Introduction
Pheochromocytomas are catecholamine-secreting tumors derived from chromaffin tissue of the adrenal medulla. Closely related tumors, called extra-adrenal paragangliomas, can arise at extra-adrenal sites. Catecholamine secretion from these tumors is often episodic, causing headache, perspiration, palpitations and hypertension. If not recognized and treated, pheochromocytoma and extra-adrenal paraganglioma(PPGL) can lead to arrhythmia, myocardial infarction, stroke, and death.
Diagnosis of PPGL relies on biochemical evidence of excess catecholamine secretion and confirmation of tumor presence by imaging studies. While many different biochemical tests have historically been used in screening for PPGL, measurement of the catecholamine breakdown products metanephrine and normetanephrine in plasma or urine are now regarded as the first line tests. Florid elevations of either of these metabolites are associated with nearly a 100% probability of PPGL. However, it can be challenging to differentiate between true-positive and false positive results when metanephrine or normetanephrine concentrations are only slightly above the respective upper reference limit.
Not too long ago, approximately 90% of PPGLs were thought to occur sporadically. However, germline mutations in 10 different genes have been shown to cause PPGLs, and at least 30% of these tumors are now known to be hereditary. Importantly, genotype-phenotype correlations have been elucidated: different mutations are associated with specific clinical features and sites of disease, the production of certain catecholamines, and varying frequency of malignancy.
In this Q&A article, 5 experts discuss the current state of the art in the diagnosis, localization, and treatment of PPGL. They also provide their opinions on the role of genetic testing in the diagnosis and management of patients with these tumors.
Questions
1. What is your estimate of the prevalence of pheochromocytoma and extra-adrenal paraganglioma (PPGL)? Are certain populations at increased risk for developing these tumors?
Dr. Graeme Eisenhofer: Early autopsy series indicated prevalences of pheochromocytoma of 1:1,000, with more recent series indicating lower prevalences of 1:2,000, suggesting that detection rates in life have improved. Nevertheless, at reported annual detection rates of 2 to 5 per million, corresponding to prevalences of 1.5 to 4:10,000, it seems that most cases remain undiagnosed in life. This probably also holds true for extra-adrenal paragangliomas, which have a prevalence of about 15% that of the adrenal tumors.
Populations at increased risk for PPGLs are those with germline mutations of the now identified 10 tumor-susceptibility genes. Other groups at increased risk who should be screened for the tumors are those with a previous history of the disease or with adrenal lesions found incidentally on imaging studies.
Dr. Karel Pacak: PPGLs are very rare neuroendocrine tumors; their prevalence is estimated to be around 0.05% in the general population. Since about 50% of these tumors are only diagnosed at autopsy, the prevalence of these tumors could be higher, perhaps even reaching 0.1%. The prevalence is higher in the population of patients with hypertension and in those families with a risk to develop these tumors (e.g. carriers of a particular gene mutation).
Dr. Eamonn R Maher: We don’t have any specific prevalence data for our local population and so I would defer to others.
In terms of the prevalence of inherited susceptibility to PPGL in individual populations, it is important to consider that the presence of founder mutations (e.g. the “Black Forest VHL gene mutation (p. Tyr98His)” that is common in south-western Germany is associated with a high risk of pheochromocytoma) may cause geographic variations in the frequency of specific inherited forms of PPGL.
Dr. William F. Young: Catecholamine-secreting tumors are rare, with an annual incidence of 2 to 8 cases per million people. Based on screening studies for secondary causes of hypertension in outpatients, the prevalence of pheochromocytoma has been estimated at 0.1% to 0.6%. Nevertheless, it is important to suspect, confirm, localize, and resect these tumors because 1) the associated hypertension is curable with surgical removal of the tumor, 2) a risk of lethal paroxysm exists, 3) at least 10% of the tumors are malignant, and 4) approximately 20% are familial and detection of this tumor in the proband may result in early diagnosis in other family members.
Case detection testing for these rare neoplasms is indicated in clinical settings where the prevalence is increased and these include: hyperadrenergic spells (e.g. episodes of palpitations, diaphoresis, headache, tremor, pallor); treatment resistant hypertension; a familial syndrome that predisposes to pheochromocytoma or paraganglioma (e.g. multiple endocrine neoplasia type 2, neurofibromatosis type 1, von Hippel Lindau syndrome, or succinate dehydrogenase mutations); a family history of pheochromocytoma; an incidentally discovered adrenal mass; pressor response to anesthesia, surgery, or angiography; onset of hypertension at a young age (e.g. <20 yrs); idiopathic dilated cardiomyopathy; or history of gastrointestinal stromal tumors or pulmonary chondromas.
Dr. Ronald R. de Krijger: I am not aware of the prevalence of pheochromocytomas (PCC) and paragangliomas (PGL)in the Dutch populations (17 million inhabitants) or worldwide. In the Netherlands I estimate that there is an incidence of 0.5 – 1.0 per 100,000 for PCC and about one tenth of this for abdominal PGL. For head and neck paragangliomas (HNPGL), the incidence is probably in the order of 0.2 – 0.3 per 100,000. In populations with founder mutations in certain genes, see below, there is an increased risk. This is the case for HNPGL in the Netherlands, given the founder mutations in succinate dehydrogenase subunit D (SDHD).
2. Plasma free and urinary fractionated metanephrines are regarded as the first-line tests in screening for PPGL. Do you feel that one of these tests is superior? Are there specific situations where one should be used over the other?
Dr. Graeme Eisenhofer: To date there have been 4 studies directly comparing the diagnostic performance of plasma free versus urinary fractionated metanephrines, all consistently indicating higher sensitivity and specificity of the plasma over the urine test. Nevertheless, all had limitations and the reported differences were small relative to those of each test compared to other tests of catecholamine excess. Therefore, until proven otherwise, either test remains suitable for first-line screening.
The plasma test is more suitable than the urine test in children and patients with renal insufficiency. Some have suggested the same for populations at increased risk of PPGLs, but this is really a matter of reference intervals. At upper cut-offs suitable for sensitive detection of tumors, diagnostic specificity is higher for the plasma than the urine test so that the plasma test may also be preferable in low risk populations.
Of more importance to choice of test is the method of measurement and experience and expertise of clinicians and laboratory staff with each test. Urinary metanephrines measured by LC-MS/MS are for example preferable over measurements of plasma metanephrines by immunoassays, particularly when personnel are not experienced in the correct preparation of patients for blood sampling.
Dr. Karel Pacak: Our experience at NIH, based on a very large number of patients, suggests that plasma metanephrines are superior to urine metanephrines as the first biochemical test. It should be noted that these tumors produce catecholamines that are metabolized inside the tumor into free metanephrines, which are continuously released from the tumor tissue into circulation. The assessment of metanephrines in urine includes the measurement of conjugated metanephrines (measured as free after their deconjugation). Conjugated metanephrines are also produced in different organs. Therefore, measurement of plasma free metanephrines provides a better diagnostic marker than urine “conjugated” metanephrines in the biochemical diagnosis of these tumors. However, the proof of this in terms of practical utility has not yet been established.
Dr. Eamonn R Maher: Here I would defer to others.
Dr. William F. Young: At Mayo Clinic, the most reliable case-detection strategy is measuring fractionated metanephrines and catecholamines in a 24-hour urine collection. If clinical suspicion is high, then plasma fractionated metanephrines should also be measured. Some groups have advocated that plasma fractionated metanephrines should be a first-line test for pheochromocytoma; the predictive value of a negative test is extremely high, and normal plasma fractionated metanephrines excludes pheochromocytoma except in patients with early preclinical disease and those with strictly dopamine-secreting neoplasms. A plasma test is also attractive because of simplicity. Although measurement of plasma fractionated metanephrines has a sensitivity of 96% to 100%, the specificity is suboptimal at 85% to 89%; the specificity falls to 77% in patients older than 60 years. It has been estimated that 97% of patients with hypertension seen in a tertiary care clinic who have plasma fractionated metanephrine measurements above the reference range will not have a pheochromocytoma; resulting in excessive healthcare expenditures because of subsequent imaging and potentially inappropriate surgery. Thus, plasma fractionated metanephrines lack the necessary specificity to be recommended as a first-line test; therefore, this measurement should be reserved for cases for which the index of suspicion is high.
Dr. Ronald R. de Krijger: No comment.
3. In instances where plasma free or urinary fractionated metanephrines are slightly or modestly elevated, what additional tests are useful in the biochemical workup of a potential case of PPGL?
Dr. Graeme Eisenhofer: For borderline test results it is important that follow-up tests have at least equal diagnostic sensitivity and ideally better specificity than the initial screening test. In cases of borderline elevations of urinary fractionated metanephrines it is therefore appropriate to follow-up with measurements of plasma metanephrines. For borderline elevations of plasma normetanephrine, the clonidine suppression test with measurements of normetanephrine before and 3 hours after the drug provides an accurate method for distinguishing true-from false-positive results.
Usually, however, most false-positive results for plasma metanephrines simply reflect inadequate preparation of patients, easily resolved by repeating the blood sampling after at least 30 minutes of supine rest with patients as comfortable as possible. A wait and re-test approach to assess for further increases in values 6 months or more after initial testing provides another approach in more difficult to resolve cases.
Dr. Karel Pacak: About 20–30% of patients with these tumors present with values that are equivocal (e.g. for plasma metanephrines below 4× above the upper reference limit) and an additional test is needed to confirm or rule out the presence of PPGL before any localization is initiated. The clonidine suppression test coupled with the measurement of plasma normetanephrine is the best test to use. The sensitivity of this test is about 97%, with 100% specificity. However, it should be noted that this test cannot be used for tumors secreting only metanephrine, but since almost 99% of metanephrine is derived from the adrenal gland, the diagnosis and localization of these epinephrine-producing tumors is usually not a difficult task. It should be also mentioned that in many patients elevated metanephrine levels can be due to various drugs (including antihypertensives); therefore, any drug interference with biochemical results must be considered first.
Dr. Eamonn R Maher: Here I would defer to others.
Dr. William F. Young: The answer to this question is dependent on clinical context. If the clinical context is an incidentally discovered 2-cm vascular adrenal mass, pheochromocytoma should be suspected even if measurements of fractionated metanephrines and catecholamines are normal. All pheochromocytomas and paragangliomas are “prebiochemical” in their early stages. Whereas, if the clinical context is a patient with marked paroxysyms, then if a pheochromocytoma is responsible for the paroxysms, the elevations in the fractionated metanephrines and catecholamines should be similarly impressive; in this clinical setting, minimal elevations in fractionated metanephrines and catecholamines are not consistent with pheochromocytoma.
Dr. Ronald R. de Krijger: No comment.
4. What imaging modalities are used in your institution to localize PPGL?
Dr. Graeme Eisenhofer: At Dresden, as at most centers, we primarily use computed tomography (CT) for initial localization, with magnetic resonance imaging (MRI)also available as called for. In most cases we also employ 123I-metaiodobenzylguanidine(MIBG) scintigraphy, but have additional availability of 18F-fluorodeoxyglucose (FDG) and 68Ga-DOTATATE for positron emission tomography (PET)/CT.
Dr. Karel Pacak: Anatomic imaging studies, either CT or MRI, are used for the initial attempts to locate a PPGL. The preference of using anatomical imaging studies over functional imaging is that surgical procedures are rarely performed without good anatomical localization of a tumor. At NIH we prefer CT over MRI. However, MRI should be used in pregnant women, children, those with an allergy to contrast dye, and in a situation where radiation exposure needs to be minimized. A CT of the abdomen should be performed first, since most of these tumors are located in that area. Functional imaging studies including FDG PET, 18F-fluorodopamine or 18F-fluorodopa PET, or 123I-MIBG scintigraphy are also used in the localization of these tumors, for several reasons. First, 18F-fluorodopamine PET and 123I-MIBG scintigraphy, for example, are PPGL-specific imaging modalities that confirm a tumor with almost 100% specificity in a patient with biochemical proof of a tumor. Second, there is a genotype-specific imaging phenotype that is very valuable in the assessment of these tumors, including their metastatic lesions. Thus, for succinate dehydrogenase subunit B (SDHB)-related PPGLs, FDG PET is the most sensitive, for head and neck PPGLs 18F-fluorodopa PET should be used, and for primary or metastatic tumors in general (e.g. when the genetics of these tumors is unknown), 18F-fluorodopamine is the preferred functional imaging modality. In the future, a cost-effective approach for tumor-specific functional imaging modalities needs to be further established, especially the role of 18F-fluorodopa in the evaluation of metastatic PPGLs or the use of functional imaging in newly discovered MAX-and TMEM127-related PPGLs.
Dr. Eamonn R Maher: Our standard screening modality to detect PPGL in individuals at increased genetic risk is MRI scanning. CT scanning or MIBG might be performed for MRI-detected abnormalities that require further investigation.
Dr. William F. Young: Localization studies should not be initiated until biochemical studies have confirmed the diagnosis of a catecholamine-secreting tumor. Computer-assisted imaging of the adrenal glands and abdomen with CT or MRI should be the first localization test. Approximately 85% of these tumors are found in the adrenal glands, and 95% are found in the abdomen and pelvis. The most common locations of catecholamine-secreting paragangliomas (in order of prevalence) include: superior abdominal para-aortic region; inferior abdominal para-aortic region; urinary bladder; thorax; skull base and neck; and, pelvis.
CT with contrast of the abdomen and pelvis is our first localization test. If a pheochromocytoma or paraganglioma is not detected with this study, the clinician should reassess the diagnosis. For example, did the clinician overlook treatment with a tricyclic antidepressant (the most common cause of false positive biochemical testing)? If the biochemical diagnosis is secure and the CT of the abdomen and pelvis is negative, we would proceed to 123I-MIBG scintigraphy, which has a sensitivity of approximately 80% and specificity of 99%. Localizing procedures that also can be used, but are rarely required, include computer-assisted imaging of the chest, neck, and skull base. The average size of a symptomatic pheochromocytoma or paraganglioma is 4.5 cm; they are not hard to find.
Dr. Ronald R. de Krijger: No comment.
5. Are there effective means to differentiate between benign and malignant PPGLs?
Dr. Graeme Eisenhofer: As yet there is no reliable histopathological method to distinguish benign from malignant PPGLs. The only accepted method to diagnose malignancy remains demonstration of metastatic lesions; this, however, does not mean that absence of metastases denotes a benign classification since such lesions often only become apparent many years after surgical resection. Thus, until there is a reliable method for predicting malignancy no PPGL should ever be classified as benign.
Despite the above shortcomings there are numerous risk factors for metastatic disease. Tumors with an extra-adrenal location have a 3.4-fold higher risk of malignancy than those with an adrenal location. Large size is also a risk factor and together with extra-adrenal location accounts for the high risk of malignancy associated with mutations of the SDHB gene.
High levels of plasma free methoxytyramine, the metabolite of dopamine, also look to provide a promising new biomarker of metastatic PPGLs, with recent evidence suggesting that when accurately measured by LC-MS/MS these measurements can detect over 80% of patients with metastatic disease at a specificity of over 90%.
Dr. Karel Pacak: At present there are no effective methods, including histopathological examination, to differentiate between benign and malignant PPGLs. Carboxypeptidase E is a promising marker, but its role must be established on a large series of PPGLs and may only be useful in particular PPGLs (e.g. SDHx-related PPGLs). However, based on large previous and recent clinical studies and observations, it is clear that patients presenting with SDHB-related PPGLs, with primary tumors over 5 cm in size, and with elevated plasma methoxytyramine have a much higher risk to develop metastatic disease.
Dr. Eamonn R Maher: In the absence of distant metastases, the presence of a germline SDHB mutation will significantly increase the prior risk of malignancy but cannot definitively inform whether an individual PPGL is malignant or not. The work of Dr Eisenhofer and colleagues suggests that plasma methoxytyramine may be a useful predictor of likelihood of metastatic spread.
Dr. William F. Young: Distinguishing between benign and malignant catecholamine-secreting tumors is difficult on the basis of clinical, biochemical, or histopathologic characteristics. The diagnosis of malignant pheochromocytoma or paraganglioma requires finding this tumor in sites that do not normally contain chromaffin tissues (e.g. liver, bone, lung, omemtum, or lymph nodes). Malignancy is rare in patients with multiple endocrine neoplasia type 2 or von Hippel Lindau syndrome, but is common in those with familial paraganglioma caused by mutations in SDHB. Patients with SDHB mutations are more likely to develop malignant disease and nonparaganglioma neoplasms (e.g. renal cell carcinoma). Although the 5-year survival rate for patients with malignant pheochromocytoma is less than 50%, the prognosis is variable: approximately 50% of patients have an indolent form of the disease, with a life expectancy of more than 20 years, and the other 50% of patients have rapidly progressive disease, with death occurring within 1 to 3 years after diagnosis.
Dr. Ronald R. de Krijger: This is a very difficult issue. The short answer still is no. When there is obvious metastasis or ingrowth in surrounding structures on radiology, nuclear imaging or at surgery, one can confidently make a diagnosis of malignancy, especially if further supported by histology. However, this is rarely the case. The vast majority of PCC and PGL present as a single lesion in an organ with no further evidence of disease. Histological criteria have been shown to be of little help in assessing the future behaviour of endocrine tumours in general. MIB-1 labelling for identification of the proliferative fraction, likewise could not sufficiently discriminate non-metastasizing from metastasizing PCC and PGL. The Pheochromocytoma of the Adrenal gland Scaled Score (PASS) has been proposed in 2002, but was shown to suffer from high interobserver variability in a paper in 2009. No immunohistochemical or molecular markers with sufficient sensitivity and specificity have been proposed so far.
6. What are the treatment options for an individual diagnosed with PPGL?
Dr. Graeme Eisenhofer: Surgical resection after appropriate pre-operative preparation provides an effective cure for most patients, but in up to a quarter there may be subsequent recurrent or metastatic disease. Therefore, post-surgical periodic screening is called for in all patients.
In patients with metastatic disease there is as yet no effective cure. Radiotherapy with 131I-MIBG is most commonly used, but is effective in only occasional patients. There are several other palliative or experimental treatment options. As yet none have demonstrated effectiveness. Combination or personalized therapies that target specific pathways according to the PPGL genetic subtype offer the best hope.
Dr. Karel Pacak: In all patients, a surgical approach, if feasible, is the first choice. For patients with metastatic disease, options are limited. If patients have slowly progressing but extensive disease and are positive on 123I-MIBG scintigraphy, radiotherapy using 131I-MIBG is usually recommended. In patients with rapidly progressing disease, CVD chemotherapy is usually used. However, both 131I-MIBG and CVD chemotherapy do not result in a cure in most patients (rarely some cured patients were described) and only about 1/3 of patients will respond. Nevertheless, new results show that about 70–80% of SDHB-related metastatic PPGLs respond to CVD chemotherapy. For SDHB-related metastatic PPGLs I do not recommend the use of Sunitinib or Affinitor; our experience did not show any response to these chemotherapeutics in these patients. Combined mTOR1 and 2 inhibitors, HIF, HSP90, AKT, or other inhibitors (or their combination) are most likely to become of some success in these patients in the near future.
Dr. Eamonn R Maher: Here I would defer to others
Dr. William F. Young: The treatment of choice for pheochromocytoma and paraganglioma is complete surgical resection. Surgical survival rates are 98% to 100% and are highly dependent on the skill of the endocrinologist-endocrine surgeon-anesthesiologist team. The most common adverse event following surgery is sustained hypertension. Careful preoperative pharmacologic preparation is crucial for successful treatment. Most catecholamine-secreting tumors are benign and can be totally excised. Tumor excision usually cures hypertension.
Dr. Ronald R. de Krijger: No comment.
7. What role should genetic testing play in the diagnosis/management of PPGL? Would you recommend widespread genetic testing for all patients with PPGL?
Dr. Graeme Eisenhofer: Genetic testing is already having substantial impact in the diagnosis and management of patients with PPGLs. Such patients and family members with identified mutations represent important groups who must be periodically screened for PPGLs and in who choice of specific tests, test interpretation and management of disease, including other manifestations, should be individualized according to the affected gene.
As an example, periodic biochemical testing in patients with mutations of the SDHB gene should include measurements of plasma methoxytyramine, with test interpretation concentrating on this analyte and normetanephrine. High risk of malignancy in these patients mandates careful management with anticipation that early detection and resection of tumors when small will reduce risk and rates of malignancy.
Despite the importance of genetics I do not recommend widespread testing until there are less expensive methods available for accurately testing panels of tumor susceptibility genes. In the mean time genetic testing is best offered for specific genes in selected patients for whom the family history or clinical presentation is consistent with a risk of a mutation for those genes.
Dr. Karel Pacak: As described above in my comments, genetic testing is very crucial for the proper diagnosis, management, and therapeutic options of each patient. Gene-specific biochemical and imaging phenotypes have already been described well. Gene-specific therapeutic phenotypes are likely to be introduced in the very near future. However, this does not justify offering genetic screening to every patient. Those patients who do not have any family history of PPGLs, have a very small epinephrine-secreting PHEO, and are 50 years old or older most likely have a sporadic tumor and do not need genetic testing, at least not initially. Any specific genetic testing must be guided by the presence of family history, biochemical phenotype, location of the tumor, the presence of metastatic disease or multiplicity, and the age at first diagnosis. When genetic testing becomes less expensive, including through the use of high throughput methods, there is a good chance that genetic testing will be offered to all patients.
Dr. Eamonn R Maher: I do think that in future all PPGL patients will be offered genetic diagnosis to inform the risk, for them and their families, of further primary tumours, malignancy etc. In the past few years the expanding number of PPGL genes and the high cost of gene testing by conventional (Sanger) sequencing has caused a shift from universal to targeted testing. However, though consideration of clinical features (family history, age at diagnosis, tumour location etc) and immunohistochemistry (e.g. SDHB, SDHA) can provide more cost effective targeting, I think that universal testing is required to detect all patients harbouring germline mutations. The advent of high throughput second generation sequencing technologies enables multiple genes to be tested inexpensively and we have developed a “PPGL gene panel” test that sequences nine PPGL genes simultaneously and so provides comprehensive and more rapid genetic testing for the approximate cost of analysing a single gene by conventional testing methods. I anticipate that the availability of this and similar genetic testing strategies will result in an expansion of genetic testing.
Dr. William F. Young: Genetic testing should be considered if a patient has one or more of the following: 1) paraganglioma; 2) bilateral adrenal pheochromocytoma; 3) unilateral adrenal pheochromocytoma and a family history of pheochromocytoma/paraganglioma; 4) unilateral adrenal pheochromocytoma onset at a young age (e.g. <45 years); or 5) other clinical findings suggestive of one of the associated syndromic disorders. The clinician may obtain a list of clinically approved molecular genetic diagnostic laboratories at www.genetests.org. Given the considerable cost of genetic testing, using a stepwise approach based on each patient’s clinical scenario is prudent.
An asymptomatic person at risk for disease on the basis of family history of pheochromocytoma/paraganglioma should have genetic testing only if an affected family member has a known mutation. Genetic testing can be complex; testing one family member has implications for related individuals. Genetic counselling is recommended to help families understand the implications of genetic test results; to coordinate testing of at-risk individuals; and to help families work through the psychosocial issues that may arise before, during, or after the testing process. If mutation testing in a patient is positive, first-degree relatives (patient’s parents, siblings, and children) should be offered genetic testing.
In addition, because some genetic causes of pheochromocytoma and paraganglioma have not yet been identified, all first-degree relatives of a patient with pheochromocytoma or paraganglioma should have biochemical testing (e.g. 24-hour urine for fractionated metanephrines and catecholamines).
Dr. Ronald R. de Krijger: The current figures for the accumulated rate of germline mutations and other germline genetic abnormalities in PCC and PGL are between 30% and 40%. This is high enough to recommend genetic testing in any individual. This should preferably be done in a stepwise manner, based on the further clinical picture (location of the tumour; presence of other lesions), biochemical profile and immunohistochemistry with SDHB (and SDHA), if tumour tissue is available. This will direct future follow up in the index patient and allows further screening of family members.
8. Do you anticipate that additional susceptibility genes for PPGL will be identified?
Dr. Graeme Eisenhofer: Without doubt there are other PPGL susceptibility genes that will be identified. I also anticipate that the day will come when it will be both technically and economically feasible to offer efficient and accurate testing of all tumor susceptibility genes in all patients with PPGLs.
Dr. Karel Pacak: Yes, I do, especially genes that may be involved in the pathogenesis of malignant/metastatic or multiple PPGLs.
Dr. Eamonn R Maher: Yes I do. There are a significant proportion (up to 30%) of familial cases and multiple tumour cases in whom we cannot detect a germline in a known inherited pheochromocytoma/paraganglioma gene. Whilst some of these cases might ultimately prove to have a mutation in a currently known gene that cannot be detected by standard mutation detection methods, I strongly suspect that further inherited pheochromocytoma/paraganglioma genes will be identified in the next few years.
Dr. William F. Young: Yes. We have families at Mayo Clinic with familial pheochromocytoma and paraganglioma who do not have germline mutations in any of currently known susceptibility genes.
Dr. Ronald R. de Krijger: Given the number of genes identified so far, and the fact that two further susceptibility genes have been identified very recently, I anticipate further genes to be found. There are still familial cases that do not seem to have abnormalities in the known genes. Thus, there appears room for other genes, potentially in pathways in which known genes play a role.