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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-2178
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 8 2851-2858
Copyright © 2006 by The Endocrine Society

REVIEW

Should Patients with Apparently Sporadic Pheochromocytomas or Paragangliomas be Screened for Hereditary Syndromes?

Camilo Jiménez, Gilbert Cote, Andrew Arnold and Robert F. Gagel

Instituto Nacional de Cancerología/Fundación Santafé de Bogotá (C.J.), Colombia, South America, Joint Baylor College of Medicine/The University of Texas M. D. Anderson Cancer Center Training Program in Endocrinology, Houston, Texas 77030; Department of Endocrine Neoplasia and Hormonal Disorders (G.C., R.F.G.), The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; and Center for Molecular Medicine (A.A.), University of Connecticut School of Medicine, Farmington, Connecticut 06030

Address all correspondence and requests for reprints to: Robert F. Gagel, M.D., Unit 433, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030. E-mail: rgagel{at}mdanderson.org.


   Abstract
Top
 Abstract
Introduction
 Definition of Pheochromocytoma...
 The Hereditary Pheochromocytoma...
 The Frequency of Germline...
 When Should Genetic Testing...
 Where to Obtain Genetic...
 The Future
 Note Added in Proof
 References
 
Context: The recent identification of germline mutations of the mitochondrial complex II genes in variants of paraganglioma/pheochromocytoma syndrome has enlarged the number of known causative genes for hereditary pheochromocytoma. A question confronting clinicians is whether they should screen patients with apparently sporadic pheochromocytomas for unsuspected germline mutations of some or all of the seven genes known to cause hereditary paraganglioma or pheochromocytoma (NF1, VHL, RET, MEN1, SDHD, SDHC, and SDHB). A positive answer was suggested by a report that placed the estimate of hereditary disease in apparently sporadic pheochromocytoma as high as 24%.

Evidence Acquisition: We applied clinically useful criteria to a review of the literature, defining cases of apparently sporadic pheochromocytoma as those without a suspicious personal or family history, with a focal, unilateral pheochromocytoma, and presenting at age less than 50 yr.

Evidence Synthesis: We reduced the overall estimate of unsuspected hereditary pheochromocytoma patients with apparently sporadic pheochromocytoma to approximately 17%. Mutations in only three genes (VHL, SDHB, and SDHD) accounted for almost this entire minority, and unsuspected RET mutation was rare. Costs, coverage by insurance, the potential effect on insurability, and deficient information for populations outside of referral centers should be considered before recommending genetic testing in patients with apparently sporadic presentations of pheochromocytomas.

Conclusion: We recommend genetic testing for patients with an apparently sporadic pheochromocytoma under the age of 20 yr with family history or features suggestive of hereditary pheochromocytoma or for patients with sympathetic paragangliomas. For individuals who do not meet these criteria, genetic testing is optional.


   Introduction
Top
 Abstract
 Introduction
Definition of Pheochromocytoma...
 The Hereditary Pheochromocytoma...
 The Frequency of Germline...
 When Should Genetic Testing...
 Where to Obtain Genetic...
 The Future
 Note Added in Proof
 References
 
DURING THE PAST decade, a series of discoveries has led to the identification of causative genes for seven of the eight known major hereditary forms of pheochromocytoma and paraganglioma (Table 1Go). In these seven syndromes, neurofibromatosis type 1 (NF1), von Hippel Lindau syndrome (VHL), multiple endocrine neoplasia type 1 (MEN1), MEN2, paraganglioma/pheochromocytoma syndrome type 1 (PGL1), PGL3, and PGL4, the genes were mapped and identified through genetic linkage analysis (1, 2, 3, 4, 5, 6). In four of these syndromes, NF1, VHL, MEN1, and MEN2, the nomenclature is straightforward, with clearly defined clinical syndromes. In contrast, the paraganglioma syndromes (PGL1–4) are less well defined. The identification of the causative gene for PGL1 (succinate dehydrogenase subunit D, SDHD), led to the identification of mutations in other genes of the same complex (i.e. SDHB, SDHC). Clinical studies have not found pheochromocytomas or sympathetic paragangliomas associated with SDHC mutations, despite the presence of these tumors in patients with SDHB and SDHD mutations. Initial reports have suggested that a high percentage of patients with apparently sporadic pheochromocytomas may have germline mutations of one of the six genes associated with pheochromocytomas and have suggested that genetic testing should be considered for all patients with apparently sporadic pheochromocytoma. In this review, we will examine the existing data and propose specific recommendations for the practicing endocrinologist.


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  		TABLE 1. Hereditary tumor syndromes that include paraganglioma or pheochromocytoma

 

   Definition of Pheochromocytoma and Paraganglioma
Top
 Abstract
 Introduction
 Definition of Pheochromocytoma...
The Hereditary Pheochromocytoma...
 The Frequency of Germline...
 When Should Genetic Testing...
 Where to Obtain Genetic...
 The Future
 Note Added in Proof
 References
 
The term paraganglia refers to a group of neuroendocrine cells that migrate during embryonic development with components of the parasympathetic or sympathetic nervous system. Paragangliomas are tumors that arise from extraadrenal chromaffin cells and can originate in either the parasympathetic or sympathetic ganglia (7). Head and neck paragangliomas are most commonly derived from parasympathetic ganglia cells and include chemodectomas and other less well-defined paragangliomas. Parasympathetic paragangliomas are most commonly, but not always, chromaffin negative, meaning they do not stain brown when exposed to potassium dichromate, a chemical reaction generally indicative of catecholamine production (8). The rare chromaffin-positive parasympathetic paraganglioma may or may not produce catecholamines. Endocrinologists are less likely to see patients with parasympathetic paragangliomas because of the absence of catecholamine production. In contrast, sympathetic paragangliomas originate from the sympathetic ganglia and pheochromocytomas from the adrenal medulla (a modified sympathetic ganglia), and they are chromaffin positive and frequently produce catecholamines (7). An endocrinologist is more likely to be consulted for a patient with hypertension and other adrenergic symptoms indicative of a sympathetic paraganglioma or a pheochromocytoma. As this discussion goes forward, the distinctions between parasympathetic paragangliomas and pheochromocytomas or sympathetic paragangliomas will assume greater importance in the decisions regarding genetic testing, forming the basis for the exclusion of parasympathetic paragangliomas from additional consideration in this review.


   The Hereditary Pheochromocytoma or Paraganglioma Syndromes
Top
 Abstract
 Introduction
 Definition of Pheochromocytoma...
 The Hereditary Pheochromocytoma...
The Frequency of Germline...
 When Should Genetic Testing...
 Where to Obtain Genetic...
 The Future
 Note Added in Proof
 References
 
Our current understanding of hereditary pheochromocytomas and paragangliomas includes eight defined genetic syndromes. Four of these, NF1, VHL, MEN1, and MEN2, are disorders composed of multiple tumor types; the other four, PGL1–4, have parasympathetic paragangliomas and/or pheochromocytomas or sympathetic paragangliomas as their only type of tumor manifestation. In the following sections, each of these syndromes will be described with a focus on paraganglioma or pheochromocytoma. The reader is referred to other sources for excellent reviews of each of these syndromes (9, 10, 11, 12, 13, 14).

NF1

NF1 is an autosomal-dominant disorder, occurring in one of 3000–4000 people (15) and characterized by neurofibromas, lightly pigmented birthmarks (café au lait spots), iris hamartomas (Lish nodules), and skin-fold freckling. NF1 is caused by inactivating mutations of neurofibromin, a tumor suppressor gene that encodes a GTPase-activating protein involved in the inhibition of Ras activity. Pheochromocytomas are rare, with frequency estimates of 0.1–5.7% but elevated to 20–50% in hypertensive patients with NF1 (16, 17). In most reported NF1 catecholamine-producing tumors, single pheochromocytomas are the most common presentation (84%), followed by bilateral pheochromocytomas (10%) and sympathetic paragangliomas (6%) (17, 18). Most are benign tumors (90%), although malignant pheochromocytomas and sympathetic paragangliomas have also been found (17, 19). These tumors have a presentation and course similar to those of the sporadic ones. Most of them occur in adults (mean age, 42 yr), with rare examples of multigenerational pheochromocytomas (20). Most pheochromocytomas produce a predominance of norepinephrine and therefore most commonly present with hypertension and adrenergic symptomatology. However, 22% of pheochromocytomas have no symptoms related to excessive catecholamine secretion (17). NF1 can be diagnosed simultaneously with pheochromocytoma; however, the typical skin lesions lead to the diagnosis of NF1 during childhood (21), making NF1 unlikely to present as apparently sporadic pheochromocytoma.

VHL

VHL is an autosomal-dominant syndrome with an incidence of one in 36,000 births (22). VHL is caused by mutations of the VHL gene, a tumor suppressor gene that encodes a protein (pVHL) that regulates hypoxia-inducible genes, the fibronectin matrix assembly, and angiogenesis (23, 24, 25). This protein inhibits the accumulation of hypoxia-induced proteins through ubiquitin-mediated degradation of hypoxia-inducible factor-1 subunits under conditions of normoxemia (25). In carriers of VHL gene germline mutations, the regulation of genes such as the vascular endothelial growth factor and other genes involved in cellular growth seems to be lost, predisposing the VHL carriers to both benign and malignant tumors in multiple organs (i.e. renal, testicular, and pancreatic cysts, renal cell cancer, islet cell tumors, central nervous system hemangioblastomas, endolymphatic sac tumors, and adrenal tumors) (26, 27, 28). Pheochromocytomas occur in 10–34% of patients with VHL (29, 30) with a mean age at presentation of 18.3 yr. The prevalence is 6–9% in people with mutations caused by partial or complete deletions of the VHL gene (VHL type 1), whereas those with missense mutations have a prevalence of 40–59% (VHL type 2), exhibiting genotype-phenotype correlation (31). These catecholamine-producing tumors could present as the first (32) or only manifestation of VHL (VHL type 2C) (25). Consequently, VHL carriers can present as apparently sporadic pheochromocytoma. VHL catecholamine-producing tumors are most commonly pheochromocytomas (90%), although sympathetic paragangliomas have been described (abdomen 8%, chest 2%, and neck 0.1%) (29). Approximately half of pheochromocytomas are bilateral (33), and most produce norepinephrine (34, 35). There are uncommon examples of malignant catecholamine-producing tumors in VHL (<10%), frequently sympathetic paragangliomas (36, 37, 38, 39).

MEN1

MEN1 is an autosomal-dominant syndrome characterized by primary hyperparathyroidism, pancreatic islet cell neoplasms, and pituitary adenomas caused by inactivating mutations of the MEN1 locus coding for the suppressor protein menin. MEN1 may be associated with pheochromocytomas. Fewer than 10 cases of pheochromocytoma have been identified in MEN1, all unilateral, rarely malignant, and most characterized by hypertension and predominant norepinephrine production (14, 40, 41, 42, 43, 44). None presented as apparently sporadic pheochromocytomas. Given the extremely rare association between MEN1 and pheochromocytomas, and the much higher prevalence of parathyroid, pancreatic, and pituitary diseases in this syndrome, it is not surprising that MEN1 has not yet been reported to present clinically as apparently sporadic pheochromocytoma.

MEN2

MEN2 is an autosomal-dominant syndrome caused by activating mutations in the RET protooncogene, which encodes a transmembrane receptor tyrosine kinase involved in the regulation of cell proliferation and apoptosis. MEN2A is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism. MEN2B is characterized by MTC, mucosal ganglioneuromas, and pheochromocytoma. Pheochromocytoma occurs in approximately half of gene carriers and is almost always located within the adrenal glands. There have been rare reports of sympathetic paragangliomas (45), although most of these have been found in the adrenal region and may represent a tumor that has developed in an adrenal rest (46), recurrence of a previously excised adrenal medullary tumor (47), or seeding from a malignant pheochromocytoma (48). Bilateral pheochromocytomas occur in approximately half of patients with MEN2 who have pheochromocytomas; their development is frequently asynchronous, with separation by as much as 15 yr (49). Pheochromocytomas tend to develop after MTC is identified; however, there are well-documented examples of MEN2-related pheochromocytomas presenting before MTC is found as the initial manifestation of this syndrome (50). Even so, most such cases do not present clinically as apparently sporadic pheochromocytoma, given that the MEN2 family history or nonsolitary tumor focus is known or suspected. Thus, whereas MEN2 has been reported to present as an apparently sporadic pheochromocytoma, such cases are rare.

Pheochromocytomas occur most commonly with codon 634 (MEN2A) or 918 (MEN2B) RET protooncogene mutations (51) and with lesser frequency in kindreds with mutations of codons 609, 611, 618, 620, 768, 790, 791, V804L, V804M, 883, and 891 (51, 52, 53, 54, 55). Pheochromocytomas have not been found in kindreds with mutations of codons 532–534 (56), 630 (55), and 912 (57). Malignant pheochromocytomas are uncommon and are generally found in patients with large tumors (58, 59, 60, 61, 62). The pattern of catecholamine production in MEN2 pheochromocytoma differs from that seen in other hereditary forms of pheochromocytoma. Epinephrine is produced in disproportionately large amounts, resulting in an early clinical phenotype characterized by attacks of palpitations, nervousness, anxiety, and headaches, rather than the more common pattern of hypertension seen with sporadic or other hereditary tumors (35, 49, 63, 64).

PGL1

PGL1 is an autosomal-dominant syndrome with maternal imprinting, characterized by familial and isolated head and neck parasympathetic paragangliomas and less frequently by sympathetic paragangliomas and pheochromocytomas (6, 65, 66, 67). PGL1 is caused by inactivating mutations in the mitochondrial complex II SDHD gene (13, 68), a tumor suppressor gene involved in the electron transport chain and the tricarboxylic acid cycle (69). SDHD mutations result in destabilization and loss of structural integrity of the complex II (65). Consequently, oxygen free radical production increases, stabilizing the hypoxia-inducible factor-1 with subsequent activation of TGF-ß, platelet-derived growth factor receptor-ß, and a ligand for the epidermal growth factor receptor, predisposing to tumor formation (70). SDHD mutations represent 97% of total germline mutations observed in pheochromocytoma/paraganglioma kindreds found with succinate dehydrogenase mutations (71, 72, 73). However, this percentage must be certainly an overstatement; more recent literature indicates that mutations of other subunits of the succinate dehydrogenase complex, mainly SDHB, account for at least one half of the mutations. These mutations exhibit a genotype-phenotype correlation. Approximately 75% of pheochromocytomas and sympathetic paragangliomas occur when mutations are localized in the 5' portion of SDHD (69). Most of these tumors exhibit a benign behavior; however, they can also be malignant (74). Pheochromocytomas can be unilateral or bilateral (66). The mean age at diagnosis is 43 yr (74), with rare cases reported in people younger than 20 yr (66). SDHD mutations can present as apparently sporadic pheochromocytoma because of the maternal imprinting and the lack of more clearly defined manifestations (66, 67).

PGL2

PGL2 is an autosomal-dominant syndrome defined by familial head and neck parasympathetic paragangliomas. Hereditary transmission occurs exclusively in children of fathers carrying the gene, pointing to the importance of maternal imprinting (75). The causative gene has been mapped to chromosome 11q13.1 but has not yet been identified (5). It is unlikely that people with this syndrome will present with an apparently sporadic pheochromocytoma because of its rarity and parasympathetic lineage. So far, no cases of PGL2 presenting as pheochromocytoma have been described.

PGL3

PGL3 is an autosomal-dominant syndrome without maternal imprinting, characterized by benign and seldom multifocal head and neck parasympathetic paragangliomas. PGL3 was initially reported in only one family. The investigators who evaluated this single kindred identified a missense mutation of SDHC, another component of the mitochondrial complex II (4). None of these family members had a catecholamine-producing tumor. Recently, an international registry of 121 individuals with head and neck paragangliomas and 371 individuals with pheochromocytomas described a prevalence of germline SDHC mutations in 4% of patients with head and neck parasympathetic paragangliomas; no SDHC mutations were identified in sympathetic paragangliomas or pheochromocytomas (76). Therefore, at present, it is unnecessary to consider this genetic disorder in patients with apparently sporadic pheochromocytomas.

PGL4

PGL4 is an autosomal-dominant syndrome, characterized by parasympathetic paragangliomas and frequently by sympathetic paragangliomas and/or pheochromocytomas. Inactivating mutations in the tumor suppressor SDHB gene are responsible for PGL4 syndrome (77, 78). These mutations cause mitochondrial complex II destabilization and may activate the hypoxic/angiogenic pathway predisposing to tumor formation, with a very strong association with a malignant intra- or extraadrenal phenotype (74, 79). Apparently sporadic pheochromocytoma has been found in carriers of SDHB mutations (67, 74), with a mean age of presentation at 34 yr (74). Although SDHB mutations have been recently described in association with renal cell carcinomas (80, 81) and papillary thyroid carcinomas (81), the lack of a frequent association with these disorders, a possible low penetrance, and a risk for new-onset SDHB mutations may explain the subset presenting as apparently sporadic pheochromocytoma.


   The Frequency of Germline Mutations in Apparently Sporadic Pheochromocytomas
Top
 Abstract
 Introduction
 Definition of Pheochromocytoma...
 The Hereditary Pheochromocytoma...
 The Frequency of Germline...
When Should Genetic Testing...
 Where to Obtain Genetic...
 The Future
 Note Added in Proof
 References
 
Only four of the eight described hereditary pheochromocytoma/paraganglioma syndromes have been reported to present as apparently sporadic pheochromocytoma (VHL, MEN2, PGL1, and PGL4). PGL2 and PGL3 have never been associated with pheochromocytomas, excluding these syndromes from further discussion, and pheochromocytomas associated with NF1 can be identified by a careful physical examination. Since the characterization of RET and VHL genes and before the clinical characterization of the mitochondrial complex II gene mutations as responsible for some hereditary pheochromocytomas, various hospital-basedseries of isolated pheochromocytomas identified a hereditary component in only seven of 201 patients analyzed for VHL mutations and two of 311 patients analyzed for RET mutations (82, 83, 84, 85, 86, 87, 88). However, one comprehensive recent report suggested that 24% of patients with apparently sporadic pheochromocytoma have an unsuspected germline mutation of VHL, RET, SDHB, or SDHD. These findings led to the recommendation that all such patients be screened for hereditary causes (67). The findings and recommendations are sobering, because they would raise the percentage of patients with hereditary pheochromocytoma to unprecedented heights and would add significant screening costs to management.

Before accepting this blanket recommendation, it is important to evaluate the literature on this point critically. Issues such as the mode of case ascertainment and clinically relevant definitions are important. We have reviewed all available literature concerning germline mutations in apparently sporadic pheochromocytoma (66, 67, 74, 77, 82, 83, 84, 85, 86, 87, 88, 89). Because no single study has included mutation analysis for all genes known to cause hereditary pheochromocytoma, we have compiled published reports that included data on the presence of germline mutations. We have excluded all reports in which tumor DNA was evaluated but for which there was no comparable data set for any source of germline DNA (90, 91, 92, 93, 94). To avoid duplication, we have also excluded earlier reports from groups that updated previously published information in a subsequent report (95). Table 2Go provides a compilation of the data included in our analysis. At first glance, global numbers suggested that 20% of patients with apparently sporadic pheochromocytoma had a germline mutation of one of the genes known to cause hereditary pheochromocytomas/paraganglioma. When these data were corrected by excluding patients with bilateral or multicentric tumors, who almost certainly have hereditary disease, the figure was reduced to 17%: 5.04% for VHL, 6.38% for PGL4, 3.72% for PGL1, and 1.55% for RET. A caveat of this calculation, however, is that some proportion of these patients may have had metastatic rather than multicentric disease and therefore would be more likely to be considered sporadic disease at the time of diagnosis.


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  		TABLE 2. Reported frequencies of germline mutations in specific endocrine syndromes associated with apparently sporadic pheochromocytomas

 
A concern that reverberates throughout the literature is the question of ascertainment bias in evaluating the true incidence of hereditary pheochromocytomas in the general population. Most reports were derived from tertiary care centers with specific expertise in the management of these disorders. Estimates from these centers may reflect a subtle bias in that more complicated or multiple pheochromocytomas may have been referred for evaluation and treatment. Another possible source of bias is the prevalence of a specific genetic disorder in a particular geographic region. Two specific examples illustrate this point. The first is the prevalence of VHL syndrome associated with pheochromocytomas in the Black Forest area of Germany, where there is an estimated VHL prevalence of one in 38,951 (96). In a 1993 report of the incidence of hereditary pheochromocytoma in patients who presented with apparently sporadic pheochromocytomas, 95% of the subjects were from the Black Forest region (97). Indeed, as many as 14 apparently unrelated kindreds in the Freiburg series have been found to have an identical VHL mutation (98). A recent report from members of this same group included a broader spectrum of geographic regions, although there was inadequate information provided about the geographic localization, particularly those with VHL mutations, to exclude the possibility of ascertainment bias (67). The second example is a founder effect for hereditary paragangliomas in The Netherlands, suggesting that tumors from this region are caused by two discrete mutations of SDHD (71). Therefore, studies that include substantial numbers of patients from these circumscribed regions are likely to be relevant to those who live in these regions but less relevant for those living elsewhere.

A second factor is the adequacy of establishing family history. As clinicians who are attuned to the importance of this information in the identification of genetic syndromes causing pheochromocytoma/paraganglioma, we are aware of how difficult it is to elicit a family history for this disorder. For the endocrinologist, incidents of sudden unexplained death, cardiac arrest (99), stroke, or hypertension in the family of a patient with apparently sporadic pheochromocytoma or paraganglioma increase the suspicion of hereditary disease. In contrast, asking whether anyone in the family has had a pheochromocytoma or paraganglioma is likely to yield looks of confusion from the patient or family. This difficulty is further compounded by the fact that most families in the United States have been fragmented by geographic dispersion, leading to further loss of detailed family medical history. Paradoxically, this dispersion may actually be an argument for performing a genetic test because of the breakdown of regional differences.

Finally, there is another factor of importance in assessing the relevance of this data set. During the past 40 yr, there has been focused activity to identify hereditary endocrine tumor syndromes. Many factors have contributed to greater recognition of these syndromes, including systematic screening efforts, the availability of genetic testing, patient and family education, and greater awareness of genetic disease. As a result of these collective efforts, families with genetic endocrine tumors are much more likely to be recognized and classified in some countries.


   When Should Genetic Testing Be Considered?
Top
 Abstract
 Introduction
 Definition of Pheochromocytoma...
 The Hereditary Pheochromocytoma...
 The Frequency of Germline...
 When Should Genetic Testing...
Where to Obtain Genetic...
 The Future
 Note Added in Proof
 References
 
Genetic testing should be performed in all pheochromocytoma patients with a family history or clinical features suggestive of a hereditary pheochromocytoma/paraganglioma syndrome. Table 3Go provides useful information that focuses on the specific genetic syndromes associated with pheochromocytoma. In this table, we have attempted to provide information that is general enough to elicit a positive response from a family member but specific enough to be useful to the physician. We have limited the total number of historical features, because the initial history is often taken in an emergency center, a clinical setting where brevity is important. Any evidence suggestive of one of these specific genetic syndromes could provide justification (e.g. to an insurance company) to perform a genetic test.


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  		TABLE 3. Clinical features suggestive of hereditary pheochromocytoma

 
Another group with a high probability of hereditary paraganglioma/pheochromocytoma is comprised of patients with bilateral or multicentric adrenal pheochromocytomas. Identification of multiple-site intraadrenal pheochromocytoma suggests mutation of either the RET or VHL gene. Although there is a statistically greater probability for VHL mutations than for RET mutations (Table 2Go), the biochemical profile of the pheochromocytoma may permit differentiation between these two syndromes and indicate which syndrome should be evaluated first, i.e. if the biochemical profile shows elevated epinephrine/metanephrine values, RET should be tested first, but if the biochemical profile shows exclusively elevated norepinephrine/normetanephrine values, VHL should be tested first. If VHL and RET analysis are negative, SDHB and SDHD should be analyzed.

A third group that should be tested is those with sympathetic paragangliomas, especially multiple tumors. In a report by Neumann et al. (67), 14 of 30 patients with extraadrenal tumors (47%) were found to harbor germline mutations, most commonly of SDHB and SDHD. Ten of 14 cases of hereditary sympathetic paragangliomas had SDHB or SDHD mutations; the remainder had VHL mutations. More recently, Gimenez-Roqueplo et al. (74) found that four of six patients with sympathetic paragangliomas had mutations in SDHB or SDHD. None of the six patients had VHL or RET germline mutations. Patients with MEN2 rarely present with sympathetic paragangliomas, making this analysis unnecessary unless there are other features suggesting this possibility.

A fourth group that should be tested includes those with an age of onset of less than 20 yr. The report by Bauters et al. (100) suggests that the likelihood of finding a hereditary basis for pheochromocytoma is increased when age of onset is young (<18 yr). The report by Neumann et al. (67) provides the largest comparative data set, finding that 31 of 57 patients (54%) presenting before age 20 had hereditary disease. Most of these younger patients had VHL (74%). The rank order for testing should be VHL first, followed by MEN2, SDHB, and SDHD. However, if the biochemical profile shows increased production of epinephrine/metanephrines, RET should be tested first. In this series, 39, 27, and 18% of patients with apparently sporadic pheochromocytomas had germline mutations when they presented in the third, fourth, and fifth decades (67). However, the presentation of data therein does not allow a clear determination of whether these percentages of patients would fulfill our working definition of apparently sporadic. Because of issues related to bias of ascertainment and selection of patients, we are uncomfortable making broad-based recommendations for patients in the third through fifth decade age groups until more experience becomes available.

Furthermore, patients older than 50 yr who presented with an apparently sporadic pheochromocytoma/paraganglioma had less than a 1.3% probability of having a VHL, MEN2, SDHB, or SDHD mutation (67), making genetic testing unnecessary and difficult to justify (Table 4Go).


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  		TABLE 4. When should genetic testing be considered?

 
Finally, there will be patients who seek assurance that they do not have a heritable genetic disease. It is difficult at present to provide a compelling benefit/cost basis for the performance of a genetic test in such a person; however, it is reasonable to consider testing on a case-by-case basis. In these cases, it is important that genetic counseling be considered so that patients understand fundamental genetic concepts and the strengths and weaknesses of current genetic testing. Patients should be advised that insurers might not pay for such testing. It is important for the physician to document discussions related to genetic risk in the medical record for all patients, because lawsuits have been filed over failure to inform family members of such risk.


   Where to Obtain Genetic Testing
Top
 Abstract
 Introduction
 Definition of Pheochromocytoma...
 The Hereditary Pheochromocytoma...
 The Frequency of Germline...
 When Should Genetic Testing...
 Where to Obtain Genetic...
The Future
 Note Added in Proof
 References
 
There is at present a commercial source of testing for each of these genetic syndromes. Because these sources change on a continuing basis, we recommend that the clinician seek current testing sources from a compilation of this information (www.genetests.org). There are two genetic laboratories that currently perform analyses for five of the six syndromes, but no single laboratory performs all of them. It seems likely that a consolidation of genetic testing, already under way, will continue and that these tests will become available as a panel from a single source in the future.


   The Future
Top
 Abstract
 Introduction
 Definition of Pheochromocytoma...
 The Hereditary Pheochromocytoma...
 The Frequency of Germline...
 When Should Genetic Testing...
 Where to Obtain Genetic...
 The Future
Note Added in Proof
 References
 
Over the past 40 yr, there has been a continuous effort to improve the quality of care for these pheochromocytoma/sympathetic paraganglioma patients. A combination of earlier ascertainment, better treatment modalities, and new therapeutic strategies that target the molecular causation has improved their outcomes. Importantly, these efforts, particularly genetic testing, have reduced costs by bringing about earlier identification of some clinical syndromes leading to more definitive and cost-effective therapy. They have also eliminated the costs of screening for family members who are not gene carriers. It seems likely that this movement toward earlier characterization of genetic disease will continue.

It also seems likely that the costs of DNA sequencing will continue to fall. At a recent genomics meeting, discussions focused on bringing the cost of sequencing below $1000 per genome over the next decade (101). At some point between now and then, analyses of the genes that cause hereditary pheochromocytoma may be available for a few dollars. At that point, the cost/benefit ratio will shift significantly toward favoring routine testing even in lower-yield settings, assuming the societal issues mentioned above have also been addressed.


   Note Added in Proof
Top
 Abstract
 Introduction
 Definition of Pheochromocytoma...
 The Hereditary Pheochromocytoma...
 The Frequency of Germline...
 When Should Genetic Testing...
 Where to Obtain Genetic...
 The Future
 Note Added in Proof
References
 
An article describing genetic testing in this condition in 314 patients was recently published in the Journal of Clinical Oncology (102). Eighty-six of these patients have been included in a previous study that has been analyzed in this paper (74).


   Footnotes
 
First Published Online May 30, 2006

Abbreviations: MEN1, Multiple endocrine neoplasia type 1; MTC, medullary thyroid carcinoma; NF1, neurofibromatosis type 1; PGL1, paraganglioma/pheochromocytoma syndrome type 1; VHL, von Hippel Lindau syndrome.

Received October 5, 2005.

Accepted May 18, 2006.


   References
Top
 Abstract
 Introduction
 Definition of Pheochromocytoma...
 The Hereditary Pheochromocytoma...
 The Frequency of Germline...
 When Should Genetic Testing...
 Where to Obtain Genetic...
 The Future
 Note Added in Proof
 References
 

  1. Wallace MR, Marchuk DA, Andersen LB 1990 Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249:181–186[Abstract/Free Full Text]
  2. Mulligan LM, Kwok JB, Healey CS 1993 Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363:458–460[CrossRef][Medline]
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H. J. L. M. Timmers, A. Kozupa, G. Eisenhofer, M. Raygada, K. T. Adams, D. Solis, J. W. M. Lenders, and K. Pacak
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