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Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)

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Last Modified: 02/14/2014

Familial Paraganglioma Syndrome

Clinical Description
Clinical Diagnosis of PGL
Genetics, Inheritance, and Genetic Testing
Genotype-Phenotype Correlations


Paragangliomas (PGLs) and pheochromocytomas are rare tumors arising from chromaffin cells, which have the ability to synthesize, store, and secrete catecholamines and neuropeptides. In 2004, the World Health Organization characterized pheochromocytomas as tumors arising in the adrenal gland.[1] (Refer to the Pheochromocytoma section of this summary for more information). Extra-adrenal neoplasms, referred to as PGLs, may arise in various sites from the glomera along the parasympathetic nerves or the paraganglia in the sympathetic trunk. PGLs may be found in the head and neck region, abdomen, or pelvis. Representing 3% of all PGLs,[2] the tumors in the cervical region are typically found in the carotid bifurcation, along the vagal nerve, in the jugular foramen, or in the middle ear space.[3] Tumors below the neck are most commonly located in the upper mediastinum, adrenal medulla (pheochromocytoma), 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] These tumors have an equal sex distribution.[5,6] PGLs can occur at any age but have the highest incidence between the ages of 40 and 50 years.[5,6]

Clinical Description

PGLs may occur sporadically, as a manifestation of a hereditary syndrome, or as the sole tumor in one of several hereditary paraganglioma/pheochromocytoma syndromes. Up to 30% of patients presenting with apparently sporadic PGLs actually have a recognizable germline mutation in one of ten genes.[7] One study found that individuals with a single tumor and a negative family history, the likelihood of an inherited mutation was 11.6%,[7] whereas another group detected mutations in 41% of such patients.[8]

PGLs 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. Malignancy of a paraganglioma and pheochromocytoma is defined by the presence of metastases at sites distant from the primary tumor in nonchromaffin tissue. Some experts view local invasion into surrounding tissue as an additional marker of malignancy.[9,10] Others have disagreed with this classification because locally invasive tumors tend to follow a more indolent course than tumors with distant metastatic involvement.[11] There are no reliable molecular, immunohistochemical, or genetic predictors to distinguish benign and malignant tumors,[12] although some studies have shown a higher rate in SDHB carriers [13] and in individuals with larger tumors.[14] Consequently, estimation of the rate of malignancy in PGLs is difficult; rates from 5% to 20% have been reported.[7,15,16] Common sites of metastases include bone, liver, and lungs.[1]

PGLs arise from cells involved in the metabolism of catecholamines, but approximately 95% of tumors located in the head and neck region are nonsecretory.[10] Only tumors arising from the sympathetic neural chain have secretory capacity. The most recognizable paraganglioma of the head and neck is the tumor arising from the carotid body. These tumors (glomus caroticum) present a significant challenge for surgeons because of their proximity to critical vessels and cranial nerves. The presence of the neoplasm in this critical location frequently results in the compromise of nearby structures; removal of the tumor may cause permanent impairment.

Clinical Diagnosis of 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 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 paraganglioma may present with an enlarging lateral neck mass, hoarseness, Horner syndrome, pulsatile tinnitus, dizziness, facial droop, or blurred vision.[1]

Imaging is the mainstay of diagnosis; the initial evaluation includes computed tomography of the neck and chest. PGLs typically appear homogeneous with intense enhancement after administration of intravenous contrast. Magnetic resonance imaging 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.[17]

Nuclear imaging in combination with anatomic imaging may be useful for localization and determination of the extent of disease (multifocality vs. distant metastatic deposits). Functional imaging with 18F-dihydroxyphenylalanine (18F-DOPA), 18F-fluorodopamine, or positron emission tomography–computed tomography (PET-CT) may be particularly helpful in localizing head and neck tumors. Additionally, 123I-metaiodobenzylguanidine plus PET-CT is very specific for PGLs. Data suggest that the selection of PET tracer utilized for tumor localization should be centered on the patient’s genetic status, based on the metabolic activity of the various tumors.[13] It has been suggested that patients with SDH and VHL mutations are more likely to have higher 18F-fluorodeoxyglucose activity, which is related to gene activation in response to hypoxia.[13,18] Some SDHB tumors only weakly concentrate 18F-DOPA, and patients with SDHx mutations may have false-negative results with such scans. Tumors with VHL mutations may likewise be missed with metaiodobenzylguanidine scans.[13] (Refer to Table 7 for a list of various mutations and their optimal imaging modality.)

Table 7. Gene-specific Imaging and Paraganglioma (PGL) Malignancy Rates
Gene Tumor Location  PGL Malignancy Rate First-line Imaging Modality Second-line Imaging Modality 
Head/NeckThoracic/ Retroperitoneal

FDG-MIBG = fluorodeoxyglucose-metaiodobenzylguanidine; 18F-DOPA = 18F-dihydroxyphenylalanine; 18F-FDA = 18F-fluorodopamine; 18F-FDG = 18F-fluorodeoxyglucose; 18F-FDOPA = 18F-fluoro-L-dihydroxyphenylalanine; 123I-MIBG = 123I-metaiodobenzylguanidine.
MA = majority (>50%); MI = minority (10%–50%); NR = not reported; R = rare (<10%).
aThese mutations are rare. There is very little information available about the best imaging modality for these mutations. This table will be updated as more information becomes available.
b18F-FDA is currently only available at the National Institutes of Health in Bethesda, MD, as an experimental tracer.
Adapted from Fishbein et al.,[19] Gimenez-Roqueplo et al.,[20] Bausch et al.,[21] and Taïeb et al.[22].

Genetics, Inheritance, and Genetic Testing

PGLs and pheochromocytomas can be seen as part of several well-described tumor susceptibility syndromes including von Hippel-Lindau, multiple endocrine neoplasia type 2, neurofibromatosis type 1, Carney-Stratakis syndrome, and familial paraganglioma (FPGL) syndrome. FPGL is most commonly caused by mutations 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. Mutations in SDHB are most common, followed by SDHD and rarely SDHC and SDHA. More recently, mutations in the SDHAF2 (also called SDH5), TMEM127, and MAX genes have been described in FPGL, but these mutations 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.[23]

The inheritance pattern of FPGL depends on the gene involved. While most families show traditional autosomal dominant inheritance, those with mutations in SDHAF2 and SDHD show almost exclusive paternal transmission of the phenotype. In other words, while the mutation can be passed down from mother or father, tumors will only develop if the mutation is inherited from the father.[24,25] In cases of FPGL not caused by SDHD or SDHAF2 mutations, first-degree relatives of an affected individual have a 50% chance of carrying the mutation and are at increased risk of developing PGLs. Because the family history can appear negative in families with lower penetrance mutations, it is important to offer genetic testing to all unaffected first-degree relatives once the mutation in the family has been identified.

Genetic testing for hereditary pheochromocytoma and PGL syndromes is largely based on published algorithms, whereby testing is performed stepwise based on factors such as tumor type and location, age at diagnosis, family history, and presence of malignancy.[7,26,27] This approach has allowed for cost-effective, targeted testing based on clinical features. Within the last several years, however, next-generation sequencing technology has led to a dramatic decrease in the cost of genetic testing, and it is now possible to test for mutations in 10 to 30 genes for the same cost of testing two or three genes. 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, it is likely that the testing algorithms may soon be obsolete for PGL and pheochromocytoma. A recent series analyzed 85 PGL and pheochromocytoma samples using a next-generation sequencing panel test for the ten known PGL susceptibility genes and showed a sensitivity of 98.7%.[28]

Genotype-Phenotype Correlations

In FPGL, the type and location of tumors, age at onset, and lifetime penetrance vary depending on the gene that is mutated. 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.

SDHD mutations 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.[29,30] 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 [29] and 90% by age 70 years in a second series.[30] A review of more than 1,700 cases reported in the literature provided similar estimates, suggesting a lifetime penetrance of 86%.[31] The rate of malignancy in SDHD carriers is lower than 5%.[31]

Mutations in the SDHB gene are associated with sympathetic PGLs, although pheochromocytoma 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%.[31] 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.[29,30] Mutations in SDHB have also been associated with several other tumors and malignancies, including gastrointestinal stromal tumors (GISTs), renal cell carcinoma, and papillary thyroid cancer.[29,30]

SDHC mutations are rare, accounting for an estimated 0.5% of all PGLs.[31] In one series of 153 patients with multiple PGLs or a single PGL diagnosed before age 40 years, three (2%) had an SDHC mutation.[32] Another series of 121 index cases from a head and neck paraganglioma registry showed a mutation rate of 4% (5/121).[33] SDHC mutations most commonly cause head and neck PGLs but have been seen in a small number of patients with abdominal PGLs.[7,34] Mutations in SDHB, SDHC, and SDHD can also cause Carney-Stratakis syndrome, which is characterized by the dyad of paragangliomas and GISTs.[35]

Mutations 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 mutations in SDHA have long been known to cause the autosomal recessive condition inherited juvenile encephalopathy/Leigh syndrome,[36] it was not until recently that monoallelic mutations 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, or in the abdomen (extra-adrenal).[37,38] 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, mutations in SDHAF2 have been described in fewer than 20 cases and only with head and neck PGLs.[39] The MAX gene was first described as a pheochromocytoma susceptibility gene in 2011 through exome sequencing of three unrelated cases.[40] Three different germline mutations were identified, and a follow-up series of 59 cases by the same group identified an additional five mutations. 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.[41] 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 mutations showed that 96% (22/23) had a pheochromocytoma and 9% (2/23) had a PGL.[31]

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