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Hereditary Paraganglioma-Pheochromocytoma Syndromes

, MD, , MS, MPH, CGC, and , MD, PhD, MTR.

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Initial Posting: ; Last Update: October 4, 2018.

Summary

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 his/her mother is at a very low but not negligible risk of developing disease. An individual who inherits an SDHD pathogenic variant from his/her father is at high risk of manifesting PGL/PCC. If the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Diagnosis

The Endocrine Society guidelines for pheochromocytoma and paraganglioma [Lenders et al 2014] and American College of Medical Genetics guidelines for cancer predisposition [Hampel et al 2015] recommend that all individuals with paraganglioma or pheochromocytoma (PGL/PCC) be referred for clinical genetic testing for pathogenic variants in susceptibility genes.

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 variant in one of the genes listed in Table 1.

Molecular Genetic Testing

Approaches for hereditary PGL/PCC syndromes include use of a multigene panel and single-gene testing (in certain circumstances).

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 at the most reasonable cost 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. 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 simplex cases, with extra-adrenal tumors [Amar et al 2007]; or in an individual with a malignant tumor
  • SDHD in individuals with nonsecretory (parasympathetic) or secretory (sympathetic) head and neck paragangliomas (HNPGLs)
  • Targeted testing for a known familial pathogenic variant

Table 1.

Molecular Genetic Testing Used in Hereditary Paraganglioma-Pheochromocytoma Syndromes

Gene 1, 2Proportion of Hereditary PGL/PCC Syndromes Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 3 Detectable by This Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
MAX~1% 6>95% 72 probands 8
SDHA0.6%-3% 6, 9~100% 10None reported
SDHAF2<0.1% 6~100% 11None reported
SDHB10%-25% 12
12%-20% of HNPGL 13
24%-44% of chest, abdomen, pelvic PGL/PCC 14
~85%-95% 12, 13, 14~5%-15% 15
SDHC2%-8% 12, 14~85% 12, 16~15% 17, 18
SDHD~8%-9% 12
~40%-50% of HNPGL 13
~15% of chest, abdomen, pelvic PGL/PCC 14
~95% 12, 13, 14~5% 17
TMEM127~2% 6~100% 19None reported
Unknown 20
1.

Genes are listed in alphabetical order.

2.
3.

See Molecular Genetics for information on allelic variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Due to pseudogenes, many labs do not perform SDHA deletion/duplication analysis.

6.
7.
8.

Whole-gene deletion reported by Burnichon et al [2012]; complex rearrangement reported by Korpershoek et al [2016]

9.
10.
11.
12.
13.
14.
15.

Single-exon (most commonly exon 1), multiexon, and whole-gene deletions have been reported [Cascón et al 2006, Burnichon et al 2009, Neumann et al 2009, Solis et al 2009, Buffet et al 2012, Rattenberry et al 2013]

16.
17.
19.
20.

KIF1B, EGLN1 (formerly known as PHD2), MDH2, EPAS1, and FH have been reported to be associated with hereditary PGL/PCC; their clinical significance is as yet unclear.

Tumor Immunohistochemistry

If germline molecular genetic testing for hereditary PGL/PCC syndromes is not readily available, the results of immunohistochemical tumor analysis may suggest the presence of an underlying germline pathogenic variant. When any component of the mitochondrial respiratory chain complex 2 is completely inactivated, it appears that the entire complex becomes unstable, resulting in degradation of the SDHB subunit. Therefore, immunohistochemistry for SDHB is negative if there is complete inactivation of SDHA, SDHB, SDHC, or SDHD. As a result, negative staining for SDHB in tumor tissue appears to occur when a germline pathogenic variant in SDHA, SDHB, SDHC, or SDHD is accompanied by inactivation of the normal allele; thus, negative staining for SDHB may suggest the presence of a germline pathogenic variant of one of the SDH subunits [van Nederveen et al 2009, Gill et al 2010, Pai et al 2014, Udager et al 2018]. Germline pathogenic variants in SDHA show loss of staining for SDHA, in addition to loss of staining for SDHB [Korpershoek et al 2011, Papathomas et al 2015].

For these reasons, some recommend SDHB immunohistochemistry in individuals with familial and apparently sporadic PGL/PCC to guide molecular genetic testing; however, evidence is currently insufficient to advocate for the routine use of immunohistochemistry to guide molecular testing as several nonconcordant cases have been reported. Pathogenic variants in VHL also appear to contribute to difficulty in interpreting SDHB immunohistochemistry results. Therefore, since there are still some challenges in interpreting SDHB immunohistochemistry, and the procedure is not widely available, it is unclear whether it should be routinely performed on PGL/PCC tumor tissue.

Clinical Characteristics

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 T2-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].

Table 2.

Distinguishing Clinical Features of PGL/PCC by Genetic Etiology

GeneDistinguishing Clinical Features 1
PGL vs PCCBilateral PCC or multiple PGLBiochemical phenotypeMalignancy riskMOI
MAXPCC~60% bilateralMixed25%Possibly paternal 2
SDHAPGL, PCCSingleMixedLowAD
SDHAF2 3PGL (skull base & neck)~90% multipleUnclearLowPaternal 2
SDHBPGL~20% multipleNorepinephrine/
normetanephrine
34%-97%AD
SDHCPGL~20% multipleNorepinephrine/
normetanephrine
LowAD
SDHDPGL (skull base & neck)~50% multipleNorepinephrine/
normetanephrine, often silent
<5%Paternal 4
TMEM127PCC, rarely PGL~25% bilateralMixedLowAD
1.

General rules of thumb; exceptions exist.

2.

Mode of inheritance is likely paternal; only a few pedigrees have been described.

3.

Phenotype is not well described as only a few families have been reported.

4.

Maternal transmission has been rarely reported.

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.

Table 3.

Estimated Penetrance for SDHB and SDHD Pathogenic Variants

GeneAge in YearsPenetrance of PGL/PCC in Non-ProbandsPenetrance of PGL/PCC in Probands and Non-ProbandsReferences
SDHA7010%50%van der Tuin et al [2018]
SDHB6021.8%-26.4%23.9%-57.6%Jochmanova et al [2017], Andrews et al [2018]
SDHC6025% 1NRAndrews et al [2018]
SDHD6043.2%NRAndrews et al [2018]

NR = not reported

1.

This estimate is higher than expected based on clinical experience.

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 historic 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 historic 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.

Differential Diagnosis

The differential diagnosis of hereditary PGL/PCC syndromes includes sporadic PCC and PGL or other syndromes that predispose to PCC or PGL development.

Sporadic pheochromocytoma. The incidence of all PCC is ~0.6/100,000, and 75% are thought to be sporadic (not associated with hereditary predisposition).

Sporadic paraganglioma. The incidence of sporadic PGL is not known. It is believed to be less common than sporadic PCC; but the association with hereditary predisposition is higher than for PCC.

Several genetic disorders (see Table 4) associated with an increased risk of pheochromocytomas (PCC) and/or paragangliomas (PGL) have additional clinical features that are not seen in individuals with hereditary PGL/PCC syndromes.

Table 4.

Disorders to Consider in the Differential Diagnosis of Hereditary PGL/PCC

DisorderGeneMOIClinical Features of This Disorder 1
Overlapping w/hereditary PGL/PCCDistinguishing from hereditary PGL/PCC
Neurofibromatosis type INF1AD
  • PCC that secrete epinephrine &/or norepinephrine
  • PGL are rare.
  • Café au lait macules
  • Axillary & inguinal freckling
  • Neurofibromas
Von Hippel-Lindau diseaseVHLAD
  • PCC that secrete norepinephrine/ normetanephrine
  • PGL are infrequent.
  • Hemangioblastomas
  • Renal, pancreatic, epididymal, & broad ligament cysts
  • Renal cell carcinoma
  • Pancreatic neuroendocrine tumors
Multiple endocrine neoplasia type 2RETAD
  • PCC that secrete epinephrine/metanephrine &/or norepinephrine/normetanephrine
  • PGL are rare.
MEN2A:
  • Medullary thyroid carcinoma
  • Hyperparathyroidism
MEN2B:
  • Mucocutaneous neuromas
  • Ganglioneuromatosis
  • Slender body habitus
  • Joint laxity
  • Skeletal malformations
Polycythemia-paraganglioma-somatostatinoma syndromeEPAS1See footnote 2PGL
  • Mainly in females
  • Polycythemia
  • Somatostatinoma

PCC = pheochromocytoma

PGL = paraganglioma

1.

General rules of thumb; exceptions exist.

2.

To date, all reported individuals with polycythemia-paraganglioma-somatostatinoma syndrome have the disorder as the result of a somatic mosaic pathogenic variant (i.e., a pathogenic variant not inherited from a parent).

Management

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 problems 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 www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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.

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 his/her father is at high risk of manifesting PGL and PCC.
  • An individual who inherits an SDHD or SDHAF2 pathogenic variant from his/her mother is usually not at risk of developing disease (although each of his/her offspring is at a 50% risk of inheriting the pathogenic variant). However, exceptions occur:
  • 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 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 is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the PGL/PCC syndrome-related pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • My46 Trait Profile
  • PheoPara Troopers and PheoPara Alliance
    To empower and support pheochromocytoma and paraganglioma patients through knowledge, a sense of community, and advocacy while sponsoring key initiatives in data collection, treatment, and patient care.
    9721 Whitley Park Place
    Bethesda MD 20814
    Email: info@pheoparatroopers.org; info@pheopara.org
  • American Hearing Research Foundation (AHRF)
    8 South Michigan Avenue
    Suite 1205
    Chicago IL 60603-4539
    Phone: 312-726-9670
    Fax: 312-726-9695
    Email: ahrf@american-hearing.org
  • Medline Plus
  • National Cancer Institute (NCI)
  • Unicorn Foundation
    PO Box 384
    Blairgowrie Victoria 3942
    Australia
    Phone: 61 419 871 975
    Email: info@unicornfoundation.org.au
  • AMEND Research Registry
    The Warehouse
    Draper Street
    Tunbridge Wells Kent TN4 0PG
    United Kingdom
    Phone: +44 1892 516076
    Email: jo.grey@amend.org.uk

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table B.

OMIM Entries for Hereditary Paraganglioma-Pheochromocytoma Syndromes (View All in OMIM)

115310PARAGANGLIOMAS 4; PGL4
154950MAX PROTEIN; MAX
168000PARAGANGLIOMAS 1; PGL1
171300PHEOCHROMOCYTOMA
185470SUCCINATE DEHYDROGENASE COMPLEX, SUBUNIT B, IRON SULFUR PROTEIN; SDHB
600857SUCCINATE DEHYDROGENASE COMPLEX, SUBUNIT A, FLAVOPROTEIN; SDHA
601650PARAGANGLIOMAS 2; PGL2
602413SUCCINATE DEHYDROGENASE COMPLEX, SUBUNIT C, INTEGRAL MEMBRANE PROTEIN, 15-KD; SDHC
602690SUCCINATE DEHYDROGENASE COMPLEX, SUBUNIT D, INTEGRAL MEMBRANE PROTEIN; SDHD
605373PARAGANGLIOMAS 3; PGL3
613019SUCCINATE DEHYDROGENASE COMPLEX ASSEMBLY FACTOR 2; SDHAF2
613403TRANSMEMBRANE PROTEIN 127; TMEM127
614165PARAGANGLIOMAS 5; PGL5

Molecular Genetic 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.

MAX

Gene structure. MAX consists of five exons and produces a 2,068-bp transcript (reference sequence NM_002382.3). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Missense, nonsense, and splicing variants and intragenic deletions have all been reported in individuals with hereditary PGL/PCC.

Normal gene product. MAX encodes a 160-amino-acid protein that is a dimerization component of the MYC-MAX-MXD1 network of basic helix-loop-helix leucine zipper (bHLHZ) transcription factors that regulate cell proliferation, differentiation, and apoptosis.

Abnormal gene product. Pathogenic variants in MAX result in absence or dysfunction of its protein product, resulting in dysregulation of a number of genes involved in cell growth and cell death.

SDHA

Gene structure. SDHA comprises 15 exons and is approximately 39 kb in length. It encodes a 2,390-bp transcript (reference sequence NM_004168.3). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Multiple missense and nonsense pathogenic variants have been identified in SDHA. A database of normal and pathogenic variants for the SDH subunit genes is maintained by the Leiden University Medical Center (see Table A).

Normal gene product. SDHA encodes a flavoprotein subunit of succinate-ubiquinone oxidoreductase.

Abnormal gene product. Pathogenic variants in SDHA result in reduced or absent succinate dehydrogenase function because of loss or dysfunction of the affected subunit, or failure of the SDH heterotetramer to assemble.

SDHAF2

Gene structure. SDHAF2 (also known as SDH5) consists of four exons and produces a 501-bp transcript (reference sequence NM_017841.1). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. See Table 5. Affected individuals from a Dutch family described by van Baars et al [1982] were found to have a single-nucleotide change (c.232G>A) in exon 2 in SDHAF2. This resulted in a p.Gly78Arg alteration in the most conserved region of the protein and is believed to be a founder variant [Hensen et al 2012]. Of note, c.232G>C (p.Gly78Arg) has also been reported [Piccini et al 2012]. Additional loss-of-function variants have been reported in SDHAF2.

Table 5.

SDHAF2 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.232G>Ap.Gly78ArgNM_017841​.1
NP_060311​.1
c.232G>Cp.Gly78Arg

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. SDHAF2 encodes succinate dehydrogenase assembly factor 2, composed of 166 amino acid residues.

Abnormal gene product. The SDHAF2 protein appears to be required for SDHA flavination, stability of the SDH complex, and therefore the function of the SDH enzyme. Evidence suggests that the c.232G>A pathogenic variant in exon 2 of SDHAF2 destabilizes the protein, impairing its interaction with SDHA.

SDHB

Gene structure. SDHB comprises eight exons and is approximately 40 kb in length. It encodes an 1,162-bp transcript (reference sequence NM_003000.2). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Nonsense, missense, splice site variants, intragenic deletions and insertions, and whole-gene SDHB deletions have been reported in individuals/pedigrees affected with hereditary PGL/PCC syndromes. More than 100 pathogenic sequence variants have been described for SDHB. A database of normal and pathogenic variants for the SDH subunit genes is maintained by the Leiden University Medical Center (see Table A). SDHB variants are predominantly found in exons 1-7.

Large SDHB deletions have been reported, most commonly involving SDHB exon 1, but also other multiexon deletions and whole-gene deletions [Cascón et al 2006, Burnichon et al 2009, Neumann et al 2009, Solis et al 2009, Buffet et al 2012, Rattenberry et al 2013].

Normal gene product. SDHB encodes succinate dehydrogenase (ubiquinone) iron-sulfur subunit, a 280-amino-acid protein (reference sequence NP_002991.2).

Abnormal gene product. Pathogenic variants in SDHB result in reduced or absent succinate dehydrogenase function because of loss or dysfunction of the affected subunit, or failure of the SDH heterotetramer to assemble.

SDHC

Gene structure. SDHC has six exons and is more than 35 kb in length. It codes for a 2,858-bp transcript (reference sequence NM_003001.3). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Nonsense, missense, splice site, regulatory, and whole-exon-deletion SDHC pathogenic variants have been reported in individuals and pedigrees affected with hereditary PGL/PCC syndromes.

Normal gene product. SDHC encodes the succinate dehydrogenase cytochrome b560 subunit, a 169-amino-acid protein (reference sequence NP_002992.1).

Abnormal gene product. Pathogenic variants in SDHC result in reduced or absent succinate dehydrogenase function because of loss or dysfunction of the affected subunit or failure of the SDH heterotetramer to assemble.

SDHD

Gene structure. SDHD consists of four exons and produces a 1,313-bp transcript (reference sequence NM_003002.1). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Nonsense, missense, and splice site variants, intragenic insertions and deletions, and a whole-gene deletion have been reported in SDHD in individuals and pedigrees with hereditary PGL/PCC syndromes. More than 70 pathogenic sequence variants have been described for SDHD (see Table A). SDHD pathogenic variants are distributed throughout the four exons of the gene.

A database of normal and pathogenic variants for the SDH subunit genes is maintained by the Leiden University Medical Center (see Table A).

Normal gene product. SDHD encodes succinate dehydrogenase (ubiquinone) cytochrome b small subunit, a 159-amino-acid protein (reference sequence NP_002993.1).

Abnormal gene product. Pathogenic variants in SDHD result in reduced or absent succinate dehydrogenase function because of loss or dysfunction of the affected subunit or failure of the SDH heterotetramer to assemble.

TMEM127

Gene structure. TMEM127 consists of four exons and produces a 6,266-bp transcript (reference sequence NM_017849.3). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Missense, nonsense, and splicing variants and intragenic deletions have all been reported in individuals with hereditary PGL/PCC syndromes.

Normal gene product. TMEM127 encodes a 238-amino-acid protein that regulates mTORC1, a member of the phosphatidylinositol-3-kinase (PI3K)-related kinase family, through inhibition. This regulation promotes cell growth, angiogenesis, cell survival, and protein translation.

Abnormal gene product. Pathogenic variants in TMEM127 result in absence or dysfunction of its protein product, causing increased phosphorylation of mTORC1 and affecting cell growth.

References

Published Guidelines / Consensus Statements

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Chapter Notes

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
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