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. 2008 Sep 30;93(12):4818–4825. doi: 10.1210/jc.2008-1290

Impact of Screening Kindreds for SDHD p.Cys11X as a Common Mutation Associated with Paraganglioma Syndrome Type 1

Mariola Pęczkowska 1, Zoran Erlic 1, Michael M Hoffmann 1, Mariusz Furmanek 1, Jarosław Ćwikła 1, Agata Kubaszek 1, Aleksander Prejbisz 1, Zbigniew Szutkowski 1, Andrzej Kawecki 1, Krzysztof Chojnowski 1, Anna Lewczuk 1, Mieczysław Litwin 1, Witold Szyfter 1, Martin A Walter 1, Maren Sullivan 1, Charis Eng 1, Andrzej Januszewicz 1, Hartmut P H Neumann 1
PMCID: PMC2626452  PMID: 18826997

Abstract

Context and Objective: Germline mutations of the genes SDHB, SDHC, and SDHD predispose to paraganglioma syndromes. Mutation-specific counseling, risk assessment, and management recommendations ideally should be performed. Here, we provide data for a single common mutation of the SDHD gene.

Methods: The European-American Pheochromocytoma-Paraganglioma Registry served as the source for unrelated index cases affected by pheochromocytoma or paraganglioma. Patients with the SDHD c.33 C→A (p.Cys11X) germline mutations were reinvestigated by whole-body magnetic resonance imaging and 24-h urinary catecholamine assay. First-degree relatives underwent genetic testing and those testing positive had same clinical investigations. Microsatellite analyses were used to test the hypothesis that all index cases were related and the mutation is a founding one.

Results: Sixteen index cases with the mutation SDHD p.Cys11X are registered. After testing their relatives, there were a total of 25 mutation carriers. We excluded seven subjects who inherited the mutation from the mother because of maternal imprinting. Thus, 18 mutation carriers were clinically affected. Among these 16 (89%) had head and neck paragangliomas, six (33%) thoracic tumors, six (33%) extraadrenal retroperitoneal, and five (28%) intraadrenal. Of note, 16 (89%) had multiple tumors at first diagnosis, and one (5%) had signs of malignancy during follow-up. Overall penetrance was 100% at age 54. Haplotype analyses revealed evidence for a founder effect.

Conclusions: The SDHD p.Cys11X mutation is a founding mutation associated with a high penetrance for paraganglial tumors of the skull base, neck, thorax, and retroperitoneum in the first four decades of life and, rarely, with malignancy.

The p.Cys11X mutation of the succinate dehydrogenase D subunit is a founding mutation associated with a high penetrance for paraganglial tumors of the skull base, neck, thorax, and retroperitoneum in the first four decades of life and rarely with malignancy.

Paraganglioma (PGL) syndrome is the term for hereditary paraganglial tumors in which germline mutations of susceptibility genes can be detected. Germline heterozygous mutations of genes encoding three of the four subunits of succinate dehydrogenase (SDH), SDHB (so-called PGL4), SDHC (PGL3), and SDHD (PGL1), the SDHx genes, have been shown to cause PGL (1,2,3). PGL3 and PGL4 follow an autosomal dominant transmission, but patients with SDHD mutations develop tumors only if the mutation was inherited from the father (termed maternal imprinting) (4). One exception to this rule has been described to date, but the case is unclear (5,6). The gene for PGL2 has still not been identified, although it appears to be peculiar to a single family from The Netherlands (7). Thus far, no mutations in SDHA have been found in PGL syndromes (8) (C. Eng, unpublished).

Our previous research on SDHx genes allowed us to describe overall gene-specific characteristic clinical features of PGL syndromes (9,10,11). Our and other studies suggest that multiple tumors are the characteristic features of SDHD mutations, whereas germline mutations of SDHB appear to be associated with susceptibility to malignant pheochromocytomas and also extraparaganglial neoplasias (9,10,11,12,13,14,15,16). A single benign head and neck tumor seems to be the most prevalent manifestation of SDHC mutations; however, rare adrenal and extraadrenal pheochromocytomas have been described recently (17,18).

Although many centers have contributed reports on PGL, our knowledge about clinical features associating with a particular mutation is mostly limited. Patients and genetic counselors, however, being confronted with a distinct mutation often wish to know clinical details peculiar to a given mutation. Here, we present detailed data for the clinical risk profile for SDHD c.33 C→A (p.Cys11X) based on extensive clinical investigations of a larger cohort of such mutation carriers.

Subjects and Methods

The terminology for paraganglial tumors is inconsistent. In contrast to the World Health Organization (WHO) classification where the term pheochromocytoma is restricted to adrenal tumors, we use the term pheochromocytoma for the virtually always vasoactive tumors including those of adrenal, extraadrenal abdominal, and thoracic location. In contrast, we use the term paraganglioma only for those located in the skull base and neck (19,20).

The terminology for paraganglial tumors is inconsistent. Our study is based in the European-American Pheochromocytoma-Paraganglioma Registry, which represents a systematic registration of demographic and clinical data of patients with paraganglial tumors of any location. Most of the registrants are population based, originating from Germany and Poland. The Registry routine is summarized as follows. Index cases were registered if a symptomatic paraganglioma or pheochromocytoma has been present and if 10 ml EDTA anticoagulated blood was available. Demographics and clinical data are collected for all registrants. Metastases were the criterion for malignancy if clearly located in nonparaganglial tissues. Analyses for germline mutations in the SDHx genes were performed as previously reported (9,11).

For purposes of this study, we searched the Registry for subjects carrying the SDHD c.33 C→A (p.Cys11X) mutation. We then followed Registry routine by offering relatives of all index cases with this mutation gene testing for the presence of this specific mutation by denaturing high performance liquid chromatography analysis and direct sequencing (forward and reverse direction) of the involved exon. All carriers of this germline mutation (index cases plus their relatives) were clinically investigated by the screening program, which included magnetic resonance imaging (MRI) or computed tomography of the skull base and neck, the thorax, and the abdomen including the pelvis and in addition measurement of catecholamines in the 24-h urine including adrenaline, noradrenaline, and total metanephrines.

To determine whether p.Cys11X represented a hotspot for mutations or resulted from a founder, haplotype analysis was performed in distinct families using known polymorphic markers upstream and downstream of the SDHD locus. These included D11S5017, D11S5015, D11S5019, D11S5030, D11S1347, spanning approximately 360 kb (13). The recombination events frequency in this area is 1.9 cM/Mb (21,22). The five markers were amplified using fluorescent dye-labeled primers and then analyzed by the MegaBACE 500 DNA Analysis System (Amersham Biosciences, Arlington Heights, IL) under standard run conditions as recommended by the manufacturer. The length of amplified fragments was established from the internal run (MegaBACE ET400-R Size Standard; Amersham Biosciences) using the MegaBACE Genetic Profiler version 2.0 software (Amersham Biosciences). To estimate the haplotype frequencies in the normal population, 100 controls were genotyped for all the markers and the maximal likelihood frequency was estimated using Arlequin software version 2.001 (Genetics and Biometry Laboratory, University of Geneva, Switzerland).

We used demographic and clinical data to calculate penetrance for the development of tumors. According to the widely accepted parent-of-origin effect (maternal imprinting) regarding the generally excluded risk for tumors in offspring of female SDHD mutation carriers, only index cases and relatives who inherited the germline mutation from the father were included for penetrance calculations.

This study has been approved by the ethical committees of all participating institutions. All patients have given written informed consent.

Results

As of June 1, 2008, a search of the European American Pheochromocytoma Paraganglioma Registry revealed 16 registered index cases with the germline SDHD mutation c.33 C→A (p.Cys11X). At initial presentation, eight of these subjects (50%) had head and neck paragangliomas, and eight (50%) had pheochromocytomas. All of the 16 subjects were confirmed to have a negative family history for paraganglial tumors. These 16 unrelated p.Cys11X mutation-positive registrants together had 32 first-degree relatives who underwent genetic testing. This included eight of 16 mothers, six of 16 fathers, and 10 of 13 siblings of seven families and eight of 10 children of six families. Eight first degree relatives were deceased and 15 refused genetic testing. Twelve relatives were found to be mutation positive. This included 1 sister, 5 children and 6 fathers. Twenty relatives were mutation negative.

Haplotype construction was possible in 10 of 16 families (Fig. 1). The identified haplotypes using markers flanking the SDHD locus showed a common shared haplotype (haplotype A) segregating with the mutated allele in seven of 10 families. The estimated frequency of this haplotype in the Polish control population was 0.19%. The likelihood that seven unrelated cases share the same haplotype (seven independent events) would be 0.894 × 10−19. This provides a high likelihood that these seven families are indeed related and thus members of one major kindred. Two of the three remaining families shared the 138_162_167_158 haplotype (estimated frequency in the control population 10%), and the third family shared only the 138_162_167 haplotype. It is possible that recombination events occurred over time and all these 10 families are part of the same ancestral family. The genotyping analyses results of the remaining six index cases suggested that four of six could potentially share the same 138_162_167_158_198 haplotype. Haplotype construction was not possible in these six index cases due to lack of other family members for analysis.

Figure 1.

Figure 1

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Haplotypes found in the eight families. Haplotype A was identified in five families; B, C and D were identified in one family each. The bars were constructed under the hypothesis of a common shared region (black).

Of the 16 families, 11 are currently living in Poland, in the province of Mazowsze, two in the northern part of Poland, in the province of Pomorze (Fig. 2). Two families live in Germany, one in east Bavaria,and one in the Ruhr district near Dortmund. Both had ancestors from Silesia, now a southwestern Polish province. One family lives in Alsace and originates probably from German settlers in Serbia (with a German surname/family name) but has no known knowledge of relations in southwestern, central, or northern Poland.

Figure 2.

Figure 2

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Map of Western Europe showing regions of residence and origins of families with the SDHD p.Cys11X mutation. The cluster around central Poland denotes the majority of families originating and currently residing there. The origin of the arrows denote regions of origin of the three families that have migrated, two from Southwestern Poland to their present residence in Germany, and one from Serbia to Alsace, France.

Twenty- five positive subjects, comprising all 16 index cases and an additional nine relatives (five children, one sister, and three fathers) underwent clinical investigations. The full program with MRI of the skull base and neck, MRI of the thorax, MRI of the abdomen, and 24-h urine catecholamine or metanephrine measurement had all except one subject who had [131I]iodo-metaiodobenzylguanidine whole-body scintigraphy depicting a paraganglioma that was regarded as equivalent.

No tumor was found in the two fathers, 64 and 62 yr old, and in five of the five children, 6, 8, 8, 10, and 14 yr old. The five tumor-free children inherited the mutation from their mothers, whereas transmission for the two fathers was unknown. For further analyses and calculations, we excluded all these seven subjects, because all of them most likely are not at risk for tumors according to the SDHD mutation parent-of-origin-effect.

Eighteen cases, comprising 16 index cases and two relatives, a sister and one father, had paraganglial tumors, either already removed or diagnosed during follow-up investigations (Tables 1–3). The ages at diagnosis range from 9–54 yr (mean 29 ± 12); 12 were female and six male. All 18 individuals presented with benign tumors. Sixteen (89%) individuals had multiple tumors at initial presentation. Initially, all subjects presented with benign tumors. One patient who eventually developed metastases to the liver at age 46 was operated on for a benign adrenal tumor at age 39, and at age 46, for bilateral adrenal (1.5 and 2 cm in diameter, respectively) and multiple extraadrenal abdominal (1.5 and 2.3 cm), thoracic (2.3 cm), and bilateral carotid body (1.2 and 2 cm) tumors. Two bilateral jugular paragangliomas also found at age 46 (both about 1 cm in diameter) were not treated surgically.

Table 1.

Clinical characteristics of 18 carriers of the SDHD p.Cys11X mutation

Clinical characteristics All patients (n = 18)
Gender (female/male) 12 (67%) /6 (33%)
Mean age at first diagnosis ± sd (yr) 29 ± 12
Pheochromocytoma at presentation 9 (50%)
Head and neck paraganglioma at presentation 9 (50%)
Multiple tumors at presentation 16 (89%)
Tumor location
 Head and neck paragangliomas
  Carotid body 16 (89%)
  Jugular 9 (50%)
  Tympanic 2 (11%)
 Pheochromocytomas
  Extraadrenal abdominal 6 (33%)
  Adrenal unilateral 3 (17%)
  Adrenal bilateral 2 (11%)
  Thoracic 6 (33%)
  Posterior mediastinum 3
  Paracardiac, close to the left coronary artery 1
  Aorto-pulmonary 2
Overall number of pheochromocytomas at the end of the observation 28
Overall number of head and neck paragangliomas at the end of the observation 47
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Table 2.

Clinical characteristics of 18 carriers of the SDHD c.33C→A (p.Cys11X) mutation

Family/case ID Birth year First diagnosis Age at first diagnosis Second diagnosis Age at second diagnosis Third diagnosis Age at third diagnosis Malignant Total tumors Total surgeries Haplotype
1/1 1980 PHEO, ea 18a G. caroticum, r+l; G. jugulare, r+l 28b 5 1 A
1/2 1958 G. jugulare, l 42a G. caroticum, r+l 49b 3 1 A
2/1 1970 PHEO, ar 27a PHEO, ea 32b PHEO, al 39b 3 2 A
3/1 1944 G. caroticum, r+l 54a G. jugulare, r 62b 3 1
4/1 1964 G. caroticum, r+l 31a PHEO, t 42b 3 2 A
5/1 1975 PHEO, al 21a G. caroticum, r+l; G. jugulare, r+l 29b PHEO, t 31b 6 3 A
6/1 1932 G. tympanicum, l; G. caroticum, r+l 37a G. jugulare, r 40a 4 2
7/1 1969 PHEO, ar+2ea 23a G. caroticum, r+l; PHEO, ea+t 39b 7 1 B
8/1 1991 PHEO, 2ea 9a 2 1
9/1 1976 PHEO, 2ea+t 15a PHEO, 3ea; G. caroticum, r+l; G. jugulare, r+l 23a PHEO, ea 29b 11 4
10/1 1960 PHEO, ar+l 39a PHEO, 2ea+t 45a G. caroticum, r+l; G. jugulare, r+l 45b Liver metastasis 9 3
11/1 1979 G. caroticum, r+l 20a G. jugulare, r+l 28b 4 1
11/2 1976 G. caroticum, r+l 31b 2 1
12/1 1970 G. caroticum, r+l 31a G. jugulare, r+l 37b 4 0 A
13/1 1979 PHEO, ar+t 13a G. caroticum, l 22b 3 2 C
14/1 1985 G. caroticum, l 22a 1 1
15/1 1940 G. caroticum, r+l 44a 2 1
16/1 1958 G. caroticum, r 44a G. tympanicum, r 46a G. caroticum, l 47b 3 0
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a, Adrenal; ea, extraadrenal; G., glomus; l, left; PHEO, pheochromocytoma; r, right; abdominal; t, extraadrenal thoracic. 

a

Diagnosis after clinical manifestation. 

b

Diagnosis made during screening program (asymptomatic). 

Table 3.

Clinical characteristics of pheochromocytoma found during screening program

Family/case ID Age at diagnosis PHEO localizations Tumor diameter (cm) Total metanephrines Epinephrine Norepinephrine Dopamine
2/1 39 Adrenal 1.4 N N N N
4/1 42 Thoracic 1.7 N N E N
5/1 31 Thoracic 0.8 N N N E
7/1 39 Extraadrenal abdominal, thoracic 1.7, 1.1 N N N N
9/1 29 Extraadrenal abdominal 2.8 E E E N
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E, Elevated; N, normal; PHEO, pheochromocytoma. 

In total, the 18 subjects had 75 paraganglial tumors. This figure includes seven adrenal tumors, 15 extraadrenal abdominal tumors, six thoracic tumors, and 47 head and neck tumors that have been or were present in the 18 subjects. Regarding treatment, nine subjects had a total of one, four subjects had two, two subjects had three, and one subject had four operations. A first operation was preformed for symptomatic tumors in all index cases and in one relative. Asymptomatic tumors were found in six patients during follow-up and were treated with subsequent surgery; three were treated with peptide receptor radiotherapy (Y90- or Lu177DOTATATE or Y90 or Lu177DOTATOC); and five subjects with head and neck paraganglioma had adjuvant external beam radiotherapy. For five subjects, a watch-and-wait strategy was chosen.

We used the data obtained from these 18 patients to calculate age-related penetrance. Except for one individual who had whole-body [131I]iodo-metaiodobenzylguanidine scintigraphy, all had MRI or computed tomography investigations of the head and neck, the thorax, and the abdomen including the pelvis. Fifty percent penetrance for any paraganglial tumor is reached at age 30 and 100% at age 54 (Fig. 3). Also, for head and neck paraganglioma, penetrance reached 50% at age 30 and 100% at age 54. Penetrance for pheochromocytoma was 50% at age 40.

Figure 3.

Figure 3

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Age-related penetrance for paraganglial tumors in carriers of the germline mutation SDHD p.Cys11X (n = 18). Green is for any paraganglial; red is for head and neck paraganglioma; black is for adrenal, extraadrenal abdominal, and thoracic pheochromocytoma. PHEO, Pheochromocytoma.

Discussion

Since the initial identification of SDHD as a PGL susceptibility gene in 2000, we and others have obtained data regarding phenotype differentiation among SDHB, SDHC, and SDHD mutation carriers (9,10,11,12,13,14,15,23). These data are currently the basis for genetic counseling and patient care. However, even within each of the SDH genes, there is some variation in clinical phenotype. A different penetrance of adrenal disease has been described between truncating and missense mutations in the SDHD gene (24). Nearly all pathogenic mutations described in exons 1 and 2 are truncating, whereas the mutations in exons 3 and 4 are missense mutations in conserved amino acids (25,26,27). Enzymatic studies in Caenorhabditis elegans and humans suggest that missense variants retain the ability of the mutated subunit of SDH to be incorporated into the heterotetrameric complex, whereas nonsense/splicing variants lead to the dissolution of the whole mitochondrial complex II (28,29). Furthermore, the SDHD p.Cys11X mutation affects the mitochondrial signal peptide and predicts the absence of nearly the entire mature protein. Subsequently, it could lead to dissolution of mitochondrial complex II and therefore may be associated with a fast growth rate, early onset of the symptoms, and high incidence of recurrence of the tumors.

Of note, pheochromocytomas were present in our study in 44% of the studied nonsense mutation SDHD Cys11X. This supports the relatively high prevalence of pheochromocytomas in another study with 20% of pheochromocytomas in patients with truncating mutations compared with 3% in patients with missense mutations (24).

Thus, in the era of personalized healthcare, genotype-specific neoplasia risk profiling to help tailor medical management may be helpful. In this report, we present clinical phenotyping data for a single SDHD mutation, p.Cys11X.

The clinical data in this report are particularly comprehensive encompassing imaging evaluation of all three body areas, namely, skull base/neck, thorax, and abdomen/pelvis, which revealed a total of 75 tumors in 18 patients. Of note, we found complete penetrance for paraganglial tumors by age 54. This contrasts with a penetrance of about 80% by age 54 for all SDHD mutation carriers combined (10). The p.Cys11X-related complete penetrance can be attributed entirely to head and neck tumors. For all SDHD mutation carriers, penetrance for head and neck paragangliomas reaches 75% by age 55 and rises to near complete by 70 yr of age (10). In particular, skull base and neck tumors, dominated by carotid body involvement, reach a penetrance of 50% by the age 30 and 100% by 54 yr, whereas the second most frequently affected area is the retroperitoneum, mostly extraadrenal, with 50% penetrance at age 40. Of note, thoracic tumors have a prevalence above 33%, compared with 18% prevalence for all SDHD mutations combined (10) and with tumors not only in the thoracic chain but also in the paracardial and aortopulmonary paraganglia.

Although there is a risk for malignancy in SDHB mutation carriers, the actual risk in SDHD mutation carriers, although finite, is unclear (30,31,32,33). In SDHD p.Cys11X, only one of 18 (5%) of the patients finally developed a malignant pheochromocytoma. Furthermore, tumors of extraparaganglial organs, which have been rarely reported, are absent in our p.Cys11X series (34).

Currently, there is only one environmental exposure that appears to be related to head and neck PGL, which is altitude (24). Thus, we considered the altitude at which our patients resided for most of their lives as a potential modifier for the phenotype in the studied population. In Poland, it is at its highest point, 115 m above sea level, and for the patients in Germany and France, the highest point is about 200 m. Because all our patients lived at about the same altitude, we could not objectively study altitudinal differences as an environmental modifier of p.Cys11X.

The challenge for clinical consensus conferences for relatively unusual disorders, such as paraganglioma syndromes, is to achieve consensus for adequate clinical management of these patients based on objective evidence. In fact, much of the practice guidelines for less common inherited cancer syndromes are based on expert opinion (e.g. see www.nccn.org), and often, there is no expert in that syndrome residing on the panel (e.g. National Comprehensive Cancer Network (NCCN) Cowden and PTEN Hamartoma Tumor syndrome practice guidelines after 2007). Two major challenges for consensus management guidelines for PGL syndromes include technique of surveillance, important regions/locations for surveillance, and time intervals for surveillance. Therefore, knowing the prevalence and necessary frequencies of medical interventions (surgery, radiotherapy, or other) is helpful. Because our study was a retrospective one and clinical follow-up of the carriers was performed regularly only recently, the precise surveillance interval could not be calculated. It is of interest that biochemical data alone did not pick up asymptomatic tumors detected by imaging studies performed after positive genetic testing in five asymptomatic patients with pheochromocytoma (Table 3). Such constellation of imaging and biochemical results have also been reported by others (35). Therefore, it is clear that at least for this particular mutation, biochemical screening is inadequate, and we suggest three body area MRI together with biochemical testing as the follow-up screening program.

The negative family histories of paraganglial tumors in all 16 index cases, even when reevaluated after testing mutation positive, are noteworthy. In this situation, the parent-of-origin effect may be one explanation (4). Mutation-positive children of female SDHD mutation carriers remain healthy and do not develop paraganglial tumors. Thus, one or, if the child is female, several generations may harbor the mutation but have no clinical manifestations and are skipped. This phenomenon is corroborated by this study with five mutation carriers who inherited the mutation from their mothers but did not show paraganglial tumors. The parent-of-origin effect has been called into question recently for one family, but the reported data are not convincing because of lack of objective documentation of paraganglial tumors and for the double and triple recombinations that had to be invoked (5,6).

Identical mutations that occur with some frequency may result from a hotspot for mutations or from a founder effect. In our case, we have shown that p.Cys11X mutations from at least eight families arise on identical haplotypes and so is most likely a founder mutation. We traced the families with the p.Cys11X mutation and found the majority living around the area of Warsaw, and even for two of the three families living outside Poland, they are in proximity to southwestern Poland. Therefore, the p.Cys11X founder mutation likely arose in Poland. Founder effects for mutations of the SDHD gene have been observed previously, e.g. in The Netherlands (p.Asp92Tyr, p.Leu95Pro and p.Leu139Pro), Tuscany-Italy (p.Gln109X), Trentino-Italy (p.Tyr114Cys), and Spain (c.337–340 delGATC and p.Trp43X) but not in Australia, France, and the United Kingdom (13,36,37,38,39,40). The relative uniqueness of each of the above founder mutations to each country suggests that each founding mutation occurred relatively recently. One exception may be the case of the p.Pro81Leu, which has been referred to as the U.S. founder mutation, although this mutation has been described in various countries predominantly in whites of European descent. However, whether this represents an older founder mutation or a hotspot is currently unclear. Knowledge of founder mutations and their relative frequency in the particular country is important for genetic management. If the frequency is relatively high, then directed mutation testing for that country’s specific founder mutations should occur solely or as the first step.

Footnotes

This work was supported by grants from the Deutsche Krebshilfe (70-3313-Ne 1 to H.P.H.N.), the Deutsche Forschungsgemeinschaft (NE 571/5-3 to H.P.H.N.), the European Union (LSHC-CT-2005-518200 to H.P.H.N. and A.J.), and the National Institutes of Health (R01HD39058-01 and R01HD39058-01S1 to C.E.). C.E. is the Sondra J. and Stephen R. Hardis Chair of Cancer Genomic Medicine at the Cleveland Clinic and a recipient of the Doris Duke Distinguished Clinical Scientist Award. A.J. is supported by grants from the Polish Ministry of Science and Higher Education.

Disclosure Statement: The authors have nothing to disclose.

First Published Online September 30, 2008

Abbreviations: PGL, Paraganglioma; SDH, succinate dehydrogenase.

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