Clinical characteristics.

Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues distributed along the paravertebral axis from the base of the skull to the pelvis) and pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base and neck (referred to as head and neck PGL [HNPGL]) and sometimes in the upper mediastinum; approximately 95% of such tumors are nonsecretory. In contrast, sympathetic extra-adrenal paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically lead to catecholamine excess. Symptoms of PGL/PCC result from either mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for developing metastatic disease is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas.

Diagnosis/testing.

The diagnosis of a hereditary PGL/PCC syndrome should be suspected in any individual with a diagnosis of paraganglioma or pheochromocytoma. A diagnosis of hereditary PGL/PCC is strongly suspected in an individual with multiple, multifocal, recurrent, or early-onset paraganglioma or pheochromocytoma and/or a family history of paraganglioma or pheochromocytoma. The diagnosis is established in a proband by identification of a germline heterozygous pathogenic variant in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127 on molecular genetic testing.

Management.

Treatment of manifestations: For secretory PGL/PCC, treatment requires using medications for alpha adrenergic receptor blockade followed by surgery. For nonsecretory HNPGLs, surgical resection should be considered only after a detailed analysis of benefits and risks of a surgical procedure. All individuals with HNPGL should be evaluated for catecholamine excess before surgical resection, which, if present, can suggest an additional primary PGL/PCC. Watchful waiting or radiation therapy are options for HNPGLs. PGL/PCCs identified in individuals known to have SDHB pathogenic variants may benefit from resection over radiation or watchful waiting because of the higher risk for metastatic disease.

Prevention of secondary complications: Early detection through surveillance and removal of tumors may prevent or minimize complications related to mass effects, unregulated catecholamine secretion, and metastatic disease.

Surveillance: Beginning between ages six and eight years, individuals at risk for hereditary PGL/PCC syndromes should have annual biochemical and clinical surveillance for signs and symptoms of PGL/PCC and biennial full-body MRI examination. Consider endoscopic evaluation for gastrointestinal stromal tumors in individuals with unexplained gastrointestinal symptoms.

Agents/circumstances to avoid: Hypoxic conditions (e.g., living at high altitude, cigarette smoking) may increase tumor incidence and promote tumor growth, although data are extremely limited.

Evaluation of relatives at risk: First-degree relatives of an individual with a known MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127 pathogenic variant should be offered molecular genetic testing to clarify their genetic status to improve diagnostic certainty and reduce the need for costly screening procedures in those who have not inherited the pathogenic variant.

Genetic counseling.

The hereditary PGL/PCC syndromes are inherited in an autosomal dominant manner. Pathogenic variants in SDHD demonstrate parent-of-origin effects and generally cause disease only when the pathogenic variant is inherited from the father. Pathogenic variants in SDHAF2 and possibly MAX exhibit parent-of-origin effects similar to those of pathogenic variants in SDHD. A proband with a hereditary PGL/PCC syndrome may have inherited the pathogenic variant from a parent or, rarely, have a de novo pathogenic variant; the proportion of individuals with a de novo pathogenic variant is unknown. Each child of an individual with a hereditary PGL/PCC syndrome-causing pathogenic variant has a 50% chance of inheriting the pathogenic variant. An individual who inherits an SDHD pathogenic variant from the individual's mother is at a very low but not negligible risk of developing disease. An individual who inherits an SDHD pathogenic variant from the individual's father is at high risk of manifesting PGL/PCC. If the pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes should be suspected in any individual with a paraganglioma or pheochromocytoma, particularly individuals with the following findings [Young 2011, Lenders et al 2014]:

• Tumors that are:
  • Multiple (i.e., >1 paraganglioma or pheochromocytoma), including bilateral adrenal pheochromocytoma
  • Multifocal with multiple synchronous or metachronous tumors
  • Recurrent
  • Early onset (i.e., age <45 years)
  • Extra-adrenal
  • Metastatic
• A family history of paraganglioma or pheochromocytoma, or relatives with unexplained or incompletely explained sudden death
  Note: Many individuals with hereditary PGL/PCC syndrome may present with a solitary tumor of the skull base or neck, thorax, abdomen, adrenal, or pelvis and no family history of paraganglioma or pheochromocytoma.

The following clinical and laboratory features suggest a paraganglioma or pheochromocytoma.

Clinical features

• Signs and symptoms of catecholamine excess (e.g., classic signs and symptoms of sustained or paroxysmal elevations in blood pressure, headache, palpitations, arrhythmia, profuse sweating, apprehension or anxiety, and non-classic signs and symptoms of pallor, nausea/vomiting, and sudden change in glycemic control)
• Symptoms may be triggered by changes in body position, increases in intra-abdominal pressure, medications (e.g., metoclopramide), anesthesia induction, exercise, or micturition.
• Palpable abdominal mass
• Enlarging mass of the skull base or neck
• Compromise of cranial nerves (VII, IX, X, XI) and sympathetic nerves in the head and neck area (e.g., hoarseness, dysphagia, soft palate paresis, Horner syndrome)
• Tinnitus

Laboratory findings. Elevated fractionated metanephrines and/or catecholamines in plasma and/or a 24-hour urine sample can include any of the following:

• Epinephrine (adrenaline) and its major metabolite metanephrine
• Norepinephrine (noradrenaline) and its major metabolite normetanephrine
• Dopamine and its major metabolite 3-methyoxytyramine

Note: (1) Measurement of fractionated metanephrine concentrations in plasma or urine is preferred, as it is more sensitive than measurement of catecholamine concentrations [Young 2011]. (2) False positive results may be reduced by follow-up testing for 24-hour urine fractionated metanephrines when plasma normetanephrine concentrations are less than fourfold above the reference range [Algeciras-Schimnich et al 2008]. (3) The secretion of epinephrine with little norepinephrine excess suggests an adrenal pheochromocytoma, which may be associated with multiple endocrine neoplasia type 2 [Young 2011].

Establishing the Diagnosis

The diagnosis of hereditary PGL/PCC should be strongly suspected in an individual with multiple, multifocal, recurrent, or early-onset paraganglioma or pheochromocytoma and/or a family history of paraganglioma or pheochromocytoma.

The diagnosis of hereditary PGL/PCC syndromes is established in a proband with a germline heterozygous pathogenic (or likely pathogenic) variant in one of the genes listed in Table 1.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous variant of uncertain significance in one of the genes listed in Table 1 does not establish or rule out the diagnosis.

Clinical Description

In individuals with hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes, tumors arise within the paraganglia – collections of neural crest cells distributed along the paravertebral axis from the base of the skull to the pelvis – as well as in some visceral locations. The 2017 World Health Organization (WHO) Classification of Endocrine Tumours classifies paragangliomas/pheochromocytomas by location and (directly or indirectly) secretory status [Lloyd et al 2017].

Paragangliomas (paraganglion tumors) arise from neuroendocrine tissues (paraganglia) distributed along the paravertebral axis from their predominant location at the skull base to the pelvis.

Head and neck paragangliomas (HNPGLs) and those in the upper mediastinum are primarily associated with the parasympathetic nervous system and typically do not secrete catecholamines or other hormones. Approximately 5% of HNPGLs secrete catecholamines. The rare secretory tumors in the head and neck area are either a subset of carotid body tumors or arise from the cervical sympathetic chain. Most HNPGLs do not metastasize, although there are many exceptions. Clinical complications of HNPGLs are typically the result of mass effect:

• Carotid body paragangliomas often present as asymptomatic, enlarging lateral neck masses. (The carotid bodies are located at or near the bifurcations of the carotid arteries, in the lateral upper neck at approximately the level of the fourth cervical vertebra.) Affected individuals may experience mass effects, including cranial nerve and sympathetic chain compression, with resulting neuropathies. On physical examination masses are vertically (but not horizontally) fixed; bruits and/or thrills may be present.
• Vagal paragangliomas present in a manner similar to carotid body paragangliomas. Signs and symptoms include neck masses, hoarseness, pharyngeal fullness, dysphagia, dysphonia (impaired use of the voice), pain, cough, and aspiration. Dysphonia may be caused by mass effects within the throat or by pressure on nerves supplying the vocal cords or tongue.
• Jugulotympanic paragangliomas may present with pulsatile tinnitus, hearing loss, and other lower cranial nerve abnormalities. Blue-colored, pulsatile masses may be visualized behind the tympanic membrane on otoscopic examination [Gujrathi & Donald 2005].

Paragangliomas in the lower mediastinum, abdomen, and pelvis are typically associated with the sympathetic nervous system and usually secrete catecholamines. Sympathetic paragangliomas located along the paravertebral axis (and not in the adrenal gland) are called "extra-adrenal sympathetic paragangliomas." Extra-adrenal sympathetic paragangliomas have an increased likelihood of malignant transformation [Ayala-Ramirez et al 2011].

Pheochromocytomas are catecholamine-secreting paragangliomas confined to the adrenal medulla. Malignancy is less likely in pheochromocytomas but certainly does occur (see Genotype-Phenotype Correlations). Pheochromocytomas are also known as adrenal chromaffin tumors.

Note: "Chromaffin cells/tumors" is another term for any sympathetic (catecholamine-secreting) neuroendocrine cells/tumors regardless of location. "Chromaffin" refers to the brown-black color that results from oxidization and polymerization of catecholamines contained in the cells/tumors by chromium salts (e.g., potassium dichromate).

Signs and symptoms of paraganglioma and pheochromocytoma are similar in individuals with hereditary PGL/PCC syndromes and individuals with sporadic (i.e., not inherited) tumors, most often coming to medical attention in the following four clinical settings:

• Signs and symptoms of catecholamine excess, including episodic or sustained elevations in blood pressure and pulse, headaches, palpitations (perceived episodic, forceful, often rapid heartbeat), arrhythmias, excessive sweating, pallor, apprehension, and anxiety. Nausea, emesis, fatigue, sudden alteration in glycemic control, and weight loss can also be seen. Paroxysmal symptoms may be triggered by changes in body position, increases in intra-abdominal pressure, medications (e.g., metoclopramide), anesthesia induction, exercise, or micturition in individuals with urinary bladder paragangliomas. Urinary bladder paragangliomas may also be accompanied by painless hematuria.
• Signs and symptoms related to mass effects from the neoplasm (particularly HNPGLs) which can compromise cranial nerves (e.g., VII, IX, X, XI) and sympathetic nerves in the head and neck area leading to hoarseness, dysphagia, soft palate paresis, Horner syndrome, and/or tinnitus
• Incidentally discovered mass on MRI/CT performed for other reasons
• Screening of at-risk relatives

Biochemical features of PGL/PCC. Catecholamines and metanephrines secreted by PGL/PCC can be any of the following:

• Epinephrine (adrenaline) and its major metabolite metanephrine
• Norepinephrine (noradrenaline) and its major metabolite normetanephrine
• Dopamine and its major metabolite 3-methoxytyramine

Plasma chromogranin A, not a catecholamine but another substance often secreted by PGL/PCC, can sometimes be useful for diagnosis. Its specificity is not great, however, as many other medical conditions (e.g., liver and kidney disease; gastrointestinal conditions such as IBS and colon cancer; other malignancies) and medications (e.g., proton pump inhibitors) can elevate plasma chromogranin A levels.

Radiographic features of PGL/PCC. Individuals with hereditary PGL/PCC syndromes should be evaluated by imaging for tumor localization. CT rather than MRI is often the imaging modality of choice, given its excellent spatial resolution of the thorax, abdomen, and pelvis [Lenders et al 2014]. MRI is a better option in individuals for whom radiation exposure must be limited, such as pregnant women, and for lifelong screening for biochemically silent PGL/PCC and other manifestations in those asymptomatic individuals with known germline pathogenic variants.

• Paragangliomas can be identified anywhere along the paravertebral axis from the skull base to the pelvis, including the para-aortic sympathetic chain, as well as some other visceral locations. Common sites of neoplasia are near the renal vessels and in the organ of Zuckerkandl (chromaffin tissues near the origin of the inferior mesenteric artery and the aortic bifurcation). A less common site is within the urinary bladder wall.
• PGL/PCC tumors usually exhibit high signal intensity on T₂-weighted MRI and have no loss of signal intensity on in- and out-of-phase imaging, which helps distinguish pheochromocytomas from benign adrenal cortical adenomas. On CT examination these tumors are characterized by heterogeneous appearance with cystic areas, high unenhanced CT attenuation (density, Hounsfield units >10), increased vascularity on contrast-enhanced CT, and slow contrast washout.
• Multiple tumors can be present.
• Whole-body MRI with targeted MRI for positive tumors may be a reasonable approach for both diagnosis and monitoring of individuals with hereditary PGL/PCC syndromes. This strategy minimizes radiation exposure associated with CT scanning, while taking advantage of the high sensitivity of T_2-weighted MRI.
• Digital subtraction angiography (DSA) is sensitive for the detection of small paragangliomas and can be diagnostically definitive. DSA is essential if preoperative embolization or carotid artery occlusion is to be performed.

Distinguishing benign and malignant PGL/PCCs. No reliable pathology studies are available to distinguish a primary benign PGL/PCC from a primary malignant PGL/PCC. Furthermore, biopsy of PGL/PCC is contraindicated because this invasive procedure carries the risk of precipitating a hypertensive crisis, hemorrhage, and tumor cell seeding [Vanderveen et al 2009], and regardless, the pathology of the primary tumor cannot reliably predict the development of metastatic disease [Wu et al 2009].

Malignancy is defined as the presence of PGL/PCC metastases to other sites, the most common of which are bone, lung, liver, and lymph nodes. In fact, the 2017 WHO replaced the term "malignant pheochromocytoma" with "metastatic pheochromocytoma" to avoid confusion in the definition. Having to wait for evidence of metastasis to establish the malignant nature of a tumor may have introduced bias into the present understanding of the natural history of these tumors.

For PGL/PCCs that have not metastasized, operative treatment can be curative. However, once metastases have occurred there is no cure, with a five-year survival rate of 50%-69% [Hescot et al 2013, Asai et al 2017, Fishbein et al 2017, Hamidi et al 2017].

To detect metastases, the following radiographic studies can be used:

• 68-Ga-DOTATATE PET CT is a more sensitive modality to detect somatostatin receptor positive disease, especially in individuals with metastatic disease [Janssen et al 2015, Chang et al 2016, Janssen et al 2016].
• ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy is a technique that measures tumor uptake of a catecholamine analog radioisotope. MIBG has greater specificity for localization than CT and MRI, but lower sensitivity. It may be used to further characterize masses detected by CT or MRI and to look for additional sites of disease, and it is used in individuals with metastatic disease where treatment with I-131 MIBG is a consideration.
• Octreotide scintigraphy, a technique that measures tumor uptake of a somatostatin analog radioisotope, may be used in addition to MIBG scintigraphy as some MIBG-negative tumors are positive with octreotide scintigraphy. The sensitivity is fairly low, however. Octreotide scintigraphy has been largely replaced by 68-Ga-DOTATATE PET CT, where available, because of the significantly higher sensitivity.
• 2- deoxy-2-(¹⁸F)-fluoro--D-glucose position emission tomography (FDG-PET), or PET using other imaging compounds, can also assist in detecting metastatic disease.

A decisional algorithm for the use of functional imaging in hereditary PGL/PCC syndromes has recently been proposed in the Endocrine Society's Clinical Practice Guideline. See Lenders et al [2014], Figure 2 (full text).

Other tumors

• Gastrointestinal stromal tumors (GISTs). The majority of GISTs associated with PGL (Carney Stratakis syndrome; OMIM 606864) occur in individuals with a germline pathogenic variant in SDHA or SDHC. Children with GISTs are more likely to have a germline pathogenic variant in a PGL/PCC susceptibility gene than an adult with a GIST. Most GISTs associated with hereditary PGL/PCC syndromes occur in the stomach and are often multifocal (>40%).
• Pulmonary chondromas can occur together with GIST and paraganglioma (Carney triad; OMIM 604287). This is an extremely rare disorder that primarily affects young women. Adrenal cortical adenoma and esophageal leiomyoma were later shown to be associated with the syndrome [Stratakis 2009]. Carney found that 78% of affected individuals had two of the three classic tumors and 22% had all three neoplasms [Carney 1999]. Although Carney triad is most often not inherited, at least a subset of individuals (~10%) has a germline pathogenic variant in an SDHx gene [Boikos et al 2016]. In some individuals without an identified germline pathogenic variant, somatic alterations in methylation patterns of SDHx genes can be found in the GIST tumors [Boikos et al 2016].
• Renal clear cell carcinoma is part of the tumor spectrum of hereditary PCC/PGL syndromes, particularly in individuals with pathogenic variants in SDHB and SDHD [Ricketts et al 2010]. The lifetime risk of developing a renal tumor for individuals with an SDHB pathogenic variant is 4.7%, compared to 1.7% in the general population [Andrews et al 2018].
• Other tumors including papillary thyroid carcinoma, pituitary adenomas, and neuroendocrine tumors have been described in individuals with SDHx germline pathogenic variants. However, whether there is an increased risk of developing these other tumors has not been established.

Longevity. With staged tumor-targeted treatment modalities some affected individuals have lived with metastatic disease for 20 or more years [Fishbein et al 2017, Hamidi et al 2017].

Phenotype Correlations by Gene

Although persons with MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, and TMEM127 pathogenic variants can develop pheochromocytomas and/or paragangliomas within any paraganglial tissue, the following correlations between the gene involved and tumor location are used to guide testing, surveillance, and, in some instances, recommended treatment (also see Table 2):

MAX. Germline MAX pathogenic variants have most commonly been reported in association with PCCs. Some affected individuals had additional PGLs; all those who have done so presented with PCCs initially [Comino-Méndez et al 2011, Burnichon et al 2012, Bausch et al 2017].

SDHA. Germline SDHA pathogenic variants have been identified in individuals with PCCs and PGLs (sympathetic and parasympathetic) [Burnichon et al 2010, Korpershoek et al 2011, Bausch et al 2017].

SDHAF2. Germline pathogenic variants in SDHAF2 have only been seen in association with HNPGLs [Hao et al 2009, Bayley et al 2010, Kunst et al 2011, Piccini et al 2012, Currás-Freixes et al 2015, Zhu et al 2015, Bausch et al 2017].

SDHB. Germline pathogenic variants in SDHB are generally associated with higher morbidity and mortality than pathogenic variants in the other SDHx genes [Ricketts et al 2010, Andrews et al 2018]. They are strongly associated with extra-adrenal sympathetic paragangliomas with an increased risk of metastatic disease, and, less frequently, with PCCs and parasympathetic PGLs [Andrews et al 2018]. Up to 50% of persons with metastatic extra-adrenal paragangliomas have a germline SDHB pathogenic variant [Fishbein et al 2013].

SDHC. Germline SDHC pathogenic variants appear to be primarily (but not exclusively) associated with HNPGL. However, up to 10% of SDHC-related tumors are observed in the thoracic cavity [Peczkowska et al 2008, Else et al 2014].

SDHD. SDHD pathogenic variants are mainly associated with HNPGL, although extra-adrenal PGL and PCC certainly occur [Ricketts et al 2010, Andrews et al 2018]. Persons with a germline SDHD pathogenic variant are more likely to have multifocal disease than persons with sporadic tumors or those with a germline SDHB pathogenic variant [Boedeker et al 2005].

TMEM127. Germline TMEM127 pathogenic variants are associated with adrenal PCC but can also be associated with HNPGL and extra-adrenal PGL [Neumann et al 2011]. Renal cell carcinoma has also been associated [Qin et al 2014].

Genotype-Phenotype Correlations

No consistent genotype-phenotype correlations have been identified.

Penetrance

Age-related penetrance. Penetrance estimates vary (see Table 3). Penetrance was initially believed to be quite high, but larger studies with less bias from probands suggest a much lower penetrance. No reliable penetrance data are currently available for MAX, SDHAF2, or TMEM127 pathogenic variants.

Nomenclature

The hereditary PGL/PCC syndromes were initially referred to as the hereditary paraganglioma syndromes prior to the discovery of their association with pheochromocytomas. Hereditary paragangliomas of the head and neck have also been referred to as familial glomus tumors and familial nonchromaffin paragangliomas. Initially these syndromes were numbered PGL1-5. However, now that the genetic basis has been determined, it makes most sense to refer to the associated affected gene; e.g., SDHB-associated hereditary PGL/PCC syndrome.

Carney-Stratakis syndrome (OMIM 606864) and Carney triad (OMIM 604287) are largely historical terms predating the use of a molecular-driven nomenclature and are best reserved for individuals with the clinical features but without SDHx germline pathogenic variants.

Pheochromocytomas are tumors of the adrenal medulla, which is a specialized paraganglion. Paragangliomas arise from paraganglial tissue anywhere in the body, usually as head and neck paragangliomas (HNPGLs; e.g., carotid body tumor, glomus jugulare tumor, glomus tympanicum tumor, glomus vagale tumor), as thoracic paragangliomas either arising from paraganglia associated with the large arteries or the paraspinal sympathetic chain, or as abdominal paragangliomas (e.g., organ of Zuckerkandl, para-adrenal, bladder wall). The term "chromaffin" tumor is largely historical and refers to positive staining by chromium salts, which react with catecholamines. Therefore, usually only catecholamine-secreting tumors, such as pheochromocytomas and sympathetic paragangliomas, are truly chromaffin – while most parasympathetic tumors are silent.

Prevalence

The incidence of hereditary PGL/PCC syndromes is not precisely known. The incidence of pheochromocytoma is approximately 0.6:100,000/year [Berends et al 2018]. About 25% of all pheochromocytomas arise in individuals with a hereditary predisposition. The incidence of paragangliomas is lower, but these tumors are more often associated with hereditary predisposition. Altogether, about 35%-40% of all PGL/PCC are associated with a hereditary predisposition.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndrome, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Refer the individual to an expert on PGL/PCC (often an endocrinologist, oncologist, and/or clinical geneticist). Involvement of other subspecialties and multidisciplinary care (e.g., ENT, cardiology, gastroenterology) should be included when appropriate. The specialist with expertise in PGL/PCC (often an endocrinologist or oncologist) should then complete the evaluation (see following). Note: Evaluate for and treat hypertension and tachycardia, as they need to be controlled prior to initiation of therapy.

For individuals with suspected PGL/PCC (based on symptoms or biochemical findings)

• Cross-sectional imaging (MRI/CT) is the preferred method to define tumor extent. CT or MRI may be preferable based on suspected tumor location. HNPGL are often best characterized by MRI examination, thoracic PGL are best characterized by CT examination, and abdominal tumors by either MRI or CT examination.
• Functional studies, such as somatostatin-receptor-based imaging (e.g., 68-Ga- DOTATATEPET CT) or less commonly other functional studies (e.g., FDG-PET, ¹²³I-MIBG) can aid in defining cross-sectional imaging findings as functional tumors.

For individuals with a suspected gastrointestinal stromal tumor (GIST) (based on symptoms). Clinical (including endoscopic) evaluation for GIST in children, adolescents, or young adults who are heterozygous for a hereditary PGL/PCC-related pathogenic variant and who have unexplained gastrointestinal symptoms (e.g., abdominal pain, upper gastrointestinal bleeding, nausea, vomiting, difficulty swallowing) or who experience unexplained intestinal obstruction or anemia [Pasini et al 2008, Rednam et al 2017]

For at-risk asymptomatic individuals

• Tumor screening for secreting and nonsecreting PGL/PCC and other associated tumors (e.g., renal cell carcinoma, GIST) utilizing non-radiating imaging (e.g., whole-body MRI every 2 years)
• Biochemical evaluation, including plasma-free fractionated metanephrines or 24-hour urine fractionated metanephrines (optional dopamine or 3-methoxytyramine) to screen for functional PGL/PCC

Other. Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Clinical practice guidelines for the management of individuals with PGL/PCC have been published [Lenders et al 2014] (full text).

The management of tumors in individuals with hereditary PGL/PCC syndromes resembles management of sporadic tumors; however, persons with hereditary PGL/PCC syndromes are more likely to have multiple tumors and multifocal and/or metastatic disease than are those with sporadic tumors.

For catecholamine-secreting tumors, treatment is directed toward containing the effect of catecholamines through antagonism of catecholamine excess with pharmacologic adrenergic blockade prior to surgical removal [Lenders et al 2014].

For nonsecretory HNPGL, early detection allows for a timely decision regarding treatment (or surveillance). Early detection is believed to reduce operative morbidity and improve prognosis [Rinaldo et al 2004, Gujrathi & Donald 2005]. However, watchful waiting and radiation therapy are often equally beneficial or better approaches. Because most HNPGL are nonsecretory, all individuals with HNPGL should be evaluated for catecholamine excess before surgical resection, which, if present, can suggest an additional primary PGL/PCC.

• For carotid body, glomus tympanicum, and vagal paragangliomas, approaches may include observation, surgical resection, and radiation. The decision should be based on the extent of the tumor (e.g., Shamblin I and II carotid body tumors are good candidates for surgery), treatment-associated risks (e.g., resection of glomus vagal tumors almost invariably leads to loss of the ipsilateral vagal and recurrent laryngeal nerve), and presumed malignant potential (e.g., SDHB-associated tumors could be considered for more aggressive therapy). Radiation therapy is an option, and there is currently no evidence for an increased incidence of secondary malignancies in this population due to the underlying genetic condition [Taïeb et al 2014].
• For jugular paragangliomas, small tumors may potentially be removed without complications or permanent nerve injuries. However, resection of larger tumors is often associated with CSF leak, meningitis, stroke, hearing loss, cranial nerve palsy, or even death. Therefore, close observation with symptomatically guided surgery may be prudent. Radiation therapy can also be considered [Taïeb et al 2014]. In selected individuals, stereotactic radiosurgery may also be performed [Taïeb et al 2014].

For pheochromocytomas, surgery, preferably laparoscopic, is the treatment of choice [Lenders et al 2014].

• Preoperative. The chronic and acute effects of catecholamine excess from adrenal chromaffin tumors must be treated preoperatively. Alpha-adrenergic blockade is required to control blood pressure and prevent intraoperative hypertensive crises. The Endocrine Society guidelines have an algorithm for medication titration [Lenders et al 2014]:
  • Alpha-adrenergic blockade (with phenoxybenzamine or prazosin/doxazosin) starting at least seven to ten days preoperatively is indicated to allow for normalization of blood pressure and volume expansion. The dose of the α-blocker is adjusted for a low normal systolic blood pressure for age.
  • Second-line treatment includes blood pressure control with calcium channel blockers (e.g., amlodipine, nicardipine) [Lenders et al 2014].
  • A liberal sodium diet and fluid intake are indicated to allow for plasma volume expansion.
  • Once adequate α-adrenergic blockade or blood pressure control with calcium channel blockers is achieved, initiation of β-adrenergic blockade may be required to control reflex tachycardia. The dose of the β-adrenergic blocker is adjusted for a target heart rate of 80 beats per minute.
• Postoperative. Approximately two to eight weeks after surgery, 24-hour urine fractionated metanephrines and/or plasma-free metanephrines should be measured.
  • If the levels are normal, resection of the biochemically active pheochromocytoma or paraganglioma should be considered complete.
  • If the levels are increased, an unresected second tumor and/or occult metastases should be suspected.

Metastatic paraganglioma or pheochromocytoma. Treatment options include blood pressure control with alpha blockade to reduce symptoms from high catecholamine levels in individuals with sympathetic tumors, surgical debulking to reduce tumor burden due to mass effect or catecholamine secretion, radiation therapy especially for bony lesions, liver-directed therapy, systemic therapy with chemotherapy (e.g., cyclophosphamide, vincristine, dacarbazine), or I-131 MIBG therapy. In August 2018, one form of MIBG, AZEDRA^® (ultratrace iobenguane I-131), was the first FDA-approved systemic therapy for inoperable and metastatic PGL/PCC [Noto et al 2018] (see www.fda.gov).

In individuals with SDHB pathogenic variants and paragangliomas or pheochromocytomas, preference is given for surgical resection over watchful waiting due to the risk for metastases. Prompt resection is particularly important for extra-adrenal sympathetic paragangliomas because of their tendency to metastasize.

Prevention of Secondary Complications

Early detection through surveillance and removal of tumors may prevent or minimize complications related to mass effects, catecholamine excess, and development of metastatic disease.

Surveillance

Individuals known to have a hereditary PGL/PCC syndrome and relatives at risk based on family history who have not undergone DNA-based testing need regular clinical monitoring by a physician or medical team with expertise in treatment of hereditary PGL/PCC syndromes. Surveillance is based on physical exam, review of systems, biochemistry, and cross-sectional imaging.

Although no clear consensus has been developed regarding when, how, and how often biochemical studies and imaging should be done in at-risk individuals, it is reasonable to consider lifelong annual biochemical and clinical surveillance. In addition, cross-sectional imaging should be recommended for all at-risk individuals, usually including imaging from skull base to pelvis. However, decision making for frequency and intensity of screening should consider the underlying genetic alteration and associated penetrance. Expert working groups recently recommended starting surveillance at age six to eight years [Rednam et al 2017]. Benn et al [2006] estimated that if lifelong screening were to begin at age ten years, disease would be detected in all persons with SDHD pathogenic variants and 96% of persons with SDHB pathogenic variants.

Monitoring includes the following:

• Annual measurement of plasma-free metanephrines to detect active catecholamine-secreting tumors or 24-hour urine for fractionated metanephrines. Dopamine (and/or 3-methyoxytyramine) can be measured as well to detect dopamine-only-secreting tumors, but measurement of dopamine is part of catecholamine testing and catecholamines are prone to a higher rate of false positives.
• Every two years, cross-sectional imaging of skull base to pelvis [Fishbein & Nathanson 2012, Eijkelenkamp et al 2017, Rednam et al 2017]. This is recommended to detect nonsecreting PGL/PCC as well as other associated tumors, such as renal cell carcinoma. Whole-body MRI has become a good option at expert centers [Jasperson et al 2014]. Whenever possible the preference should be given to non-radiation-containing imaging procedures (e.g., MRI) to avoid unnecessary radiation exposure in this population that requires lifetime surveillance. Cross-sectional imaging will detect most PCC and PGL as well as renal cell cancers. Functional scans, such as 68-Ga-DOTATATE PET CT, ¹²³I-MIBG, or FDG-PET, are helpful in identifying metastatic disease and the functional nature of tumors observed on cross-sectional imaging, but should remain reserved for selected individuals (e.g., those with concern for metastatic tumors). Imaging surveillance should be considered starting at age six to eight years. However, discussion with the family regarding risks (e.g., anesthesia necessary for MRI in children) vs benefits (tumor detection) is important.
• In individuals (especially children, adolescents, or young adults) who have unexplained gastrointestinal symptoms (e.g., abdominal pain, upper gastrointestinal bleeding, nausea, vomiting, difficulty swallowing) or who experience unexplained intestinal obstruction or anemia, endoscopic evaluation for GISTs should be considered (e.g., esophagogastroduodenoscopy) as the majority of tumors will be in the stomach [Pasini et al 2008, Rednam et al 2017].

Agents/Circumstances to Avoid

There is some limited evidence that the penetrance of hereditary PGL/PCC syndromes may be increased in those who live in high altitudes or are chronically exposed to hypoxic conditions [Astrom et al 2003]. However, no recommendation can be based on this very limited evidence.

Activities such as cigarette smoking that predispose to chronic lung disease should be discouraged.

Evaluation of Relatives at Risk

Evaluation of apparently asymptomatic older and younger at-risk relatives of an affected individual is recommended. Identification of at-risk family members improves diagnostic certainty and reduces the need for costly screening procedures in those at-risk family members who have not inherited a pathogenic variant. Early detection of tumors can facilitate surgical removal, decrease related morbidity, and potentially result in removal prior to malignant transformation or metastasis. Evaluations can include the following:

• Molecular genetic testing. If the pathogenic variant in the family is known, molecular testing of the family members of the proband should be offered by age six to eight years. Note: Pathogenic variants in SDHD and SDHAF2 (and possibly MAX) demonstrate parent-of-origin effects and cause disease almost exclusively when they are paternally inherited. However, a thorough family history and risk assessment should be used in determining surveillance strategies in these families regardless of suspected parent-of-origin effects.
• Screening. If the pathogenic variant in the family is not known, screening for PGL/PCC can be considered in families with more than one individual with PGL/PCC. Of note, there are only very rare families with more than one individual with PGL/PCC in which no germline pathogenic variant was found.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

There are no published consensus management guidelines for the diagnosis and management of hereditary PGL/PCC syndromes during pregnancy. A high index of suspicion for these tumors in pregnant women is indicated, since there are other more common causes of hypertension during pregnancy (e.g., preeclampsia). Secretory PGLs/PCCs are more likely to present at any time during pregnancy (whereas preeclampsia is more common in the 2nd or 3rd trimester) and are typically not associated with weight gain, edema, proteinuria, or thrombocytopenia. Individuals with PGLs/PCCs are more likely to present with palpitations, sweating pallor, orthostatic hypotension, and glucosuria, and the hypertension may be episodic.

Every individual with hereditary PGL/PCC syndrome should be evaluated for an active catecholamine-secreting tumor prior to planned pregnancy or as soon as pregnancy is known. This evaluation can be done by measurement of fractionated metanephrines and catecholamines in a 24-hour urine sample or measurement of plasma-free metanephrines. There is no consensus regarding the frequency of follow-up biochemical evaluation during pregnancy, but obtaining levels during the second trimester (preferred window for surgery) and prior to delivery should be considered. MRI without gadolinium administration should be the first-line test used to localize a tumor, since CT examination will expose the fetus to radiation. Radioisotope imaging studies should be deferred until after pregnancy in nonlactating mothers for similar reasons.

Surgery is the definitive treatment for these tumors, with appropriate α-adrenergic and (if needed) subsequent β-adrenergic blockade to prevent a hypertensive crisis. Phenoxybenzamine is the α-blocker of choice in pregnant individuals [Reisch et al 2006]. For intra-abdominal PGL/PCC, a laparoscopic surgical approach is ideal if the tumor size allows. After 24 weeks' gestation, surgery may need to be delayed until fetal maturity is reached (~34 weeks) because of issues with tumor accessibility. An open surgical approach combined with elective C-section may be necessary in these situations. A good outcome with vaginal delivery has only been described in a few individuals [Junglee et al 2007].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

For metastatic PGL/PCC, several therapies are under investigation. Preliminary studies with peptide receptor radionuclide therapy (PRRT) have shown clinical and biochemical responses that suggest increased survival in PGL/PCC [Kong et al 2017]. Furthermore, tyrosine kinase inhibitors such as cabozantinib are under investigation (see ClinicalTrials.gov), and sunitinib showed a modest increase in progression-free survival [Ayala-Ramirez et al 2012]. There are a number of open studies in North America and Europe.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

The hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are inherited in an autosomal dominant manner.

Pathogenic variants in SDHD, SDHAF2, and possibly MAX demonstrate parent-of-origin effects and cause disease almost exclusively when they are paternally inherited [Hensen et al 2004, Kunst et al 2011, Burnichon et al 2012, Hoekstra et al 2015]. It is notable that SDHAF2- and MAX-related hereditary PGL/PCC syndromes are rare and information is limited; therefore, a thorough family history and risk assessment should be used in determining surveillance strategies in these families regardless of suspected parent-of-origin effects.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with a hereditary PGL/PCC syndrome inherited a PGL/PCC-related pathogenic variant from a parent.
• Rarely, a proband with a hereditary PGL/PCC syndrome has the disorder as the result of a de novo pathogenic variant [Neumann et al 2004, Imamura et al 2016]. The proportion of cases caused by a de novo pathogenic variant is unknown.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include testing for the pathogenic variant identified in the proband.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible in simplex cases, no instances of germline mosaicism have been reported in the genes for hereditary PGL/PCC syndrome. However, it remains a possibility in simplex cases.
• The age-dependent penetrance and variable expressivity of MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, and TMEM127 pathogenic variants, as well as the parent-of-origin effects associated with SDHD, SDHAF2, and possibly MAX pathogenic variants, predict that a substantial number of individuals who have inherited these pathogenic variants will appear to be simplex cases (i.e., appear to have a negative family history). Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents.

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, sibs of a proband are still at increased risk for a hereditary PGL/PCC syndrome because of the possibility of (age-related) reduced penetrance in a heterozygous parent or parent-of-origin effects.

Offspring of a proband. Each child of an individual with a hereditary PGL/PCC syndrome has a 50% chance of inheriting the pathogenic variant:

• An individual who inherits an SDHD or SDHAF2 pathogenic variant from the individual's father is at high risk of manifesting PGL and PCC.
• An individual who inherits an SDHD or SDHAF2 pathogenic variant from the individual's mother is usually not at risk of developing disease (although each of the individual's offspring is at a 50% risk of inheriting the pathogenic variant). However, exceptions occur:
  • Yeap et al [2011] identified a woman age 26 years with pathologically confirmed pheochromocytoma who had an SDHD pathogenic variant inherited from her mother, and also had a right glomus jugulare tumor.
  • Bayley et al [2014] and Burnichon et al [2017] also identified examples of SDHD tumor susceptibility from maternal-origin variants.
• It is unclear whether the same parent-of-origin effect holds true for pathogenic variants in MAX. The total number of individuals identified with MAX pathogenic variants is limited, but thus far, tumor formation has not occurred in individuals who inherited a MAX pathogenic variant on the maternal allele.

Other family members. The risk to other family members depends on the genetic status of the proband's parents and the biological relationship to the proband. If a parent of the proband is affected or has a pathogenic variant, risk can be determined by pedigree analysis and, if the familial pathogenic variant is known, molecular genetic testing.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with a hereditary PGL/PCC syndrome has the pathogenic variant or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the PGL/PCC syndrome-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

SDHA, SDHB, SDHC, and SDHD are four nuclear genes responsible for hereditary PGL/PCC syndromes. They encode the four subunits of the mitochondrial enzyme succinate dehydrogenase (SDH). SDH catalyzes the conversion of succinate to fumarate in the Krebs cycle and serves as complex II of the electron transport chain. A fifth nuclear gene, SDHAF2 (also known as SDH5), encodes a protein that appears to be necessary for flavination of another SDH subunit, SDHA, as well as stabilization of the SDH complex. These five genes are collectively known as the SDHx genes.

SDHA, SDHAF2, SDHB, SDHC, and SDHD are tumor suppressor genes. Somatic second-hit variants in tumors include gross chromosomal rearrangements, recombination, single-nucleotide variants, or epigenetic changes that result in allelic inactivation.

The common neural crest derivation of skull base and neck paragangliomas, sympathetic extra-adrenal paragangliomas, and pheochromocytomas characterize this syndrome.

Inactivation of SDHA, SDHB, SDHC, or SDHD may cause the generation of a pseudohypoxic cellular state due to elevation of cellular succinate concentrations and/or the increased production of reactive oxygen species. Increased succinate in the cell can competitively inhibit the 2-oxoglutarate-dependent dioxygenases such as HIF prolyl-hydroxylases and histone and/or DNA demethylases. This can lead to increases in HIF-1α stimulating hypoxia pathways and leads to epigenetic modifications such as hypermethylation [Pollard et al 2005, Letouzé et al 2013].

Much less is known about the role of TMEM127 and MAX in PGL/PCC tumorigenesis. TMEM127 is a transmembrane-spanning protein involved in regulating the mTOR pathway. MAX is a transcription factor that heterodimerizes with MYC to regulate transcription of downstream genes involved in tumorigenesis.

Author History

Tobias Else, MD (2018-present)
Lauren Fishbein, MD, PhD, MTR (2018-present)
Samantha Greenberg, MS, MPH, CGC (2018-present)
Salman Kirmani, MBBS; Aga Khan University, Pakistan (2012-2018)
Roger D Klein, MD, JD; Blood Center of Wisconsin (2008-2012)
Ricardo V Lloyd, MD, PhD; Mayo Clinic, Rochester (2008-2012)
William F Young, MD, MSc; Mayo Clinic, Rochester (2008-2018)

Revision History

• 4 October 2018 (sw) Comprehensive update posted live
• 6 November 2014 (me) Comprehensive update posted live
• 30 August 2012 (me) Comprehensive update posted live
• 3 September 2009 (cd) Revision: mutation in SDHAF2 (SDH5) identified as causing PGL2
• 7 April 2009 (cd) Revision: deletion/duplication analysis available clinically for SDHB, SDHC and SDHD; prenatal testing available for SDHB
• 23 September 2008 (cd) Revision: prenatal diagnosis for SDHC mutations available clinically
• 21 May 2008 (me) Posted live
• 14 November 2007 (rdk) Original submission

Published Guidelines / Consensus Statements

• Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, Naruse M, Pacak K, Young WF Jr, Endocrine Society. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. 2014. Available online. Accessed 12-19-22.

Literature Cited

• Algeciras-Schimnich A, Preissner CM, Young WF Jr, Singh RJ, Grebe SKG. Plasma chromogranin A or urine fractionated metanephrines follow-up testing improves the diagnostic accuracy of plasma fractionated metanephrines for pheochromocytoma. J Clin Endocrinol Metab. 2008;93:91–5. [PMC free article: PMC2729153] [PubMed: 17940110]
• Amar L, Baudin E, Burnichon N, Peyrard S, Silvera S, Bertherat J, Bertagna X, Schlumberger M, Jeunemaitre X, Gimenez-Roqueplo A-P, Plounin P-F. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab. 2007;92:3822–8. [PubMed: 17652212]
• Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, Chamontin B, Delemer B, Giraud S, Murat A, Niccoli-Sire P, Richard S, Rohmer V, Sadoul JL, Strompf L, Schlumberger M, Bertagna X, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP. Genetic testing in pheochromocytoma and functional paraganglioma. J Clin Oncol. 2005;23:8812–8. [PubMed: 16314641]
• Andrews KA, Ascher DB, Pires DEV, Barnes DR, Vialard L, Casey RT, Bradshaw N, Adlard J, Aylwin S, Brennan P, Brewer C, Cole T, Cook JA, Davidson R, Donaldson A, Fryer A, Greenhalgh L, Hodgson SV, Irving R, Lalloo F, McConachie M, McConnell VPM, Morrison PJ, Murday V, Park SM, Simpson HL, Snape K, Stewart S, Tomkins SE, Wallis Y, Izatt L, Goudie D, Lindsay RS, Perry CG, Woodward ER, Antoniou AC, Maher ER. Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet. 2018;55:384–94. [PMC free article: PMC5992372] [PubMed: 29386252]
• Asai S, Katabami T, Tsuiki M, Tanaka Y, Naruse M. Controlling tumor progression with cyclophosphamide, vincristine, and dacarbazine treatment improves survival in patients with metastatic and unresectable malignant pheochromocytomas/paragangliomas. Horm Cancer. 2017;8:108–18. [PubMed: 28108930]
• Astrom K, Cohen JE, Willett-Brozick JE, Aston CE, Baysal BE. Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect. Hum Genet. 2003;113:228–37. [PubMed: 12811540]
• Ayala-Ramirez M, Chougnet CN, Habra MA, Palmer JL, Leboulleux S, Cabanillas ME, Caramella C, Anderson P, Al Ghuzlan A, Waguespack SG, Deandreis D, Baudin E, Jimenez C. Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas. J Clin Endocrinol Metab. 2012;97:4040–50. [PMC free article: PMC3683800] [PubMed: 22965939]
• Ayala-Ramirez M, Feng L, Johnson MM, Ejaz S, Habra MA, Rich T, Busaidy N, Cote GJ, Perrier N, Phan A, Patel S, Waguespack S, Jimenez C. Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and sympathetic paragangliomas: primary tumor size and primary tumor location as prognostic indicators. J Clin Endocrinol Metab. 2011;96:717–25. [PubMed: 21190975]
• Bausch B, Schiavi F, Ni Y, Welander J, Patocs A, Ngeow J, Wellner U, Malinoc A, Taschin E, Barbon G, Lanza V, Söderkvist P, Stenman A, Larsson C, Svahn F, Chen JL, Marquard J, Fraenkel M, Walter MA, Peczkowska M, Prejbisz A, Jarzab B, Hasse-Lazar K, Petersenn S, Moeller LC, Meyer A, Reisch N, Trupka A, Brase C, Galiano M, Preuss SF, Kwok P, Lendvai N, Berisha G, Makay Ö, Boedeker CC, Weryha G, Racz K, Januszewicz A, Walz MK, Gimm O, Opocher G, Eng C, Neumann HPH., European-American-Asian Pheochromocytoma-Paraganglioma Registry Study Group. Clinical characterization of the pheochromocytoma and paraganglioma susceptibility genes SDHA, TMEM127, MAX, and SDHAF2 for gene-informed prevention. JAMA Oncol. 2017;3:1204–12. [PMC free article: PMC5824290] [PubMed: 28384794]
• Bayley JP, Kunst HP, Cascon A, Sampietro ML, Gaal J, Korpershoek E, Hinojar-Gutierrez A, Timmers HJ, Hoefsloot LH, Hermsen MA, Suarez C, Hussain AK, Vriends AH, Hes FJ, Jansen JC, Tops CM, Corssmit EP, de Knijff P, Lenders JW, Cremers CW, Devilee P, Dinjens WN, de Krijger RR, Robledo M. SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncol. 2010;11:366–72. [PubMed: 20071235]
• Bayley JP, Oldenburg RA, Nuk J, Hoekstra AS, van der Meer CA, Korpershoek E, McGillivray B, Corssmit EP, Dinjens WN, de Krijger RR, Devilee P, Jansen JC, Hes FJ. (2014) Paraganglioma and pheochromocytoma upon maternal transmission of SDHD mutations. BMC Med Genet. 10;15:111.
• Baysal BE, Willett-Brozick JE, Filho PA, Lawrence EC, Myers EN, Ferrell RE. An Alu-mediated partial SDHC deletion causes familial and sporadic paraganglioma. J Med Genet. 2004;41:703–9. [PMC free article: PMC1735880] [PubMed: 15342702]
• Baysal BE, Willett-Brozick JE, Lawrence EC, Drovdlic CM, Savul SA, McLeod DR, Yee HA, Brackmann DE, Slattery WH, Myers EN, Ferrell RE, Rubinstein WS. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet. 2002;39:178–83. [PMC free article: PMC1735061] [PubMed: 11897817]
• Benn DE, Gimenez-Roqueplo AP, Reilly JR, Bertherat J, Byth K, Croxson M, Dahia PL, Elston M, Gimm O, Henley D, Herman P, Murday V, Niccoli-Sire P, Pasieka JL, Rohmer V, Tucker K, Jeunemaitre X, Marsh DJ, Plouin PF, Robinson BG. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab. 2006;91:827–36. [PubMed: 16317055]
• Berends AMA, Buitenwerf E, de Krijger RR, Veeger NJGM, van der Horst-Schrivers ANA, Links TP, Kerstens MN. Incidence of pheochromocytoma and sympathetic paraganglioma in the Netherlands: a nationwide study and systematic review. Eur J Intern Med. 2018;51:68–73. [PubMed: 29361475]
• Boedeker CC, Ridder GJ, Schipper J. Paragangliomas of the head and neck: diagnosis and treatment. Fam Cancer. 2005;4:55–9. [PubMed: 15883711]
• Boikos SA, Pappo AS, Killian JK, LaQuaglia MP, Weldon CB, George S, Trent JC, von Mehren M, Wright JA, Schiffman JD, Raygada M, Pacak K, Meltzer PS, Miettinen MM, Stratakis C, Janeway KA, Helman LJ. Molecular subtypes of KIT/PDGFRA wild-type gastrointestinal stromal tumors: a report from the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol. 2016;2:922–8. [PMC free article: PMC5472100] [PubMed: 27011036]
• Buffet A, Venisse A, Nau V, Roncellin I, Boccio V, Le Pottier N, Boussion M, Travers C, Simian C, Burnichon N, Abermil N, Favier J, Jeunemaitre X, Gimenez-Roqueplo AP. A decade (2001-2010) of genetic testing for pheochromocytoma and paraganglioma. Horm Metab Res. 2012;44:359–66. [PubMed: 22517557]
• Burnichon N, Brière JJ, Libé R, Vescovo L, Rivière J, Tissier F, Jouanno E, Jeunemaitre X, Bénit P, Tzagoloff A, Rustin P, Bertherat J, Favier J, Gimenez-Roqueplo AP. SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet. 2010;19:3011–20. [PMC free article: PMC2901140] [PubMed: 20484225]
• Burnichon N, Cascón A, Schiavi F, Morales NP, Comino-Méndez I, Abermil N, Inglada-Pérez L, de Cubas AA, Amar L, Barontini M, de Quirós SB, Bertherat J, Bignon YJ, Blok MJ, Bobisse S, Borrego S, Castellano M, Chanson P, Chiara MD, Corssmit EP, Giacchè M, de Krijger RR, Ercolino T, Girerd X, Gómez-García EB, Gómez-Graña A, Guilhem I, Hes FJ, Honrado E, Korpershoek E, Lenders JW, Letón R, Mensenkamp AR, Merlo A, Mori L, Murat A, Pierre P, Plouin PF, Prodanov T, Quesada-Charneco M, Qin N, Rapizzi E, Raymond V, Reisch N, Roncador G, Ruiz-Ferrer M, Schillo F, Stegmann AP, Suarez C, Taschin E, Timmers HJ, Tops CM, Urioste M, Beuschlein F, Pacak K, Mannelli M, Dahia PL, Opocher G, Eisenhofer G, Gimenez-Roqueplo AP, Robledo M. MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin Cancer Res. 2012;18:2828–37. [PubMed: 22452945]
• Burnichon N, Mazzella JM, Drui D, Amar L, Bertherat J, Coupier I, Delemer B, Guilhem I, Herman P, Kerlan V, Tabarin A, Wion N, Lahlou-Laforet K, Favier J, Gimenez-Roqueplo AP. Risk assessment of maternally inherited SDHD paraganglioma and phaeochromocytoma. J Med Genet. 2017;54:125–33. [PubMed: 27856506]
• Burnichon N, Rohmer V, Amar L, Herman P, Leboulleux S, Darrouzet V, Niccoli P, Gaillard D, Chabrier G, Chabolle F, Coupier I, Thieblot P, Lecomte P, Bertherat J, Wion-Barbot N, Murat A, Venisse A, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab. 2009;94:2817–27. [PubMed: 19454582]
• Carney JA. Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney triad): natural history, adrenocortical component, and possible familial occurrence. Mayo Clin Proc. 1999;74:543–52. [PubMed: 10377927]
• Cascón A, Montero-Conde C, Ruiz-Llorente S, Mercadillo F, Letón R, Rodríguez-Antona C, Martínez-Delgado B, Delgado M, Díez A, Rovira A, Díaz JA, Robledo M. Gross SDHB deletions in patients with paraganglioma detected by multiplex PCR: a possible hot spot? Genes Chromosomes Cancer. 2006;45:213–9. [PubMed: 16258955]
• Casey RT, Ascher DB, Rattenberry E, Izatt L, Andrews KA, Simpson HL, Challis B, Park SM, Bulusu VR, Lalloo F, Pires DEV, West H, Clark GR, Smith PS, Whitworth J, Papathomas TG, Taniere P, Savisaar R, Hurst LD, Woodward ER, Maher ER. SDHA related tumorigenesis: a new case series and literature review for variant interpretation and pathogenicity. Mol Genet Genomic Med. 2017;5:237–50. [PMC free article: PMC5441402] [PubMed: 28546994]
• Chang CA, Pattison DA, Tothill RW, Kong G, Akhurst TJ, Hicks RJ, Hofman MS. (68)Ga-DOTATATE and (18)F-FDG PET/CT in paraganglioma and pheochromocytoma: utility, patterns and heterogeneity. Cancer Imaging. 2016;16:22. [PMC free article: PMC4989291] [PubMed: 27535829]
• Comino-Méndez I, Gracia-Aznarez FJ, Schiavi F, Landa I, Leandro-Garcia LJ, Leton R, Honrado E, Ramos-Medina R, Caronia D, Pita G, Gomez-Grana A, de Cubas AA, Inglada-Perez L, Maliszewska A, Taschin E, Bobisse S, Pica G, Loli P, Hernandez-Lavado R, Diaz JA, Gomez-Morales M, Gonzalez-Neira A, Roncador G, Rodriguez-Antona C, Benitez J, Mannelli M, Opocher G, Robledo M, Cascon A. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet. 2011;43:663–7. [PubMed: 21685915]
• Currás-Freixes M, Inglada-Pérez L, Mancikova V, Montero-Conde C, Letón R, Comino-Méndez I, Apellániz-Ruiz M, Sánchez-Barroso L, Aguirre Sánchez-Covisa M, Alcázar V, Aller J, Álvarez-Escolá C, Andía-Melero VM, Azriel-Mira S, Calatayud-Gutiérrez M, Díaz JÁ, Díez-Hernández A, Lamas-Oliveira C, Marazuela M, Matias-Guiu X, Meoro-Avilés A, Patiño-García A, Pedrinaci S, Riesco-Eizaguirre G, Sábado-Álvarez C, Sáez-Villaverde R, Sainz de Los Terreros A, Sanz Guadarrama Ó, Sastre-Marcos J, Scolá-Yurrita B, Segura-Huerta Á, Serrano-Corredor Mde L, Villar-Vicente MR, Rodríguez-Antona C, Korpershoek E, Cascón A, Robledo M. Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients. J Med Genet. 2015;52:647–56. [PubMed: 26269449]
• Eijkelenkamp K, Osinga TE, de Jong MM, Sluiter WJ, Dullaart RP, Links TP, Kerstens MN, van der Horst-Schrivers AN. Calculating the optimal surveillance for head and neck paraganglioma in SDHB-mutation carriers. Fam Cancer. 2017;16:123–30. [PMC free article: PMC5243881] [PubMed: 27573198]
• Else T, Marvin ML, Everett JN, Gruber SB, Arts HA, Stoffel EM, Auchus RJ, Raymond VM. The clinical phenotype of SDHC-associated hereditary paraganglioma syndrome (PGL3). J Clin Endocrinol Metab. 2014;99:E1482–6. [PMC free article: PMC4121019] [PubMed: 24758179]
• Fishbein L, Ben-Maimon S, Keefe S, Cengel K, Pryma DA, Loaiza-Bonilla A, Fraker DL, Nathanson KL, Cohen DL. SDHB mutation carriers with malignant pheochromocytoma respond better to CVD. Endocr Relat Cancer. 2017;24:L51–L55. [PubMed: 28566531]
• Fishbein L, Merrill S, Fraker DL, Cohen DL, Nathanson KL. Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing. Ann Surg Oncol. 2013;20:1444–50. [PMC free article: PMC4291281] [PubMed: 23512077]
• Fishbein L, Nathanson KL. Pheochromocytoma and paraganglioma: understanding the complexities of the genetic background. Cancer Genet. 2012;205:1–11. [PMC free article: PMC3311650] [PubMed: 22429592]
• Gill AJ, Benn DE, Chou A, Clarkson A, Muljono A, Meyer-Rochow GY, Richardson AL, Sidhu SB, Robinson BG, Clifton-Bligh RJ. Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes. Hum Pathol. 2010;41:805–14. [PubMed: 20236688]
• Gujrathi CS, Donald PJ. Current trends in the diagnosis and management of head and neck paragangliomas. Curr Opin Otolaryngol Head Neck Surg. 2005;13:339–42. [PubMed: 16282761]
• Hamidi O, Young WF Jr, Iñiguez-Ariza NM, Kittah NE, Gruber L, Bancos C, Tamhane S, Bancos I. Malignant pheochromocytoma and paraganglioma: 272 patients over 55 years. J Clin Endocrinol Metab. 2017;102:3296–3305. [PMC free article: PMC5587061] [PubMed: 28605453]
• Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL., Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17:70–87. [PubMed: 25394175]
• Hao HX, Khalimonchuk O, Schraders M, Dephoure N, Bayley JP, Kunst H, Devilee P, Cremers CW, Schiffman JD, Bentz BG, Gygi SP, Winge DR, Kremer H, Rutter J. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science. 2009;325:1139–42. [PMC free article: PMC3881419] [PubMed: 19628817]
• Hensen EF, Jordanova ES, van Minderhout IJ, Hogendoorn PC, Taschner PE, van der Mey AG, Devilee P, Cornelisse CJ. Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families. Oncogene. 2004;23:4076–83. [PubMed: 15064708]
• Hensen EF, van Duinen N, Jansen JC, Corssmit EP, Tops CM, Romijn JA, Vriends AH, van der Mey AG, Cornelisse CJ, Devilee P, Bayley JP. High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands. Clin Genet. 2012;81:284–8. [PubMed: 21348866]
• Hescot S, Leboulleux S, Amar L, Vezzosi D, Borget I, Bournaud-Salinas C, de la Fouchardiere C, Libé R, Do Cao C, Niccoli P, Tabarin A, Raingeard I, Chougnet C, Giraud S, Gimenez-Roqueplo AP, Young J, Borson-Chazot F, Bertherat J, Wemeau JL, Bertagna X, Plouin PF, Schlumberger M, Baudin E. French group of Endocrine and Adrenal tumors (Groupe des Tumeurs Endocrines-REseau NAtional des Tumeurs ENdocrines and COrtico-MEdullo Tumeurs Endocrines networks). One-year progression-free survival of therapy-naive patients with malignant pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2013;98:4006–12. [PubMed: 23884775]
• Hoekstra AS, Devilee P, Bayley JP. Models of parent-of-origin tumorigenesis in hereditary paraganglioma. Semin Cell Dev Biol. 2015;43:117–24. [PubMed: 26067997]
• Hoekstra AS, van den Ende B, Julià XP, van Breemen L, Scheurwater K, Tops CM, Malinoc A, Devilee P, Neumann HP, Bayley JP. Simple and rapid characterization of novel large germline deletions in SDHB, SDHC and SDHD-related paraganglioma. Clin Genet. 2017;91:536–44. [PubMed: 27485256]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Imamura H, Muroya K, Tanaka E, Konomoto T, Moritake H, Sato T, Kimura N, Takekoshi K, Nunoi H. Sporadic paraganglioma caused by de novo SDHB mutations in a 6-year-old girl. Eur J Pediatr. 2016;175:137–41. [PubMed: 26283294]
• Janssen I, Blanchet EM, Adams K, Chen CC, Millo CM, Herscovitch P, Taïeb D, Kebebew E, Lehnert H, Fojo AT, Pacak K. Superiority of [68Ga]-DOTATATE PET/CT to other functional imaging modalities in the localization of SDHB-associated metastatic pheochromocytoma and paraganglioma. Clin Cancer Res. 2015;21:3888–95. [PMC free article: PMC4558308] [PubMed: 25873086]
• Janssen I, Chen CC, Millo CM, Ling A, Taïeb D, Lin FI, Adams KT, Wolf KI, Herscovitch P, Fojo AT, Buchmann I, Kebebew E, Pacak K. PET/CT comparing (68)Ga-DOTATATE and other radiopharmaceuticals and in comparison with CT/MRI for the localization of sporadic metastatic pheochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging. 2016;43:1784–91. [PMC free article: PMC8194362] [PubMed: 26996779]
• Jasperson KW, Kohlmann W, Gammon A, Slack H, Buchmann L, Hunt J, Kirchhoff AC, Baskin H, Shaaban A, Schiffman JD. Role of rapid sequence whole-body MRI screening in SDH-associated hereditary paraganglioma families. Fam Cancer. 2014;13:257–65. [PubMed: 23934599]
• Jochmanova I, Wolf KI, King KS, Nambuba J, Wesley R, Martucci V, Raygada M, Adams KT, Prodanov T, Fojo AT, Lazurova I, Pacak K. SDHB-related pheochromocytoma and paraganglioma penetrance and genotype-phenotype correlations. J Cancer Res Clin Oncol. 2017;143:1421–35. [PMC free article: PMC5505780] [PubMed: 28374168]
• Junglee N, Harries SE, Davies N, Scott-Coombes D, Scanlon MF, Rees DA. Pheochromocytoma in pregnancy: when is operative intervention indicated? J Womens Health (Larchmt). 2007;16:1362–5. [PubMed: 18001193]
• Kong G, Grozinsky-Glasberg S, Hofman MS, Callahan J, Meirovitz A, Maimon O, Pattison DA, Gross DJ, Hicks RJ. Efficacy of peptide receptor radionuclide therapy for functional metastatic paraganglioma and pheochromocytoma. J Clin Endocrinol Metab. 2017;102:3278–87. [PubMed: 28605448]
• Korpershoek E, Favier J, Gaal J, Burnichon N, van Gessel B, Oudijk L, Badoual C, Gadessaud N, Venisse A, Bayley JP, van Dooren MF, de Herder WW, Tissier F, Plouin PF, van Nederveen FH, Dinjens WN, Gimenez-Roqueplo AP, de Krijger RR. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J Clin Endocrinol Metab. 2011;96:E1472–6. [PubMed: 21752896]
• Korpershoek E, Koffy D, Eussen BH, Oudijk L, Papathomas TG, van Nederveen FH, Belt EJ, Franssen GJ, Restuccia DF, Krol NM, van der Luijt RB, Feelders RA, Oldenburg RA, van Ijcken WF, de Klein A, de Herder WW, de Krijger RR, Dinjens WN. Complex MAX rearrangement in a family with malignant pheochromocytoma, renal oncocytoma, and erythrocytosis. J Clin Endocrinol Metab. 2016;101:453–60. [PubMed: 26670126]
• Kunst HP, Rutten MH, de Mönnink JP, Hoefsloot LH, Timmers HJ, Marres HA, Jansen JC, Kremer H, Bayley JP, Cremers CW. SDHAF2 (PGL2-SDH5) and hereditary head and neck paraganglioma. Clin Cancer Res. 2011;17:247–54. [PubMed: 21224366]
• Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, Naruse M, Pacak K, Young WF Jr. Endocrine Society. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:1915–42. [PubMed: 24893135]
• Letouzé E, Martinelli C, Loriot C, Burnichon N, Abermil N, Ottolenghi C, Janin M, Menara M, Nguyen AT, Benit P, Buffet A, Marcaillou C, Bertherat J, Amar L, Rustin P, De Reyniès A, Gimenez-Roqueplo AP, Favier J. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell. 2013;23:739–52. [PubMed: 23707781]
• Lloyd RV, Osamura RY, Kloppel G, Rosai J. WHO Classification of Tumours: Pathology and Genetics of Tumours of Endocrine Organs. 4 ed. Lyon: IARC; 2017.
• Neumann HP, Erlic Z, Boedeker CC, Rybicki LA, Robledo M, Hermsen M, Schiavi F, Falcioni M, Kwok P, Bauters C, Lampe K, Fischer M, Edelman E, Benn DE, Robinson BG, Wiegand S, Rasp G, Stuck BA, Hoffmann MM, Sullivan M, Sevilla MA, Weiss MM, Peczkowska M, Kubaszek A, Pigny P, Ward RL, Learoyd D, Croxson M, Zabolotny D, Yaremchuk S, Draf W, Muresan M, Lorenz RR, Knipping S, Strohm M, Dyckhoff G, Matthias C, Reisch N, Preuss SF, Esser D, Walter MA, Kaftan H, Stöver T, Fottner C, Gorgulla H, Malekpour M, Zarandy MM, Schipper J, Brase C, Glien A, Kühnemund M, Koscielny S, Schwerdtfeger P, Välimäki M, Szyfter W, Finckh U, Zerres K, Cascon A, Opocher G, Ridder GJ, Januszewicz A, Suarez C, Eng C. Clinical predictors for germline mutations in head and neck paraganglioma patients: cost reduction strategy in genetic diagnostic process as fall-out. Cancer Res. 2009;69:3650–6. [PubMed: 19351833]
• Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, Hoegerle S, Boedeker CC, Opocher G, Schipper J, Januszewicz A, Eng C., European-American Paraganglioma Study Group. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004;292:943–51. [PubMed: 15328326]
• Neumann HP, Sullivan M, Winter A, Malinoc A, Hoffmann MM, Boedeker CC, Bertz H, Walz MK, Moeller LC, Schmid KW, Eng C. Germline mutations of the TMEM127 gene in patients with paraganglioma of head and neck and extraadrenal abdominal sites. J Clin Endocrinol Metab. 2011;96:E1279–82. [PubMed: 21613359]
• Noto RB, Pryma DA, Jensen J, Lin T, Stambler N, Strack T, Wong V, Goldsmith SJ. Phase 1 study of high-specific-activity I-131 MIBG for metastatic and/or recurrent pheochromocytoma or paraganglioma. J Clin Endocrinol Metab. 2018;103:213–20. [PubMed: 29099942]
• Pai R, Manipadam MT, Singh P, Ebenazer A, Samuel P, Rajaratnam S. Usefulness of succinate dehydrogenase B (SDHB) immunohistochemistry in guiding mutational screening among patients with pheochromocytoma-paraganglioma syndromes. APMIS. 2014;122:1130–5. [PubMed: 24735130]
• Papathomas TG, Oudijk L, Persu A, Gill AJ, van Nederveen F, Tischler AS, Tissier F, Volante M, Matias-Guiu X, Smid M, Favier J, Rapizzi E, Libe R, Currás-Freixes M, Aydin S, Huynh T, Lichtenauer U, van Berkel A, Canu L, Domingues R, Clifton-Bligh RJ, Bialas M, Vikkula M, Baretton G, Papotti M, Nesi G, Badoual C, Pacak K, Eisenhofer G, Timmers HJ, Beuschlein F, Bertherat J, Mannelli M, Robledo M, Gimenez-Roqueplo AP, Dinjens WN, Korpershoek E, de Krijger RR. SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a multinational study of the European Network for the Study of Adrenal Tumors (ENS@T). Mod Pathol. 2015;28:807–21. [PubMed: 25720320]
• Pasini B, McWhinney SR, Bei T, Matyakhina L, Stergiopoulos S, Muchow M, Boikos SA, Ferrando B, Pacak K, Assie G, Baudin E, Chompret A, Ellison JW, Briere J-J, Rustin P, Gimenez-Roqueplo A-P, Eng C, Carney JA, Stratakis C. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, SDHD. Eur J Hum Genet. 2008;16:79–88. [PubMed: 17667967]
• Peczkowska M, Cascon A, Prejbisz A, Kubaszek A, Cwikla JB, Furmanek M, Erlic Z, Eng C, Januszewicz A, Neumann HPH. Extra-adrenal and adrenal pheochromocytomas associated with a germline SDHC mutation. Nat Clin Pract Endocrinol Metab. 2008;4:111–5. [PubMed: 18212813]
• Piccini V, Rapizzi E, Bacca A, Di Trapani G, Pulli R, Giachè V, Zampetti B, Lucci-Cordisco E, Canu L, Corsini E, Faggiano A, Deiana L, Carrara D, Tantardini V, Mariotti S, Ambrosio MR, Zatelli MC, Parenti G, Colao A, Pratesi C, Bernini G, Ercolino T, Mannelli M. Head and neck paragangliomas: genetic spectrum and clinical variability in 79 consecutive patients. Endocr Relat Cancer. 2012;19:149–55. [PubMed: 22241717]
• Pollard PJ, Briere JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ, Hargreaves IP, Heales SJ, Chung YL, Griffiths JR, Dalgleish A, McGrath JA, Gleeson MJ, Hodgson SV, Poulsom R, Rustin P, Tomlinson IPM. Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations. Hum Mol Genet. 2005;14:2231–9. [PubMed: 15987702]
• Qin Y, Deng Y, Ricketts CJ, Srikantan S, Wang E, Maher ER, Dahia PL. The tumor susceptibility gene TMEM127 is mutated in renal cell carcinomas and modulates endolysosomal function. Hum Mol Genet. 2014;23:2428–39. [PMC free article: PMC3976335] [PubMed: 24334765]
• Qin Y, Yao L, King EE, Buddavarapu K, Lenci RE, Chocron ES, Lechleiter JD, Sass M, Aronin N, Schiavi F, Boaretto F, Opocher G, Toledo RA, Toledo SP, Stiles C, Aguiar RC, Dahia PL. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet. 2010;42:229–33. [PMC free article: PMC2998199] [PubMed: 20154675]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR. UK10K Consortium, Hurles ME. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Rattenberry E, Vialard L, Yeung A, Bair H, McKay K, Jafri M, Canham N, Cole TR, Denes J, Hodgson SV, Irving R, Izatt L, Korbonits M, Kumar AV, Lalloo F, Morrison PJ, Woodward ER, Macdonald F, Wallis Y, Maher ER. A comprehensive next generation sequencing-based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2013;98:E1248–56. [PubMed: 23666964]
• Rednam SP, Erez A, Druker H, Janeway KA, Kamihara J, Kohlmann WK, Nathanson KL, States LJ, Tomlinson GE, Villani A, Voss SD, Schiffman JD, Wasserman JD. Von Hippel-Lindau and hereditary pheochromocytoma/paraganglioma syndromes: clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 2017;23:e68–e75. [PubMed: 28620007]
• Reisch N, Peczkowska M, Januszewicz A, Neumann HP. Pheochromocytoma: presentation, diagnosis and treatment. J Hypertens. 2006;24:2331–9. [PubMed: 17082709]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Ricketts CJ, Forman JR, Rattenberry E, Bradshaw N, Lalloo F, Izatt L, Cole TR, Armstrong R, Kumar VK, Morrison PJ, Atkinson AB, Douglas F, Ball SG, Cook J, Srirangalingam U, Killick P, Kirby G, Aylwin S, Woodward ER, Evans DG, Hodgson SV, Murday V, Chew SL, Connell JM, Blundell TL, Macdonald F, Maher ER. Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat. 2010;31:41–51. [PubMed: 19802898]
• Rinaldo A, Myssiorek D, Devaney KO, Ferlito A. Which paragangliomas of the head and neck have a higher rate of malignancy? Oral Oncol. 2004;40:458–60. [PubMed: 15006616]
• Schiavi F, Boedeker C, Bausch B, Peczkowska M, Fuentes-Gomez C, Strassburg T, Pawlu C, Buchta M, Salzmann M, Hoffmann MM, Berlis A, Brink I, Cybulla M, Muresan M, Walter MA, Forrer F, Välimäki M, Kawecki A, Szutkowski Z, Schipper J, Walz MK, Pigny P, Bauters C, Willet-Brozick JE, Baysal BE, Januszewicz A, Eng C, Opocher G, Neumann HH. Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. JAMA. 2005;294:2057–63. [PubMed: 16249420]
• Solis DC, Burnichon N, Timmers HJ, Raygada MJ, Kozupa A, Merino MJ, Makey D, Adams KT, Venisse A, Gimenez-Roqueplo AP, Pacak K. Penetrance and clinical consequences of a gross SDHB deletion in a large family. Clin Genet. 2009;75:354–63. [PMC free article: PMC4718153] [PubMed: 19389109]
• Stratakis CA. New genes and/or molecular pathways associated with adrenal hyperplasias and related adrenocortical tumors. Mol Cell Endocrinol. 2009;300:152–7. [PMC free article: PMC2668239] [PubMed: 19063937]
• Taïeb D, Kaliski A, Boedeker CC, Martucci V, Fojo T, Adler JR Jr, Pacak K. Current approaches and recent developments in the management of head and neck paragangliomas. Endocr Rev. 2014;35:795–819. [PMC free article: PMC4167435] [PubMed: 25033281]
• Udager AM, Magers MJ, Goerke DM, Vinco ML, Siddiqui J, Cao X, Lucas DR, Myers JL, Chinnaiyan AM, McHugh JB, Giordano TJ, Else T, Mehra R. The utility of SDHB and FH immunohistochemistry in patients evaluated for hereditary paraganglioma-pheochromocytoma syndromes. Hum Pathol. 2018;71:47–54. [PubMed: 29079178]
• van Baars F, Cremers C, van den Broek P, Geerts S, Veldman J. Genetic aspects of nonchromaffin paraganglioma. Hum Genet. 1982;60:305–9. [PubMed: 6286462]
• van der Tuin K, Mensenkamp AR, Tops CMJ, Corssmit EPM, Dinjens WN, van de Horst-Schrivers AN, Jansen JC, de Jong MM, Kunst HPM, Kusters B, Leter EM, Morreau H, van Nesselrooij BMP, Oldenburg RA, Spruijt L, Hes FJ, Timmers HJLM. Clinical aspects of SDHA-related pheochromocytoma and paraganglioma: a nationwide study. J Clin Endocrinol Metab. 2018;103:438–45. [PubMed: 29177515]
• van Nederveen FH, Gaal J, Favier J, Korpershoek E, Oldenburg RA, de Bruyn EM, Sleddens HF, Derkx P, Rivière J, Dannenberg H, Petri BJ, Komminoth P, Pacak K, Hop WC, Pollard PJ, Mannelli M, Bayley JP, Perren A, Niemann S, Verhofstad AA, de Bruïne AP, Maher ER, Tissier F, Méatchi T, Badoual C, Bertherat J, Amar L, Alataki D, Van Marck E, Ferrau F, François J, de Herder WW, Peeters MP, van Linge A, Lenders JW, Gimenez-Roqueplo AP, de Krijger RR, Dinjens WN. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol. 2009;10:764–71. [PMC free article: PMC4718191] [PubMed: 19576851]
• Vanderveen KA, Thompson SM, Callstrom MR, Young WF Jr, Grant CS, Farley DR, Richards ML, Thompson GB. Biopsy of pheochromocytomas and paragangliomas: potential for disaster. Surgery. 2009;146:1158–66. [PubMed: 19958944]
• Welander J, Garvin S, Bohnmark R, Isaksson L, Wiseman RW, Söderkvist P, Gimm O. Germline SDHA mutation detected by next-generation sequencing in a young index patient with large paraganglioma. J Clin Endocrinol Metab. 2013;98:E1379–80. [PubMed: 23750034]
• Wu D, Tischler AS, Lloyd RV, DeLellis RA, de Krijger R, van Nederveen F, Nosé V. Observer variation in the application of the Pheochromocytoma of the Adrenal Gland Scaled Score. Am J Surg Pathol. 2009;33:599–608. [PubMed: 19145205]
• Yao L, Schiavi F, Cascon A, Qin Y, Inglada-Pérez L, King EE, Toledo RA, Ercolino T, Rapizzi E, Ricketts CJ, Mori L, Giacchè M, Mendola A, Taschin E, Boaretto F, Loli P, Iacobone M, Rossi GP, Biondi B, Lima-Junior JV, Kater CE, Bex M, Vikkula M, Grossman AB, Gruber SB, Barontini M, Persu A, Castellano M, Toledo SP, Maher ER, Mannelli M, Opocher G, Robledo M, Dahia PL. Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas. JAMA. 2010;304:2611–9. [PubMed: 21156949]
• Yeap PM, Tobias ES, Mavraki E, Fletcher A, Bradshaw N, Freel EM, Cooke A, Murday VA, Davidson HR, Perry CG, Lindsay RS. Molecular analysis of pheochromocytoma after maternal transmission of SDHD mutation elucidates mechanism of parent-of-origin effect. J Clin Endocrinol Metab. 2011;96:E2009–13. [PubMed: 21937622]
• Young WF Jr. Endocrine hypertension. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinology. 12 ed. Philadelphia, PA: Saunders Elsevier; 2011:545-80.
• Zhu WD, Wang ZY, Chai YC, Wang XW, Chen DY, Wu H. Germline mutations and genotype-phenotype associations in head and neck paraganglioma patients with negative family history in China. Eur J Med Genet. 2015;58:433–8. [PubMed: 26096992]