid gland. MTC occurs in sporadic and familial forms and may be preceded by CCH, although CCH is a relatively common abnormality in middle-aged adults. 10 11

Average survival for MTC is lower than that for more common thyroid cancers (e.g., 83% 5-year survival for MTC compared with 90% to 94% 5-year survival for papillary and follicular thyroid cancer). 27 28 Survival is correlated with stage at diagnosis, and decreased survival in MTC can be accounted for in part by a high proportion of late-stage diagnosis. 27 28 29

In addition to early stage at diagnosis, other factors associated with improved survival in MTC include smaller tumor size, younger age at diagnosis, familial versus sporadic form, and diagnosis by biochemical screening (i.e., screening for calcitonin elevation) versus symptoms. 29 30 31 32

A Surveillance, Epidemiology, and End Results population-based study of 1,252 MTC patients found that survival varied by extent of local disease. For example, the 10-year survival rates ranged from 95.6% for those with disease confined to the thyroid gland to 40% for those with distant metastases. 30

Hereditary MTC

While the majority of MTC cases are sporadic, approximately 20% to 25% are hereditary because of mutations in the RET proto-oncogene. 33 34 35 Mutations in the RET gene cause MEN2, an autosomal dominant disorder associated with a high lifetime risk of MTC. Multiple endocrine neoplasia type 1 (MEN1) (OMIM) is an autosomal dominant endocrinopathy that is genetically and clinically distinct from MEN2; however, the similar nomenclature for MEN1 and MEN2 may cause confusion. There is no increased risk of thyroid cancer for MEN1. (Refer to the MEN1 section of this summary for more information.)

Pheochromocytoma

Pheochromocytomas (OMIM) arise from the catecholamine-producing chromaffin cells of the adrenal medulla. They are a relatively rare tumor and are suspected among patients with re