SDHAF2 (PGL2-SDH5) and Hereditary Head and Neck Paraganglioma

Published OnlineFirst January 11, 2011; DOI: 10.1158/1078-0432.CCR-10-0420

Clinical Cancer Human Cancer Biology Research

Henricus P.M. Kunst1,4, Martijn H. Rutten1, Jan-Pieter de Monnink€ 6, Lies H. Hoefsloot2, Henri J.L.M. Timmers3, Henri A.M. Marres1, Jeroen C. Jansen7, Hannie Kremer1,4,5, Jean-Pierre Bayley8, and Cor W.R.J. Cremers1,4

Abstract Purpose: Hereditary head and neck paraganglioma (HNPGL) syndromes are associated with mutations in the SDHD(PGL1), SDHC(PGL3), and SDHB(PGL4) genes encoding succinate dehydrogenase subunits. We recently described mutations in a previously uncharacterized human gene, now called SDHAF2, and showed that this was the long-sought "imprinted" PGL2 gene. Here, we present a new branch of the Dutch SDHAF2 (PLG2-SDH5) family. Experimental Design: The SDHAF2 family has been collected over a 30-year period. The family described here was linked to PGL2 and at-risk family members were invited to participate in this study. Patients were investigated and treated dependent on tumor size and localization. All family members have now been analyzed for the SDHAF2 mutation status. Results: Among the 57 family members, 23 were linkage positive including 7 risk-free carriers (maternal imprinting). Of the 16 at-risk individuals, 11 had a total of 24 tumors with primarily carotid (71%) and vagal locations (17%). Multifocality of tumors was prominent (91%). Malignancy was not detected. The average age at onset was 33 years, and many patients (42%) were asymptomatic prior to screening. SDHAF2 mutation analysis confirmed the findings of the previously performed linkage analysis without detection of discrepancies. Conclusions: We established the SDHAF2 mutation status of PGL2 family members. Phenotypic characterization of this family confirms the currently exclusive association of SDHAF2 mutations with HNPGL. This SDHAF2 family branch shows a young age at onset and very high levels of multifocality. A high percentage of patients were asymptomatic at time of detection. Clin Cancer Res; 17(2); 247–54. 2011 AACR.

Introduction tympanic body and the jugular body (17.5%) and as neoplasms of the nodose ganglion associated with the Paragangliomas arise from the paraganglia, small clus- vagus nerve (4.5%; ref. 3). Other localizations of HNPGL ters of neuroendocrine tissue found throughout the body incidentally reported in literature are those in the larynx, in the vascular and neuronal adventitia. Parasympathetic the nose, the paranasal sinuses, and the orbit. paraganglia of the head and neck generally lack endocrine HNPGL is often present within families. Heredity in activity, in contrast to the sympathetic paraganglia in the HNPGL was first recognized by Chase (4) and is currently abdomen and thorax (1). Head and neck paraganglioma identified in 9.5% to 50% of all cases; the remainder is (HNPGL) are named according to their site of origin (2). defined as isolated cases or sporadic tumors (3, 5, 6). The majority of these paraganglioma occur in the carotid Germline mutations of genes encoding succinate dehy- body (78%), as (difficult to differentiate) tumors of the drogenase (SDH), SDHD (PGL1), SDHC (PGL3), and SDHB (PGL4) are a frequent cause of paraganglioma (7–9). We recently identified germline mutations in a Authors' Affiliations: Departments of 1Otorhinolaryngology, Head and previously uncharacterized gene at the PGL2 locus. This Neck Surgery, 2Human Genetics, and 3Endocrinology, Radboud Univer- gene, named SDHAF2 (succinate dehydrogenase complex sity Nijmegen Medical Center, and 4Donders Institute for Brain, Cognition assembly factor 2), encodes an evolutionarily highly con- and Behavior and 5Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, the Netherlands; 6Department of Otorhi- served flavin-adenine dinucleotide factor (10). SDHAF2 is nolaryngology, Maxima Medical Centre, Eindhoven, the Netherlands; and involved in the flavination of SDHA. For a long period 7 8 Departments of Otorhinolaryngology and Human Genetics, Leiden after the discovery of SDHD, no mutations of SDHA were University Medical Center, Leiden, the Netherlands reported in paraganglioma patients, despite the fact that Corresponding Author: H.P.M. Kunst, Department of Otorhinolaryngol- SDHA ogy, Radboud University Nijmegen Medical Centre, Box 9101, 6500 HB is the largest gene and protein of the SDH complex Nijmegen, the Netherlands. Phone: 31-243-613506; Fax: 31-243-540251; and the major catalytic subunit. Very recently, the first E-mail: [email protected]. SDHA gene mutation was identified. The patient had a doi: 10.1158/1078-0432.CCR-10-0420 catecholamine-secreting, extra-adrenal paraganglioma 2011 American Association for Cancer Research. and no family history of disease (11).

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Translational Relevance mass noted clinically or radiographically. Sporadic and hereditary HNPGL show a variety of differences in clinical Hereditary head and neck paraganglioma (HNPGL) manifestations. Hereditary HNPGL presents at a younger syndromes are associated with mutations in the SDHD age and tumors at multiple sites are more commonly (PGL1), SDHC (PGL3), and SDHB (PGL4) genes encod- observed, compared with sporadic. Malignancy, present ing succinate dehydrogenase subunits. We recently in approximately 10% of all paraganglioma (15, 16), is described mutations in a previously uncharacterized also more common in patients with a hereditary syn- SDHB human gene, now called SDHAF2, and showed that this drome, particularly those with mutations (up to was the long-sought "imprinted" PGL2 gene. Here, we 54% of cases; ref 16). Treatment options for HNPGL present a new branch of the Dutch SDHAF2 (PLG2- include surgical removal, radiotherapy, and a wait-and- SDH5) family and establish the SDHAF2 mutation scan policy. Choosing a treatment modality is dependent status of PGL2 family members. The identification of on the localization and growth of tumor, surrounding the SDHAF2 mutation provides a useful aid in the tissues, age, condition, symptoms experienced, and the screening for HNPGL syndromes. The phenotypic preferences of the patient. SDHAF2 ( characterization of this SDHAF2 (PLG2-SDH5) family Alarge PGL2-SDH5) family showing fre- as given in this study could be used in future counselling quent occurrence of HNPGL was collected by the Depart- of SDHAF2 (PLG2-SDH5) patients and families. ment of Otorhinolaryngology at the Radboud University Nijmegen Medical Centre over a 30-year period and was originally described in 1981 by van Baars et al. (3). Here, we present a phenotypic and genetic description of a large The loss of SDHAF2 results in the loss of SDH function novel branch of this unique paraganglioma family (3, and a reduction in the stability of the SDH complex, 17), presently the only large SDHAF2 family known. We leading to reduced levels of all subunits (10). We found present the results of linkage analysis, mutation analysis, a missense mutation of SDHAF2, c.232G>A (p.Gly78Arg), and the observed inheritance characteristics. Phenotypic in a conserved region of the gene in our family and analysis includes the description of observed tumor loca- demonstrated that it is present in all affected members lization(s), tumor size(s), multifocality, malignancy, gen- of this family and in several unaffected individuals who der distribution, age at onset of symptoms/detection, and inherited the inactivated gene via maternal transmission. presenting symptoms. In addition, we place these findings The SDHAF2 mutation, similar to mutations in SDHD, in the context of recent literature of other SDH-associated shows a striking parent-of-origin inheritance of tumor paraganglioma genes and the previous SDHAF2 (PGL2) susceptibility, with onset of tumor development only upon studies. inheritance via the paternal line (6, 12). Both of these genes are located on chromosome 11. This phenotypic expres- Families and Methods sion of the mutation only upon paternal inheritance sug- gests imprinting of the gene. In contrast, paraganglioma A hereditary paraganglioma syndrome was suspected associated with mutation in the SDHB and SDHC in a family that was known with paraganglioma at the genes (both located on chromosome 1) do not show this Radboud University Nijmegen Medical Centre. Linkage parent-of-origin inheritance. Van der Mey et al attempted analysis was performed as described (18) that indicated to explain this phenomenon by invoking gene activation/ linkage to the PGL2 locus on Chr11q13.1, previously silencing during female oogenesis and male spermatogen- detected in another Dutch PGL2 family. Further genetic esis. This hypothesis became untenable once it was recog- testing confirmed the suspicion of a relationship between nized that PGL1 encoded an essential gene involved in these 2 families. Additional at-risk family members were energy metabolism and was expressed by both parental identified using telephone questionnaires and invited alleles in all tissues tested (8). More recently, an alternative to participate in a clinical genetic study. Patients treated hypothesis has been proposed that takes note of the fact elsewhere were also invited to participate and their clin- that the major imprinted locus of the human genome is ical data were gathered. Linkage analysis was used to also located on chromosome 11, at p15.5, and has been identify mutation carriers, and all carriers underwent a shown to contain genes with a tumor suppressor function thorough clinical screening including otolaryngological (13, 14). This hypothesis, postulated by Hensen, takes into examination and magnetic resonance imaging (MRI) of account the frequent loss of the entire maternal copy of the head and neck region. MRI of thorax/abdomen and chromosome 11 in paragangliomas and proposes a "three- catecholamine secretion screening have not been per- hit" model in which the loss of the maternal chromosome formed. Treatment options, including surgery, radiother- results in the deletion of the remaining copy of SDHD apy, or a wait-and-scan policy were advised, dependent and a maternally expressed gene at Chr11p15.5, in addi- on size and localization of detected tumor(s). Upon tion to the germline mutation present on the paternal the identification of the SDHAF2 mutation, c.232G>A, chromosome (13) p.Gly78Arg, all family members were analyzed by se- In general, HNPGL exhibit a slow rate of growth, and quencing for the presence of the mutation. The following most often present asymptomatically as a space occupying primers were used for the amplification of exon 2 of the

248 Clin Cancer Res; 17(2) January 15, 2011 Clinical Cancer Research

SDHAF2 (PGL2-SDH5) and Hereditary HNPGL

C11orf79/SDHAF2 gene: (SDH5–2F: 50-GTTGACCTTCC- neck region and confirmed the absence of tumors. The CAGGCTC-30 and SDH5–2R: 50-GAGGTTCAGCTGCTT- remaining 16 family members were at risk for developing TTCTG-30). Thirty nanogram of genomic DNA from paraganglioma due to paternal inheritance. MRI investiga- each patient was amplified, and primer annealing was tion was offered to all, and 13 individuals were investi- performed at 60C. PCR fragments were purified using gated, showing tumors in 11. Five of these individuals were the Nucleofast 96-Well kit (Macherey-Nagel). Sequencing already patients under treatment. In total, 12 of the 16 was performed using standard protocols. Sequences were investigated at-risk family members (paternal transmis- analyzed using the Mutation Surveyor software package sion) were considered to be affected (75%). All clinical (Softgenetics). data are summarized in Table 1. The pedigree of the novel family branch is shown in Results Figure 1. The observed inheritance pattern is autosomal dominant, with the characteristics of maternal genomic In 3 generations, 72 living family members were traced. imprinting. This genealogic tree also depicts the relation Linkage analysis was carried out in 57 members willing to with the family as previously described families (3). The participate. Of the cases in which reliable conclusions relationship was confirmed genetically. On pedigree exam- could be drawn, 31 did not carry the disease halotype ination, the families appeared to be linked to the same and 23 did (13 male and 10 female) including 7 risk-free ancestor dating back to the year 1771. carriers showing inheritance via maternal transmission. In total, 24 tumors were detected in 11 of the 13 radio- Our experience with this family indicated an "imprinting" graphically investigated individuals at-risk for developing phenomenon with no observed cases of maternal trans- HNPGL. The most commonly detected HNPGL was the mission (17). These family members would not develop carotid body tumor (CBT), of which 17 were detected in a paraganglioma and hence are called risk-free carriers. We total of 10 patients, representing 71% of all tumors. Vagal examined 4 of these cases by MRI scanning of the head and paraganglioma accounted for 17% (n ¼ 4) of all tumors

Table 1. The clinical profile of individuals with the disease haplotype

No. Individual Sex Status Presented Imaging Age of Localization and size pedigree with onset number symptoms Left Right

CBT VT JTT CBT VT JTT

1 16.13.01.02.14a M Affected (Hx) Yes None ? 2 16.13.01.02.16.01a F Affected Yes MRI ? O RT O 3 16.13.01.02.14.14a M Affected Presumably MRI 47 O C 4 16.13.01.02.14.05a F Affected Presumably MRI ? OC 5 16.13.01.02.01.02.03a F Affected No MRI 27 O O 6 16.13.01.02.18.10.01 F Affected Yes MRI/DSA 35 O OO 7 16.13.01.02.18.10.08 M Affected Yesb MRI 36 O OO 8 16.13.01.02.18.10.10 M Affected No MRI 33 O O 9 16.13.01.02.18.10.03 F Affected Yesb MRI 32 O O 10 16.13.01.02.18.10.05 F Affected No MRI 28 O C 11 16.13.01.02.18.06.06 M Affected No MRI 35 C C 12 16.13.01.02.18.06.02 M Affected No MRI 22 C 13 16.13.01.02.01.02.02 M Carrier No none - 14 16.13.01.02.18.10.11 F Carrier No MRI - 15 16.13.01.02.18.06.03 F Carrier No none - 16 16.13.01.02.18.08.06 M Carrier No MRI -

NOTE: All inherited the haplotype paternally and can thus be affected. Information is given on genetic status, imaging, tumor site(s), age of onset, and treatment. Carriers are those who inherited the disease gene paternally (at-risk, potentially affected) and showed no tumors on examination. Abbreviations: DSA, digital subtraction angiography; O, treated by operation; RT, treated with radiotherapy; C, followed conserva- tively; and Hx, by history. aPatients under treatment elsewhere. bSymptoms reported on screening.

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16.08 16.12 16.13

16.13.01

16.13.01.02

Figure 1: Pedigree of family 16.13.01.02 and related families described in previious publications.

Coding system: Every generation adds a new number. Female family members have odds number (1,3,4, etc.), male family members have even numbers (2,4,6, etc). Starting with number 1 or 2, depending on gender Male (female respectively male), continuing with 3 or 4, and so on. Female Not affected Patients 16.08.06, 16.08.16 , and 16.12.07 and their offspring are described in previous publication by van Baaars et al. ( → ) The pedigree shows the relation with family 16.13.01.02, both sharing the same ancestor, number 16, dating back to 1771. Affected Affected by hearsay Carrier Gene linkage analysis in patients 16.13.01.02.07, 16.13.01.02.05.10, and 16.13.01.02.16.03 aare inconclusive. Unknown Gene linkage inconclusive

Figure 1. Pedigree of family 16.13.01.02 and related families described in previous publications. Coding system: every generation adds a new number. Female family members have odd numbers (1, 3, 5, etc.); male family members have even numbers (2, 4, 6, etc.). Starting with number 1 or 2, depending on gender (female respectively male), continuing with 3 or 4, and so on. Patients 16.08.06, 16.08.08, 16.08.16, and 16.12.07 and their offspring are described in previous publications by van Baars et al. The pedigree shows the relation with family 16.13.01.02, both sharing the same ancestor, number 16, dating back to 1771. Gene linkage analysis in patients 16.13.01.02.07, 16.13.01.02.05.10, and 16.13.01.02.16.03 are inconclusive.

and jugulotympanic paraganglia for the remaining 12% was reported in 58% of all proven affected individuals. (n ¼ 3). Tumors at multiple sites (multifocality) were Their symptoms at presentation are summarized in Table 2. detected in all affected patients, with the exception of The average age at detection in the asymptomatic group was patient 12 (91%). HNPGL at other less common sites in at age 29 years (range: 22–35 years; n ¼ 5). In the group the head and neck region were not detected. presenting with symptoms, the average age of presentation/ The average age at onset of symptoms/detection was 33 onset was 38 years (n ¼ 4; range: 32–47; in 2, the age was years (range: 22–47 years). A symptomatic presentation unknown).

Table 2. Symptomatic and asymptomatic presentation (during screening) in all proven patients (n ¼ 12) Total

Presentation/detection Average age n (%) n (%) of tumors of detection

Symptomatic 38 Tumor noticed in neck (CBT) 4 (33.3) 7 (58) Conductive hearing loss (JTT) 1 (8.3) Unknown 2 (16.7) Asymptomatic 29 On ORL examination and imaging 1 (8.3) 5 (42) Imaging only (MRI, DSA) 4 (33.3) Total 12 (100) 12 (100)

Abbreviation: ORL: otolaryngological tumor.

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Table 3. Recognizable genotypic characteristics in the investigated PGL2 family and an overview of the test results Inheritance pattern Autosomal dominant trait with maternal imprinting.

Genetic aspects SDHAF2 (PGL2) Linkage SDHAF2 mutation analysis, n (%) analysis, n (%) Genetic investigation Negative 31 (55) 33 (58) Unknown 3 (5) - Positive 23 (40) 24 (42) Maternal inheritance 7 (30) 7 (29) Carrier, not affected Paternal inheritance 16 (70) 17 (71) At-risk carrier, potentially affected Total 57 (100) 57 (100)

Of the 24 detected tumors, 17 were treated surgically, demonstrated that the PLG2 families show the same inheri- 1 using radiotherapy and the remaining 6 were treated tance pattern (17, 18). In no case did a child of a female followed (imaging) closely but surgically untreated. Surgi- carrier develop disease, with all affected patients inheriting cal excision of 11 of these tumors was carried out at the the trait exclusively from their father. Radboud University Nijmegen Medical Centre (1 Vagal tumor, VT; 1 Jugulotympanicum tumor, JTT; 9 CBT), Gender distribution of affected offspring the 6 remaining were operated elsewhere and will not be The overall gender distribution of HNPGL patients subject of this article due to lack of information. No major shows a slight female predominance (female:male, technical problems were encountered during surgery. 60% vs. 40%; ref. 20). A PLG2 family was reported with Malignancy was not detected. Postoperative complications obvious male predominance (female:male, 33% vs. were encountered with 4 of the 11 operated tumors (36%). 77%), but only included clinically affected individuals In 3 patients, postoperative hypertension with related (3). In the novel family branch described here, there is symptoms was reported after unilateral CBT resection. an equal gender contribution between all individuals The complaints resolved after several months and sponta- neously normotension was eventually achieved in 2 patients and after drug treatment in 1. Table 4. Recognizable phenotypic characteris- Vagal nerve damage was reported in 1 patient after tics in the investigated PGL2 family removal of a carotid tumor. Speech therapy improved the voice within 1 year after resection and laryngoscopy Phenotypic characteristics n showed recurrence of mobility of the right vocal cord. SDHAF2 mutation analysis confirmed the findings of Gender distribution Equal distribution 16 the previously performed linkage analysis. No discrepan- (8:8) cies were detected. Of the 3 patients in whom linkage was Age of onset/ Average 33 9 inconclusive, 2 were tested negative. The third patient at detection, y (range: 22–47) risk for developing paraganglioma due to possible pater- At-risk carriers, 75% 16 nal inheritance, tested positive on PGL2 mutation analy- with detected tumors sis and will be further investigated and treated when Tumor localization Percentages 24 necessary (tumors) All the genotypic and phenotypic characteristics of this CBT 71% 17 PGL2 family are summarized in Tables 3 and 4. JTT 12% 3 VT 14% 4 Discussion Other sites 0% 0 Multifocality 91% 11 Inheritance pattern and genomic imprinting Malignancy Not detected 11 A large related Dutch PLG2 family was originally Presentation (patients) Percentages 12 described in 1981, and a pattern of autosomal dominant Asymptomatic 42% 7 inheritance and generation skipping was noted (19). In (on screening) 1989, a genomic imprinting hypothesis was proposed to Presenting with 58% 5 explain the striking lack of disease expression upon mater- symptoms nal inheritance in SDHD (PGL1) families (6) and we later

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at-risk for developing HNPGL (n ¼ 16). If we exclude the been performed, but is now part of the routine clinical at-risk individuals without tumors (carriers, at risk), the care. male:female ratio is calculated to be also an equal dis- n ¼ tribution ( 12). Struycken et al. reported that the sex Multifocality ratio among affected offspring appears to be influenced Another interesting aspect of hereditary paraganglioma is by the paternal or maternal origin of the gene of the tendency to be multifocal. Only 10% of sporadic the transmitting father (17). In our study, no such con- paragangliomas are multifocal, compared with incidences clusion could be drawn. of 70% to 87% in hereditary cases (23). van Baars et al. reported multifocality of tumors in only 50% in the first Presenting symptoms described PGL2 family (3, 19), in contrast to the present A symptomatic presentation is reported in only 58% family branch, with 10 of the 11 proven affected subjects of all affected individuals. The symptoms are summar- showing tumors at multiple sites (91%). This discrepancy ized in Table 2. The average age at detection of tumors may be a result of improved imaging techniques leading to in the asymptomatic group is 29 years (range: 22–35), detection of otherwise occult or symptomless tumors and which is below the average age at onset of symptoms/ hence higher multifocality of tumors. We anticipate that detection of the whole investigated family (33 years). multifocality increases during follow-up. These patients In the group presenting with symptoms, the average will be followed clinically and radiographically, which n ¼ age at presentation is 38 years ( 4, range: 32–47). may verify this assumption later on. The growth rate of paragangliomas is low, with a med- ian increase of 1 mm per year and a doubling time of 4.2 years (21). This is reflected in the time lag of Treatment 9 years to the development of clinical symptoms in this Of the patients treated operatively, postoperative com- family. plications, including postoperative hypertension, were reported in 4 of the 11 (36%) tumors (all CBT) operated Age at onset of symptoms/detection at the Radboud University Nijmegen Medical Centre that Patients with hereditary paraganglioma tend to resolved without sequelae. Hypertension is a known develop the disease at a younger age than those with complication bilateral carotid body resection and is sporadic paraganglioma. In a PGL2 family, an average attributed to a failure of the baroreflex. In the long term, age at onset of 37 years has been described (range 16 to the blood pressure may remain slightly elevated with 80 years; ref. 22). The average age at onset of symptoms/ markedly increased variability (24). The rates of post- detection in our family branch is 33 years (n ¼ 9). Only 2 operative morbidity and serious sequelae reported in genetically at-risk individuals, aged 24 and 39, were literature are in general higher than in our series (25). negative for tumors on MRI scanning. The term age at In our opinion, the low rates in our series justify the onset of symptoms/detection is used, because 42% of "wait-and-scan" policy often used at our medical centre, the tumors are detected in asymptomatic individuals leading to less operation of extensive tumors that would after screening. Clearly, active genetic screening and result in a higher complication and mortality percentages. advanced high-resolution imaging have led to the earlier Paraganglioma of the head and neck region are generally detection of otherwise occult or symptomless tumors, asymptomatic and slow-growing benign tumors. With consequently decreasing the age at onset of symptoms/ more sophisticated and precise imaging techniques at detection. We anticipate that with advances in imaging hand, the growth of these tumors and the association techniques and wider genetic screening for the SDHAF2 with surrounding tissues could be better assessed, giving mutation, the age at onset of symptoms/detection will us the opportunity to postpone or even avoid an opera- further decrease. tion. Prior to possible surgical intervention, a variety of issues should be taken into account including tumor Tumor localization growth, tumor localization, surrounding tissues, possible In the present family branch, CBTs are most common symptoms, age, condition, and the wishes of the patient. representing 71% of all tumors. This is in accordance Follow-up on the natural course of tumor development in with the literature (78%; ref. 3). JTTs were detected in these patients is ongoing to test this policy and to be 12% (n ¼ 3) and are relatively underrepresented com- published in due time. pared with values reported previously (17.5%; ref. 3). In contrast, VTs are overrepresented at 17% (n ¼ 4) com- Comparison with other hereditary HNPGL syndromes pared with Van earlier studies (4.5%). Only a larger study After establishing the genetic and clinical aspects of this of this pedigree would allow definite conclusions to be novel branch of the SDHAF2 family, a comparison with the drawnontherelationshipofSDHAF2 and tumor inci- other hereditary head and neck paraganglioma syndromes dence. As expected, tumors at other less common sites in could be made, as presented in Table 5. the head and neck region were not detected because they This comparison shows a young age at onset and early are very rare. Screening for thoracic and abdominal full penetrance. Mutifocality levels are high compared with paraganglioma and catecholamines secretion has not other HNPGL.

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Table 5. Comparison between the 4 hereditary HNPGL syndromes

PGL1 SDHAF2 (PGL2) PGL3 PGL4

Mutation SDHD (8) SDHAF2 (10) SDHC (9) SDHB (7) Genomic imprinting Yes (6) Yes (12) No (6) No (6) Average age of diagnosis, 36 (13–73) (27) 33 (22–47) 46 (21–66) (27) 39 (13–67) (27) y (range) Age related penetrancea (50%) 31 (27) 33 Unknown 35 (27) Percentage affected at age 50 86 (27) 100 Unknown 77 (27) Multifocality, % 30–74 (26) 91 Mostly solely (26) 12–18 (26) Adrenal Possible (27, 29, 31) Unknown Rare (31) Frequent (27, 31) HNPGL Very frequent (27, 31) Exclusively Very frequent (31) Frequent (27, 31) Extra-adrenal Possible (27, 31) Unknown Rare (31) Very frequent (27, 31) (thorax-abdomen-pelvis) Malignancy, % 0–7 (26–29) Not reported 4.5% (27, 30) 22%–84% (27, 31)

aAge-related penetrance; the percentage of gene carriers manifesting the signs or symptoms of the disease by a given age.

Conclusions Disclosure of Potential Conflicts of Interest

We established the SDHAF2 mutation status of PGL2 No potential conflicts of interest were disclosed. family members. Phenotypic characterization of this family SDHAF2 The costs of publication of this article were defrayed in part by the payment confirms the association of mutations with of page charges. This article must therefore be hereby marked advertisement in HNPGL. This family shows a young age at onset and a accordance with 18 U.S.C. Section 1734 solely to indicate this fact. high level of multifocality. A high percentage of patients Received May 20, 2010; revised July 27, 2010; accepted August 1, 2010; were asymptomatic at time of detection. published OnlineFirst January 11, 2011.

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254 Clin Cancer Res; 17(2) January 15, 2011 Clinical Cancer Research

SDHAF2 (PGL2-SDH5) and Hereditary Head and Neck Paraganglioma

Henricus P.M. Kunst, Martijn H. Rutten, Jan-Pieter de Mönnink, et al.

Clin Cancer Res 2011;17:247-254. Published OnlineFirst January 11, 2011.

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