References

1. 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.
2. Carney JA, Stratakis CA: Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet 108 (2): 132-9, 2002. [PubMed: 11857563]
3. McWhinney SR, Pasini B, Stratakis CA, et al.: Familial gastrointestinal stromal tumors and germ-line mutations. N Engl J Med 357 (10): 1054-6, 2007. [PubMed: 17804857]
4. Pasini B, McWhinney SR, Bei T, et al.: Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet 16 (1): 79-88, 2008. [PubMed: 17667967]

Clinical Description

Multiple endocrine neoplasia type 1 (MEN1) (OMIM) is an autosomal dominant syndrome, with an estimated prevalence of about 1 in 30,000 individuals.[1] The major endocrine features of MEN1 include the following:

• Parathyroid tumors and primary hyperparathyroidism (PHPT).
• Duodenopancreatic neuroendocrine tumors (NETs).
• Pituitary tumors.

A clinical 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 (FDR) with one of these three tumors, or two FDRs with a germline pathogenic variant.[2-4]

Initial clinical presentation of symptoms typically occurs between the ages of 20 years and 30 years, although a diagnosis of MEN1 may not be confirmed for many more years. The age-related penetrance of MEN1 is 45% to 73% by age 30 years, 82% by age 50 years, and 96% by age 70 years.[2,5,6]

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.[2,7-9] Unlike the solitary adenoma seen in sporadic cases, MEN1-associated parathyroid tumors are typically multiglandular and often hyperplastic.[10] The mean 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.[11-14]

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.[15-17] (Refer to the Interventions section of this summary for more information.)

Duodenopancreatic NETs

Duodenopancreatic NETs are the second most common endocrine manifestation in MEN1, occurring in 30% to 80% of patients by age 40 years.[2,9]

Duodenopancreatic NETs seen in MEN1 include the following:

• Gastrinomas.
• Nonfunctioning NETs.
• Insulinomas.
• Vasoactive intestinal peptide tumors (VIPomas).
• Glucagonomas.
• Somatostatinomas.

Gastrinomas represent 50% of the gastrointestinal NETs in MEN1 and are the major cause of morbidity and mortality in MEN1 patients.[2,15] Gastrinomas are usually multicentric, with small (<0.5 cm) foci throughout the duodenum.[22] Most result in peptic ulcer disease (Zollinger-Ellison syndrome), and half are malignant at the time of diagnosis.[15,22,23]

Nonfunctioning duodenopancreatic NETs were originally thought to be relatively uncommon tumors in individuals with MEN1. 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 carriers of MEN1 pathogenic variants undergoing prospective endoscopic ultrasound of the pancreas.[20,24] These tumors can be metastatic. One study of 108 carriers of MEN1 pathogenic variants with nonfunctioning duodenopancreatic NETs 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.[25] (Refer to the Molecular Genetics of MEN1 section of this summary for more information about MEN1 gene pathogenic variants.)

Pituitary Tumors

Approximately 15% to 50% of MEN1 patients will develop a pituitary tumor.[2,9] Two-thirds are microadenomas (<1.0 cm in diameter), and the majority are prolactin-secreting.[26] Other pituitary tumors can include somatotropinomas and corticotropinomas, or they may be nonfunctioning.

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).[27] 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.[28-30] The following manifestations have also been reported:[31-33]

• 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 pathogenic variant 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.[34] This time lapse is likely 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. The median time between the first presenting symptom and diagnosis of MEN1 ranges from 7.6 years to 12 years.[5,29] 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).[34] In another study of 154 individuals with MEN1, probands were diagnosed at a mean age of 39.5 years (range: 18–74 years), compared with a mean age of 27 years (range: 14–56 years; P < .05) in family members diagnosed by predictive genetic testing.[35] Nonetheless, the lag time between the diagnosis of MEN1 in an index case and the diagnosis of MEN1 in family members can be significant, leading to increased morbidity and mortality.[36] This was demonstrated in a recent Dutch MEN1 Study Group analysis, which showed that 10% to 38% of non-index cases already had an MEN1-related manifestation at diagnosis; 4% of these individuals died of an MEN1-related cause that developed during or before the lag time. In family members, the majority of the morbidity related to lag time was due to metastatic duodenopancreatic NETs, pituitary macroadenomas, and multiple MEN1 manifestations.[36] 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. Figure 1 illustrates some of the challenges in identifying MEN1 in a family.

Figure 1. MEN1 pedigree. MEN1 can be very difficult to identify in a pedigree. The pedigree on the left was constructed based on self-report, and the pedigree on the right depicts the same family following a review of available medical records. This pedigree shows some of the features of a family with an MEN1 pathogenic variant across four generations, including affected family members with hyperparathyroidism, a pituitary adenoma, gastrinoma, and a suspected pancreatic tumor. The tumors in MEN1 typically occur at an earlier age than their sporadic counterparts. MEN1 families may exhibit some or all of these features. As an autosomal dominant syndrome, transmission can occur through maternal or paternal lineages, as depicted in the figure.

Since many of the tumors in MEN1 are underdiagnosed or misdiagnosed, identifying an MEN1 gene pathogenic variant 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 pathogenic variants among patients with apparently sporadic MEN1-related tumors. For example, approximately one-third of patients with Zollinger-Ellison syndrome will carry an MEN1 pathogenic variant.[37,38] In individuals with apparently isolated PHPT or pituitary adenomas, the pathogenic variant prevalence is lower, on the order of 2% to 5%,[26,39,40] but the prevalence is higher in individuals diagnosed with these tumors before age 30 years. Some authors suggest referral for genetics consultation and/or genetic testing for pathogenic variants in MEN1 if one of the following conditions is present:[18,41,42]

• Gastrinoma at any age in the individual or an FDR.
• Multifocal duodenopancreatic NETs at any age.
• PHPT 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).
• Combination of at least two of the following in one individual: parathyroid adenoma; thymic, bronchial, or foregut carcinoid tumor; duodenopancreatic NET; pituitary tumor; adrenal tumor.
• Parathyroid adenoma and a family history of hyperparathyroidism, pituitary adenoma, duodenopancreatic NET, or foregut carcinoid tumor.
• Multiple primary duodenopancreatic NETs in the same person.

Molecular Genetics of MEN1

The MEN1 gene is located on chromosome 11q13 and encodes the protein menin.[3,43,44] Over 1,300 pathogenic variants have been identified in the MEN1 gene to date, and these are scattered across the entire coding region.[45] Most (~65%) of these are nonsense or frameshift variants. The remainder are missense variants (20%), which lead to expression of an altered protein, splice-site variants (9%), or partial- or whole-gene deletions (1%–4%). There is some evidence of genotype-phenotype correlations, but inter- and intra-familial variability is common.[46,47] One large study demonstrated the highest rates of heritability for pituitary, adrenal, and thymic NETs.[48]

Genetic Testing and Differential Diagnosis

Genetic testing for MEN1 pathogenic variants 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 pathogenic variant detection rate is approximately 75% to 90%.[46,49] Still, germline pathogenic variant yield ranged from 16% to 38% for apparently sporadic cases of parathyroid (15.8%), pancreatic islet (25.0%), or pituitary (37.5%) tumors, warranting consideration of genetic testing in these individuals because a diagnosis of MEN1 would prompt screening for other MEN1-related tumors.[50] Many commercial laboratories currently offering MEN1 testing use DNA sequencing as their primary method. Several offer additional analysis for partial- or whole-gene deletion and/or duplication, although such variants 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 pathogenic variants 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 pathogenic variants in the HRPT2 gene, is associated with PHPT, ossifying lesions of the maxilla and mandible, and renal lesions, usually bilateral renal cysts, hamartomas, and in some cases, Wilms tumor.[51,52] Unlike MEN1, HPT-JT is associated with an increased risk of parathyroid carcinoma.[53] FIHP, as its name suggests, is characterized by isolated PHPT with no additional endocrine features; in some families, FIHP is the initial diagnosis of what later develops into MEN1, HPT-JT, or FHH.[54-56] Approximately 20% of families with a clinical diagnosis of FIHP carry germline MEN1 pathogenic variants.[55,57,58] Pathogenic variants in the calcium-sensing receptor (CaSR) gene cause FHH, which can closely mimic the hyperparathyroidism 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 hyperparathyroidism and results in unnecessary surgery without relief of symptoms.[59] 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 hyperparathyroidism may play an important role in the management of these patients and their families.[60] Refer to Table 3 for a summary of the clinical features of MEN1 and other forms of hereditary hyperparathyroidism.

Surveillance

Screening and surveillance for MEN1 may employ a combination of biochemical tests and imaging. Available recommendations are summarized in Table 4.[4,18]

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 before 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.

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68. Qiu W, Christakis I, Silva A, et al.: Utility of chromogranin A, pancreatic polypeptide, glucagon and gastrin in the diagnosis and follow-up of pancreatic neuroendocrine tumours in multiple endocrine neoplasia type 1 patients. Clin Endocrinol (Oxf) 85 (3): 400-7, 2016. [PMC free article: PMC4988913] [PubMed: 27256431]
69. Ramundo V, Del Prete M, Marotta V, et al.: Impact of long-acting octreotide in patients with early-stage MEN1-related duodeno-pancreatic neuroendocrine tumours. Clin Endocrinol (Oxf) 80 (6): 850-5, 2014. [PubMed: 24443791]
70. Triponez F, Goudet P, Dosseh D, et al.: Is surgery beneficial for MEN1 patients with small (< or = 2 cm), nonfunctioning pancreaticoduodenal endocrine tumor? An analysis of 65 patients from the GTE. World J Surg 30 (5): 654-62; discussion 663-4, 2006. [PubMed: 16680582]
71. Bettini R, Partelli S, Boninsegna L, et al.: Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor. Surgery 150 (1): 75-82, 2011. [PubMed: 21683859]
72. Brunner SM, Weber F, Werner JM, et al.: Neuroendocrine tumors of the pancreas: a retrospective single-center analysis using the ENETS TNM-classification and immunohistochemical markers for risk stratification. BMC Surg 15: 49, 2015. [PMC free article: PMC4451725] [PubMed: 25928025]
73. Bartsch DK, Langer P, Wild A, et al.: Pancreaticoduodenal endocrine tumors in multiple endocrine neoplasia type 1: surgery or surveillance? Surgery 128 (6): 958-66, 2000. [PubMed: 11114630]
74. Bartsch DK, Fendrich V, Langer P, et al.: Outcome of duodenopancreatic resections in patients with multiple endocrine neoplasia type 1. Ann Surg 242 (6): 757-64, discussion 764-6, 2005. [PMC free article: PMC1409888] [PubMed: 16327485]
75. Norton JA, Jensen RT: Role of surgery in Zollinger-Ellison syndrome. J Am Coll Surg 205 (4 Suppl): S34-7, 2007. [PubMed: 17916516]
76. Lopez CL, Waldmann J, Fendrich V, et al.: Long-term results of surgery for pancreatic neuroendocrine neoplasms in patients with MEN1. Langenbecks Arch Surg 396 (8): 1187-96, 2011. [PubMed: 21805182]
77. Drymousis P, Raptis DA, Spalding D, et al.: Laparoscopic versus open pancreas resection for pancreatic neuroendocrine tumours: a systematic review and meta-analysis. HPB (Oxford) 16 (5): 397-406, 2014. [PMC free article: PMC4008158] [PubMed: 24245906]
78. Imamura M, Komoto I, Ota S, et al.: Biochemically curative surgery for gastrinoma in multiple endocrine neoplasia type 1 patients. World J Gastroenterol 17 (10): 1343-53, 2011. [PMC free article: PMC3068271] [PubMed: 21455335]
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82. Ito T, Igarashi H, Uehara H, et al.: Causes of death and prognostic factors in multiple endocrine neoplasia type 1: a prospective study: comparison of 106 MEN1/Zollinger-Ellison syndrome patients with 1613 literature MEN1 patients with or without pancreatic endocrine tumors. Medicine (Baltimore) 92 (3): 135-81, 2013. [PMC free article: PMC3727638] [PubMed: 23645327]
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86. Sakurai A, Yamazaki M, Suzuki S, et al.: Clinical features of insulinoma in patients with multiple endocrine neoplasia type 1: analysis of the database of the MEN Consortium of Japan. Endocr J 59 (10): 859-66, 2012. [PubMed: 22785103]
87. Vezzosi D, Cardot-Bauters C, Bouscaren N, et al.: Long-term results of the surgical management of insulinoma patients with MEN1: a Groupe d'étude des Tumeurs Endocrines (GTE) retrospective study. Eur J Endocrinol 172 (3): 309-19, 2015. [PubMed: 25538206]
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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) (referred to as C-cell neoplasia or C-cell carcinoma in situ in more recent publications)[1]; pheochromocytoma (PHEO); and parathyroid adenomas and/or hyperplasia. MEN2-associated MTC is often bilateral and/or multifocal and arises in the background of CCH clonal C-cell proliferation. In contrast, sporadic MTC is typically unilateral and/or unifocal. Because approximately 75% to 80% of sporadic cases also have associated CCH, this histopathologic feature cannot be used as a predictor of familial disease.[2] 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.[3,4] Although less than 1% of PHEOs 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 on the basis of 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) (sometimes referred to as MEN3).

Current stratification is moving away from a solely phenotype-based classification and more toward one that is based on genotype (i.e., the pathogenic variant) and phenotype.[5] Current recommendations propose two MEN2 syndromes: MEN2A and MEN2B. The MEN2A syndrome is further classified on the basis of the presence of associated conditions. For example, classical MEN2A includes those with MTC, PHEO, and/or hyperparathyroidism. Additional categories include MEN2A with cutaneous lichen amyloidosis (CLA), MEN2A with Hirschsprung disease (HSCR), and FMTC (presence of a RET germline pathogenic variant and MTC but no family history of PHEO or hyperparathyroidism).[1] Classifying a patient or family by MEN2 subtype is useful in determining prognosis and management.

The prevalence of MEN2 has been estimated to be approximately 1 in 35,000 individuals.[6] The vast majority of MEN2 cases are MEN2A.

MTC and CCH

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 a controversial diagnosis, but most pathologists agree that it is defined as more than seven C-cells per cluster, complete follicles surrounded by C-cells, and C-cells in a distribution beyond normal anatomical location.[1,7-9] Individuals with RET (REarranged during Transfection) pathogenic variants and CCH are at substantially increased risk of progressing to MTC, although such progression is not universal.[10,11] 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.[12] 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.[10,11,13]

MTC accounts for 2% to 3% of new cases of thyroid cancer diagnosed annually in the United States,[14] 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.[3,15] 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.[16]

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 pathogenic variants,[17,18] larger series indicate a prevalence range of 1% to 7%.[19,20] On the basis of these data, testing for pathogenic variants in the RET gene is widely recommended for all cases of MTC.[1,21-23]

Level of evidence (Screening): 3

MEN2-Related PHEO

PHEOs (OMIM) arise from the catecholamine-producing chromaffin cells of the adrenal medulla. They are a relatively rare tumor and are suspected among patients with refractory hypertension or when biochemical screening reveals elevated excretion of catecholamines and catecholamine metabolites (i.e., norepinephrine, epinephrine, metanephrine, and vanillylmandelic acid) in 24-hour urine collections or plasma. In the past, measurement of urinary catecholamines was considered the preferred biochemical screening method. However, given that catecholamines are only released intermittently and are metabolized in the adrenal medulla into metanephrine and normetanephrine, the measurement of urine or plasma fractionated metanephrines has become the gold standard.[34-39] When biochemical screening in an individual who has or is at risk of MEN2 suggests PHEO, localization studies, such as magnetic resonance imaging (MRI) or computed tomography, can be performed.[40] Confirmation of the diagnosis can be made using iodine I 131-metaiodobenzylguanidine scintigraphy or positron emission tomography imaging.[11,40-42]

A diagnosis of MEN2 is often considered in individuals with bilateral PHEO, those with an early age of onset (age <35 years), and those with a personal and/or family history of MTC or hyperparathyroidism. However, MEN2 is not the only genetic disorder that includes a predisposition to PHEO. Other disorders include neurofibromatosis type 1 (NF1), von Hippel-Lindau disease (VHL),[43] and the hereditary paraganglioma syndromes.[44] (Refer to the von Hippel-Lindau Syndrome section in the PDQ summary on the Genetics of Kidney Cancer for more information about VHL.) A large European consortium that included 271 patients from Germany,[45] 314 patients from France,[46] and 57 patients from Italy (total = 642) with apparently sporadic PHEO analyzed the known PHEO/functional paraganglioma susceptibility genes (NF1, RET, VHL, SDHB, and SDHD).[47] The diagnosis of NF1 in this series was made clinically, while all other conditions were diagnosed on the basis of the presence of a germline pathogenic variant in the causative gene. The disease was associated with a positive family history in 166 (25.9%) patients; germline pathogenic variants were detected in RET (n = 31), VHL (n = 56), NF1 (n = 14), SDHB (n = 34), or SDHD (n = 31). Rigorous clinical evaluation and pedigree analysis either before or after testing revealed that of those with a positive family history and/or a syndromic presentation, 58.4% carried a pathogenic variant, compared with 12.7% who were nonsyndromic and/or had no family history. Of the 31 individuals with a germline RET pathogenic variant, 28 (90.3%) had a positive family history and/or syndromic presentation, suggesting that most individuals with RET pathogenic variants and PHEO will have a positive family history or other manifestations of the disease.

Primary Hyperparathyroidism (PHPT)

PHPT is the third most common endocrine disorder in the general population. The incidence increases with age with the vast majority of cases occurring after the sixth decade of life. Approximately 80% of cases are the result of a single adenoma.[48] PHPT can also be seen as a component tumor in several different hereditary syndromes, including the following:

• MEN1.
• Hyperparathyroidism–jaw tumor syndrome.
• Familial isolated hyperparathyroidism.
• MEN2.[49-51]

Hereditary PHPT is typically multiglandular, presents earlier in life, and can have histologic evidence of both adenoma and glandular hyperplasia.

Clinical Diagnosis of MEN2 Subtypes

The diagnosis of the two MEN2 clinical subtypes relies on a combination of clinical findings, family history, and molecular genetic testing of the RET gene (chromosomal region 10q11.2).

MEN2A

Classical MEN2A

MEN2A is diagnosed clinically by the occurrence of two specific endocrine tumors in addition to MTC: PHEO and/or parathyroid adenoma and/or hyperplasia in a single individual or in close relatives.[1]

The classical MEN2A subtype makes up about 60% to 90% of MEN2 cases. The MEN2A subtype was initially called Sipple syndrome.[52] Since genetic testing for RET pathogenic variants has become available, it has become apparent that about 95% of individuals with MEN2A will develop MTC.[11,53-55]

MTC is generally the first manifestation of MEN2A. In asymptomatic at-risk individuals, stimulation testing may reveal elevated plasma calcitonin levels and the presence of CCH or MTC.[11,54] In families with MEN2A, the biochemical manifestations of MTC generally appear between the ages of 5 years and 25 years (mean, 15 years).[11] If presymptomatic screening is not performed, MTC typically presents as a neck mass or neck pain between the ages of about age 5 years and 20 years. More than 50% of such patients have cervical lymph node metastases.[3] Diarrhea, the most frequent systemic symptom, occurs in patients with a markedly elevated plasma calcitonin level or bulky disease and/or hepatic metastases and implies a poor prognosis.[1,3,56,57] Up to 30% of patients with MTC present with diarrhea and advanced disease.[58]

MEN2-associated PHEOs are more often bilateral, multifocal, and associated with extratumoral medullary hyperplasia.[59-61] They also have an earlier age of onset and are less likely to be malignant than their sporadic counterparts.[59,62] MEN2-associated PHEOs usually present after MTC, typically with intractable hypertension.[63]

Unlike the PHPT seen in MEN1, hyperparathyroidism in individuals with MEN2 is typically asymptomatic or associated with only mild elevations in calcium.[58,64] A series of 56 patients with MEN2-related hyperparathyroidism has been reported by the French Calcitonin Tumors Study Group.[64] The median age at diagnosis was 38 years, documenting that this disorder is rarely the first manifestation of MEN2. This is in sharp contrast to MEN1, in which the vast majority of patients (87%–99%) initially present with primary hyperparathyroidism.[65-67] Parathyroid abnormalities were found concomitantly with surgery for medullary thyroid carcinoma in 43 patients (77%). Two-thirds of the patients were asymptomatic. Among the 53 parathyroid glands removed surgically, there were 24 single adenomas, 4 double adenomas, and 25 hyperplastic glands.

MEN2A with cutaneous lichen amyloidosis

A small number of families with MEN2A have pruritic skin lesions known as cutaneous lichen amyloidosis. This lichenoid skin lesion is located over the upper portion of the back and may appear before the onset of MTC.[68,69]

MEN2A with Hirschsprung disease (HSCR)

HSCR (OMIM), a disorder of the enteric plexus of the colon that typically results in enlargement of the bowel and constipation or obstipation in neonates, is observed in a small number of individuals with RET pathologic variants.[70] Up to 40% of familial cases of HSCR and 3% to 7% of sporadic cases are associated with germline pathogenic variants in the RET proto-oncogene and are designated HSCR1.[71 ,72] Some of these RET pathogenic variants are more commonly located in codons that lead to the development of MEN2A or FMTC (i.e., codons 609, 618, and 620).[70,73]

In a study of 44 families, seven families (16%) had cosegregation of MEN2A and HSCR1. The probability that individuals in a family with MEN2A and an exon 10 Cys variant would manifest HSCR1 was estimated to be 6% in one series.[71] Furthermore, in a multicenter international RET variant consortium study, 6 of 62 kindreds carrying either the C618R or C620R variant also had HSCR.[53]

A novel analytic approach employing family-based association studies coupled with comparative and functional genomic analysis revealed that a common RET variant within a conserved enhancer-like sequence in intron 1 makes a 20-fold greater contribution to HSCR compared with all known RET pathogenic variants.[74] This pathogenic variant has low penetrance and different genetic effects in males and females. Transmission to sons leads to a 5.7-fold increase in susceptibility and transmission to daughters leads to a 2.1-fold increase in susceptibility. This finding is consistent with the greater incidence of HSCR in males. Demonstrating this strong relationship between a common noncoding variant in RET and the risk of HSCR also accounts for previous failures to detect coding pathogenic variants in RET-linked families.

Figure 2 depicts some of the classic manifestations of MEN2A in a family.

Figure 2. MEN2A pedigree. This pedigree shows some of the classic features of a family with a RET pathogenic variant across four generations, including affected family members with medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism. Age at onset can vary widely, even within families. Medullary thyroid cancer can present with earlier onset and more aggressive disease in successive generations, depending on the genotype. MEN2A families may exhibit some or all of these features. As an autosomal dominant syndrome, transmission can occur through maternal or paternal lineages.

In a child, the presence of oral and ocular neuromas and/or a tall and lanky appearance may warrant further investigation.[75] Some authors have recommended referral to genetic counseling for an individual with MTC or any of the following features:[75,76]

• Benign oral and submucosal neuromas.
• Elongated face and large lips.
• Ganglioneuromatosis.
• Inability to cry tears (biologic mechanism unknown).

Familial medullary thyroid carcinoma (FMTC)

The FMTC subtype makes up 5% to 49% of MEN2 cases and is defined as families with four or more cases of MTC in the absence of PHEO or parathyroid adenoma/hyperplasia.[53,77] Families with two or three cases of MTC and incompletely documented screening for PHEO and parathyroid disease may actually represent MEN2A; it has been suggested that these families should be considered unclassified.[16,78] Misclassification of families with MEN2A as having FMTC (because of too-small family size or later onset of other manifestations of MEN2A) may result in overlooking the risk of PHEO, a disease with significant morbidity and mortality. For this reason, there is debate about whether FMTC represents a separate entity or is a variation of MEN2A in which there is a lack of or delay in the onset of the other (nonthyroidal) manifestations of the MEN2A syndrome.[79] Some authors recommended,[1] therefore, that patients thought to have pure FMTC also be screened for PHEO and hyperparathyroidism. Whether and how often to perform this screening are matters of ongoing debate. (Refer to the Screening at-risk individuals for PHEO and Screening at-risk individuals for hyperparathyroidism sections of this summary for more information.)

Molecular Genetics of MEN2

MEN2 syndromes are the result of inherited pathogenic variants in the RET gene, located on chromosome region 10q11.2.[87-89] The RET gene is a proto-oncogene composed of 21 exons over 55 kilobase of genomic material.[90,91]

RET encodes a receptor tyrosine kinase with extracellular, transmembrane, and intracellular domains. Details of RET receptor and ligand interaction in this signaling pathway have been reviewed.[92] Briefly, the extracellular domain consists of a calcium-binding cadherin-like region and a cysteine-rich region that interacts with one of four ligands identified to date. These ligands, e.g., glial cell line–derived neurotrophic factor (GDNF), neurturin, persephin, and artemin, also interact with one of four coreceptors in the GDNF-family receptor–alpha family.[92] The tyrosine kinase catalytic core is located in the intracellular domain, which causes downstream signaling events through a variety of second messenger molecules. Normal tissues contain transcripts of several lengths.[93-95]

Genotype-Phenotype Correlations and Risk Stratification

Genotype-phenotype correlations in MEN2 are well-established and have long been used to guide clinicians in making medical management recommendations. Several groups have developed pathogenic variant–stratification tables based on clinical phenotype, age of onset, and aggressiveness of MTC.[1,22,78] This classification strategy was first put forth after the Seventh International Workshop on MEN in 2001, which provided guidelines for the age of genetic testing and prophylactic thyroidectomy.[22] This stratification has been revised by the American Thyroid Association (ATA).[1,104] The specific pathogenic variants and their ATA classification are summarized in Table 5 below. The ATA's classification scheme has not been prospectively validated as a basis for clinical decision-making.

ATA-Highest Risk (HST) (previously labeled ATA-D) pathogenic variants are the most aggressive and carry the highest risk of developing MTC.[1] This category includes those with MEN2B and RET codon M918T pathogenic variants and is associated with the youngest age at disease onset and the highest risk of mortality. ATA-High Risk (H) (previously called ATA-C) pathogenic variants, codons 634 and A883F, are associated with a slightly lower risk, yet the MTC in patients with these pathogenic variants is still quite aggressive and may present at an early age. Former ATA-levels A and B pathogenic variants are now combined into a single group called Moderate Risk (MOD) and are associated with a lower risk of aggressive MTC relative to the risk seen in carriers of ATA-HST and ATA-H pathogenic variants. However, the risk of MTC is still substantially elevated over the general population risk and consideration of risk-reducing thyroidectomy is warranted.[1] Common pathogenic variants in the ATA-MOD category include codons 609, 618, and 804.

A European multicenter study of 207 carriers of RET pathogenic variants supported previous suggestions that some pathogenic variants are associated with early-onset disease. For example, this study found that individuals with the C634Y pathogenic variant developed MTC at a significantly younger age (mean 3.2 years; 95% confidence interval [CI], 1.2–5.4) than individuals with the C634R pathogenic variant (mean 6.9 years; 95% CI, 4.9–8.8). In the former group of patients, risk-reducing thyroidectomy warrants consideration before the age of 5 years. Although limited by small numbers, the same study did not support a need for risk-reducing thyroidectomy in asymptomatic carriers of pathogenic variants in codons 609, 630, 768, 790, 791, 804, or 891 before the age of 10 years or for central lymph node dissection before the age of 20 years.[105] Some authors suggest using these differences as the basis for decisions on the timing of risk-reducing thyroidectomy and the extent of surgery.[22] Two other studies have found conflicting results suggesting that the C634R pathogenic variant is associated with a higher penetrance of MTC-related PHEO and hyperparathyroidism and a higher likelihood of lymph node and distant metastases at an earlier age than is C634Y.[106] Additional studies in larger populations are needed to further clarify this issue. Others have advocated using basal and stimulated calcitonin levels as a basis for determining the appropriate timing of thyroidectomy.[107,108]

Level of evidence (calcitonin level as a basis for the timing of thyroidectomy): 4aii

Pathogenic variants at codons 883 and 918 have been seen only in MEN2B and are associated with the earliest age of onset and the most aggressive form of MTC.[109-113] Approximately 95% of individuals with MEN2B will have the M918T pathogenic variant.[109-111,114] As discussed above, 50% of individuals with MEN2B will develop PHEO but PHPT is rare. In addition to variants at codons 883 and 918, some individuals with an MEN2B-like phenotype have been found to carry two germline variants.[115-119] It is likely that as testing for RET becomes more common in clinical practice, additional double variant phenotypes will be described.

Pathogenic variants at codon 634 (ATA-H) are by far the most frequent finding in families with MEN2A. One study of 477 RET carriers showed that 52.1% had the C634R pathogenic variant, 26.0% carried the C634Y pathogenic variant, and 9.1% had the C634G pathogenic variant.[53] In general, pathogenic variants at codon 634 are associated with PHEOs and PHPT.[53,120] Until recently, MEN2A with cutaneous lichen amyloidosis had been seen almost exclusively in patients with pathogenic variants at codon 634.[53,55,121] However, a recent report described MTC and cutaneous lichen amyloidosis in an individual previously thought to have FMTC due to a codon 804 pathogenic variant.[122] Codon 634 pathogenic variants have also been described in FMTC but are almost exclusively C634Y.[53]

In summary, ATA-HST and ATA-H (previously levels D and C, respectively) pathogenic variants confer the highest risk of MTC (about 95% lifetime risk) with a more aggressive disease course. There is an increased risk of PHEO (up to 50%).[53,123] Individuals with codon 634 pathogenic variants (but not codon 883 or 918 variants) also have an increased risk of PHPT.[53]

Moderate-risk variants located in exon 10 of the RET gene include variants at codons 609, 611, 618, 620, and 630. These variants involve cysteine residues in the extracellular domain of the RET protein and have been seen in families with MEN2A and those with MTC only (FMTC).[19,53,78,124-128] The risk of MTC in individuals with these pathogenic variants is approximately 95% to 100%; the risk of PHEO and hyperparathyroidism is lower than that seen in individuals with other moderate-risk pathogenic variants. In a large series of 518 probands with MTC undergoing RET testing, most individuals with codon 609, 611, 618, 620, or 630 variants had only MTC and no other features suggestive of MEN2. The authors attributed this to the relatively short follow-up time, incomplete screening of family members, or the method of ascertainment (population-based).[31] Another large study of 390 carriers of exon 10 pathogenic variants showed an age-related risk of PHEO for individuals carrying any exon 10 pathogenic variant of 23.1% by age 50 years and 33% by age 60 years. Overall prevalence of PHEO was 17%. This study reported a 3.9% risk of developing hyperparathyroidism by age 60 years.[129]

Individuals with pathogenic variants previously classified as ATA-level A (now classified with ATA-level B as ATA-MOD, i.e., codons 321, 515, 533, 600, 603, 606, 531/9 base pair duplication, and 532 duplication) have a lower, albeit still elevated, lifetime risk of MTC. MTC associated with these pathogenic variants tends to follow a more indolent course and have a later age at onset, although there are several reports of individuals with these pathogenic variants who developed MTC before age 20 years.[53,130-134] Although PHEO and PHPT are not commonly associated with these pathogenic variants, they have been described.[134]

In addition to the pathogenic variants categorized in Table 5, a number of rare or novel RET variants have been described. Some of these represent pathogenic variants that lead to an FMTC or MEN2 phenotype. Others may represent low penetrance alleles or modifying alleles that confer only a modest risk of developing MTC. Still others may be benign polymorphisms of no clinical significance. For example, some studies demonstrate compelling evidence that RET variants p.Tyr791Phe and p.Ser649Leu are likely benign polymorphisms, on the basis of equal frequencies among cases and healthy controls and co-occurrence with other disease-causing variants that cosegregate with disease in the family.[135,136] Therefore, carriers of these variants are not treated as having MEN2 syndrome and asymptomatic family members are generally not tested for these variants. Comprehensive testing of all hotspot variants in exons 8 and 10–16 may be performed to rule out any other RET pathogenic variants, and more extensive testing of other disease-related genes may be warranted because of a diagnosis of PHEO. (Refer to the Familial Pheochromocytoma and Paraganglioma Syndrome section of this summary for more information.)

Research is ongoing into the role of neutral RET sequence variants in modifying the clinical presentation of patients with MEN2A. The presence of certain RET polymorphisms is being analyzed for its impact on the likelihood for development of PHEO, hyperparathyroidism, and metastatic involvement with MTC.[137-139] A variety of approaches, including segregation analyses, in silico analyses, association studies, and functional assays, can be employed to determine the functional and clinical significance of a given genetic variant. A publicly available RET variant online database repository was recently developed and includes a complete list of variants and their associated pathogenicity, phenotype, and other associated clinical information and literature references.[140]

Surveillance

Interventions

Genetic Counseling

References

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Introduction

Paragangliomas (PGLs) and pheochromocytomas (PHEOs) are rare tumors arising from chromaffin cells, which have the ability to synthesize, store, and secrete catecholamines and neuropeptides. Individuals may present with secondary hypertension. In 2004, the World Health Organization characterized adrenal gland tumors as PHEOs.[1] The term paraganglioma is reserved for non-adrenal (or extra-adrenal) neoplasms and may arise in various sites from the paraganglia along the parasympathetic nerves or the sympathetic trunk. PGLs may be found in the head and neck region, abdomen, or pelvis. Only those arising from sympathetic neural chains have secretory capacity. PGLs found in the skull base or head and neck region typically arise in the glomus cells, near the carotid body, along the vagal nerve or jugular fosse, and are usually from parasympathetic paraganglia and therefore rarely secrete catecholamines.[2,3] The most recognizable tumors are found at the carotid body. PGLs below the neck are most commonly located in the upper mediastinum or the urinary bladder.[3] The reported incidence of these tumors in the general population is variable because they may be asymptomatic but ranges from 1 in 30,000 to 1 in 100,000 individuals.[3] One autopsy study found a much greater incidence of 1 in 2,000 individuals, suggesting a high frequency of occult tumors.[4] PGLs have an equal sex distribution and can occur at any age but have the highest incidence between the ages of 40 and 50 years.[5,6]

Clinical Description

PGLs and PHEOs may occur sporadically, as a manifestation of a hereditary syndrome, or as the sole tumor in one of several hereditary PGL/PHEO syndromes.

PGLs and PHEOs are typically slow-growing tumors, and some may be present for many years before coming to clinical attention. Conversely, a minority of these tumors may be malignant and present with a more aggressive clinical course. PGL and PHEO malignancy is defined by the presence of metastases at sites distant from the primary tumor in nonchromaffin tissue. Common sites of metastases include bone, liver, and lungs.[1]

There are no reliable molecular, immunohistochemical, or genetic predictors to distinguish benign and malignant tumors,[7] although some studies have shown a higher malignancy rate in SDHB carriers [8] and in individuals with larger tumors.[9] Some experts view local invasion into surrounding tissue as an additional marker of malignancy.[10,11] Others have disagreed with this classification because locally invasive tumors tend to follow a more indolent course than tumors with distant metastatic involvement.[12] Consequently, estimation of the rate of malignancy in PGLs is difficult; rates ranging from 5% to 20% have been reported.[13-15]

Clinical Diagnosis of PGL and PHEO

A PGL may cause a variety of symptoms depending on the location of the tumor and whether the tumor has secretory capacity. PGLs of the head and neck are rarely associated with elevated catecholamines. Secretory PGLs and PHEOs may cause hypertension, headache, tachycardia, sweating, and flushing. Typically, nonsecretory tumors are painless, coming to attention only when growth of the lesion into surrounding structures causes a mass effect. Patients with a head or neck PGL may present with an enlarging lateral neck mass, hoarseness, Horner syndrome, pulsatile tinnitus, dizziness, facial droop, or blurred vision.[1]

Patients with clinically apparent catecholamine excess generally undergo biochemical testing to evaluate the secretory capacity of the tumor(s).[16] This evaluation is best performed by measuring urine and/or plasma fractionated metanephrines (normetanephrine and metanephrine), which yields a higher sensitivity and specificity than directly measuring catecholamines (norepinephrine, dopamine, and epinephrine).[17-19] For patients whose plasma metanephrines levels are measured, blood is collected after an intravenous catheter has been inserted and the patient has been in a supine position for 15 to 20 minutes.[20] Additionally, the patient should not have food or caffeinated beverages, smoke cigarettes, or engage in strenuous physical activity in the 8 to 12 hours before the blood draw.[20]

Imaging of PGLs is the mainstay of diagnosis; the initial evaluation includes computed tomography (CT) of the neck and chest. Magnetic resonance imaging (MRI) also has utility for the head and neck. PGLs typically appear homogeneous with intense enhancement after administration of intravenous contrast. MRI may also be used to distinguish the tumor from adjacent vascular and skeletal structures. On T2-weighted images, a tumor that is larger than 2 cm is likely to display a classic "salt and pepper" appearance, a reflection of scattered areas of signal void mingled with areas of high signal intensity from increased vascularity.[21]

Nuclear imaging, particularly somatostatin receptor scintigraphy (SRS) in combination with anatomic imaging, may be useful for localization and determination of the extent of disease (multifocality vs. distant metastatic deposits).[22] Benign tumors are reported to be more sensitive to SRS than iodine I 123-metaiodobenzylguanidine (123I-MIBG) imaging. Sensitivity is highest for the head and neck region compared with abdomen PGLs or PHEOs (91% vs. 40% and 42%, respectively).[23] SRS has been reported to be superior to MIBG in detecting metastatic tumors (95% vs. 23%, respectively).[23] 123I-MIBG, however, is highly sensitive for PHEO [23] and positron emission tomography–computed tomography (PET-CT) is very specific for PGLs. Functional imaging for PGLs and/or PHEOs with fluorine F 18-dihydroxyphenylalanine (18F-DOPA), 18F-fluorodopamine, or PET-CT may be particularly helpful in localizing head and neck tumors. Data suggest that the selection of PET tracer utilized for tumor localization should be centered on the patient’s genetic status, on the basis of the metabolic activity of the various tumors.[8] It has been suggested that patients with SDHx and VHL pathogenic variants are more likely to have higher 18F-fludeoxyglucose activity, which is related to gene activation in response to hypoxia.[8,24] Some SDHB tumors only weakly concentrate 18F-DOPA, and patients with SDHx pathogenic variants may have false-negative results with such scans. Gallium Ga 68-DOTATATE PET-CT shows promise as a potential imaging modality for determining the extent of disease in patients with metastatic involvement.[25] Tumors with VHL pathogenic variants may likewise be missed with MIBG scans.[8]

Imaging of PHEOs usually consists of a dedicated CT of the adrenal gland. When biochemical screening in an individual who has or is at risk of multiple endocrine neoplasia type 2 (MEN2) suggests PHEO, localization studies, such as MRI or CT, can be performed.[26] Confirmation of the diagnosis can be made using iodine I 131-MIBG scintigraphy or PET imaging.[26-29]

Genetics, Inheritance, and Genetic Testing

A significant proportion of individuals presenting with apparently sporadic PHEO or PGL are carriers of germline pathogenic variants. Up to 33% of patients with apparently sporadic PHEO, and up to 40% of patients with apparently sporadic PGLs, actually have a recognizable germline pathogenic variant in one of the known PGL/PHEO susceptibility genes.[14,30-34] One study found that in individuals with a single tumor and a negative family history, the likelihood of an inherited pathogenic variant was 11.6%,[14] whereas other groups detected pathogenic variants in 41% of such patients.[34,35] For example, even among carriers of SDHB pathogenic variants, there is low penetrance and delayed onset of disease, which may further obscure the hereditary nature of the disease.[36] As such, all patients with PHEO or PGL, even those with apparently sporadic tumors, may be considered for genetic testing because of the high frequency of pathogenic variants associated with these conditions.[37]

PGLs and PHEOs can be seen as part of several well-described tumor susceptibility syndromes including von Hippel-Lindau (VHL), MEN2, neurofibromatosis type 1, Carney-Stratakis syndrome, and familial paraganglioma (FPGL) syndrome. FPGL is most commonly caused by pathogenic variants in one of the following four genes: SDHA, SDHB, SDHC, and SDHD (collectively referred to as SDHx). The SDHx proteins form part of the succinate dehydrogenase (SDH) complex, which is located on the inner mitochondrial membrane and plays a critical role in cellular energy metabolism.[38] Pathogenic variants in SDHB are most common, followed by SDHD and rarely SDHC and SDHA. More recently, pathogenic variants in the SDHAF2 (also called SDH5), TMEM127, and MAX genes have been described in FPGL/PHEO,[39-42] but these variants are rare. The mechanism of tumor formation has remained elusive. One study suggests that SDHx-associated tumors display a hypermethylator phenotype that is associated with downregulation of important genes involved in the differentiation of neuroendocrine tissues.[43]

The inheritance pattern of FPGL depends on the gene involved. While most families show traditional autosomal dominant inheritance, those with pathogenic variants in SDHAF2 and SDHD show almost exclusive paternal transmission of the phenotype. In other words, while the pathogenic variant can be passed down from mother or father, tumors will develop only if the pathogenic variant is inherited from the father.[44,45] In cases of FPGL not caused by SDHD or SDHAF2 pathogenic variants, first-degree relatives (FDRs) of an affected individual have a 50% chance of carrying the pathogenic variant and are at increased risk of developing PGLs. Because the family history can appear negative in families with lower penetrance pathogenic variants, it is important to offer genetic testing to all unaffected FDRs once the pathogenic variant in the family has been identified.

Genetic testing for hereditary PHEO and PGL syndromes is largely based on published algorithms,[37] whereby testing is performed stepwise on the basis of factors such as tumor type and location, age at diagnosis, family history, and presence of malignancy.[14,46,47] This approach has allowed for cost-effective, targeted testing on the basis of clinical features. Within the last several years, however, next-generation sequencing (NGS) technology has led to a dramatic decrease in the cost of genetic testing, and testing for pathogenic variants in 10 to 30 genes for the same cost of testing two or three genes is now possible. These tests may be more appropriate for individuals and families who have an atypical presentation or overlapping clinical features. If the cost associated with multigene testing panels continues to decrease, the testing algorithms may soon be obsolete for PGL and PHEO. A recent series analyzed 85 PGL and PHEO samples using an NGS panel test for the ten known PGL susceptibility genes and showed a sensitivity of 98.7%.[48]

Genotype-Phenotype Correlations

In FPGL/PHEO, the type and location of tumors, age at onset, and lifetime penetrance vary depending on the genetic variant. While these correlations can help guide genetic testing and screening decisions, caution must be used given the high degree of variability seen in this condition. FPGL/PHEO syndromes are among the rare inherited diseases in which genomic imprinting occurs. For example, the SDHD pathogenic variant is normally not activated when inherited from the mother, and the risk of FPGL/PHEO syndromes is not increased. However, the pathogenic variant is turned on when the gene is inherited from the father, and the risk is increased.

SDHD pathogenic variants are mainly associated with an increased risk of parasympathetic PGLs. These are more commonly multifocal and located in the head and neck, while tumors in SDHB carriers are more often located in the abdomen.[49,50] One series showed a risk of 71% for a head and neck tumor in SDHD carriers, as opposed to a 29% risk in SDHB carriers. The lifetime risk for any PGL in any location in SDHD carriers was estimated to be as high as 77% by age 50 years in one series [49] and 90% by age 70 years in a second series.[50] A review of more than 1,700 cases reported in the literature provided similar estimates, suggesting a lifetime penetrance of 86%.[51] The rate of malignancy in SDHD carriers is lower than 5%.[51]

Pathogenic variants in the SDHB gene are associated with sympathetic PGLs, although PHEO and parasympathetic PGLs also have been described. SDHB PGLs are more commonly located in the abdomen and mediastinum than in the head and neck. A review of 1,700 cases suggested a lifetime penetrance of 77%.[51] However, many early studies examining penetrance were subject to ascertainment bias due to sampling of highly suggestive individuals affected at young ages, with limited inclusion of asymptomatic pathogenic variant carriers. More recent family-based studies have found lower penetrance estimates, ranging from 9% to 35% by age 50 years.[36,52-54] The rate of malignancy is higher with SDHB than with the other SDH genes, with up to one-third of patients having malignant tumors in most series.[49,50] Pathogenic variants in SDHB have also been associated with several other tumors and malignancies, including gastrointestinal stromal tumors (GISTs), renal cell carcinoma, and papillary thyroid cancer.[49,50]

SDHC pathogenic variants are rare, accounting for an estimated 0.5% of all PGLs.[51] In one series of 153 patients with multiple PGLs or a single PGL diagnosed before age 40 years, three (2%) had an SDHC pathogenic variant.[31] Another series of 121 index cases from a head and neck PGL registry showed a pathogenic variant rate of 4% (5 of 121).[55] SDHC pathogenic variants most commonly cause head and neck PGLs but have been seen in a small number of patients with abdominal PGLs.[14,56] Pathogenic variants in SDHB, SDHC, and SDHD can also cause Carney-Stratakis syndrome, which is characterized by the dyad of PGLs and GISTs.[57]

Pathogenic variants in SDHA, SDAHF2, MAX, and TMEM127 have been described in a small number of cases. Collectively, they account for less than 2% to 3% of all cases. Although biallelic pathogenic variants in SDHA have long been known to cause the autosomal recessive condition inherited juvenile encephalopathy/Leigh syndrome,[58] it was not until recently that monoallelic pathogenic variants were linked to an increased risk of developing PGL. Only a handful of cases have been described. Tumors can develop in the head and neck, the adrenal glands, or in the abdomen (extra-adrenal).[59,60] The SDHAF2 gene encodes a protein that is responsible for flavination of SDHA and proper functioning of the SDHA subunit of the SDH complex. To date, pathogenic variants in SDHAF2 have been described in fewer than 20 cases and only with head and neck PGLs.[42] The MAX gene was first described as a PHEO susceptibility gene in 2011 through exome sequencing of three unrelated cases.[39] Three different germline pathogenic variants were identified, and a follow-up series of 59 cases by the same group identified an additional five variants. The MAX protein is part of MYC-MAX-MXD1 network, which plays a key role in the development and progression of neural crest cell tumors.[61] The TMEM127 gene is located on chromosome 2q11.2 and encodes a transmembrane protein known to be a negative regulator of mTOR, which regulates multiple cellular processes. A review of 23 patients with TMEM127 pathogenic variants showed that 96% (22 of 23) had a PHEO and 9% (2 of 23) had a PGL.[51]

Surveillance

Patients with an identified germline pathogenic variant in one of the SDH genes are at a significantly increased risk of developing PGLs, PHEOs, renal tumors, and GISTs. PHEOs and PGLs typically have a slow growth pattern, but unchecked growth can lead to mass effect and, ultimately, neurologic compromise. Further, although most of these tumors are benign, some may undergo malignant transformation. As such, periodic screening for interval development of a tumor is of critical importance because early detection and removal can minimize risk to the patient. Although limited studies have been performed to delineate the ideal protocol, total-body MRI has been proposed as a reasonable method for screening because of its high sensitivity and minimal radiation exposure.[37,62] In one study, 37 carriers of SDHx pathogenic variants underwent annual biochemical testing and annual or biennial whole-body MRI beginning at age 10 years.[63] This screening protocol identified six tumors in five patients. The sensitivity of MRI was 87.5%, and the specificity was 94.7%. The sensitivity of biochemical testing was significantly lower at 37.5%, with a specificity similar to MRI at 94.9%.[63] A more-recent retrospective study of 157 patients evaluated a rapid contrast-enhanced angio-MRI protocol for the detection of head and neck paragangliomas in carriers of SDH pathogenic variants.[64] This protocol had a high sensitivity and specificity of 88.7% and 93.7%, respectively.

Although the optimal imaging protocol for surveillance in carriers of SDH pathogenic variants remains unclear, annual biochemical testing and clinical surveillance may be considered. Biochemical testing can be performed by measuring plasma-free metanephrines/catecholamines or 24-hour urinary excretion of fractionated catecholamines (including methoxytyramine, a dopamine metabolite, if available). Clinical surveillance may include physical examination and blood pressure measurement. Clinical surveillance and biochemical testing may begin between ages 5 years and 10 years, or 10 years earlier than the earliest age at diagnosis in the family.[65,66]

Level of evidence: 4

Interventions

References

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Clinical Description

Carney-Stratakis syndrome (CSS; also known as Carney-Stratakis dyad) was first described in 2002. Although similarly named, this syndrome is distinctly different from Carney Complex and Carney Triad (refer to Table 6). CSS is characterized by an autosomal dominant germline pathogenic variant in the succinate dehydrogenase (SDH) subunit B, C, or D (SDHx) genes that demonstrates incomplete penetrance. Affected individuals develop multifocal, locally aggressive gastrointestinal stromal tumors (GISTs) and multiple neck, intrathoracic, and intra-abdominal paragangliomas (PGLs) at relatively early ages.[1-3] CSS-associated GISTs and PGLs display phenotypes that differ from their sporadically occurring, more-common counterparts; as a result, it is important to understand the unique features of imaging, treatment, and surveillance in patients with CSS.

Genetics, Inheritance, and Genetic Testing

The tumorigenesis of CSS-associated GISTs appears to involve succinate dehydrogenase deficiency rather than gain-of-function variants in the KIT or PDGFRA gene, as is seen in the vast majority of GISTs.[9] SDH deficiency is also a characteristic finding of pediatric-type GISTs; CSS-associated GISTs display clinical findings similar to these tumors, including young age at onset (median age, 19 years), specificity to the stomach, multifocality, and resistance to imatinib.[3,10-12] Furthermore, tumor size and mitotic rate do not accurately predict metastatic potential or survival, as SDH-deficient GISTs frequently metastasize to regional lymph nodes, the peritoneal cavity, and the liver; however, long-term survival is common.[6,13]

Refer to the Genetics, Inheritance, and Genetic Testing section in the Familial PGL section of this summary for more information about genetic testing for the genes involved in CSS.

Surveillance

Although the natural history of CSS is poorly understood, experts recommend that ongoing surveillance include the following: close patient follow-up with annual history that focuses on symptoms of anemia and catecholamine excess, physical exam, biochemical analysis with plasma metanephrine level and chromogranin A to detect recurrent PGLs, and cross-sectional imaging. Although many PGLs do not secrete catecholamines, chromogranin A has been found to be elevated in PGLs and may be a useful marker for tumor recurrence. The appropriate screening imaging modality is unknown at this time, but fluorine F 18-fludeoxyglucose positron emission tomography–computed tomography (18F-FDG PET-CT) is highly sensitive at identifying extra-adrenal PGLs and GISTs. Because of the risks of ionizing radiation exposure from CT, some suggest using MRI for annual surveillance.[14,15]

Level of evidence: 4

Interventions

Because multiple primary GISTs and PGLs are common with CSS, preoperative imaging is paramount to accurately identify the extent of disease before surgical planning. Most patients will present having already undergone imaging with CT or magnetic resonance imaging (MRI). Both methods have excellent sensitivity for identifying PGLs, but additional functional imaging is recommended because of the diffuse nature of these tumors. 18F-FDG PET-CT is superior to iodine I 123-metaiodobenzylguanidine at identifying SDHx-associated PGLs and, because of the high metabolic activity of GISTs, has excellent sensitivity in identifying them.[14,16] Thus, in patients with SDHx pathogenic variants, including those with CSS, 18F-FDG PET-CT is the preferred functional imaging modality to optimally detect and stage all GISTs and PGLs.[15] Some evidence suggests that 18F-fluoro-L-dihydroxyphenylalanine (18F-FDOPA) PET-CT is superior at identifying the primary PGL, while 18F-FDG PET-CT is superior at identifying metastases.

There are no prospective treatment studies involving patients with CSS; therefore, recommendations are based on limited clinical experience, single case series, and extrapolations from genetically-similar tumors with similar clinical behavior. The mainstay of treatment for CSS-associated GISTs and PGLs is complete surgical resection of the tumor. The timing of the operation correlates with the presentation of the tumor. Surgical resection can be accomplished with laparoscopic or open techniques. For PGLs, vascular reconstruction is uncommon. Although PGLs are commonly present in the paraaortic region, the need for major vascular reconstruction is uncommon. GIST tumors can be resected with wedge resection and primary closure and re-anastomosis. Ensuring negative margins is important, as patients for whom a complete resection is accomplished experience the longest survival.[17] In the rare setting of synchronous disease, combined resection is appropriate if tolerable by the patient. More commonly, tumors develop metachronously, with GISTs arising first; individual resection occurs at the time of diagnosis of each tumor.

A thorough preoperative endoscopy and complete surgical exploration of the stomach are essential, as multiple separate GISTs are frequently encountered. The high frequency of multifocality and the likelihood of tumor recurrence do not justify a prophylactic total gastrectomy because of its substantial associated morbidity. Furthermore, a total gastrectomy is generally only performed when the current disease burden precludes a lesser resection. To this end, gastric wedge resection with gross negative margins is the surgical goal.[18] Sampling of any suspicious nodes at the time of resection is commonly performed. Evidence suggests that locally advanced CSS-associated GISTs demonstrate a rather indolent course;[19] thus, the concern for nodal involvement based on preoperative imaging or abdominal exploration need not deter resection of the primary tumor. While a role for neoadjuvant imatinib in locally advanced adult-type GISTs has been widely described to improve resectability or reduce the burden of resection, it is unlikely to have any effect in locally advanced SDH-deficient GISTs.[20] Evidence suggests that for these tumors, the second-line targeted agents, including sorafenib, sunitinib, dasatinib, and nilotinib, may be beneficial in the adjuvant setting.[21,22] No data support using these agents in the neoadjuvant setting at this time.

Regarding treatment of CSS-associated PGLs, patients are commonly initiated on alpha-blockade preoperatively to minimize perioperative cardiac morbidity and mortality. PGLs typically occur in the para-aortic chain from the urinary bladder and the aortic bifurcation to the superior mediastinum and head and neck. As in the treatment of GISTs, the operative goal is resection of all known disease. Preoperative imaging and intra-operative exploration are essential to achieving this goal. Multiple tumors are common; when disease is present in the bilateral adrenal glands, the surgeon faces the possibility of rendering a patient steroid dependent with a lifelong risk of a fatal Addisonian crisis. In this setting, a surgeon proficient in performing a cortical-sparing adrenalectomy may be consulted.

Level of evidence: 5

References

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3. Pasini B, McWhinney SR, Bei T, et al.: Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet 16 (1): 79-88, 2008. [PubMed: 17667967]
4. Gaal J, Stratakis CA, Carney JA, et al.: SDHB immunohistochemistry: a useful tool in the diagnosis of Carney-Stratakis and Carney triad gastrointestinal stromal tumors. Mod Pathol 24 (1): 147-51, 2011. [PMC free article: PMC3415983] [PubMed: 20890271]
5. Agaimy A, Pelz AF, Corless CL, et al.: Epithelioid gastric stromal tumours of the antrum in young females with the Carney triad: a report of three new cases with mutational analysis and comparative genomic hybridization. Oncol Rep 18 (1): 9-15, 2007. [PubMed: 17549339]
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8. Correa R, Salpea P, Stratakis CA: Carney complex: an update. Eur J Endocrinol 173 (4): M85-97, 2015. [PMC free article: PMC4553126] [PubMed: 26130139]
9. Hensen EF, Bayley JP: Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma. Fam Cancer 10 (2): 355-63, 2011. [PMC free article: PMC3100491] [PubMed: 21082267]
10. Agaram NP, Laquaglia MP, Ustun B, et al.: Molecular characterization of pediatric gastrointestinal stromal tumors. Clin Cancer Res 14 (10): 3204-15, 2008. [PMC free article: PMC3805121] [PubMed: 18483389]
11. Miettinen M, Wang ZF, Sarlomo-Rikala M, et al.: Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol 35 (11): 1712-21, 2011. [PMC free article: PMC3193596] [PubMed: 21997692]
12. Sawhney SA, Chapman AD, Carney JA, et al.: Incomplete Carney triad--a review of two cases. QJM 102 (9): 649-53, 2009. [PubMed: 19561114]
13. Rege TA, Wagner AJ, Corless CL, et al.: "Pediatric-type" gastrointestinal stromal tumors in adults: distinctive histology predicts genotype and clinical behavior. Am J Surg Pathol 35 (4): 495-504, 2011. [PubMed: 21358303]
14. Ayala-Ramirez M, Callender GG, Kupferman ME, et al.: Paraganglioma syndrome type 1 in a patient with Carney-Stratakis syndrome. Nat Rev Endocrinol 6 (2): 110-5, 2010. [PubMed: 20098451]
15. Timmers HJ, Kozupa A, Chen CC, et al.: Superiority of fluorodeoxyglucose positron emission tomography to other functional imaging techniques in the evaluation of metastatic SDHB-associated pheochromocytoma and paraganglioma. J Clin Oncol 25 (16): 2262-9, 2007. [PubMed: 17538171]
16. Timmers HJ, Chen CC, Carrasquillo JA, et al.: Comparison of 18F-fluoro-L-DOPA, 18F-fluoro-deoxyglucose, and 18F-fluorodopamine PET and 123I-MIBG scintigraphy in the localization of pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 94 (12): 4757-67, 2009. [PMC free article: PMC2795662] [PubMed: 19864450]
17. Abadin SS, Ayala-Ramirez M, Jimenez C, et al.: Impact of surgical resection for subdiaphragmatic paragangliomas. World J Surg 38 (3): 733-41, 2014. [PubMed: 24390286]
18. Demetri GD, Benjamin RS, Blanke CD, et al.: NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 5 (Suppl 2): S1-29; quiz S30, 2007. [PubMed: 17624289]
19. Maki RG, Blay JY, Demetri GD, et al.: Key Issues in the Clinical Management of Gastrointestinal Stromal Tumors: An Expert Discussion. Oncologist 20 (7): 823-30, 2015. [PMC free article: PMC4492234] [PubMed: 26070915]
20. Ganjoo KN, Villalobos VM, Kamaya A, et al.: A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib. Ann Oncol 25 (1): 236-40, 2014. [PMC free article: PMC4271129] [PubMed: 24356634]
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Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of endocrine and neuroendocrine neoplasias. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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• Kathleen A. Calzone, PhD, RN, AGN-BC, FAAN (National Cancer Institute)
• Sarah Nielsen, MS, LCGC (The University of Chicago)
• Suzanne M. O'Neill, MS, PhD, CGC (Northwestern University)
• Nancy D. Perrier, MD, FACS (University of Texas, M.D. Anderson Cancer Center)
• Beth N. Peshkin, MS, CGC (Lombardi Comprehensive Cancer Center at Georgetown University Medical Center)
• Susan K. Peterson, PhD, MPH (University of Texas, M.D. Anderson Cancer Center)
• Jennifer Sipos, MD (The Ohio State University)
• Susan T. Vadaparampil, PhD, MPH (H. Lee Moffitt Cancer Center & Research Institute)
• Catharine Wang, PhD, MSc (Boston University School of Public Health)

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