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 paragangliomas [HNPGLs]) and sometimes in the upper mediastinum; approximately 95% of such tumors are nonsecretory. In contrast, extra-adrenal sympathetic 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/PCCs 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. Additional tumors reported in individuals with hereditary PGL/PCC syndromes include gastrointestinal stromal tumors (GISTs), pulmonary chondromas, and clear cell renal cell carcinoma.

Diagnosis/testing.

A diagnosis of a hereditary PGL/PCC syndrome 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 with a personal or family history of paraganglioma or pheochromocytoma and a germline heterozygous pathogenic variant in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127 identified by molecular genetic testing.

Management.

Treatment of manifestations: SDHB-related PGL/PCCs are typically treated with surgical resection because of the higher risk for metastatic disease. In general, most HNPGLs (carotid body, glomus jugulotympanicum, vagal, and jugular paragangliomas) are nonsecretory and may be treated with active observation, surgical resection, or radiation therapy. For secretory PGL/PCCs, alpha-adrenergic receptor blockade followed by surgical resection. All individuals with HNPGLs should be evaluated for catecholamine excess before surgical resection, which, if present, can suggest an additional primary PGL/PCC. Metastatic PGL/PCCs are treated with blood pressure control, surgical debulking, radiation therapy especially for bony lesions, liver-directed therapy, systemic chemotherapy, or radionuclide therapy. GIST treatment includes surgical resection and/or tyrosine kinase inhibitor. Clear cell renal cell carcinoma treatment is early surgical resection and standard treatments for metastatic disease.

Surveillance: Individuals at risk for hereditary PGL/PCC syndromes should have annual clinical assessment for manifestations of PGL/PCCs and GISTs, plasma-free fractionated metanephrines or 24-hour urine fractionated metanephrines every two years in childhood and then annually in adults, and whole-body MRI every two to three years. Age of initiation for screening varies by gene. Consider endoscopic evaluation for GISTs in individuals with unexplained anemia and gastrointestinal symptoms.

Agents/circumstances to avoid: As for all cancer predisposition syndromes, activities such as cigarette smoking that predispose to chronic lung disease should be discouraged. Hypoxic conditions (e.g., cyanotic heart disease, 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 hereditary PGL/PCC syndrome and 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.

Hereditary PGL/PCC syndromes are inherited in an autosomal dominant manner. 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. Each child of an individual with a hereditary PGL/PCC syndrome-causing pathogenic variant has a 50% chance of inheriting the pathogenic variant. Pathogenic variants in SDHD, SDHAF2, and possibly MAX demonstrate parent-of-origin effects and cause disease almost exclusively when they are paternally inherited: an individual who inherits an SDHD or SDHAF2 pathogenic variant from the individual's father is at high risk of manifesting PGLs and PCCs; an individual who inherits an SDHD or SDHAF2 pathogenic variant from the individual's mother is usually not at risk of developing disease – however, exceptions occur. Once the PGL/PCC syndrome-related pathogenic variant has been identified in an affected family member, predictive molecular genetic testing for at-risk family members and prenatal and preimplantation genetic testing are possible.

Suggestive Findings

A hereditary PGL/PCC syndrome should be suspected in any individual with a paraganglioma or pheochromocytoma, particularly individuals with the following findings [Lenders et al 2014, Hampel et al 2015, Fishbein et al 2021, Horton et al 2022]:

• 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 a hereditary PGL/PCC syndrome may present with a solitary tumor of the skull base or neck, thorax, abdomen, adrenal medulla, or pelvis and no family history of paraganglioma or pheochromocytoma.

The following clinical and laboratory features suggest a paraganglioma or pheochromocytoma. Note that many paragangliomas and pheochromocytomas are discovered incidentally on imaging done for other reasons.

• Clinical features
  • Signs and symptoms of catecholamine excess, including classic signs and symptoms (e.g., sustained or paroxysmal elevations in blood pressure, headache, palpitations, arrhythmia, profuse sweating, apprehension or anxiety), and non-classic signs and symptoms (e.g., 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:
  • Metanephrine or its precursor epinephrine (adrenaline)
  • Normetanephrine or its precursor norepinephrine (noradrenaline)
  • 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 [Eisenhofer et al 2023]. (2) False positive results may be reduced by follow-up testing for 24-hour urine fractionated metanephrines when plasma normetanephrine concentrations are less than twofold above the reference range [Eisenhofer et al 2023]. (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 a hereditary PGL/PCC syndrome 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 personal or family history of paraganglioma or pheochromocytoma and a germline heterozygous pathogenic (or likely pathogenic) variant in one of the genes listed in Table 1 identified by molecular genetic testing.

Note: (1) Some families have multiple individuals with a paraganglioma or pheochromocytoma and no identifiable pathogenic variant in a known susceptibility gene. These families likely have a hereditary PGL/PCC syndrome either from a pathogenic variant in a regulatory element not found through standard molecular analysis or from a pathogenic variant in an unidentified susceptibility gene. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (3) 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.

Molecular genetic testing approaches include the use of a multigene panel and single-gene testing depending on the phenotype.

• A multigene panel that includes MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, and TMEM127 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. (5) For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Single-gene testing. Given the cost-effectiveness of multigene panel testing and overlap of phenotype in hereditary PGL/PCC syndromes, single-gene testing is not commonly used. However, in certain situations, it may be more cost-effective to use single-gene testing. Prioritized genetic testing may be pursued as single-gene testing based on clinical features:
  • SDHB in an individual with a metastatic pheochromocytoma or paraganglioma
  • SDHD in individuals with head and neck paragangliomas (HNPGLs); SDHD germline pathogenic variants account for 40%-50% of HNPGLs.

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 2022 World Health Organization (WHO) Classification of Endocrine Tumours classifies paragangliomas by location and (directly or indirectly) secretory status (adrenal paraganglioma [called pheochromocytoma], sympathetic abdominal paraganglioma, sympathetic head and neck paraganglioma, and parasympathetic paraganglioma) [Mete et al 2022].

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 (e.g., hoarseness, Horner syndrome). 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].
• Jugulare paragangliomas may present with difficulty swallowing, hoarseness, dysphagia, dizziness, hearing loss or pulsations in the ear, facial nerve palsy, or pain.

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 are associated with a higher risk of metastasizing [Ayala-Ramirez et al 2011].

Pheochromocytomas are catecholamine-secreting paragangliomas confined to the adrenal medulla. Metastatic disease is less likely in pheochromocytomas but can occur (see Phenotype Correlations by Gene).

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:

• Metanephrine or its precursor epinephrine (adrenaline)
• Normetanephrine or its precursor norepinephrine (noradrenaline)
• Dopamine and its major metabolite 3-methoxytyramine

Note: Plasma chromogranin A is not a catecholamine but is a protein often secreted by PGL/PCCs and can suggest a diagnosis of a PGL/PCC. However, elevation of plasma chromogranin A is not specific, as many other medical conditions (e.g., liver and kidney disease; gastrointestinal conditions such as atrophic gastritis, irritable bowel syndrome, and colon cancer; other malignancies and neuroendocrine tumors) and medications (e.g., proton pump inhibitors) can cause elevated plasma chromogranin A levels. Therefore, it is not recommended to measure plasma chromogranin A in those with suspected PGL/PCC.

Radiographic features of PGL/PCC. CT is often the imaging modality of choice to identify a PGL/PCC in a symptomatic person with suggestive biochemical testing, 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/PCCs 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 pheochromocytoma 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.
• 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.
• Some experts suggest using ⁶⁸Ga-DOTATATE PET-CT in individuals with hereditary PGL/PCC syndromes [Taïeb et al 2023] given high sensitivity and specificity for this imaging.

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

The most common sites of PGL/PCC metastases are bone, lung, liver, and lymph nodes.

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:

• ⁶⁸Ga-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, Patel et al 2022].
• 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 significantly lower sensitivity. For this reason, it is typically not used for detection of metastatic PGL/PCCs but will be used to determine if the metastatic disease can be treated with I-131-MIBG radionuclide therapy.
• Octreotide scintigraphy has been largely replaced by ⁶⁸Ga-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.

Other tumors

• Gastrointestinal stromal tumors (GISTs). The majority of GISTs associated with hereditary PGL/PCC syndromes occur in individuals with a germline pathogenic variant in SDHA or SDHC but can also occur in individuals with a germline pathogenic variant in SDHB or SDHD. Molecular genetic testing of SDHA, SDHB, SDHC, and SDHD should be considered in individuals with a wild type GIST (those that lack KIT or PDGFRA pathogenic variants) either by immunohistochemistry on tumor tissue or germline genetic testing. 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 have been described in individuals with a germline pathogenic variant in an SDHx gene [Boikos et al 2016].
• Clear cell renal cell carcinoma is more common in individuals with a pathogenic variant in SDHB or SDHD [Ricketts et al 2010]. The lifetime risk of developing a clear cell renal cell carcinoma 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.

Prognosis. With staged tumor-targeted treatment modalities, some affected individuals have lived with metastatic disease for more than 20 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 (see also Table 2).

MAX. Germline MAX pathogenic variants have most commonly been reported in association with pheochromocytomas; all individuals with MAX-related hereditary PGL/PCC presented initially with pheochromocytoma. Some individuals also had paragangliomas [Comino-Méndez et al 2011, Burnichon et al 2012, Bausch et al 2017].

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

SDHAF2. Germline SDHAF2 pathogenic variants have been identified in individuals 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 genes encoding the other SDH subunits [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, pheochromocytomas and parasympathetic paragangliomas [Andrews et al 2018]. Up to 45% 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 most often associated with HNPGLs. 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 paragangliomas and pheochromocytomas also occur [Ricketts et al 2010, Andrews et al 2018]. Seventy-five percent of persons with a germline SDHD pathogenic variant have multifocal primary paraganglioma [Taïeb et al 2023].

TMEM127. Germline TMEM127 pathogenic variants are associated with pheochromocytoma but can also be associated with HNPGLs and extra-adrenal paragangliomas [Armaiz-Pena et al 2021]. Clear cell 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 before 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.

Prior to the identification of the genes underlying hereditary PGL/PCC syndrome loci, the syndromes were referred to by their locus (i.e., PGL1, PGL2, PGL3, PGL4, and PGL5). A dyadic gene and phenotype-based naming approach is now preferred (e.g., SDHB-related hereditary PGL/PCC syndrome).

In 2017 WHO replaced the term "malignant pheochromocytoma" with "metastatic pheochromocytoma" to avoid confusion in the definition. PGL/PCCs are now considered localized or metastatic, not benign or malignant.

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 in 100,000 per 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 a hereditary predisposition. Altogether, about 35%-40% of all PGL/PCCs 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 PGL/PCC syndrome, the evaluations summarized in Table 6 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

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 [Fishbein et al 2021, NCCN 2022, Taïeb et al 2023].

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.

Although no clear data regarding when to start, best method, and how frequent biochemical studies and imaging should be done in at-risk individuals exist, it is reasonable to consider surveillance for all at-risk individuals [Amar et al 2021]. Surveillance recommendations should take into account the associated gene and penetrance. Gene-specific recommendations from expert consensus groups have been published but are based on limited data (see Table 8) [Hanson et al 2023, Taïeb et al 2023].

Agents/Circumstances to Avoid

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

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.

Evaluation of Relatives at Risk

Evaluation of apparently asymptomatic older and younger at-risk relatives of an individual with hereditary PGL/PCC syndrome 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 the development of metastatic disease. Evaluations can include the following:

• Predictive molecular genetic testing. If the pathogenic variant in the family is known, predictive molecular genetic testing should be offered to at-risk family members. Because the recommended gene-specific ages for initiation of surveillance is in childhood for all hereditary PGL/PCC-related genes (see Table 8), predictive molecular genetic testing is offered to at-risk children and adolescents. (Note: The frequency and intensity of surveillance should be tailored for the individual and family.)
  Pathogenic variants in SDHD and SDHAF2 (and possibly MAX) demonstrate parent-of-origin effects and cause disease almost exclusively when they are paternally inherited. In the case of maternal inheritance, predictive molecular genetic testing of family members can be deferred until age 18 years, at which time the individual can make an autonomous decision regarding predictive testing. 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.
• Surveillance. If the pathogenic variant in the family is not known, surveillance 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 PGL/PCCs are more likely to present at any time during pregnancy (whereas preeclampsia is more common in the second or third trimester) and are typically not associated with weight gain, edema, proteinuria, or thrombocytopenia. Individuals with PGL/PCCs are more likely to present with palpitations, sweating, pallor, orthostatic hypotension, and glucosuria, and the hypertension may be episodic. A retrospective multicenter cohort study of pregnancy outcomes in women with PGL/PCCs showed better outcomes for the woman and the fetus in women treated with alpha-adrenergic blockade [Bancos et al 2021].

Every individual with a 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. The retrospective multicenter cohort study did not show improved outcomes with surgery in the second trimester compared to medical therapy with alpha-adrenergic blockade [Bancos et al 2021]. MRI without gadolinium administration should be the first-line test used to localize a tumor, as 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 alpha-adrenergic and (if needed) subsequent beta-adrenergic blockade to prevent a hypertensive crisis. For intra-abdominal PGL/PCCs, 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 cesarean section may be necessary in these situations. A good outcome with vaginal delivery has only been described in those with appropriate alpha-adrenergic blockade [Bancos et al 2021].

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 [Kong et al 2017]. There are currently ongoing clinical trials with PRRT (Lutathera^®) and newer alpha-emitting molecules (see ClinicalTrials.gov). There is also an ongoing clinical trial with the HIF2α inhibitor belzutifan that has closed for recruitment and analysis is pending. 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 [Imamura et al 2016, Mauer et al 2020]. The proportion of individuals with a hereditary PGL/PCC syndrome caused by a de novo pathogenic variant is unknown.
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• 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 without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in 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 and/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

Testing of at-risk asymptomatic individuals. Consideration of molecular genetic testing of young, at-risk family members is appropriate. 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 (see Management, Surveillance and Evaluation of Relatives at Risk).

• Molecular genetic testing can be used with certainty to clarify the genetic status of at-risk family members if a clinically diagnosed relative has undergone molecular genetic testing and is found to have a germline PGL/PCC-related pathogenic variant.
• Because the recommended gene-specific ages for initiation of surveillance is in childhood for all hereditary PGL/PCC-related genes (see Table 8), molecular genetic testing is offered to at-risk children and adolescents. Special consideration should be given to education of the children and their parents prior to genetic testing, and older children and adolescents should be given the option of assenting to the test. A plan should be established for the manner in which results are to be given to the parents and their children.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – health professional version (part of PDQ^®, National Cancer Institute).

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.
• For those with a known hereditary PGL/PCC syndrome, screening for sympathetic PGL/PCC prior to conception is optimal. Otherwise, at a minimum, screening during pregnancy should be done to allow for optimal medical management for both the mother and the fetus (see Pregnancy Management).

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 HIF1α-stimulating hypoxia pathways and 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.

Mechanism of disease causation. Loss of function

Author Notes

Tobias Else (ude.hcimu.dem@eslet), Samantha Greenberg (ude.nretsewhtuostu@grebneerg.ahtnamas), and Lauren Fishbein (ude.ztuhcsnauc@niebhsif.nerual) are actively involved in clinical research regarding individuals with hereditary PGL/PCC syndromes. They would be happy to communicate with persons who have any questions regarding diagnosis of a hereditary PGL/PCC syndrome or other considerations.

Tobias Else (ude.hcimu.dem@eslet), Samantha Greenberg (ude.nretsewhtuostu@grebneerg.ahtnamas), and Lauren Fishbein (ude.ztuhcsnauc@niebhsif.nerual) are also interested in hearing from clinicians treating families affected by a hereditary PGL/PCC syndrome in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in hereditary PGL/PCC syndromes.

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

• 21 September 2023 (sw) Comprehensive update posted live
• 4 October 2018 (sw) Comprehensive update posted live
• 6 November 2014 (me) Comprehensive update posted live
• 30 August 2012 (me) Comprehensive update posted live
• 21 May 2008 (me) Posted live
• 14 November 2007 (rdk) Original submission

Published Guidelines / Consensus Statements

• Amar L, Pacak K, Steichen O, Akker SA, Aylwin SJB, Baudin E, Buffet A, Burnichon N, Clifton-Bligh RJ, Dahia PLM, Fassnacht M, Grossman AB, Herman P, Hicks RJ, Januszewicz A, Jimenez C, Kunst HPM, Lewis D, Mannelli M, Naruse M, Robledo M, Taïeb D, Taylor DR, Timmers HJLM, Treglia G, Tufton N, Young WF, Lenders JWM, Gimenez-Roqueplo AP, Lussey-Lepoutre C. International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers. Nat Rev Endocrinol. 2021;17:435-44. [PubMed]
• Fishbein L, Del Rivero J, Else T, Howe JR, Asa SL, Cohen DL, Dahia PLM, Fraker DL, Goodman KA, Hope TA, Kunz PL, Perez K, Perrier ND, Pryma DA, Ryder M, Sasson AR, Soulen MC, Jimenez C. The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma. Pancreas. 2021;50:469-93. [PubMed]
• Hanson H, Durkie M, Lalloo F, Izatt L, McVeigh TP, Cook JA, Brewer C, Drummond J, Butler S, Cranston T, Casey R, Tan T, Morganstein D, Eccles DM, Tischkowitz M, Turnbull C, Woodward ER, Maher ER; UK Cancer Genetics Centres. UK recommendations for SDHA germline genetic testing and surveillance in clinical practice. J Med Genet. 2023;60:107-11. [PubMed]
• 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]
• 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]
• Taïeb D, Wanna GB, Ahmad M, Lussey-Lepoutre C, Perrier ND, Nölting S, Amar L, Timmers HJLM, Schwam ZG, Estrera AL, Lim M, Pollom EL, Vitzthum L, Bourdeau I, Casey RT, Castinetti F, Clifton-Bligh R, Corssmit EPM, de Krijger RR, Del Rivero J, Eisenhofer G, Ghayee HK, Gimenez-Roqueplo AP, Grossman A, Imperiale A, Jansen JC, Jha A, Kerstens MN, Kunst HPM, Liu JK, Maher ER, Marchioni D, Mercado-Asis LB, Mete O, Naruse M, Nilubol N, Pandit-Taskar N, Sebag F, Tanabe A, Widimsky J, Meuter L, Lenders JWM, Pacak K. Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants. Lancet Diabetes Endocrinol. 2023;11:345-61. [PubMed]

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