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Hereditary Paraganglioma-Pheochromocytoma Syndromes

Includes: MAX-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome, SDHA-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome (Paragangliomas 5), SDHAF2-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome (Paragangliomas 2), SDHD-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome (Paragangliomas 1), SDHB-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome (Paragangliomas 4), SDHC-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome (Paragangliomas 3)

, MBBS and , MD, MSc.

Author Information
, MBBS
Assistant Professor of Medical Genetics & Pediatrics
Mayo Clinic
Rochester, Minnesota
, MD, MSc
Professor of Medicine
Chair, Division of Endocrinology
Mayo Clinic
Rochester, Minnesota

Initial Posting: ; Last Update: August 30, 2012.

Summary

Disease characteristics. Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues symmetrically distributed along the paravertebral axis from the base of the skull to the pelvis) and by pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas hypersecrete catecholamines; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base, neck, and upper medistinum; 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 hypersecrete catecholamines. Symptoms of PGL/PCC result either from 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 malignant transformation is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas or skull base and neck paragangliomas.

Diagnosis/testing. The diagnosis of hereditary PGL/PCC syndromes is based on physical examination, family history, imaging studies, biochemical testing, and molecular genetic testing. SDHA, SDHB, SDHC and SDHD are four nuclear genes that encode the four subunits of the mitochondrial enzyme succinate dehydrogenase (SDH). A fifth nuclear gene, SDHAF2 (also known as SDH5) encodes a protein that appears to be required for flavination of another SDH subunit, SDHA. These are collectively known as the SDHx genes. Mutations in MAX predispose to PCC; a subset of individuals with mutations in MAX will also develop PGL. KIF1B and EGLN1 (formerly known as PHD2) have been reported to be associated with hereditary PGL/PCC, but their clinical significance is still unclear.

Management. Treatment of manifestations: For secretory tumors including pheochromocytomas, antagonism of catecholamine excess with pharmacologic adrenergic receptor blockade followed by surgery. For nonsecretory skull base and neck paragangliomas, surgical resection if feasible. PGL/PCCs identified in individuals known to have SDHB mutations require resection promptly because of the high risk for malignant transformation.

Prevention of secondary complications: Early detection through surveillance and removal of tumors may prevent or minimize complications related to mass effects, catecholamine hypersecretion, and malignant transformation.

Surveillance: Beginning at age ten years or at least ten years before the earliest age at diagnosis in the family, individuals at risk for hereditary PGL/PCC syndromes need to begin lifelong biochemical and clinical surveillance for signs and symptoms of PGL/PCC.

Agents/circumstances to avoid: Hypoxia, cigarette smoking.

Evaluation of relatives at risk: First-degree relatives (age ≥10 years) of an individual with a known SDHA, SDHB, SDHC, SDHD, SDHAF2, or MAX mutation 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 disease-causing mutation.

Genetic counseling. The hereditary PGL/PCC syndromes are inherited in an autosomal dominant manner. Mutations in SDHD (PGL1) demonstrate parent-of-origin effects and generally cause disease only when the mutation is inherited from the father. Initial data suggest that mutations in SDHAF2 (PGL2) and MAX exhibit parent-of-origin effects similar to those of mutations in SDHD. A proband with a hereditary PGL/PCC syndrome may have inherited the mutation from a parent or have a de novo mutation; the proportion of cases caused by de novo mutations is unknown. Each child of an individual with a hereditary PGL/PCC syndrome has a 50% chance of inheriting the disease-causing mutation. An individual who inherits a SDHD mutation from his/her mother is at a low but not negligible risk of developing disease; each of his/her offspring is at a 50% risk of inheriting the disease-causing allele. An individual who inherits an SDHD mutation from his/her father is at high risk of manifesting paragangliomas and, to a lesser extent, pheochromocytomas. If the disease-causing mutation in the family is known, prenatal testing for pregnancies at increased risk is possible through laboratories offering either testing for the gene of interest or custom testing.

Diagnosis

Clinical Diagnosis

Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes should be considered in all individuals with paragangliomas and/or pheochromocytomas, particularly those with the following findings [Young 2011]:

  • Tumors that are:
    • Multiple (i.e., more than one paraganglioma or pheochromocytoma), including bilateral adrenal pheochromocytoma
    • Multifocal with multiple synchronous or metachronous tumors
    • Recurrent
    • Early onset (i.e., age <45 years)
  • A family history of such tumors

    Note: Many individuals with a 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 the disorder (i.e., simplex cases: a single known occurrence in a family) [Baysal et al 2002, Neumann et al 2002, Badenhop et al 2004, Amar et al 2005].

The 2004 WHO Classification of Endocrine Tumours [DeLellis et al 2004] classifies paragangliomas/pheochromocytomas by location and, directly or indirectly, secretory status (i.e., sympathetic [which hypersecrete catecholamines] vs parasympathetic [which do not]).

The following discussion of tumor types is based on the World Health Organization Classification of endocrine tumors [Kimura et al 2004a, Kimura et al 2004b, Lloyd et al 2004, McNicol et al 2004, Thompson et al 2004, Tischler & Komminoth 2004].

Paragangliomas (paraganglion tumors) arise from neuroendocrine tissues (paraganglia) symmetrically distributed along the paravertebral axis from their predominant location at the base of the skull and neck to the pelvis:

  • Paragangliomas in the skull base, upper mediastinum, and neck are primarily associated with the parasympathetic nervous system and generally do not hypersecrete catecholamines or other hormones. Approximately 5% of skull base and neck paragangliomas hypersecrete catecholamines.
  • Paragangliomas in the lower mediastinum, abdomen, and pelvis are typically associated with the sympathetic nervous system and usually hypersecrete catecholamines.

    Note: Sympathetic paragangliomas located along the paravertebral axis (and not in the adrenal gland) are called “extra-adrenal sympathetic paragangliomas.”

Pheochromocytomas are catecholamine-secreting paragangliomas confined to the adrenal medulla. 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).

The diagnosis of paragangliomas and pheochromocytomas is based on physical examination, imaging studies, and biochemical testing (see Testing).

Patient evaluation includes the following:

  • Detailed family history, including specific knowledge of any relatives with unexplained or incompletely explained sudden death
  • Personal medical history for the following:
    • Symptoms of catecholamine excess that can include sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, palpitations (perceived episodic, forceful, often rapid heartbeat), pallor, and apprehension or anxiety
    • Paroxysmal symptoms that may be triggered by changes in body position, increases in intra-abdominal pressure, medications (e.g., metoclopramide), anesthesia induction, exercise, or micturition in the case of urinary bladder paragangliomas. Urinary bladder paragangliomas may also be accompanied by painless hematuria.
    • Evidence of skull base and neck paragangliomas. These tumors may present as enlarging masses that are asymptomatic or associated with symptoms of mass effects from the size and/or location of the tumors. Associated symptoms may include unilateral hearing loss, pulsatile tinnitus, cough, hoarseness of voice, pharyngeal fullness, swallowing difficulty, pain, and/or problems with tongue motion.
  • Physical examination directed toward signs suggestive of PGL/PCC:
    • For sympathetic paragangliomas and pheochromocytomas, signs may include documentation of elevated blood pressure, tachyarrhythmias or other arrhythmias, and palpable abdominal masses.
    • For skull base and neck paragangliomas, signs may include skull base and neck masses:
      • A carotid body tumor is likely to be vertically adherent and may be associated with bruits or palpable thrills.

        Note: 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.
      • A jugulotympanic tumor may be visible as a blue-colored pulsating mass behind the intact tympanic membrane [Gujrathi & Donald 2005].

Imaging studies

For diagnosis and tumor localization, the following studies can be used [Lenders et al 2005, Young 2006, Pacak et al 2007, Young 2007].

MRI/CT

  • Paragangliomas may be identified anywhere along the paravertebral axis from the skull base to the pelvis, including the paraortic sympathetic chain. 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, which helps distinguish pheochromocytomas from benign adrenal cortical adenomas. On CT these tumors are characterized by heterogeneous appearance with cystic areas, high unenhanced CT attenuation (density), increased vascularity on contrast-enhanced CT, and slow contrast washout.
  • Multiple tumors can be present.
  • The diagnostic sensitivities and specificities of CT and MRI are equivalent, approximately 90%-100% and 70%-80%, respectively.
  • Whole-body short tau inversion recovery (STIR) MRI with targeted MRI for positive tumors may be a reasonable approach for both diagnosis and monitoring. This strategy minimizes radiation exposure associated with CT scanning, while taking advantage of the high sensitivity of T2-weighted MRI.

Note: MRI and CT are also used for tumor staging [Lenders et al 2005, Young 2006, Pacak et al 2007].

Sonography. B-mode sonography coupled with color-coded Doppler sonography is useful for diagnosis of carotid body and vagal paragangliomas.

Digital subtraction angiography (DSA)

  • 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.

To detect metastases, the following studies can be used [Gujrathi & Donald 2005].

  • 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;
      • Look for additional sites of disease;
      • Identify tumors when CT or MRI results are negative [Young 2011].
  • 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.
  • 2-18F-fluoro-2-deoxy-D-glucose position emission tomography (FDG-PET), or PET using other imaging compounds, can also assist in detecting metastatic disease.

Testing

Biochemical testing. Catecholamines and metanephrines hypersecreted 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 methyoxytyramine

When a catecholamine-secreting tumor is suspected, plasma and/or 24-hour urinary fractionated metanephrines and catecholamines are evaluated for catecholamine hypersecretion.

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].

Biopsy. Biopsy of skull base and neck paragangliomas is not normally required and may be contraindicated because this invasive procedure has the risk of precipitating a hypertensive crisis, hemorrhage, and tumor cell seeding. In addition, biopsy of adrenal pheochromocytoma or abdominal paraganglioma should be avoided [Vanderveen et al 2009].

Tumor immunohistochemistry. When any component of the mitochondrial 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 whenever there is complete inactivation of SDHA, SDHB, SDHC, SDHD, or SDHAF2. As a result, negative immunohistochemical staining for SDHB seems to occur whenever there is germline mutation of SDHA, SDHB, SDHC, or SDHD accompanied by inactivation of the normal allele; thus, negative staining for SDHB would appear to be a promising marker suggestive of a germline mutation of any of the SDH subunits [Gill et al 2010]. Germline mutations in SDHA show loss of staining for SDHA, in addition to loss of staining for SDHB [Korpershoek et al 2011]. It is being proposed that SDHB immunohistochemistry be used in both familial and apparently sporadic PGL/PCC cases to guide molecular genetic testing.

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.

Molecular Genetic Testing

Genes. The individual hereditary PGL/PCC syndromes and their associated genes:

Genes possibly associated with PGL/PCC syndromes KIF1B and EGLN1 (formerly known as PHD2) have been reported to be associated with hereditary PGL/PCC, but their clinical significance is still unclear (see Molecular Genetics)

Evidence for locus heterogeneity. The absence of known mutations in families with multiple affected members supports the possibility of additional PGL/PCC susceptibility genes.

Clinical testing

  • Sequence analysis. Sequence analysis of the coding regions of SDHB, SDHC, and SDHD, and associated intron-exon junctions detects approximately 70% of familial cases of skull base and neck paraganglioma [Baysal et al 2002]. Click here (pdf) for a summary of reports of mutations in these genes in different populations.

Table 1. Summary of Molecular Genetic Testing Used in Hereditary Paraganglioma-Pheochromocytoma Syndromes

Gene 1
(Locus)
Proportion of Hereditary PGL/PCC Attributed to Mutations in This GeneTest MethodMutations Detected 2
SDHD
(PGL1)
~30% 3
~40%-50% of skull base and neck PGL 4
~15% of chest, abdomen, pelvic PGL/PCC 5
Sequence analysis / mutation scanning 6, 7Sequence variants 8, 9
Deletion/duplication analysis 10Partial- and whole-gene deletions 11
SDHB
(PGL4)
22%-38% 3
12%-20% of skull base and neck PGL 4
24%-44% of chest, abdomen, pelvic PGL/PCC 5
Sequence analysis / mutation scanning 12, 13Sequence variants 8
Deletion/duplication analysis 10Partial- and whole-gene deletions 11
SDHC
(PGL3)
4-8% 3,14Sequence analysis / mutation scanning 12Sequence variants 8
Deletion/duplication analysis 10Partial- and whole-gene deletions 11
SDHA
(PGL5)
0.6-3% 3,15Sequence analysisSequence variants 8
SDHAF2
(PGL2)
Unknown Sequence analysis / mutation scanning 12Sequence variants 8, 16
Sequence analysis of select exonsSequence variants of exon6
Targeted mutation analysis c.232G>A 17
MAXUnknown Sequence analysisSequence variants 8
Deletion/duplication analysis 10Partial- and whole-gene deletions 18

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Burnichon et al [2009], Buffet et al [2012]

4. Pedigrees with familial/syndromic presentations of skull base and neck PGL [Baysal et al 2002, Burnichon et al 2009]

5. Pedigrees with inherited and extra-adrenal sympathetic PGL and PCC [Amar et al 2005, Burnichon et al 2009]

6. Exons may vary by laboratory.

7. Three SDHD mutations (p.Asp92Tyr, p.Leu95Pro, p.Leu139Pro) are responsible for almost all cases of hereditary paraganglioma in the Dutch population [Taschner et al 2001, Dannenberg et al 2002]. The mutations p.Asp92Tyr and p.Leu139Pro were identified in 30 of 32 Dutch families with familial skull base and neck paragangliomas (94%) and 20/55 (36%) of simplex cases [Taschner et al 2001]. It has been proposed that the SDHD mutation p.Met1Ile is a founder mutation in the Chinese population [Lee et al 2003].

8. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

8. In the Netherlands, 94% of inherited skull base and neck PGL is caused by two SDHD founder mutations: p.Asp92Tyr and p.Leu139Pro [Taschner et al 2001].

10. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

11. One study found gross deletions in SDHB in 12% of individuals in whom sequence analysis failed to identify a causative mutation [Cascón et al 2006]. In one study from a large French registry, 9.1% of individuals had a large deletion in SDHB, SDHC or SDHD [Burnichon et al 2009]. In the decade-long French study, the frequency of large deletions was 13.1% of all mutations in SDHB, 5% in SDHD and 16.7% in SDHC [Buffet et al 2012].

12. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably among laboratories depending on the specific protocol used.

13. A whole-exon deletion of SDHB exon 1 appears to be a founder mutation in the Spanish population [Cascón et al 2008].

14. Five of 121 individuals included in a European Skull base and Neck Paraganglioma Registry were found to have SDHC mutations [Schiavi et al 2005].

15. Korpershoek et al [2011]

16. Hao et al [2009]

17. Three individuals with hereditary PGL/PCC from the Dutch family described by van Baars et al [1982] were identified as having a single-nucleotide change (c.232G>A) in exon 2 of SDHAF2 (also known as SDH5) [Hao et al 2009].

18. Burnichon et al [2012]

Testing Strategy

To confirm/establish the diagnosis in a proband. There is no universally agreed-upon consensus or standard protocol regarding a diagnostic approach to individuals with hereditary PGL/PCC. The strategy employed should use all available clinical data (family history, physical exam, tumor location, presence of metastases and biochemical phenotype) to make the best clinical judgment with regard to the most likely genetic etiology in each affected individual or family. The decision can then be made for pursuing genetic testing in a step-wise fashion, and multiple algorithms have been suggested using this approach [Erlic et al 2009, Neumann et al 2009, Welander et al 2011]. A novel approach is to use multi-gene testing panels, which may end up saving time, although there is no clear consensus on which approach is the best.

Single gene testing. The most common strategy for molecular diagnosis of a proband suspected of having a PGL/PCC syndrome is molecular genetic testing for SDHD, SDHB, SDHC, SDHA, and SDHAF2 in all individuals known to have or suspected of having a PGL/PCC syndrome. In an individual who had a PCC and then developed a PGL, molecular genetic testing of MAX should also be considered. The role of KIF1B and EGLN1 is unclear, and need not be considered for routine testing. Features such as young age at onset, presence of bilateral, extra-adrenal or multiple tumors, or malignancy suggest an inherited disorder [Gimenez-Roqueplo et al 2006, Pacak et al 2007]:

Note: The absence of family history or other features suggestive of a hereditary syndrome should not preclude genetic testing.

  • Persons with nonsecretory (parasympathetic) or secretory (sympathetic) skull base and neck paragangliomas should initially be tested for mutations in SDHD, followed by SDHB and SDHC, and finally SDHAF2.
  • Because of the relatively low age-related penetrance, the tendency of chromaffin tumors to undergo malignant transformation, and the adverse prognosis associated with malignant paragangliomas and pheochromocytomas [Amar et al 2007], testing for SDHB mutations should be considered for all simplex cases, particularly those with extra-adrenal tumors.
  • Persons with extra-adrenal sympathetic paragangliomas should initially be tested for mutations in SDHB, followed by SDHD, VHL (see Differential Diagnosis), and then SDHC.

    Note: A substantial proportion of individuals with an SDHB mutation present as simplex cases [Amar et al 2005, Timmers et al 2007, Klein et al 2008].
  • Persons with pheochromocytomas without evidence for neurofibromatosis type I, von Hippel-Lindau syndrome (caused by mutation of VHL), or multiple endocrine neoplasia type 2 (MEN2, caused by mutation of RET) should be evaluated for SDHB and SDHD mutations, followed by TMEM127 and MAX (see Differential Diagnosis):
    • Individuals with VHL- and RET-related disease especially tend to present at younger ages.
    • Bilateral pheochromocytoma is particularly associated with von Hippel-Lindau disease and MEN2 [Gimenez-Roqueplo et al 2006].
    • The First International Symposium on Pheochromocytoma identified early age of onset as an important consideration in the decision to test for mutations in disease-causing genes, and has endorsed a stepwise approach to genetic testing, which includes the type of catecholamine produced by the tumor [Pacak et al 2007].
    • Pheochromocytomas in individuals with von Hippel-Lindau appear to universally produce norepinephrine and normetanephrine, whereas those in individuals with MEN2 always produce epinephrine and metanephrine [Pacak et al 2007].
  • An individual with a malignant tumor should initially be tested for mutations in SDHB.

Table 2. Distinguishing Clinical Features of PGL/PCC by Genetic Etiology

Mutated GeneDistinguishing Clinical Features 1
PGL vs PCCBilateral PCC or multiple PGLBiochemical phenotypeMalignancy riskTransmission
RETPCC~60% bilateralEpinephrine<5%AD
VHLPCC~40% bilateralNorepinephrine<5%AD
NF1PCC~15% bilateralEpinephrine~9%AD
SDHDPGL (skull base and neck)~50% multipleNorepinephrine / Dopamine<5%Paternal 2
SDHBPGL~20% multipleNorepinephrine / Dopamine34%-97%AD
SDHCPGL~20% multipleNorepinephrine / DopamineLow AD
SDHAF2PGL (skull base and neck)~90% multiple Unclear LowPaternal
SDHAPGLSingleMixed Low AD
TMEM127PCC~40% bilateralMixed < 5%AD
MAXPCC~60% bilateralMixed25%Paternal

AD = autosomal dominant

1. General rules of thumb; exceptions exist.

2. One case of maternal transmission has been reported.

See Figure 1 for a genetic testing algorithm based on the clinical features of the tumor(s) [Welander et al 2011].

Figure 1

Figure

Figure 1. A genetic testing algorithm for individuals with pheochromocytoma or paraganglioma based on the clinical features of the tumor(s). Genes are listed in descending priority from top to bottom and from left to right.

From Welander (more...)

Multi-gene panel testing. Another strategy for molecular diagnosis of a proband suspected of having hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes is use of a multi-gene panel. These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative mutation or mutations in any given individual also varies.

Predictive testing for at-risk asymptomatic family members should be preceded by prior identification of the disease-causing mutation in the family whenever possible.

Note: Identification of the disease-causing mutation (or the absence thereof) in an affected individual is essential for interpretation of negative molecular genetic test results in an at-risk asymptomatic relative.

Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

In the hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes, tumors arise within the paraganglia, collections of neural crest cells symmetrically distributed along the paravertebral axis from the base of the skull to the pelvis.

Paraganglia in the skull base and neck are generally associated with the parasympathetic nervous system, with the largest tissue collections located in the areas surrounding the carotid body, vagus nerve, and jugulotympanic region. Paragangliomas in these sites typically do not hypersecrete catecholamines. Most skull base and neck paragangliomas do not metastasize; their untoward consequences are typically the result of mass effects:

  • Carotid body paragangliomas classically present as asymptomatic, enlarging lateral neck masses. 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].

Paraganglia in the thorax, abdomen, and pelvis are normally associated with the sympathetic nervous system, and tumors of these paraganglioma may hypersecrete catecholamines. The adrenal medulla has the largest collection of sympathetic paraganglion cells.

Pheochromocytomas and extra-adrenal sympathetic paragangliomas in PGL/PCC syndromes present in a manner similar to those in persons with sporadic (i.e., not inherited) tumors, most often coming to medical attention in the following four clinical settings:

  • Signs and symptoms associated with catecholamine hypersecretion, including elevations in blood pressure and pulse, headaches, forceful palpitations, excessive sweating, and anxiety. Nausea, emesis, fatigue, and weight loss can also be seen. Symptoms are often episodic [Lenders et al 2005, Young 2006].
  • Signs and symptoms related to mass effects from the neoplasm
  • Incidentally discovered mass on MRI/CT performed for other reasons
  • Screening of at-risk relatives [Young 2011]

Extra-adrenal sympathetic paragangliomas have an increased likelihood of malignant transformation [Proye et al 1992]. Malignancy is much less likely in pheochromocytomas but does occur (see Genotype-Phenotype Correlations).

Manifestations of PGL/PCCs. Compared to persons with sporadic tumors, individuals with germline mutations in SDHx genes tend to present at younger ages and to be more likely to have multifocal, bilateral, and recurrent disease, or to have multiple synchronous neoplasms.

Because SDHC mutations are rare, data on phenotypic characteristics associated with SDHC mutations are limited. In a review of 22 individuals with SDHC mutations who had skull base and neck paragangliomas (15 from the literature, 7 from an internally evaluated series), Schiavi et al [2005] found no clinical, pathologic, or demographic features that clearly differentiated persons with SDHC mutations from 88 index cases and two simplex cases from the literature with skull base and neck paragangliomas in whom mutations in SDHD, SDHB, SDHC, VHL, and RET were not detected.

Benign PGL/PCCs are generally slow growing — approximately 0.5 to 1.0 cm increase in diameter per year [Young 2007]. By contrast, malignant tumors are typically more aggressive, although malignant tumors with indolent courses have been documented [Young et al 2002].

No reliable pathology studies are available to distinguish a primary benign PGL/PCC from a primary malignant PGL/PCC. Consequently, establishing the malignant nature of a tumor relies on the presence of metastases to non-chromaffin sites, the most common of which are bone, lung, liver, and lymph nodes. 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 the disease is uniformly fatal, with only 50% of affected individuals surviving beyond five years [Thompson et al 2004, Young 2011].

Other tumors

  • Gastrointestinal stromal tumors may occur in individuals with hereditary PGL/PCC syndromes caused by mutations in any one of the four genes encoding the SDH subunits [Pasini et al 2008].
  • Renal clear cell carcinoma and papillary thyroid carcinoma have been reported with mutations in SDHB and SDHD [Neumann et al 2002, Neumann et al 2004, Vanharanta et al 2004]. However, the significance of these findings is unclear.

Longevity. With staged tumor targeted treatment modalities some affected individuals have lived with their disease for 20 or more years [Young et al 2002].

Genotype-Phenotype Correlations

Although persons with SDHA, SDHB, SDHC, SDHD, and SDHAF2, and MAX mutations can develop pheochromocytomas and/or paragangliomas within any paraganglion tissue, the following correlations between the gene involved and tumor location are used to guide diagnostic testing and, in some instances, patient care:

Germline mutations in SDHB are generally associated with higher morbidity and mortality than mutations in the other SDHx genes [Gimenez-Roqueplo et al 2003]. They are strongly associated with extra-adrenal sympathetic paragangliomas [Gimenez-Roqueplo et al 2003, Neumann et al 2004, Benn et al 2006, Young 2006] with a high risk of malignancy, and, less frequently, with benign or malignant PCCs and parasympathetic PGLs. Chromaffin tumors in persons with germline SDHB mutations are sixfold more likely to be extra-adrenal than chromaffin tumors in general [Van Nederveen et al 2006].

  • Mutations in SDHD and SDHC are more frequently associated with parasympathetic skull base and neck paragangliomas than other tumor types [Neumann et al 2004]:
    • Persons with a germline SDHD mutation have an odds ratio of approximately 24 of developing a skull base and neck paraganglioma compared with persons with a germline SDHB mutation [Benn et al 2006].
    • Persons with a germline SDHD mutation have an odds ratio of 0.28 of developing abdominal paragangliomas compared with persons with a germline SDHB mutation [Benn et al 2006].
  • Paragangliomas in persons with a germline SDHB mutation are more likely to become malignant than sporadic paragangliomas or those that develop in persons with germline SDHD and SDHC mutations. SDHB mutations may also predict a shorter survival in persons with malignant pheochromocytomas and paragangliomas [Amar et al 2007]. Persons with a germline SDHB mutation can develop malignant disease at any paraganglion site [Young et al 2002, Gimenez-Roqueplo et al 2003, Neumann et al 2004, Benn et al 2006, Jimenez et al 2006].
  • Up to 50% of persons with malignant extra-adrenal paragangliomas have a germline SDHB mutation [Brouwers et al 2006, Klein et al 2008]. Because extra-adrenal sympathetic paragangliomas have long been known to have a greater predisposition to malignancy than pheochromocytomas and skull base and neck paragangliomas [Proye et al 1992], it is not clear whether this effect is the result of location, mutation status, or both [Lima et al 2007, Klein et al 2008].
  • Although less common than malignant extra-adrenal sympathetic paragangliomas, malignant pheochromocytomas do occur, and may be more common in individuals with a germline SDHB mutation than in those with a germline SDHD or SDHC mutation or with a sporadic pheochromocytoma.
  • Skull base and neck paragangliomas in persons with a germline SDHD mutation, in particular, are more likely to be multifocal than in persons with sporadic tumors or those with a germline SDHB mutation [Boedeker et al 2005]. However, phenotypes vary among individuals and even among family members with the same mutation.

    Note: Despite the common association of SDHD mutations with skull base and neck paragangliomas, variation in the prevalence, penetrance, and phenotypic expression of SDH subunit gene mutations may be population specific [Lima et al 2007].
  • Germline SDHC mutations appear to be primarily (but not exclusively) associated with skull base and neck paragangliomas [Schiavi et al 2005, Mannelli et al 2007, Pasini et al 2008, Peczkowska et al 2008].
  • Approximately 75% of pheochromocytomas and sympathetic paragangliomas in persons with germline SDHD mutations reportedly occur when the mutation is in the 5’ portion of the gene [Eng et al 2003].
  • A possible relationship between SDHB exon 1 deletions and abdominal extra-adrenal PGLs has been proposed [Cascón et al 2008].
  • Germline SDHA mutations have been seen with PCCs and PGLs (sympathetic and parasympathetic) [Burnichon et al 2010, Korpershoek et al 2011].
  • The germline p.Gly78Arg mutation in SDHAF2 has only been seen in association with skull base and neck PGLs [Hao et al 2009, Bayley et al 2010].
  • Germline MAX mutations have been reported in association with PCCs. Some affected individuals go on to develop PGLs; all those who have done so presented with PCCs initially [Burnichon et al 2012].

Penetrance

Age-related penetrance. Mutations in the genes encoding the subunits of SDH appear to have a high but age-related penetrance (Table 3). Data, however, are limited [Neumann et al 2004, Benn et al 2006].

Table 3. Estimated Age-Related Penetrance for SDHD and SDHB Mutations

SDHDSDHBReference
Age in YearsPenetranceAge in YearsPenetrance
3048%3029%Benn et al [20061
3150%3550%Neumann et al [2004] 2
4073%4045%Benn et al [20061
5086%5077%Neumann et al [2004] 2

1. The age-related penetrance was higher in persons with a germline SDHD mutation than in persons with a germline SDHB mutation.

2. The difference in age-related penetrance between individuals with SDHB and SDHD mutations was not statistically significant.

Site-related penetrance. Estimated penetrance for skull base and neck paragangliomas and extra-adrenal abdominal or thoracic tumors is shown in Table 4 [Benn et al 2006].

Table 4. Estimated Site-Related Penetrance for SDHD and SDHB Mutations

Tumor SitesMutationPenetrance
Skull base and neck paragangliomas 1 SDHD68%
SDHB15%
Extra-adrenal abdominal or thoracic tumors 2 SDHD35%
SDHB69%

1. By age 40 years

2. By age 60 years

Anticipation

Anticipation is not observed in the PGL/PCC syndromes.

Nomenclature

The PGL/PCC syndromes were initially referred to as the hereditary paraganglioma syndromes prior to the discovery of their association with pheochromocytomas.

The diseases included in the designation PGL/PCC syndromes are named for the specific loci involved: PGL1 (SDHD), PGL2 (SDHAF2, also known as SDH5), PGL3 (SDHC), and PGL4 (SDHB).

Prevalence

The prevalence of pheochromocytoma/paraganglioma is not precisely known. The incidence of these tumors appears to be approximately 1:300,000/year.

Differential Diagnosis

Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are within the differential diagnosis for all individuals with paragangliomas and pheochromocytomas.

Most inherited paragangliomas and pheochromocytomas are attributable to mutations in VHL, RET, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and MAX. See Pheochromocytoma: OMIM Phenotype Series.

Of all affected individuals where a germline mutation is found, 90% will have a mutation in SDHB, SDHD, VHL, RET or NF1. Only 10% will have a mutation in SDHC, SDHA, SDGAF2, TMEM127 or MAX.

  • MAX-associated susceptibility to pheochromocytoma. In 1694 individuals with PGL/PCC from 17 independent referral centers, a germline mutation in MAX was found in 1.12% [Burnichon et al 2012]. All affected individuals had PCCs; some went on to develop PGLs.
  • TMEM127-associated susceptibility to pheochromocytoma. Germline TMEM127 mutations have only been reported with PCCs and not with PGLs [Yao et al 2010, Abermil et al 2012].

Pheochromocytomas and catecholamine-secreting paragangliomas are also found in the following disorders:

  • Neurofibromatosis type I (NF1), an autosomal dominant disorder caused by mutation of NF1. Prevalence is estimated at 1:3000 to 1:4000. Major features of NF1 include neurofibromas, café au lait spots, iris hamartomas referred to as Lisch nodules, and axillary and inguinal freckling. Gastrointestinal stromal tumors (GISTs) [Stewart et al 2007a] and carcinoid tumors [Stewart et al 2007b] have also been reported in individuals with NF1.

    Although pheochromocytomas are rare in NF1, their frequency is as high as 20%-50% in individuals with NF1 and hypertension. Most (84%) pheochromocytomas are unilateral. Extra-adrenal sympathetic paragangliomas can occur. These tumors are benign in most cases.

    Because NF1 is large and there do not appear to be discrete mutation “hot spots” associated with development of pheochromocytoma [Bausch et al 2007], genetic testing for NF1 mutations is not routinely performed. NF1 is usually diagnosed clinically at an early age, and generally is easily distinguished from the hereditary PGL/PCC syndromes [Jimenez et al 2006].
  • Von Hippel-Lindau syndrome (VHL), an autosomal dominant disorder caused by mutation of VHL. Prevalence is approximately 1:36,000 live births. Features of VHL include retinal angiomas, central nervous system hemangioblastomas, clear cell renal cell carcinoma, pancreatic islet cell tumors, endolymphatic sac tumors, renal, pancreatic, and epididymal cysts, and pheochromocytomas.

    The frequency of pheochromocytoma in individuals with VHL is 10%-20% overall but varies by disease subtype. The mean age of onset of pheochromocytoma in VHL is approximately 30 years, although some individuals present with this neoplasm before age ten years [Lonser et al 2003]. Pheochromocytomas occur in only 6%-9% of individuals with VHL type 1; the prevalence rises to 40%-59% in persons with type 2 disease. In type 2C VHL, pheochromocytomas are the sole manifestation of the syndrome and may present as simplex cases.

    Approximately 50% of pheochromocytomas are bilateral. Pheochromocytomas in VHL secrete primarily norepinephrine and normetanephrine. Approximately 5% of VHL-related catecholamine-secreting tumors become malignant, most commonly extra-adrenal sympathetic paragangliomas [Maher 2004]. Extra-adrenal sympathetic paragangliomas occur infrequently [Jimenez et al 2006, Pacak et al 2007].

    VHL can be distinguished from hereditary PGL/PCC syndromes on clinical grounds in many instances, but may require molecular genetic testing [Jimenez et al 2006]. When sequence analysis and deletion analysis are used, the sensitivity of molecular genetic testing for VHL approaches 100% [Lonser et al 2003].
  • Multiple endocrine neoplasia type 2 (MEN2), an autosomal dominant syndrome caused by mutation of RET. MEN2 prevalence is estimated at 1:30,000. The MEN2A subtype is characterized by medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism; MEN2A accounts for more than 80% of cases of MEN2. The MEN2B subtype lacks hyperparathyroidism but includes mucocutaneous neuromas and/or diffuse ganglioneuromatosis of the gastroenteric mucosa, slender body habitus, joint laxity, and skeletal malformations. MEN2B accounts for approximately 5% of MEN2. The subtype familial medullary thyroid carcinoma (FMTC) has medullary thyroid carcinoma as its only feature.

    Approximately 50% of individuals with MEN2A and MEN2B develop pheochromocytoma; it is the first manifestation of disease in 25% of affected individuals. Pheochromocytomas are bilateral in 50%-80% of cases but are almost always benign. The tumors primarily secrete epinephrine and metanephrine. Sympathetic extra-adrenal paragangliomas rarely occur in MEN2 [Erickson et al 2001, Jimenez et al 2006, Marini et al 2006, Pacak et al 2007].

    Medullary thyroid cancer is the most common presenting feature of MEN2. MEN2 is often suspected on the basis of family history; individuals with pheochromocytomas infrequently present as simplex cases.
  • Carney triad is an extremely rare disorder that primarily affects young women. As initially described in 1977, the classic Carney triad included extra-adrenal sympathetic paraganglioma, gastric stromal sarcoma, and pulmonary chondroma. 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]. No mutations in genes associated with hereditary PGLs or hereditary GISTs have been found in any of the reported individuals [Matyakhina et al 2007, Stratakis 2009]. However, chromosomal changes that appeared to correlate with the syndrome, including possible loss of regions on the short arm (1p) and the long arm (1q) of chromosome 1, were noted. The additional neoplasms associated with this syndrome should differentiate it from the hereditary PGL/PCC syndromes.
  • Carney-Stratakis dyad (Carney-Stratakis syndrome) is the association of paragangliomas and GISTS described in Carney & Stratakis [2002]. Carney-Stratakis dyad appears to be distinct from the Carney triad. Carney & Stratakis [2002] described five families with paragangliomas and GISTs that appeared to be inherited in an autosomal dominant manner with incomplete penetrance. Paragangliomas occurred in the skull base and neck, thorax, and abdomen. Both secretory and nonsecretory tumors were identified. In six individuals from six unrelated families with the Carney-Stratakis dyad, McWhinney et al [2007] reported mutations in SDHB in three, SCHC in two, and SDHD in one. The significance of these findings is not yet clear.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with a hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndrome, the following are recommended:

  • Imaging studies using MRI/CT, 123I-MIBG, and possibly PET to localize tumors and quantify the disease burden
  • Evaluation of individuals with extra-adrenal sympathetic paragangliomas and pheochromocytomas for blood pressure elevations, tachycardia, and other signs and symptoms of catecholamine hypersecretion that must be controlled prior to definitive therapy
  • Consideration of evaluation for GISTs in 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 [Pasini et al 2008]
  • Consideration of screening for renal cell carcinoma in individuals with SDHB mutations
  • Medical genetics consultation

Treatment of Manifestations

The management of tumors in individuals with hereditary PGL/PCC syndromes resembles management of sporadic tumors [Young 2011]; however, persons with hereditary PGL/PCC syndromes are more likely to have multiple tumors and multifocal and/or malignant disease than are those with sporadic tumors.

For secretory tumors, treatment is directed toward containing the disease through antagonism of catecholamine excess with pharmacologic adrenergic blockade prior to surgical removal; treatment for malignant tumors is directed toward surgical removal and mitigation of the deleterious effects of metastatic spread [Eisenhofer et al 2004, Lenders et al 2005].

For nonsecretory skull base and neck paragangliomas, early detection allows for timely surgical resection and is believed to reduce operative morbidity and improve prognosis [Rinaldo et al 2004, Gujrathi & Donald 2005].

  • For carotid body and low vagal paragangliomas, surgical resection is the treatment of choice in almost all cases. Most are benign and can be completely excised.

    Note: In elderly individuals or those with clinically important comorbidities, surgery may be delayed and tumors monitored by serial imaging. Radiation therapy can also be considered in these patients [Gujrathi & Donald 2005].
  • For jugulotympanic paragangliomas, small tumors can usually be removed without difficulty; resection of larger tumors may be 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, but potential long-term risks include malignant transformation of the primary tumor and other radiation-induced malignancies. In selected patients, stereotactic radiosurgery may also be performed [Gujrathi & Donald 2005].

For pheochromocytomas, surgery, preferably laparoscopic, is the treatment of choice [Lenders et al 2005, Young 2011].

  • Preoperative. The chronic and acute effects of catecholamine hypersecretion from adrenal chromaffin tumors must be reversed preoperatively. Combined α- and β- adrenergic blockade is required to control blood pressure and prevent intraoperative hypertensive crises. Using the following approach, only 7% of patients undergoing catecholamine-secreting tumor resection at the Mayo Clinic needed postoperative hemodynamic management [Young 2006, Young 2011]:
    • Alpha-adrenergic blockade starting at least seven to ten days preoperatively to allow for normalization of blood pressure and volume expansion. The dose of the alpha blocker is adjusted for a low normal systolic blood pressure for age.
    • A liberal sodium diet
    • Once adequate α-adrenergic blockade is achieved, initiation of β-adrenergic blockade (e.g., 3 days prior to surgery). The dose of the β-adrenergic blocker is adjusted for a target heart rate of 80 beats per minute.
  • Postoperative. Approximately one to two weeks after surgery, 24-hour urinary fractionated metanephrines and catecholamines and/or plasma fractionated 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.

In individuals with SDHB mutations, paragangliomas or pheochromocytomas should be resected as soon as possible after tumor discovery. 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 hypersecretion, and malignant transformation.

Surveillance

Individuals known to have a hereditary PGL/PCC syndrome, individuals without clinical manifestations of a hereditary PGL/PCC syndrome but known to have a disease-causing SDHA, SDHB, SDHC, SDHD, SDHAF2, or MAX mutation, 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.

Screening should begin at age ten years or at least ten years before the earliest age at diagnosis in the family. 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 mutations and 96% of persons with SDHB mutations.

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. The findings of these evaluations should guide imaging studies [Mannelli 2006, Pacak et al 2007]. Monitoring includes the following:

  • Twenty-four hour urinary excretion of fractionated metanephrines and catecholamines, and/or plasma fractionated metanephrines to detect metastatic disease, tumor recurrence, or the development of additional tumors
  • Follow-up imaging by CT, MRI, 123I-MIBG, or FDG-PET if the fractionated metanephrine and/or catecholamine levels become elevated, or if the original tumor had minimal or no catecholamine/fractionated metanephrine excess. In some individuals the image modality that was most effective in identifying the original tumor may prove to be equally effective in surveillance.
  • In persons with SDHD and SDHC mutations, periodic (e.g., every 2 years) MRI or CT of the skull base and neck to detect paragangliomas and periodic (e.g., every 4 years) body MRI or CT and 123I-MIBG scintigraphy to detect paragangliomas or metastatic disease that may occur beyond the neck and skull base
  • In persons with SDHB mutations, periodic (e.g., every 2 years) MRI or CT of the abdomen, thorax, and pelvis to detect paragangliomas and periodic (e.g., every 4 years) 123I-MIBG scintigraphy to detect paragangliomas or metastatic disease that may not be detected with MRI or CT
  • 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, consideration of evaluation for GISTs [Pasini et al 2008]
  • Consideration of screening for renal cell carcinoma in individuals with an SDHB mutation

Agents/Circumstances to Avoid

Penetrance of hereditary PGL/PCC syndromes may be increased in those who live in high altitudes or are chronically exposed to hypoxic conditions [Pacheco-Ojeda et al 1988, Astrom et al 2003]. Avoidance of habitation at high altitudes and activities that promote long-term exposure to hypoxia should be considered.

Activities such as cigarette smoking that predispose to chronic lung disease should be discouraged in persons who have a mutation in SDHA, SDHB, SDHC, SDHD, SDHAF2, or MAX.

Evaluation of Relatives at Risk

Because early diagnosis and treatment is very likely to change the outcome for individuals (especially in the context of SDHB mutations, which portend aggressive disease), it is recommended that relatives at risk be offered genetic testing as early as possible when the family mutation is known.

By age ten years or at least ten years before the earliest age at diagnosis in the family, presymptomatic testing, including genetic testing, should be offered to all first-degree relatives of an individual in whom a mutation in SDHA, SDHB, SDHC, and SDHD, SDHAF2, or MAX has been detected.

Use of molecular genetic testing for early 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 disease-causing mutation. Early detection of tumors can facilitate surgical removal, decrease related morbidity, and potentially result in removal prior to malignant transformation or metastasis [Young et al 2002]:

  • In families with a previously identified mutation, relatives who do not have the family-specific mutation are spared the cost and anxiety associated with regular clinical, biochemical, and imaging studies.
  • Family members who have the family-specific mutation can be informed of their heightened risks for paragangliomas and pheochromocytomas and encouraged to undergo biochemical and imaging studies as described in Surveillance.

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 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., pre-eclampsia). Secretory PGLs/PCCs are more likely to present at any time during pregnancy (whereas pre-eclampsia is more common in the second or third 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.

A 24-hour urine collection for fractionated metanephrines and catecholamines should be used as a first-line test, as there is little experience with the use of plasma fractionated metanephrines during pregnancy. MRI without gadolinium administration should be the first-line test used to localize the tumor, since CT will expose the fetus to radiation. Radioisotope imaging studies should be deferred until after pregnancy in non-lactating 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. Phenoxybenzamine is the alpha blocker of choice in both pregnant and non-pregnant individuals with catecholamine-secreting tumors [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 need to be performed in these situations. A good outcome has only been described with vaginal delivery in select cases [Junglee et al 2007].

Therapies Under Investigation

Attempts to inhibit or regulate the effects of hypoxia-inducible factor (HIF) activation, for example by enhancing prolyl hydroxylase activity, are being investigated and could provide the basis for useful therapy in the hereditary PGL/PCC syndromes [Lee et al 2005, Selak et al 2005]:

  • One compound, R59949, enhances prolyl hydroxylase activity, preventing HIF1α accumulation in cell lines under both normal and hypoxic conditions [Temes et al 2005].
  • Other drugs that cause downregulation of HIF include mTOR inhibitors, HSP90 inhibitors, HDAC inhibitors, thioredoxin-1 inhibitors, and some microtubule inhibitors.

Vascular endothelial growth factor (VEGF) receptor inhibitors (e.g., SU11248 and BAY43-9006) could potentially be useful in treating hereditary PGL/PCC syndromes [Kaelin 2005]. Other substances currently under investigation include tyrosine kinase inhibitors such as pazopanib and sunitinib.

Search ClinicalTrials.gov for access to 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. Mutations in SDHD (PGL1) and possibly SDHAF2 (PGL2) and MAX demonstrate parent-of-origin effects, and cause disease almost exclusively when they are paternal in origin [Baysal 2004].

Risk to Family Members

Parents of a proband

  • Many individuals diagnosed with a hereditary PGL/PCC syndrome have inherited the mutation from a parent. However, the age-dependent penetrance and variable expressivity of SDHA, SDHB, SDHC, SDHD, SDHAF2, and MAX mutations, as well as the parent-of-origin effects associated with SDHD, SDHAF2, and MAX mutations, predict that a substantial number of individuals who have inherited these mutations will be simplex cases.
  • A proband with a hereditary PGL/PCC syndrome may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown. In one study a de novo mutation was identified in 2/24 persons with SDHD mutations; no de novo mutations were identified in 25 persons with SDHB mutations [Neumann et al 2004].
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility in simplex cases.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include testing for the mutation identified in the proband. Evaluation of parents may determine that one parent is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although many individuals diagnosed with a hereditary PGL/PCC syndrome have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the mutation first occurred s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected, although this has not been reported in the hereditary PGL/PCC syndromes.

Sibs of a proband

Offspring of a proband. Each child of an individual with a hereditary PGL/PCC syndrome has a 50% chance of inheriting the disease-causing mutation:

  • An individual who inherits an SDHD, SDHAF2, or MAX mutation 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 disease-causing allele). However, exceptions occur: Pigny et al [2008] reported an 11-year-old boy with a maternally inherited SDHD mutation associated with skull base and neck paraganglioma.
  • An individual who inherits an SDHD, SDHAF2, or MAX mutation from his/her father is at high risk of manifesting PGL and PCC.

Other family members of a proband. The risk to other family members depends on the mutation status of the proband's parents and the biological relationship to the proband. If a parent is affected or has a mutation in one of the PGL/PCC-causing genes, risk can be determined by pedigree analysis and/or 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 mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Such testing may be available through laboratories that offer either testing for the gene of interest or custom testing.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

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.

  • Pheo Para Trooperers
    A Pheo Para Trooper is someone who is passionate about fighting pheochromocytoma and paraganglioma. Our goal is to empower and support patients while contributing anything we can to finding a cure for these diseases.
    The Pheo Para Patient Initiative or Pheo Para Troopers
    PO Box 2064
    Kokomo IN 46904-2064
    Email: info@pheoparatroopers.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)
  • 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
614165PARAGANGLIOMAS 5; PGL5

Molecular Genetic Pathogenesis

The four nuclear genes responsible for hereditary PGL/PCC encode the four subunits of the mitochondrial enzyme succinate dehydrogenase (SDH), which 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. The protein is therefore necessary for SDH function. These are collectively known as the SDHx genes.

The role of EGLN1 and KIF1B in hereditary PGL/PCC is still unclear (see Other).

It is believed that SDHA, SDHB, SDHC, SDHD, and SDHAF2 act as tumor suppressor genes in accordance with the Knudson two-hit hypothesis. Thus, the first hit (an inactivating mutation in the first allele of the gene) is inherited as a germline mutation, whereas the second hit (an inactivating mutation in the remaining allele of the same gene) occurs during mitosis of cells in somatic tissue(s). The second mutation may be caused by gross chromosomal rearrangements, recombination, point mutations, 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 accounts for their association within a single syndrome. Competing and possibly complementary theories propose to explain the relationship between succinate dehydrogenase/mitochondrial complex II mutations and tumor formation.

The protein products of the genes implicated in hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes represent the four subunits of the mitochondrial enzyme succinate dehydrogenase. SDHAF2 encodes a protein that appears to be required for flavination of SDHA. Succinate dehydrogenase catalyzes the conversion of succinate to fumarate in the Krebs cycle and serves as complex II of the electron transport chain and acts as a link between the two. The nuclear genes SDHD and SDHC code for two membrane-spanning proteins, subunits D and C that anchor the catalytic site to the inner mitochondrial membrane. Subunit B, an iron-sulfur protein encoded by the nuclear gene SDHB, is required for catalytic activity. This protein transfers the electrons released during the conversion of succinate to fumarate to coenzyme Q, which is bound to subunits D and C within the inner mitochondrial membrane [Eng et al 2003, Gottlieb & Tomlinson 2005].

One hypothesis for the mechanism of tumorigenesis mediated by homozygous inactivating mutations in SDHA, SDHB, SDHC, or SDHD proposes the generation of a pseudohypoxic state within cells resulting from elevations in cellular succinate concentrations and/or the increased production of reactive oxygen species. Increased succinate concentrations appear to stabilize the transcription factor HIF1α by inhibiting prolyl hydroxylases. HIF1α is thought to be continuously produced and degraded within the cell. Prolyl hydroxylase function is necessary for VHL protein-mediated ubiquitination, which leads to HIF1α degradation. By inhibiting prolyl hydroxylases, increased intracellular succinate concentrations result in increased HIF1α levels and upregulation of cellular hypoxia/angiogenesis pathways. Increased levels of HIF1α enhance glucose uptake and increase expression of angiogenic, growth, and mitogenic factors such as VEGF and platelet-derived growth factor β polypeptide (PDGFβ), erythropoietin, and transforming growth factor α (TGFα) [Maher 2004, Gottlieb & Tomlinson 2005, Pollard et al 2005, Selak et al 2005].

Note: Autosomal recessive mutations in SDHA, the gene encoding the fourth SDH subunit, are associated with late-onset optic atrophy and Leigh syndrome (see Mitochondrial Disorders Overview for a discussion of Leigh syndrome caused by mtDNA mutations), a neurodegenerative disorder characterized by early-onset, progressive encephalopathy. Mutations in SDHA have very recently been found to be associated with hereditary PGL/PCC syndromes.

SDHA

Normal allelic variants. SDHA comprises 15 exons and is approximately 39 kb in length. It encodes a 2390-bp transcript (reference sequence NM_004168.2) There are known normal allelic variants in SDHA along with variants of undetermined clinical significance. A database of normal and pathogenic variants for the SDH subunit genes is maintained by the Leiden University Medical Center (see Table A).

Pathogenic allelic variants. Two missense mutations (p.Arg585Trp and p.Arg589Trp) and one nonsense mutation (p.Arg31Ter) have been reported in individuals with hereditary PGL/PCC. 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 encodes a flavoprotein subunit of succinate-ubiquinone oxidoreductase.

Abnormal gene product. Mutations 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.

SDHB

Normal allelic variants. SDHB comprises eight exons and is approximately 40 kb in length. It encodes an 1162-bp transcript (reference sequence NM_003000.2). There are known normal allelic variants in SDHB along with variants of undetermined clinical significance. A database of normal and pathogenic variants for the SDH subunit genes is maintained by the Leiden University Medical Center (see Table A).

Pathogenic allelic variants. Nonsense, missense, and splice-site mutations, intragenic deletions and insertions, and whole-gene SDHB deletions have been reported in individuals/pedigrees affected with hereditary paraganglioma 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.

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

Abnormal gene product. Mutations 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

Normal allelic variants. SDHC has six exons and is more than 35 kb in length. It codes for a 2858-bp transcript (reference sequence NM_003001.3). There are known normal allelic variants in SDHC along with variants of undetermined clinical significance. A database of normal and pathogenic variants for the SDH subunit genes is maintained by the Leiden University Medical Center (see Table A).

Pathogenic allelic variants. Nonsense, missense, splice-site, regulatory, and exon deletion SDHC mutations have been reported in individuals and pedigrees affected with hereditary paraganglioma syndromes. Approximately 14 pathogenic sequence variants have been described for SDHC. The pathogenic variants are found throughout the coding region of the gene, with the exception of exon 3.

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

Abnormal gene product. Mutations 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

Normal allelic variants. SDHD consists of four exons and produces a 1313-bp transcript. There are known normal allelic variants in SDHD along with variants of undetermined clinical significance. A database of normal and pathogenic variants for the SDH subunit genes is maintained by the Leiden University Medical Center (see Table A).

Pathogenic allelic variants. See Table 5. Nonsense, missense, splice-site, intragenic insertions and deletions, and a whole-gene deletion have been reported in SDHD in individuals and pedigrees affected with hereditary paraganglioma 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. Three SDHD founder mutations (p.Asp92Tyr, p.Leu139Pro, p.Leu95Pro) identified in the Dutch population account for most cases of hereditary PGL/PCC syndrome in this population. Additional founder mutations have been proposed in other population groups.

Two recurrent SDHD mutations (p.Pro81Leu, p.Arg38Ter) identified in the US appear to have arisen independently in some families [Taschner et al 2001, Baysal et al 2002].

Table 5. Selected SDHD Pathogenic Allelic Variants

DNA Nucleotide Change Protein Amino Acid Change Reference Sequences
c.3G>C p.Met1IleNM_003002​.1
NP_002993​.1
c.112C>Tp.Arg38Ter
c.242C>Tp.Pro81Leu
c.274G>Tp.Asp92Tyr
c.284T>Cp.Leu95Pro
c.416T>Cp.Leu139Pro

Note on variant classification: Variants listed in the table have been provided by the author(s). 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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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

Abnormal gene product. Mutations 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.

SDHAF2

Normal allelic variants. SDHAF2 (also known as SDH5) consists of four exons and produces a 501-bp transcript (reference sequence NM_017841.1). Benign allelic variants and variants of unknown significance have not yet been reported in the coding sequence of the gene.

Pathogenic allelic variants. Three individuals with hereditary PGL/PCC from the Dutch family described by van Baars et al [1982] were identified as having a single-nucleotide change (c.232G>A) in exon 2 in SDHAF2 (also known as SDH5), which resulted in a p.Gly78Arg alteration in the most conserved region of the protein. Four hundred unaffected control individuals did not have the mutation [Hao et al 2009].

Table 6. Selected SDHAF2 Pathogenic Allelic Variants

DNA Nucleotide Change Protein Amino Acid Change Reference Sequences
c.232G>Ap.Gly78ArgNM_017841​.1
NP_060311​.1

Note on variant classification: Variants listed in the table have been provided by the author(s). 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 (www​.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. SDHAF2 encodes for a protein that 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 mutation in exon 2 of SDHAF2 destabilizes the protein, impairing its interaction with SDHA.

MAX

Normal allelic variants. MAX consists of five exons and produces a 2068-bp transcript (reference sequence NM_002382.3). Benign allelic variants have been reported in the coding sequence of the gene.

Pathogenic allelic variants. Missense, nonsense, and splicing mutations 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. Mutations 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.

Other

Genes possibly associated with PGL/PCC syndromes KIF1B and EGLN1 (formerly known as PHD2) have been reported to be associated with hereditary PGL/PCC, but their clinical significance is still unclear. The role of KIF1B and EGLN1 is unknown, and need not be considered for routine testing for PGL/PCC syndromes.

  • KIF1B. A germline KIF1B mutation has been reported in a single individual with PCC, although somatic mutations were seen in a handful of individuals with PCC where germline DNA was not available for testing [Schlisio et al 2008]. Thus the role of KIF1B mutations in hereditary PGL/PCC is unclear.
    • Germline KIF1B loss-of-function mutations have been reported in individuals who had neuroblastoma [Schlisio et al 2008].
    • KIF1B encodes a protein that works as a monomeric motor for anterograde transport of mitochondria
  • EGLN1. In 82 individuals with hereditary PCC who had tested negative for known susceptibility genes, no mutations were found in EGLN1 [Astuti et al 2010].
    • Germline EGLN1 mutations have also been reported in individuals with familial erythrocytosis [Ladroue et al 2008].
    • A germline EGLN1 mutation has only been reported in one individual who had erythrocytosis and recurrent PGL [Ladroue et al 2008]. No tumors were reported in relatives with the same mutation; thus the role of EGLN1 mutations in hereditary PGL/PCC is unclear.
    • EGLN1 encodes a protein that plays a critical role in regulating hypoxia inducible factor (HIF) levels in erythropoetin-producing cells in humans.
  • Succinate inhibition of prolyl hydroxylases may also cause a decrease in the apoptosis of neural crest precursors that normally occurs during development in response to reduction in nerve growth factor levels. Cells within this residual pool are hypothesized to subsequently undergo malignant transformation [Lee et al 2005]. The kinesin KIF1Bβ was recently shown to act downstream of the prolyl hydroxylase, EGLN3, and to be necessary and sufficient for neuronal apoptosis. KIF1B maps to chromosome 1p36.2, which is frequently deleted in neural crest-derived tumors, providing further support for this hypothesis [Schlisio et al 2008].

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Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

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Suggested Reading

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Chapter Notes

Author History

Salman Kirmani, MBBS (2012-present)
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 (2008-present)

Revision History

  • 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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