This executive summary reviews the topics covered in this PDQ summary on the genetics of endocrine and neuroendocrine neoplasias, with hyperlinks to detailed sections below that describe the evidence on each topic.
Several hereditary syndromes involve the endocrine or neuroendocrine glands. Multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2 (MEN2), multiple endocrine neoplasia type 4 (MEN4), familial pheochromocytoma (PHEO) and paraganglioma (PGL) syndrome (FPPL), Carney-Stratakis syndrome (CSS), and familial nonmedullary thyroid cancer (FNMTC) are discussed in this summary. Autosomal dominant pathogenic variants cause most of these syndromes. PHEOs and PGLs may also be found in individuals with von Hippel-Lindau disease. For more information, see von Hippel-Lindau Disease.
MEN1, which is primarily associated with the development of parathyroid tumors and primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors (NETs), and pituitary tumors, is caused by germline pathogenic variants in the MEN1 gene. The primary endocrine features of MEN2, which is subdivided into MEN2A and MEN2B, include medullary thyroid cancer (MTC); its precursor, C-cell hyperplasia; PHEO; and parathyroid adenomas and/or hyperplasia. MEN2 is caused by germline pathogenic variants in the RET gene. MEN4 is a rare syndrome with clinical features that overlap with the other MEN syndromes; the most common features are primary hyperparathyroidism and pituitary adenomas. MEN4 is caused by germline pathogenic variants in the CDKN1B gene. Both FPPL and CSS are caused by germline pathogenic variants in the SDH genes. PHEOs and PGLs commonly occur sporadically as well, although up to 33% of apparently sporadic PHEOs in individuals with no known family history and up to 40% of apparently sporadic PGLs have a recognizable germline pathogenic variant in one of the known PGL/PHEO susceptibility genes. Multifocal, locally aggressive gastrointestinal stromal tumors (GISTs) are also found in individuals with CSS. FNMTC is a polygenic disease with no single locus responsible for the majority of cases or easily identifiable phenotype and is likely modified by multiple low-penetrance alleles and environmental factors.
Regular surveillance is a mainstay in individuals found to have or be at risk of carrying a pathogenic variant in MEN1, RET, CDKN1B, or one of the SDH genes. Surveillance recommendations include regular screening for both endocrine and nonendocrine manifestations of disease.
Surgical management of pituitary and parathyroid tumors in MEN1 is based on disease presentation and management of symptoms of the organ. Surgical management of duodenopancreatic NETs of MEN1 is more specific to preventing disease progression.
The decision to operate on PHEOs and PGLs in MEN2 is based on hormonal hypersecretion and symptomatology. Treatment of MTC consists of surgical removal of the entire thyroid gland, including the posterior capsule, and central lymph node dissection. In addition, risk-reducing thyroidectomy has been shown to reduce the subsequent incidence of persistent or recurrent disease in MEN2 patients who had thyroidectomy earlier in life. The timing of risk-reducing thyroidectomy is guided by the risks associated with specific RET variants, although basal calcitonin levels may be used to determine the optimal timing of the procedure. MEN2-related parathyroid disease may also be treated surgically or with medical therapy in high-risk surgical patients.
Parathyroid and pituitary tumors associated with MEN4 are also managed surgically, in accordance with treatment for other familial syndromes such as MEN1.
FPPL-associated PHEOs and PGLs are also treated surgically. Preoperative management aimed at preventing catecholamine-induced complications of the surgery is common.
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.
Thyroid cancers associated with FNMTC are also managed surgically, commonly with a total thyroidectomy. Patients who undergo a total thyroidectomy must receive lifelong thyroid hormone replacement therapy.
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.
Many of the genes and conditions described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) catalog. For more information, see OMIM.
A concerted effort is being made within the genetics community to shift terminology used to describe genetic variation. The shift is to use the term "variant" rather than the term "mutation" to describe a difference that exists between the person or group being studied and the reference sequence, particularly for differences that exist in the germline. Variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term pathogenic variant to describe a disease-causing mutation. For more information about variant classification, see Cancer Genetics Overview.
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), multiple endocrine neoplasia type 4 (MEN4), pheochromocytoma (PHEO), paraganglioma (PGL), Li-Fraumeni syndrome, familial adenomatous polyposis, and von Hippel-Lindau disease. This summary currently focuses on MEN1, MEN2, MEN4, familial PHEO and PGL syndrome, Carney-Stratakis (CSS) syndrome, and familial nonmedullary thyroid cancer (FNMTC). Li-Fraumeni syndrome, familial adenomatous polyposis, Cowden syndrome, and von Hippel-Lindau disease are discussed in the following PDQ summaries: Genetics of Breast and Gynecologic Cancers, Genetics of Colorectal Cancer, and von Hippel-Lindau Disease.
The term multiple endocrine neoplasia is used to describe a group of heritable tumors in endocrine tissues, which can be benign or malignant. Multiple endocrine neoplasias are typically classified into two main categories: MEN1 (also known as Wermer syndrome) and MEN2. Historically, MEN2 was further divided into three subtypes based on the presence or absence of certain endocrine tumors in an individual or family: MEN2A, familial medullary thyroid cancer (FMTC), and MEN2B (which is sometimes referred to as MEN3). FMTC is now considered a subtype of MEN2A.[
PGLs and PHEOs are rare tumors arising from chromaffin cells, which have the ability to synthesize, store, and secrete catecholamines and neuropeptides.[
Affected individuals with Carney-Stratakis syndrome (CSS) have multifocal, locally aggressive gastrointestinal stromal tumors and multiple neck, intrathoracic, and intra-abdominal PGLs at relatively young ages.[
Familial nonmedullary thyroid cancer (FNMTC) is thought to account for 5% to 10% of all differentiated thyroid cancer cases.[
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome, with an estimated prevalence of about 1 in 30,000 individuals.[
A clinical diagnosis of MEN1 may be made when an individual has two of the three major endocrine tumors listed above, especially if he/she was diagnosed with these tumors at a young age. Alternatively, familial MEN1 may be defined as having at least one MEN1 case in the family plus at least one first-degree relative (FDR) with one of these three tumors, or two FDRs with a germline pathogenic variant.[
Initial clinical presentation of symptoms typically occurs between the ages of 20 and 30 years. However, in many cases, an MEN1 diagnosis may not be confirmed for many years after initial symptoms occur. 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.[
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.[
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:
Since MEN1-associated hypercalcemia is directly related to the presence of parathyroid tumors, surgical removal of these tumors may normalize calcium and PTH levels. This can help relieve an individual's symptoms. However, there have been high recurrence rates of parathyroid tumors after surgery in some series.[
Duodenopancreatic NETs are the second most common endocrine manifestation in MEN1, occurring in 30% to 80% of patients by age 40 years.[
Duodenopancreatic NETs seen in MEN1 include the following:
|Tumor type||Estimated Penetrance||Symptoms|
|MEN1 = multiple endocrine neoplasia type 1.|
||Peptic ulcer disease and esophagitis|
||Local compressive symptoms: abdominal pain, jaundice, anorexia, weight loss|
||Whipple's triad: symptomatic hypoglycemia reversed by glucose administration with associated elevation of insulin, C-peptide, and proinsulin levels|
|Vasoactive intestinal peptide||1%[
|Necrolytic migratory erythema|
Gastrinomas represent 50% of the gastrointestinal NETs in MEN1 and are the major cause of morbidity and mortality in MEN1 patients.[
Originally, nonfunctioning duodenopancreatic NETs were thought to be uncommon in individuals with MEN1. However, recognition of these tumors has increased with advanced genetic testing and improved imaging techniques. For example, a prospective study showed that MEN1 pathogenic variant carriers had a nonfunctioning duodenopancreatic NET frequency of 55% by age 39 years when they underwent endoscopic ultrasonography of the pancreas.[
Approximately 15% to 50% of MEN1 patients will develop a pituitary tumor.[
|Tumor type||Estimated Penetrance||Symptoms|
|MEN1 = multiple endocrine neoplasia type 1.|
||Coarse facial features|
|Soft tissue overgrowth: enlargement of hands/feet|
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).[
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.[
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.[
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.[
Molecular Genetics of MEN1
The MEN1 gene is located on chromosome 11q13 and encodes the protein menin.[
Genetic Testing and Differential Diagnosis for MEN1
Genetic testing for MEN1 pathogenic variants is recommended for individuals meeting clinical diagnostic criteria and may be considered in individuals with less common MEN1-associated tumors. For more information, see the Making the diagnosis of MEN1 section. For individuals meeting diagnostic criteria, the pathogenic variant detection rate is approximately 75% to 90%.[
A multigene panel that includes MEN1 and other genes associated with an increased risk of endocrine tumors may also be used. Such genetic testing can be used to distinguish between MEN1 and other forms of hereditary hyperparathyroidism, such as familial isolated hyperparathyroidism (FIHP), hyperparathyroidism–jaw tumor syndrome (HPT-JT), and familial hypocalciuric hypercalcemia (FHH). 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 CDC73 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.[
Genetic diagnosis will help guide management for patients with early-onset hyperparathyroidism. This is especially crucial, since many of the above conditions have different management guidelines that correspond with their features. For example, distinguishing between MEN1 and FHH can be critical for a patient's disease management. Removing the parathyroid glands in FHH does not correct the hyperparathyroidism that is seen in patients with MEN1. This could result in an unnecessary surgery that would not relieve the patient's symptoms. In addition, HPT-JT is unique because it increases parathyroid carcinoma risk. Hence, individuals with this syndrome have different management guidelines than individuals with other forms of hereditary hyperparathyroidism.[
|Condition||Gene(s)||Major Clinical Features|
|FHH = familial hypocalciuric hypercalcemia; FIHP = familial isolated hyperparathyroidism; HPT-JT = hyperparathyroidism–jaw tumor syndrome; MEN1 = multiple endocrine neoplasia type 1 (gene is italicized); NETs = neuroendocrine tumors; PHPT = primary hyperparathyroidism.|
|MEN1||MEN1||PHPT, pituitary adenomas, duodenopancreatic NETs[
|HPT-JT||CDC73||PHPT; osteomas of maxilla and mandible; renal cysts or hamartomas; and rarely, Wilms tumor and parathyroid carcinoma[
|FHH||CASR(type 1),GNA11(type 2),AP2S1(type 3)||Hyperparathyroidism (not primary)[
Screening and surveillance for MEN1 may include a combination of biochemical tests and imaging techniques.
Traditionally, magnetic resonance imaging (MRI) was used for surveillance and staging. However, ongoing studies have evaluated the role of MRI in functional imaging, including gallium Ga 68-DOTATATE (68Ga-DOTATATE) positron emission tomography (PET)–computed tomography (CT) scanning. A multicenter retrospective study examined 108 MEN1 patients undergoing PET-CT for screening, staging, restaging, or targeted radiotherapy selection. This study demonstrated that PET-CT has the potential to increase diagnostic sensitivity when searching for MEN1-associated NETs.[
A study analyzed thoracic screening techniques in 50 patients with MEN1. It found that when patients with MEN1 underwent functional imaging with fluorine F 18-fludeoxyglucose (18F-FDG) PET-CT screening, they had a similar number of lung nodules as individuals in the general population. However, when lesions in MEN1 patients were FDG-avid, they were more likely to progress during the follow-up period. Therefore, further observation and follow up of FDG-avid lesions may be warranted in patients with MEN1.[
Recommendations for MEN1 surveillance are summarized in Table 4.[
|Biochemical Test or Procedure||Condition Screened For||Age Screening Initiated (y)||Frequency|
|CT = computed tomography; MEN1 = multiple endocrine neoplasia type 1; MRI = magnetic resonance imaging; NETs = neuroendocrine tumors; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone.|
| a Adapted from Brandi et al.[
| b The recommendations for abdominal imaging differ between two published guidelines for the diagnosis and management of MEN1.[
| c The age to initiate screening and the screening frequency for pituitary tumors may be debatable because the clinical significance of small, nonfunctional tumors is unclear;[
| d Adapted from Niederle et al.[
| e Adapted from Shirali et al.[
|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||Duodenopancreatic gastrinoma||20||Every 1 y|
|Chromogranin A, pancreatic polypeptide, glucagon, and vasointestinal polypeptided||Duodenopancreatic NETs||10–16||Up to every 3 years (consider every 3 years if asymptomatic; consider shorter screening intervals depending on the clinical scenario)|
|Fasting glucose and insulin||Insulinoma||5||Every 1 y|
|Brain MRIc||Pituitary tumors||5||Every 3–5 y based on biochemical results|
|Chest MRIe||Thymic and bronchial NETs||<20||About every 3 years. Consider more frequent screening for men, smokers, or individuals with a positive family history. Baseline chest MRI is done prior to parathyroidectomy|
|Abdominal CT or MRIb[
||Duodenopancreatic NETs||20||Every 3–5 y based on biochemical results|
|Abdominal CT, MRI, or endoscopic ultrasonographyb[
||Duodenopancreatic NETs||<10||Every 1 y|
Surgical management of MEN1 is complex and controversial, given the multifocal and multiglandular nature of the disease. Patients with MEN1 have a high risk of tumor recurrence, even after surgery. Additionally, these patients may have an increased risk of developing venous thromboembolisms.[
Treatment for parathyroid tumors
Once evidence of parathyroid disease is established biochemically, surgical removal of the hyperfunctional parathyroid tissue is recommended to achieve eucalcemia and euparathyroidism. However, the timing and the amount of parathyroid and thymus gland tissue that is removed during surgery remains controversial.[
Some groups reserve surgical intervention for symptomatic patients, with continued annual biochemical screening for those without objective signs of disease. Subtotal parathyroidectomy (removal of 3–3.5 glands) is commonly suggested as the initial surgical treatment when a provider decides to proceed with surgery.[
Total parathyroidectomy with autotransplantation of parathyroid tissue to a distant site, such as the forearm, is a less commonly recommended option. Likelihood of cancer recurrence is lowered with total parathyroidectomy. However, this procedure also renders the patient aparathyroid for a period of time while the autotransplanted tissue becomes functional. This can cause a permanent PTH deficiency (no detectable PTH in the body).[
Treatment for duodenopancreatic NETs
The timing and extent of surgery for duodenopancreatic NETs are controversial and depend on many factors, including severity of symptoms, extent of disease, functional component, location and necessity of simple enucleation, subtotal or total pancreatectomy, and pancreaticoduodenectomy (Whipple procedure). Surgical enucleation has been associated with higher recurrence compared with distal pancreatectomy, and a decreased rate of endocrine insufficiency compared with a Whipple procedure.[
Individuals with MEN1 who are diagnosed with NETs often have multiple tumors of various types throughout the pancreas and duodenum, some of which can be identified using magnetic resonance imaging or computed tomography (CT). Combining functional tracer accumulation with anatomic imaging improves tumor localization. 68Ga-DOTATATE PET-CT demonstrates excellent sensitivity in mapping duodenopancreatic NET disease. This modality may guide the initial workup and appears to be superior to standard somatostatin octreotide, especially for lesions smaller than 10 mm.[
In the current era of effective treatment for hyperfunctional hormone excess states, most MEN1-related deaths are due to the malignant nature of duodenopancreatic NETs. A less common but important risk of death is from malignant thymic carcinoid tumors. Indicators of a poor MEN1 prognosis include elevated fasting serum gastrin, the presence of functional hormonal syndromes, liver or distant metastases, aggressive duodenopancreatic NET growth, large duodenopancreatic NET size, or the need for multiple parathyroidectomies. The most common cause of non-MEN1–related death in this patient cohort is from cardiovascular disease.[
Other duodenopancreatic NETs
Glucagonomas, VIPomas, and somatostatinomas are rare but often have higher rates of malignancy than other duodenopancreatic NETs.[
Medical management of insulinoma using diet and medication is often unsuccessful; the mainstay of treatment for this tumor is surgical resection.[
Most MEN1-associated gastrinomas originate in the duodenum. These tumors are typically multifocal and cause hyper-secretion of gastrin, with resultant peptic ulcer disease (Zollinger-Ellison syndrome).[
Several published series have shown a positive correlation between primary tumor size and rate of distant metastasis. One retrospective study showed that 61% of patients with tumors larger than 3 cm had liver metastases.[
The type of surgery for gastrinoma depends on many factors. A Whipple procedure is typically discouraged as an initial surgery, given the high postoperative morbidity and long-term complications, such as diabetes mellitus and malabsorption. Less extensive operations have been described with varying results. At a minimum, duodenectomy with intraoperative palpation and/or ultrasonography to locate and excise duodenal tumors and peri-pancreatic lymph node dissection are performed.[
Approximately 50% of individuals with MEN1 will develop nonfunctioning NETs.[
Medical therapy to suppress hypersecretion is often the first line of therapy for MEN1-associated pituitary tumors. In one series of 136 patients, medical therapy was successful in approximately one-half of patients with secreting tumors (49 of 116, 42%), and successful suppression was correlated with smaller tumor size.[
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)[
Historically, individuals with MEN2 were given one of the following clinical subtypes based on the presence or absence of certain endocrine tumors in the individual/family:
Current stratification has moved away from a solely phenotype -based classification to one that is based on genotype (i.e., the pathogenic variant) and phenotype.[
The prevalence of MEN2 has been estimated to be approximately 1 in 35,000 individuals.[
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.[
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.[
MTC accounts for 1% to 2% of new cases of thyroid cancer diagnosed annually in the United States.[
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,[
Level of evidence (Screening): 3
Natural history of MTC
Thyroid cancer represents approximately 2.2% of new malignancies occurring annually in the United States, with an estimated 43,720 cancer diagnoses and 2,120 cancer deaths expected in 2023.[
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.[
Average survival for MTC is lower than that for more common thyroid cancers (e.g., 86%–89% 5-year survival for MTC compared with 94%–98% 5-year survival for papillary and follicular thyroid cancer).[
In addition to early stage at diagnosis, other factors associated with improved survival in MTC include smaller tumor size, younger age at diagnosis, and diagnosis by biochemical or genetic screening (i.e., screening for calcitonin elevation, RET variants) versus symptoms.[
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.[
While most MTC cases are sporadic, approximately 20% to 25% are hereditary caused by pathogenic variants in the RET proto-oncogene.[
PHEOs arise from the catecholamine-producing chromaffin cells of the adrenal medulla. They are relatively rare tumors 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.[
In individuals with a personal history of PHEO, an MEN2 diagnosis is often considered in those with bilateral PHEOs, those with early age of PHEO onset (age <35 y), and those with a personal and/or family history of MTC or hyperparathyroidism. For more information, see the Familial PHEO and PGL Syndrome section. However, MEN2 is not the only genetic disorder with a predisposition to PHEOs; other disorders include neurofibromatosis type 1 (NF1), von Hippel-Lindau disease (VHL),[
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.[
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.
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.[
The classical MEN2A subtype makes up about 60% to 90% of MEN2 cases. The MEN2A subtype was initially called Sipple syndrome.[
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.[
MEN2-associated PHEOs are more often bilateral, multifocal, and associated with extratumoral medullary hyperplasia.[
Unlike the PHPT seen in MEN1, hyperparathyroidism in individuals with MEN2 is typically asymptomatic or associated with only mild elevations in calcium.[
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.[
MEN2A with Hirschsprung disease (HSCR)
HSCR, a disorder of the enteric plexus of the colon that typically results in enlargement of the bowel and constipation or obstipation in neonates, occurs in a small number of individuals with MEN2A-associated RET pathogenic variants.[
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. MEN2A families may exhibit some or all of these features. As an autosomal dominant syndrome, transmission can occur through maternal or paternal lineages.
Familial medullary thyroid cancer (FMTC)
Up to 50% of MEN2A cases are of the FMTC subtype, and are defined as families or single individuals with germline RET pathogenic variants and MTC alone in the absence of PHEO or parathyroid adenoma/hyperplasia.[
MEN2B is diagnosed clinically by the presence of mucosal neuromas of the lips and tongue, medullated corneal nerve fibers, distinctive facies with enlarged lips, an asthenic Marfanoid body habitus, and MTC.[
The MEN2B subtype makes up about 5% of MEN2 cases. The MEN2B subtype was initially called mucosal neuroma syndrome or Wagenmann-Froboese syndrome.[
Patients with MEN2B may have diffuse ganglioneuromatosis of the gastrointestinal tract with associated symptoms that include abdominal distension, megacolon, constipation, and diarrhea.[
About 75% of patients have a Marfanoid habitus, often with kyphoscoliosis or lordosis, joint laxity, and decreased subcutaneous fat. Proximal muscle wasting and weakness can also be seen.[
A retrospective review of the clinical presentation of 35 cases of MEN2B with de novo pathogenic variants treated at a single institution found that 22 cases were diagnosed because of endocrine manifestations of the syndrome.[
It is critical for pediatricians to maintain a high index of suspicion when evaluating patients with any of the clinical manifestations associated with MEN2B. In a child, the presence of oral and ocular neuromas and/or a tall and lanky appearance may warrant further investigation.[
Molecular Genetics of MEN2
MEN2 syndromes are the result of inherited pathogenic variants in the RET gene, located on chromosome region 10q11.2.[
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.[
Genetic testing for MEN2
MEN2 is a well-defined hereditary cancer syndrome. Genetic testing is an important management tool for individuals and/or family members who are at risk for MEN2. The American Thyroid Association and NCCN recommend that all patients with MTC consider genetic testing, even if they have other known risk factors that contribute to MTC.[
Germline DNA testing for RET pathogenic variants is generally recommended to all individuals with a diagnosis of MTC, regardless of whether there is a personal or family history suggestive of MEN2.[
There is no evidence for the involvement of other genetic loci, and all pathogenic variant–negative families analyzed to date have demonstrated linkage to the RET gene. For families that do not have a detectable pathogenic variant, clinical recommendations can be based on the clinical features in the affected individual and in the family.
There is considerable diversity in the techniques used and the approach to RET pathogenic variant testing among the various laboratories that perform this procedure. Methods used to detect variants in RET include polymerase chain reaction (PCR) followed by restriction enzyme digestion of PCR products, heteroduplex analysis, single-stranded conformation polymorphism analysis, denaturing high-performance liquid chromatography, and DNA sequencing.[
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.[
ATA-Highest Risk (HST) (previously labeled ATA-D) pathogenic variants are the most aggressive and carry the highest risk of developing MTC.[
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.[
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.[
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%).[
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).[
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.[
|RETPathogenic variant||Exon||Risk of Aggressive MTC||Approximate Incidence of PHEO||Approximate Incidence of HPTH||Presence of CLA||Presence of HSCR|
|CLA = cutaneous lichen amyloidosis; HSCR = Hirschsprung disease; HPTH = hyperparathyroidism; MTC = medullary thyroid cancer; PHEO = pheochromocytoma.|
| a Adapted from Wells et al.[
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 MEN2A phenotypes. Others may represent low-penetrance alleles or modifying alleles that confer only a modest risk of developing MTC.[
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 or haplotypes is being analyzed for its impact on the likelihood for development of PHEO, hyperparathyroidism, HSCR, and age at onset of metastatic involvement with MTC.[
Screening at-risk individuals for PHEO
The presence of a functioning PHEO can be excluded by appropriate biochemical screening before thyroidectomy in any patient with MEN2A or MEN2B. However, childhood PHEOs are rare in MEN2.[
Level of evidence: 5
Screening at-risk individuals for hyperparathyroidism
MEN2-related hyperparathyroidism is generally associated with mild, often asymptomatic hypercalcemia early in the natural history of the disease, which, left untreated, may become symptomatic.[
Level of evidence: 5
Screening at-risk individuals in kindreds without an identifiableRETpathogenic variant
Risk-reducing thyroidectomy is not routinely offered to at-risk individuals unless MEN2A is confirmed. The screening protocol for MTC in patients with MEN2A is annual calcitonin stimulation test; however, caution must be used in interpreting test results because CCH that is not a precursor to MTC occurs in about 5% of the population.[
For patients at risk of FMTC, annual screening for MTC is the same as for patients with MEN2A.
Level of evidence: 5
Treatment for MTC
Risk-reducing thyroidectomy (also referred to as early thyroidectomy and previously referred to as prophylactic thyroidectomy) is the oncologic treatment of choice for patients with MEN2. Children with the M918T RET pathogenic variant may benefit from a thyroidectomy in the first year of life, perhaps in the first months of life.[
A multidisciplinary team caring for the patient, including the pediatrician, pediatric endocrinologist, and surgeon should determine the timing of surgery in conjunction with the child's parents on the basis of the trend in serum calcitonin levels, ultrasonographic findings, preference of the family, and experience of the treating physicians.[
In children with some ATA-H or ATA-MOD RET pathogenic variants, some studies have suggested that basal and pentagastrin-stimulated calcitonin levels could be used to determine the timing of total thyroidectomy.[
For patients with RET germline variants, older age at prophylactic thyroidectomy has been significantly associated with a higher risk of postoperative persistent or recurrent disease.[
Although thyroidectomy before biochemical evidence of disease (normal preoperative calcitonin) may reduce the risk of recurrent disease, a selective strategy for postoperative and lifelong surveillance might depend on the final pathologic determination of whether a carcinoma was present and whether it was micromedullary or macromedullary.[
Questions remain concerning the natural history of MEN2. As more information is acquired, recommendations regarding the optimal age for thyroidectomy and the potential role for genetics and biochemical screening may change. Earliest reports of MTC in MEN2B before age 3 years, and before age 6 years in MEN2A cases with ATA-H or ATA-MOD RET variants have been documented.[
Level of evidence: 4b
The standard treatment for adults with MTC is surgical removal of the entire thyroid gland, including the posterior capsule and central lymph node dissection.[
The MEN2B RET variant M918T is associated with approximately 100% incidence of MTC in the first years of life [
The ATA recommends compartment-directed lymph node dissection for local or regional disease (no evidence of distant metastases) in the following situations:[
Although basal calcitonin levels may not be able to identify all patients with MTC preoperatively, this test has utility as a predictor of postoperative remission, lymph node metastases, and distant metastases.[
With regard to prognosis, structural and metastatic disease recurrence is common in germline RET pathogenic variant carriers and can happen up to 20 years after initial treatment. Despite this, overall survival (OS) is generally favorable, with one study citing an OS rate of 92% at 10 years.[
Patients who have had total thyroidectomy will require lifelong thyroid hormone replacement therapy. The dosing of medication is age-dependent, and treatment may be initiated on the basis of ideal body weight. For healthy adults aged 60 years and younger with no cardiac disease, a reasonable starting dose is 1.6 µg/kg to 1.8 µg/kg given once daily.[
Level of evidence (central neck dissection): 5
Level of evidence (hormone replacement therapy): 3c
Level of evidence (therapeutic thyroidectomy): 4
Chemotherapy and radiation therapy are generally not effective against MTC.[
There are two U.S. Food and Drug Administration–approved RET inhibitors (pralsetinib and selpercatinib) that are now available for patients with MTC who have a RETpoint mutation. These RET inhibitors are also available for patients who have differentiated thyroid cancers with a RET fusion. A multicenter, phase I/II trial (ARROW) was conducted to evaluate the efficacy of pralsetinib in patients with RET-mutant MTC with or without prior treatment with vandetanib or cabozantinib. Among 55 patients who were previously treated with a multikinase inhibitor, the overall response rate was 60% (95% confidence interval [CI], 46%–73%) and 1-year progression-free survival (PFS) rate was 75% (95% CI, 63%–86%). Among 21 treatment-naïve patients, the overall response rate was 71% (95% CI, 48%–89%) and the 1-year PFS rate was 81% (95% CI, 63%–98%).[
The use of vandetanib and cabozantinib is approved by the U.S. Food and Drug Administration for adult patients with progressive metastatic MTC who are ineligible for surgery. A phase III study found that progression-free survival (PFS) was longer in adults who received vandetanib than in those who received placebo.[
Level of evidence (pralsetinib): 4
Level of evidence (selpercatinib): 3dii
Level of evidence (vandetanib): 2
Level of evidence (cabozantinib): 1
For more information, see Thyroid Cancer Treatment.
Treatment for MEN2-related PHEO
A cognitive shift has occurred in the field regarding the risks and benefits of whole organ resection. This is especially relevant for endocrine glands that are difficult to manage postresection and may require replacement therapy. PHEO may be either unilateral or bilateral in patients with MEN2. Laparoscopic adrenalectomy (anterior or posterior) is the recommended approach after appropriate preoperative medical blockade for the treatment of unilateral PHEO.[
Regarding the operative approach, several studies examined the value of a posterior retroperitoneoscopic adrenalectomy and found it to be safe and effective, with very low mortality and a low rate of minor complications, and conversion to open surgery required rarely.[
Level of evidence: 4
Treatment for hyperparathyroidism
Most patients with MEN2-related parathyroid disease are either asymptomatic or diagnosed incidentally in the preoperative planning or at the time of thyroidectomy. Typically, the hypercalcemia (when present) is mild, although it may be associated with increased urinary excretion of calcium and nephrolithiasis. As a consequence, the indications for surgical intervention are generally similar to those recommended for patients with sporadic PHPT.[
Treatment of hyperparathyroidism typically employs some extent of surgical removal of the involved glands. Cure of hyperparathyroidism was achieved surgically in 89% of one large series of patients;[
Some investigators have suggested using the MEN2 subtype to decide where to place the parathyroid glands that are identified at the time of thyroid surgery. For patients with MEN2B in whom the risk of parathyroid disease is quite low, the parathyroid glands may be left in situ in the neck. For adult patients with MEN2A, in whom the glands have been inadvertently devascularized during primary surgical treatment for MTC, it is suggested that the glands needing reimplantation be implanted in the nondominant forearm. This approach minimizes the need for further surgical intervention in the neck should hyperparathyroidism develop or recur.[
Medical therapy of hyperparathyroidism has gained popularity with the advent of calcimimetics, agents that sensitize the calcium-sensing receptors on the parathyroid glands to circulating calcium levels and thereby reduce circulating PTH levels. In a randomized, double-blind, placebo-controlled trial, cinacalcet hydrochloride was shown to induce sustained reduction in circulating calcium and PTH levels in patients with PHPT.[
Level of evidence: 5
Mode of inheritance
All of the MEN2 subtypes are inherited in an autosomal dominant manner. For the child of someone with MEN2, the risk of inheriting the MEN2 pathogenic variant is 50%. Some individuals with MEN2, however, carry a de novo pathogenic variant; that is, they carry a new pathogenic variant that was not present in previous generations of their family and thus do not have an affected parent. The proportion of individuals with MEN2 who have an affected parent varies by subtype.
MEN2A: About 95% of affected individuals have an affected parent. It is appropriate to evaluate the parents of an individual with MEN2A for manifestations of the disorder. In the 5% of cases that are not familial, either de novo pathogenic variants or incomplete penetrance of the mutant allele is possible.[
FMTC: Multiple family members are affected; therefore, all affected individuals inherited the mutant gene from a parent.
MEN2B: About 50% of affected individuals have de novo RET gene pathogenic variants, and 50% have inherited the pathogenic variant from a parent.[
Siblings of a proband: The risk to siblings depends on the genetic status of the parent, which can be clarified by pedigree analysis and/or DNA-based testing. In situations of apparent de novo pathogenic variants, germline mosaicism in an apparently unaffected parent must be considered, even though such an occurrence has not yet been reported.
Attitudes toward preimplantation genetic testing
One study explored the attitudes of individuals with MEN1 and MEN2 toward preimplantation genetic testing (PGT).[
The psychosocial impact of genetic testing for pathogenic variants in RET has not been extensively studied. Published studies have had limitations such as small sample size and heterogeneous populations; thus, the clinical relevance of these findings should be interpreted with caution. Identification as the carrier of a pathogenic variant may affect self-esteem, family relationships, and quality of life.[
One study examined levels of psychological distress in the interval between submitting a blood sample and receiving genetic test results. Those individuals who experienced the highest level of distress were younger than 25 years, single, and had a history of responding to distressful situations with anxiety.[
A small qualitative study (N = 21) evaluated how patients with MEN2A and family members conceptualized participation in lifelong high-risk surveillance.[
Multiple endocrine neoplasia type 4 (MEN4) is a novel, rare syndrome with clinical features that overlap with the other MEN syndromes. The most common phenotype of the 19 established cases of MEN4 that have been described to date is primary hyperparathyroidism (PHPT), followed by pituitary adenomas. MEN4 is caused by germline pathogenic variants in the tumor suppressor gene CDKN1B (12p13.1).[
PHPT due to parathyroid neoplasia affects approximately 80% of the reported cases of MEN4. PHPT occurs at a later age in MEN4 than in MEN1 (mean age ~56 y vs. ~25 y, respectively), with a female predominance.[
Genetics, Inheritance, and Genetic Testing for MEN4
The CDKN1B variant codes for p27Kip1 (commonly referred to as p27 or KIP1), a putative tumor suppressor gene that regulates cell cycle progression. Alterations in this gene lead to a decrease in expression of p27 protein, triggering uncontrolled cell cycle progression. Although the loss of one allele of p27 is a frequent event in many human cancers, the remaining allele is rarely mutated or lost by loss of heterozygosity in human cancers.[
To date, only 19 cases having CDKN1B germline variants have been reported in the medical literature.[
Index cases or individuals with MEN1-like features and negative results of MEN1 genetic testing are offered genetic counseling and testing for MEN4. Confirmation of an MEN4 diagnosis is only made with genetic testing for CDKN1B variants. In clinical practice, patients with asymptomatic or symptomatic PHPT who are also young (typically <30 y) and have multigland disease, parathyroid carcinoma, or atypical adenoma, or those with a family history or evidence of syndromic disease and negative for MEN1 or RET, are candidates for genetic testing for CDKN1B using accredited laboratories.[
Surveillance of CDKN1B pathogenic variant carriers should be performed, though guidelines have not been established yet.[
Similar to the treatment used in other familial syndromes, surgical treatment is recommended for parathyroid and pituitary disease. For more information, see the MEN1 section.
A study of 293 MEN1 pathogenic variant–positive cases and 30 MEN1 pathogenic variant–negative cases, all with the MEN1 phenotype, showed that the pathogenic variant–negative cohort developed disease manifestations later in life, with improved life expectancy.[
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.[
PHEOs and PGLs may occur sporadically, as manifestations of a hereditary syndrome, or as the sole tumor in one of several hereditary PHEO/PGL syndromes. Some individuals with a predisposition to PHEOs/PGLs do not have a known family history of these tumors. For example, a study of 108 patients with PHEOs/PGLs found that 33% of patients with a germline pathogenic variant did not have family histories of a hereditary PHEO/PGL syndrome. Similarly, 36% of the patients with SDHB germline pathogenic variants did not have family histories of PHEOs/PGLs or personal histories of PHEOs/PGLs at presentation.[
Most sporadic PHEOs occur unilaterally. Bilateral PHEOs are more likely to occur in a hereditary condition. A single-center study of patients with PHEOs found that up to 7% of adults and 37.5% of children had bilateral PHEOs. Synchronous tumors were seen in 80% of patients with bilateral PHEOs. When metachronous PHEOs were identified, the median time to develop a second PHEO was 4.5 years (range 1–38 y). Hereditary cancer syndromes were identified in 80% of individuals with bilateral PHEOs. These syndromes included multiple endocrine neoplasia type 2A (MEN2A) (found in 42.6% of patients), von Hippel-Lindau Disease (VHL) (found in 19.1% of patients), MEN2B (found in 9.6% of patients), and neurofibromatosis type 1 (found in 8.5% of patients).[
PGLs and PHEOs are typically slow-growing tumors, and some may be present for many years before coming to clinical attention. A minority of these tumors are malignant and present with an 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 the bone, liver, and lungs.[
There are a lack of reliable molecular, immunohistochemical, and genetic predictors that distinguish between benign and malignant tumors.[
Clinical Diagnosis of PHEO and PGL
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.[
Patients with clinically apparent catecholamine excess generally undergo biochemical testing to evaluate the secretory capacity of the tumor(s).[
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.[
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).[
While further study is needed to determine the optimal imaging strategy for each PHEO/PGL case, gallium Ga 68-DOTATATE (68Ga-DOTATATE) PET-CT is a more recently developed, highly sensitive imaging modality that can identify PHEOs/PGLs.[
Genetics, Inheritance, and Genetic Testing for Familial PHEO and PGL Syndrome
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 classical PGL/PHEO susceptibility genes.[
PGLs and PHEOs can be seen as part of several well-described tumor susceptibility syndromes including von Hippel-Lindau disease (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.[
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. FPGL/PHEO syndromes are among the rare inherited diseases in which genomic imprinting contributes to the risk of disease. 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. There are reports of disease in individuals with maternally inherited SDHD pathogenic variants,[
Genetic testing for hereditary PHEO and PGL syndromes has until recently been largely based on published algorithms,[
In FPGL/PHEO, the type and location of tumors, age at onset, and lifetime penetrance vary depending on which genetic variant an individual has. While these correlations can help guide genetic testing and screening decisions, caution must be used since there is a high degree of variability in these conditions. For more information, see Table 6.
|Gene||Risk of PGL/PHEO||Primary Location||Risk of Metastatic or Recurrent Disease||Other Associated Features|
|CNS = central nervous system; FPGL = familial paraganglioma; GIST = gastrointestinal stromal tumor; HNPGL = head and neck paraganglioma; MTC = medullary thyroid cancer; NETs = neuroendocrine tumors; PGL = paraganglioma; PHEO = pheochromocytoma; PHPT = primary hyperparathyroidism; RCC = renal cell carcinoma.|
| a Adapted from Fishbein et al.[
|NF1||Up to 13%||PHEO (rare case reports of PGL)||~12%||Neurofibromas, Lisch nodules, café au lait spots, optic gliomas, skeletal dysplasia|
|VHL||20%||PHEO (bilateral) (rare case reports of PGL)||<5%||RCC (clear cell type), pancreatic NETs, CNS hemangioblastomas (including the retina)|
|RET||50%||PHEO (bilateral) (rare case reports of PGL)||<5%||MTC, PHPT|
|SDHA||10%||PGL, PHEO||12%||RCC (clear cell type), GIST|
|SDHB||25%||PGL, HNPGL, PHEO||25%–50%|
|SDHC||Low||HNPGL (unifocal), thoracic PGL||<5%|
|SDHD||45%||HNPGL (multifocal), PGL, PHEO||<5%–8%|
|TMEM127||Low||PHEO, PGL less common||<5%||RCC|
|FH||Very Low||PGL||May be high||RCC (papillary type), cutaneous leiomyomas, uterine fibroids|
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, with a low rate of malignancy.[
The SDHD pathogenic variant p.Pro81Leu (P81L) is common, especially among individuals of European ancestry, and has been previously described as having a distinct phenotype with a low risk for PHEO and sympathetic PGL, and almost exclusive presentation of head and neck PGL.[
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. While older studies reported a high age-related penetrance,[
Symptoms of hormonal hypersecretion in those with pediatric-onset PGL/PHEO were common in one series of pediatric carriers of SDHB germline pathogenic variants; hypertension was seen in 76%, followed by headache in 68%, sweating/diaphoresis in 51%, palpitations in 40%, nausea and/or vomiting in 31%, and flushing in 25%.[
SDHC pathogenic variants are rare, accounting for an estimated 0.5% of all PGLs.[
Pathogenic variants in SDHA, SDHAF2, MAX, and TMEM127 have also been described; collectively, they account for up to 6% of cases without pathogenic variants in the classical PGL/PHEO genes, with about one-half of these in SDHA.[
Although biallelic pathogenic variants in SDHA have long been known to cause the autosomal recessive condition inherited juvenile encephalopathy/Leigh syndrome,[
Initially, pathogenic variants in SDHAF2 were described only in head and neck PGLs.[
The MAX gene was first described as a PHEO susceptibility gene in 2011 through exome sequencing of three unrelated cases.[
The TMEM127 gene is located on chromosome 2q11.2. It encodes a transmembrane protein that is 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.[
Another study looked at TMEM127 and other genes. Here, an additional 58 patients from the European-American-Asian Pheochromocytoma-Paraganglioma Registry Study Group more than doubled the number of previously reported carriers of rare PGL/PHEO predisposition genes SDHA (n = 29), SDHAF2 (n = 1), MAX (n = 8), and TMEM127 (n = 20).[
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 the optimal imaging protocol in SDH pathogenic variant carriers remains unclear, annual biochemical testing and clinical surveillance may be considered. A combined approach of imaging and biochemical testing may be beneficial, since biochemical testing can miss up to 29% of SDH-related tumors, and imaging has varying sensitivity rates based on the radioisotope that is used.[
Level of evidence: 4
Medical management is the bridge to surgical resection of PGLs/PHEOs. Preoperative medical therapy is not essential for patients without evidence of catecholamine hypersecretion, although some advocate its use regardless of the results of hormonal testing.[
In the absence of a randomized controlled trial comparing the various regimens, there is no universally recommended approach. The alpha-adrenoreceptor blocker phenoxybenzamine (Dibenzyline) is most frequently used to control blood pressure and expand the blood volume.[
A high-volume tertiary care center proposed deviating from the general recommendation for perioperative alpha-receptor blockade. In a closed-case series that compared patients with and without blockade, there was no significant difference in maximal intraoperative systolic arterial pressure or hypertensive episodes.[
Once the alpha blockade is initiated, expansion of the blood volume is often necessary, as these patients are typically volume contracted.[
Calcium channel blockers such as nicardipine or nifedipine also have been employed to control the hypertension preoperatively.[
Consideration of preoperative imaging is warranted if a pathogenic variant has been identified in a PHEO/PGL syndrome gene. This may alter an individual's surgical plan and approach.[
Surgical resection is the treatment of choice for PGL and PHEO. Both open resection and laparoscopic approaches are safe, but if feasible, laparoscopic removal is preferred.[
PGLs are commonly located in the para-aortic retroperitoneal sympathetic chain above the aortic bifurcation, below the takeoff of the inferior mesenteric artery (organ of Zuckerkandl), or near the dome of the bladder.[
Genetic testing is best performed before the initial surgery to inform the risk of recurrent or contralateral disease and to guide the extent of resection (e.g., whether to preserve the cortex) because synchronous or metachronous bilateral disease is quite common in hereditary PHEO. Preoperative knowledge of a germline pathogenic variant significantly affects variables associated with a cortical-sparing adrenalectomy. Preserving the cortex is important in patients with a known pathogenic variant because they are at risk of developing a contralateral tumor. Cortical sparing reduces the possibility of future adrenal insufficiency with contralateral adrenalectomy. This consideration must be weighed against the high risk of malignancy in SDHB carriers. Cortical-sparing surgery is an attractive option because it minimizes the risk of adrenal insufficiency and the need for lifelong steroid supplementation. In large series of patients, cortical-sparing surgery has a 3% to 7% recurrence rate after cortical preservation versus a 2% to 3% recurrence rate after total resection (recurrence in the adrenal bed).[
Level of evidence: 5
Carney-Stratakis syndrome (CSS; also known as Carney-Stratakis dyad) was first described in 2002. CSS is distinct from similarly named syndromes, Carney Complex and Carney Triad (for more information, see Table 7). 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.[
|Syndrome||Inheritance Pattern||Mean Age at Onset (y)||Affected Sex||Associated Lesions||Pathogenic Variants||Tumor Behavior|
|AD = autosomal dominant; GIST = gastrointestinal stromal tumor; F = female; M = male.|
||AD||23||M, F||Paraganglioma, stomach epithelioid GIST||GermlineSDHxpathogenic variants common; noKITorPDGFRApathogenic variants||GIST metastasis but protracted course; paraganglioma aggressive|
||None||<30||>95% F||Lung chondroma, paraganglioma, stomach epithelioid GIST||NoKITorPDGFRApathogenic variants; rarely,SDHxpathogenic variants (9.5% in one series)[
||GIST metastasis but protracted course|
||AD||20||M, F||Lentigines, myxomas, schwannoma, thyroid follicular adenomas or carcinoma, primary pigmented nodular adrenocortical disease, pituitary adenomas||GermlinePRKAR1Apathogenic variants||N/A|
Genetics, Inheritance, and Genetic Testing for CSS
The tumorigenesis of CSS-associated GISTs appears to involve succinate dehydrogenase deficiency rather than gain-of-function mutation in the KIT or PDGFRA gene, as is seen in the vast majority of GISTs.[
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.[
Level of evidence: 4
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.[
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.[
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.[
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
Papillary and follicular cancers, along with their various histologic subtypes, arise from the follicular cells of the thyroid and are collectively referred to as differentiated thyroid cancer or nonmedullary thyroid cancer (NMTC). Papillary thyroid cancer (PTC) is the most common form of thyroid cancer, comprising over 85% of all cases, and is rapidly increasing in incidence worldwide.[
Radiation exposure, particularly during childhood, has been extensively studied as a causative factor in the development of thyroid cancer; however, it accounts for only a small minority of cases.[
Further confounding the distinction between inherited and sporadic disease is the high prevalence of incidental microcarcinomas, which may be found in 10% to 15% of surgeries or autopsies.[
FNMTC may be part of a larger syndrome associated with tumors involving other organs or may represent a stand-alone condition. Table 8 outlines the various hereditary syndromes associated with NMTC.
Genetics, Inheritance, and Genetic Testing for Familial NMTC
The genetics of familial medullary thyroid cancer (FMTC) in the context of multiple endocrine neoplasia type 2 are well established. Genetic factors also clearly contribute to NMTC, as it has one of the highest heritabilities of any cancer site, with a relative risk of fivefold to tenfold for relatives of patients, especially (female) siblings.[
Ruling out syndromic FNMTC
As there is no clinical genetic testing for nonsyndromic FNMTC, identification of at-risk families must rely on astute clinicians obtaining a thorough clinical examination and detailed personal and family history of any patient presenting with thyroid cancer or disease. Aspects of a history that suggest FNMTC include multiple generations affected, early-onset bilateral/multifocal thyroid tumors (especially in males) with a more aggressive clinical course, and association with benign thyroid pathologies.[
|Syndrome||Gene||Inheritance||Incidence of Thyroid Cancer (%)||Type of Thyroid Cancer||Extrathyroidal Clinical Features|
|FAP = familial adenomatous polyposis; FTC = follicular thyroid cancer; MNG = multinodular goiter; PTC = papillary thyroid cancer.|
| a Adapted from Nose,[
|FAP/Gardner syndrome||APC||Autosomal dominant||2||PTC (cribriform morular variant)||Gastrointestinal adenomatous polyps; Gardner syndrome also includes desmoid tumors, supernumerary teeth, fibrous dysplasia of skull, osteomas, epidermoid cysts, hypertrophy of retinal epithelium|
|Cowden syndrome (PTENhamartoma syndrome)||PTEN(rarelySDHx,KLLN,AKT1,PIK3CA)||Autosomal dominant||10–35||FTC, PTC||Malignant tumors and hamartomas of breast, endometrium, thyroid, kidney, gastrointestinal tract, brain, skin|
|Carney complex||PRKAR1α||Autosomal dominant||11–15||FTC, PTC||Myxomas of soft tissues, skin and mucosal pigmentation (blue nevi), schwannomas, tumors of adrenal, pituitary and testicle|
|Werner syndrome||WRN||Autosomal recessive||18||FTC, anaplastic PTC||Premature aging (adult progeria), scleroderma-like skin changes, cataracts, subcutaneous calcifications, muscular atrophy, diabetes|
|DICER1syndrome||DICER1||Autosomal dominant||Unknown||PTC (and MNG)||Familial pleuropulmonary blastoma; cystic nephroma; ovarian Sertoli-Leydig cell tumors|
|McCune-Albright syndrome||GNAS||Mosaicsomatic mutations||Unknown||FTC||Polyostotic fibrous dysplasia, café-au-lait spots, endocrine hyperfunction of pituitary, adrenal, gonadal tissues|
|Peutz-Jeghers syndrome||STK11 (LKB1)||Autosomal dominant||Unknown||Primarily PTC||Hamartomas of small intestine, mucocutaneous hyperpigmentation, Sertoli cell testicular tumors|
|Ataxia-telangiectasia||ATM||Autosomal recessive||Unknown||Primarily PTC||Cerebellar ataxia and nystagmus, oculocutaneous telangiectasia, immunodeficiency, lymphoreticular cancers|
|Multiple endocrine neoplasia type 1 (MEN1)||MEN1||Autosomal dominant||Unknown||Primarily PTC||Tumors of parathyroid glands, endocrine gastroenteropancreatic tract, anterior pituitary gland|
Identifying genes and inherited variants associated with nonsyndromic FNMTC
Various methods have been employed to uncover the landscape of genetic variation associated with FNMTC, mainly genome-wide linkage analysis using microsatellite markers evenly distributed across the genome and informative large pedigrees with multiple affected family members. More than 15 genetic loci have been linked to FNMTC, which are summarized in Table 9. The loci that are italicized represent those where the susceptibility gene has been identified; the causal genes at the other loci remain unknown. The first four loci were identified by microsatellite linkage analysis. The remaining loci have been identified by increasingly dense single nucleotide variant (SNV) arrays as well as microRNA arrays and, most recently, next-generation sequencing. Most of these studies have been done on groups of families with pedigrees consistent with FNMTC; however, two of the loci were identified through large, population level SNV array analysis. Notably, several studies have excluded the genes that are most commonly somatically altered in association with sporadic NMTC as having a role in FNMTC, namely BRAF, RET, RET/PTC, MET, MEK1, MEK2, RAS, and NTRK.[
|Locus||Location||Tumor Type||Sample Sizea||Study Type||Original Cohort Country of Origin||Year||References|
|FTC = follicular thyroid cancer; MNG = multinodular goiter; miRNA = microRNA; NMTC = nonmedullary thyroid cancer; PRN = papillary renal neoplasia; PTC = papillary thyroid cancer; SNV = single nucleotide variant; WES =whole-exome sequencing.|
|a Combined across studies.|
|MNG1||14q31||MNG with PTC||1kindred||Microsatellite linkage||Canada||1997||[
|TCO||19p13.2||PTC with oxyphilia||1 kindred||Microsatellite linkage||France||1998||[
|fPTC/PRN||1q21||PTC with PRN||1 kindred||Microsatellite linkage||United States||2000||[
|NMTC1||2q21||PTC (follicular variant)||1 kindred, 80 pedigrees||Microsatellite linkage||Tasmania||2001||[
|FTEN||8p23.1-p22||PTC (classic)||1 kindred||10K SNV array||Portugal||2008||[
|Unknown||8q24||PTC with melanoma||26 families||50K SNV array||United States||2009||[
|FOXE1||9q22.33||PTC/FTC||60 families||300K SNV array||Iceland/Spain/United States||2009||[
|NKX2-1/TITF-1||14q13.3||PTC and MNG||60 families||300K SNV array||Iceland/United States/Spain||2009||[
|Unknown||6q22||PTC/FTC (classic)||38 families||50K SNV array||United States/Italy||2009||[
|miR-886-3p||5q31.2||PTC||21 PTC||3K miRNA array||United States||2011||[
|10 normal thyroid tissue|
|miR-20a||13q31.3||PTC||21 PTC||3K miRNA array||United States||2011||[
|10 normal thyroid tissue|
|Telomere-telomerase complex (TERT, TRF1, TFR2, RAP1, TIN2, TPP1, POT1)||5p15.3 (TERT), etc.||PTC||47 PTC||2008||[
|SRGAP1||12q14||PTC||38 families||250K SNV array||United States/Poland||2013||[
|HAPB2||10q25-26||PTC, follicular adenoma||1 kindred||WES||United States||2015||[
|RTFC (c14orf93)||14q11.2||PTC||15 families||WES||China||2017||[
Susceptibility loci identified through linkage analyses
MNG1, TCO, fPTC/PRN and NMTC1 are proposed FNMTC susceptibility loci identified in families with multiple affected individuals and are summarized in Table 9. Conflicting evidence exists regarding the linkage to the loci described above. MNG1 has shown strong evidence of linkage in only one Canadian kindred with multiple multinodular goiters (MNGs) and linkage analyses in 124 additional families failed to find an association between MNG1 and FNMTC. Therefore, the locus may be important for MNG alone but not for FNMTC.[
Susceptibility loci identified through genome-wide SNV arrays
Five FNMTC loci have been identified through increasingly dense SNV arrays, also listed in Table 9. The first FNMTC study done by SNV array along with microsatellite analysis was in 2008 in a Portuguese family.[
In 2009, a population-level study was done in Iceland on 197 cases of PTC or FTC and compared with genotypes of 37,196 Icelandic controls.[
MicroRNA (miRNA) susceptibility loci
miRNAs are small noncoding RNAs that regulate gene expression. Whole-genome miRNA microarrays were used to evaluate 21 sporadic and seven familial NMTC cases, as well as ten normal thyroid tissue samples.[
Telomeres are noncoding chromosomal ends consisting of tandem repeats that are important in maintaining chromosomal stability. Telomere length is maintained by a telomerase complex that includes telomerase reverse transcriptase (TERT), along with six other proteins: TRF1, TFR2, RAP1, TIN2, TPP1, and POT1.[
Other recently identified FNMTC susceptibility genes and variants
SRGAP1 is a gene that was identified in 2013 through genome-wide linkage analysis of 38 FNMTC families with PTC from the United States and Poland.[
HAPB2 was identified in 2015 through whole-exome sequencing (WES) in seven affected members of an FNMTC kindred with PTC and follicular adenoma, using unaffected spouses as controls.[
Lastly, RTFC (c14orf93) was identified through WES of FNMTC families in China.[
In summary, although multiple susceptibility loci have been identified in FNMTC families, no single locus accounts for the majority of nonsyndromic FNMTC and no gene identified shows strong enough associations to warrant clinical genetic testing. Newer sequencing techniques, including WES, will allow for new genes to be discovered and evaluated. Identifying susceptibility genes will allow for screening and early diagnosis, which in turn would lead to improved outcomes for patients and families.
Differentiated thyroid cancer, whether inherited or sporadic, may be associated with a high rate of recurrence, depending on the clinicopathologic features of the disease. Disease recurrence may occur as late as 40 years after initial diagnosis.[
Thyroglobulin, a protein produced by both benign and malignant thyroid follicular cells, is used as a tumor marker for patients with differentiated thyroid cancer. Thyroglobulin measurement is most sensitive after a total thyroidectomy, so detection of thyroglobulin—particularly an increasing trend in the serum concentration—is often an early indicator of recurrent or progressive disease.[
Whether a patient has received radioactive iodine or only surgery, careful ultrasonography of all compartments in the anterior neck is an important tool to determine if there is recurrent or residual disease because most disease is localized in this region. The initial ultrasonography is typically performed 6 to 12 months after surgery.[
Ultrasonography combined with a serum thyroglobulin test has a very high sensitivity for identifying nodal disease, far superior to the radioiodine diagnostic whole-body scans that were historically the mainstay of surveillance.[
Once a thyroid nodule is detected, further work-up includes complete ultrasonography of the thyroid, as well as a comprehensive neck ultrasonography to evaluate the central and lateral neck lymph nodes. Comprehensive preoperative neck ultrasonography not only provides the opportunity for fine-needle aspiration (FNA) biopsy of any suspicious nodes before surgery but also allows the surgeon to plan the appropriate surgery and counsel the patient regarding a surgical procedure and its associated risks.[
FNA is indicated for cytologic evaluation of suspicious nodules based on size of the nodule, imaging characteristics, and associated patient risk factors.[
Although positron emission tomography scanning is not recommended for thyroid nodule assessment, concentrated uptake of contrast in the thyroid gland may be detected when the scan is obtained for other reasons. Incidental increase in fluorine F 18-fludeoxyglucose avidity, and an increase in nodule size (more than 50% volume) during surveillance may also be indications for FNA biopsy of nodules.[
Cytologic evaluation and indeterminate thyroid nodules
The Bethesda Thyroid Cytology Classification standardizes the cytologic interpretation of thyroid biopsies. Pathologic results are classified into one of the following six categories:[
Patients with biopsy-proven malignant nodules (or nodules suspicious for malignancy) may be considered for surgical resection as discussed below. Nodules classified as AUS/FLUS fall into the indeterminate category because the extent of architectural or cytologic atypia excludes a benign diagnosis, but the degree of atypia is insufficient for a definitive malignant classification.[
Surgical treatment of thyroid cancer
Patients with a diagnosis of FNMTC may have increased aggressiveness of disease in comparison with sporadic cases.[
After total thyroidectomy, patients will need lifelong thyroid hormone replacement therapy.[
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Multiple Endocrine Neoplasia Type 1 (MEN1)
Revised text to state that a clinical diagnosis of MEN1 may be made when an individual has two of the three major endocrine tumors (parathyroid tumors, duodenopancreatic neuroendocrine tumors, pituitary tumors), especially if he/she was diagnosed with these tumors at a young age (cited Niederle et al. as reference 5).
Added text to state that to date, there are no well-established genotype-phenotype correlations to guide clinical management of patients with MEN1.
Added Bashford et al. as reference 47.
The Surveillance subsection was extensively revised.
The Treatment for parathyroid tumors subsection was extensively revised.
Multiple Endocrine Neoplasia Type 2 (MEN2)
Updated National Comprehensive Cancer Network (NCCN) (Thyroid Carcinoma) as reference 23.
Updated statistics with estimated new cancer cases and deaths for 2023 (cited American Cancer Society as reference 24).
Added Bashford et al. as reference 81.
Revised text to state that genetic testing is an important management tool for individuals and/or family members who are at risk for MEN2.
Added text to state that risk-reducing thyroidectomy is also referred to as early thyroidectomy and was previously referred to as prophylactic thyroidectomy.
Added Ordóñez et al. as reference 154.
Added text to state that a cognitive shift has occurred in the field regarding the risks and benefits of whole organ resection. This is especially relevant for endocrine glands that are difficult to manage postresection and may require replacement therapy.
Added text to state that in a series of RET p.Cys634 variant carriers, only 1 in 5 developed a second ipsilateral pheochromocytoma (PHEO) after a follow-up period of 8 to 11 years when the cortical preservation technique was used. This technique allows patients to continue making steroid hormones on their own, which makes it a viable surgical option (cited Machens et al. as reference 182).
Familial PHEO and Paraganglioma (PGL) Syndrome
The Clinical Description subsection was extensively revised.
The Clinical Diagnosis of PHEO and PGL subsection was extensively revised.
Revised text to state that genetic testing is recommended for all patients with PHEOs/PGLs because of the high frequency of pathogenic variants associated with PHEO/PGL predisposition syndromes (cited Yip et al. as reference 48).
Added text to state that is unknown whether continued surveillance beyond age 50 to 60 years is beneficial when a patient with familial PHEO/PGL syndrome is asymptomatic. This is an active area of investigation (cited Greenberg et al. as reference 92).
Added text to state that preoperative imaging usually includes a dedicated computed tomography scan of the adrenal glands to visualize PHEOs prior to surgery. This scan can help determine if a cortical-sparing adrenalectomy approach is feasible.
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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 in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
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PDQ® Cancer Genetics Editorial Board. PDQ Genetics of Endocrine and Neuroendocrine Neoplasias. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/thyroid/hp/medullary-thyroid-genetics-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389271]
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Last Revised: 2023-06-16
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