Should genetic testing be performed in each patient with sporadic pheochromocytoma at presentation?
ABSTRACT According to previous studies, around 15% of patients with an apparently sporadic pheochromocytoma and a negative family history had a hereditary disease. This high frequency together with the financial support provided to reference laboratories of molecular genetics by the French government led to a nearly systematic screening in each patient with a pheochromocytoma.
To check the efficiency of systematic genetic screening in patients with apparently sporadic pheochromocytoma, by analysing the 6 years experience of a multidisciplinary team in this field.
One hundred patients with a pheochromocytoma-only phenotype and no family history were included. Patients with extra-adrenal tumours were excluded. Prevalence of hereditary forms was determined and analyzed according to age at onset, sex. Cost of the genetic analysis was calculated.
A germline mutation in one of the five susceptibility genes (VHL, RET, SDHD, SDHC, SDHB) was identified in eight patients (8%) with an age of onset between 13 and 57 years. Among them, six had a bilateral pheochromocytoma and only two had a unilateral tumour. If the guidelines for genetic screening were age of onset less than 50 or bilateral pheochromocytoma, no patients with a hereditary tumour would be missed and a 24% cost reduction would be achieved.
According to these data, a genetic predisposition test for hereditary pheochromocytoma seems not recommended in patients with a unilateral adrenal tumour diagnosed after 50 in the absence of familial, clinical, biological or imaging features for a familial disease.
Article: Pheochromocytoma: A review.[Show abstract] [Hide abstract]
ABSTRACT: Pheochromocytomas are catecholamine producing neuroendocrine tumors that can be adrenal or extra-adrenal in origin. The classic symptoms of pheochromocytoma are headache, palpitation, anxiety and diaphoresis and the tumor can occur at any age with equal gender distribution. In patients with an established mutation or hereditary syndrome the condition may manifest at a younger age than in those with sporadic disease. Pheochromocytoma can be associated with certain genetic syndromes such as multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis (NF) and von Hippel-Lindau (VHL) syndrome. Pheochromocytoma is diagnosed with biochemical confirmation of hormonal excess followed by anatomical localization (CT or MRI). The mainstay of definitive therapy is surgical resection. In this review, we discuss in detail about the symptomatology, diagnosis, genetic aspects and management of pheochromocytoma.Maturitas 01/2014; · 2.84 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Genetic testing of tumor susceptibility genes is now recommended in most patients with pheochromocytoma or paraganglioma (PPGL), even in the absence of a syndromic presentation. Once a mutation is diagnosed there is rarely follow-up validation to assess the possibility of misdiagnosis. This study prospectively examined the prevalence of von Hippel-Lindau (VHL) gene mutations among 182 patients with non-syndromic PPGLs. Follow-up in positive cases included comparisons of biochemical and tumor gene expression data in 64 established VHL patients, with confirmatory genetic testing in cases with an atypical presentation. VHL mutations were detected by certified laboratory testing in 3 of the 182 patients with non-syndromic PPGLs. Two of the 3 had an unusual presentation of diffuse peritoneal metastases and substantial increases in plasma metanephrine, the metabolite of epinephrine. Tumor gene expression profiles in these 2 patients also differed markedly from those associated with established VHL syndrome. One patient was diagnosed with a partial deletion by Southern blot analysis and the other with a splice site mutation. Quantitative polymerase chain reaction, multiplex ligation-dependent probe amplification, and comparative genomic hybridization failed to confirm the partial deletion indicated by certified laboratory testing. Analysis of tumor DNA in the other patient with a splice site alteration indicated no loss of heterozygosity or second hit point mutation. In conclusion, VHL germline mutations represent a minor cause of non-syndromic PPGLs and misdiagnoses can occur. Caution should therefore be exercised in interpreting positive genetic test results as the cause of disease in patients with non-syndromic PPGLs.Hormone and Metabolic Research 03/2012; 44(5):343-8. · 2.15 Impact Factor
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ABSTRACT: CONTEXT: Germline mutations in four genes (RET, VHL, SDHB and SDHD) are detected in about 17% of patients with apparently sporadic pheochromocytoma. Thus, genetic screening of all patients with this disease is suggested for a rational diagnostic approach and management. OBJECTIVE: To report the clinical, biochemical and genetic analysis of three unrelated patients affected by pheochromocytoma. DESIGN AND PATIENTS: All the coding regions and exon-intron boundaries of RET, VHL, SDHB and SDHD genes were sequenced in three unrelated patients with intra-adrenal pheochromocytoma: a 17 year-old female, a 15 year-old boy and a 73 year-old man. The family history of all three cases was negative for von Hippel-Lindau lesions or other types of endocrine tumours. Structural modelling of the VHL protein was then performed. RESULTS: We identified a novel germ-line VHL gene point mutation, a G to A nucleotide substitution in exon 3, leading to an aspartate to asparagine amino acid change in codon 197 (D197N). No mutations were found in RET, SDHB and SDHD genes. Structural modelling of the VHL protein suggests that the D197N mutation could have a functional role. CONCLUSIONS: Our study expands the number of VHL gene known mutations and indicates the usefulness of performing the genetic analysis in all patients with apparently sporadic pheochromocytoma. © 2012 Blackwell Publishing Ltd.Clinical Endocrinology 09/2012; · 3.40 Impact Factor
Should genetic testing be performed in each patient with
sporadic pheochromocytoma at presentation?
Pascal Pigny, Catherine Cardot-Bauters1, Christine Do Cao1, Marie Christine Vantyghem1, Bruno Carnaille2,
Franc ¸ois Pattou2, Philippe Caron3, Jean-Louis Wemeau1and Nicole Porchet
Laboratoire de Biochimie ‘Hormonologie, Me ´tabolisme-Nutrition, Oncologie’, Centre de Biologie et Pathologie, CHRU de Lille, France,1Service
d’Endocrinologie et Me ´tabolismes, Clinique Marc Linquette, CHRU de Lille, 59037 France,2Service de Chirurgie Endocrinienne, Ho ˆpital Claude Huriez,
CHRU de Lille, France and3Service d’Endocrinologie et Maladies Me ´taboliques, Ho ˆpital Larrey, CHU de Toulouse, 31059 France
(Correspondence should be addressed to P Pigny; Email: email@example.com)
Background: According to previous studies, around 15% of patients with an apparently sporadic
pheochromocytoma and a negative family history had a hereditary disease. This high frequency
together with the financial support provided to reference laboratories of molecular genetics by the
French government led to a nearly systematic screening in each patient with a pheochromocytoma.
Objective: To check the efficiency of systematic genetic screening in patients with apparently sporadic
pheochromocytoma, by analysing the 6 years experience of a multidisciplinary team in this field.
Methods: One hundred patients with a pheochromocytoma-only phenotype and no family history were
included. Patients with extra-adrenal tumours were excluded. Prevalence of hereditary forms was
determined and analyzed according to age at onset, sex. Cost of the genetic analysis was calculated.
Results: A germline mutation in one of the five susceptibility genes (VHL, RET, SDHD, SDHC, SDHB)
was identified in eight patients (8%) with an age of onset between 13 and 57 years. Among them, six
had a bilateral pheochromocytoma and only two had a unilateral tumour. If the guidelines for genetic
screening were age of onset less than 50 or bilateral pheochromocytoma, no patients with a hereditary
tumour would be missed and a 24% cost reduction would be achieved.
Conclusions: According to these data, a genetic predisposition test for hereditary pheochromocytoma
seems not recommended in patients with a unilateral adrenal tumour diagnosed after 50 in the
absence of familial, clinical, biological or imaging features for a familial disease.
European Journal of Endocrinology 160 227–231
Pheochromocytomas are rare catecholamine-produ-
cing tumours that arise from chromaffin cells of the
adrenal medulla. They are closely linked to paragan-
gliomas that develop from others extra-adrenal neural
crest derived cells such as parasympathetic or sym-
pathetic paraganglia (1). However, pheochromocyto-
mas are more commonly recognized because clinicians
often focus on adrenal glands as the main source of
Until 1999, only 10% of all pheochromocytomas were
considered as hereditary tumours, and were part of
multiple tumour syndromes such as multiple endocrine
neoplasia type 2 (due to a germline mutation of the
RET proto-oncogene), von Hippel–Lindau disease (VHL
tumour-suppressor gene) or neurofibromatosis type 1
(NF1 tumour-suppressor gene) that are inherited on an
autosomal-dominant mode. In the early 2000s, new
susceptibility genes for hereditary pheochromocytomas
and/or paragangliomas were discovered. These genes
named SDHD, SDHB and SDHC encode three of the four
protein subunits of the succinate dehydrogenase (SDH)
least six susceptibility genes for familial pheochromocy-
tomas are now known (a number that could still expand
data from the bench to the bedside has allowed
re-evaluation of the true prevalence of hereditary forms
of these adrenal tumours. Thus, in 2002, Prof Neumann
from Freiburg University first demonstrated, by perform-
ing genetic testing in a cohort of 271 patients who
presented apparently sporadic pheochromocytoma (in
fact 241 with isolated pheochromocytoma), that about
24% of the patients did harbour a germline mutation of
RET, SDHD, VHL or SDHB thus revealing a hereditary
syndrome (4). However, exclusion of patients with a
positive family history would decrease the rate of
hereditary forms to 15.5% (4). In 2003, we reported a
similar prevalence(15%) by studyingsimultaneously five
susceptibility genes (the former and SDHC) in 13 index
cases (5). At the same time in France, President J. Chirac
improve the access to genetic testing by providing a
European Journal of Endocrinology (2009) 160 227–231 ISSN 0804-4643
q 2009 European Society of EndocrinologyDOI: 10.1530/EJE-08-0574
Online version via www.eje-online.org
financial support to a network of reference laboratories
specialized in molecular oncogenetics through the
support) explain that, in the last 5 years, genetic
predisposition testing was nearly systematically proposed
and done in each patient with a non-syndromic
pheochromocytoma, at least in specialized medical
centres. Our aim was to evaluate the efficiency of this
systematic approach by analysingour 6 years experience
were especially interested in the sensitivity and cost of
systematic genetic testing. To get accurate guidelines, we
decided to focus on patients with only pheochromocy-
paraganglioma, as frequently done in the literature (6).
Research design and patients
In our medical centre, all patients with an apparently
sporadic pheochromocytoma or paraganglioma (surgi-
cally removed and pathologically confirmed) had a
skill in oncogenetics or a geneticist with a specific skill in
endocrine tumours. Only patients who gave their signed
informed consent for genetic testing were studied at the
germline level. During the last 6 years (2002–2007) one
hundred and forty index cases were recruited. Since our
aim was to focus on patients with an apparently sporadic
pheochromocytoma, we thus decided to exclude the 22
patients who suffered from an extra-adrenal abdominal
paraganglioma first. Then we also excluded five patients
who had a pheochromocytoma and a paraganglioma,
eight patients with a pheochromocytoma and a positive
familial history of adrenal tumour by inquiry and five
history of von Hippel–Lindau disease by inquiry. There-
fore, the sample analyzed here comprised of 100 patients
who had either one or two non-syndromic pheochromo-
cytoma without a positive familial history, without any
other endocrine tumours, without any clinical signs for
von Hippel–Lindau disease, MEN type 2 or neurofibro-
radiological investigations proposed in Table 1. In this
cohort of patients, pheochromocytoma was unilateral in
92 cases and bilateral in eight patients.
Genetic testing was proposed and performed once the
patient gave his/her informed consent to do so either on
his/her DNA or on those or her/his affected minor child.
Genetic analysis consists in the search of germ line
mutation of VHL, SDHB, SDHD, SDHC (all coding exons
and intron-exon junctions are investigated) or RET (only
exons 10, 11, 15and 16 are studied) by PCR-sequencing
on both strands of DNA, as previously described (5). For
in the medical literature and/or ii) it was recorded in
international genetic databases such as human gene
mutation database or LOVD (7). By contrast, mutation
was classified as not clearly pathogenic (nucleotide
variant) if the available data were not convincing (new
mutation without any functional study such as those
or if its status was controversial in the literature (for
example VHL P25L variant (8)). For patients with
bilateral pheochromocytoma who were mutation
negative, a search for a deletion of VHL or SDHs was
carried out by multiplex PCR or/and multiplex-ligation
dependent probe assay (MLPA) respectively. The labora-
tory participates in the proficiency testing organized by
the European Molecular genetics Quality Network–DNA
sequencing scheme) and to the quality assurance testing
organized by the French network of molecular biology
laboratories working on endocrine tumours (GTE).
A pathogenic germline mutation in one of the five
susceptibility genes was found in eight patients (8%),
who revealed their pheochromocytoma between 13 and
57 years. There were four males and four females.
As shown in Table 2, six patients had a bilateral
pheochromocytoma due to a RET mutation (three
unrelated cases), a VHL mutation (one case), a SDHD
splice mutation (one case) or a partial deletion of SDHB
Table 1 Clinical features to be searched to identify a familial pheochromocytoma.
Disease Clinical investigation Biological investigationImaging data
MEN-2 Thyroid nodule
Serum calcium, phosphate and PTH
VHLAbdominal CT scan
Renal cysts or clear cell carcinomas
Pancreatic cysts or endocrine tumours
NF1 Cafe ´-au-lait spots
Iris hamartomas (Lisch nodules)
P Pigny and others
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160
(one case). Two patients had a unilateral pheochromo-
cytoma due to a SDHD or a VHL mutation. Moreover,
the last two patients of this cohort with a bilateral
pheochromocytoma who were mutation negative did
not harbour a partial or complete deletion of VHL,
SDHD, SDHB or SDHC. Eight patients (8%), with a
unilateral pheochromocytoma occurring between 24
and 70 years, had a non-clearly pathogenic nucleotide
variant. In four cases, this variant was a -7GOT
nucleotide change in the proximal NRF-2 cis-regulatory
element of SDHB promoter. Relationships between
prevalence of the familial forms and age at discovery
are shown in Table 3.
As already shown in previous studies (4, 5) the younger
the age at onset of pheochromocytoma, the higher the
prevalence of hereditary tumours. On the contrary, the
prevalence strongly decreases when age at onset is
above 20 and becomes null when the age at discovery is
strictly higher than 60. Sample size of the subgroups
was, however, too small to perform a statistical analysis.
Based on these prevalence data, if we had decided not to
perform genetic testing in cases with an age of discovery
strictly above 50, we would have lost one patient with a
hereditary tumour (sensitivityZ87.5%) but have saved
32 useless genetic tests. If the age limit was set at 40, we
would have lost four patients with a true familial
tumour, and thus decreased the sensitivity to 50%. It
should also be stressed that six (75%) out of the eight
patients with a bilateral pheochromocytoma had a
hereditary form instead of only two (2.2%) out of the 92
ones with a unilateral tumour. Therefore, if the decision
criteria for genetic testing were age at onset less than 50
or bilateral pheochromocytoma, no patient with a
hereditary tumour would be missed.
In our cohort of patients, only 8% had a familial pheo-
chromocytoma, a frequency strongly lower than the
This number is indeed also lower than the 12.7%
prevalence recently reported by the European network
patients with an apparently sporadic pheochro-mocy-
toma or a functional paraganglioma (6). However, our
data fit well with those recently published by the French
National Cancer Institute (INCa) in its 2002–2006
on the 314 index cases who had a germline analysis of
VHL and SDHB, and therefore probably harboured a
pheochromocytoma, only 7% had a germline mutation.
Who should benefit from genetic testing?
Since 2002, the guidelines for genetic testing in patients
with an apparently sporadic pheochromocytoma have
performance of a genetic predisposition test to familial
pheochromocytoma if i) the tumour is discovered before
20 years, ii) the pheochromocytoma is bilateral or iii) in
case of an extra-adrenal pheochromocytoma with
catecholamine synthesis. Based on the data reported
here, one can notice that all these clinical situations are
characterized by a high prevalence of familial forms
varying from between 33 and 75%. More importantly,
these American authors considered as useless or not
justified the performance of genetic testing if age at
lower: only 3% in our cohort of patients, 1.3% according
to the analysis of Gagel and coworkers (10). Between 20
and 50 years, genetic testing is considered as optional,
notably if the patient had no clinical signs in favour of a
syndromic pheochromocytoma. In contrast, the
European practice still considered that genetic testing
should be systematic in every patient with either a
pheochromocytoma or a paraganglioma (6). These
authors recommend to select the genes to be screened
Table 2 Clinical data of the patients with a hereditary phaeochromocytoma.
Patient number Age at onset (years) Sex (M/F)Germ line mutationUnilateral/bilateral phaeochromocytoma
SDHB exons 7–8 deletion
Table 3 Influence of the age at presentation on the prevalence of hereditary pheochromocytomas.
Age of onset (years)0–10 11–20 21–3031–4041–5051–60
Patients with a germline mutation
Prevalence of hereditary pheos (%)
Genetic testing in pheochromocytoma
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160
according to the clinical presentation and suggested
analysis of SDHB and VHL in first intention in these
recommended by the experts attending the first inter-
national symposium on pheochromocytomas (11).
The cost of the genetic test should also be
Health has no price but is a cost to the whole society. In
France, genetic predisposition tests to hereditary cancers
are performed in reference laboratories and are not
charged to the patients because those labs received a
the cost of these tests could be evaluated using a method
proposed by the French association of molecular geneti-
cost of each genetic test by adding the individual costs of
each technical step performed, for example DNA extrac-
tion plus PCR-sequencing of each exon on both DNA
strands. According to this method, the cost for searching
for a germline VHL mutation by nucleotide sequencing
exon 10, 11, 15 or 16) 270 euros, and for a complete
analysis of the 3 SDH genes is 1250 euros. Therefore, the
cost of a complete genetic analysis of these five
susceptibility genes by nucleotide sequencing is around
1755 euros. This cost does not include the search of
complex molecular events not detected by nucleotide
sequencing such as deletion(s)/insertion(s) or gene
rearrangements. As shown in Fig. 1, we performed a
cost analysis to compare two algorithms, systematic
genetic testing versus target genetic testing. The first
algorithm(consultation and systematicgenetictesting)is
those presently used in our medical centre. The second
algorithm consists of testing only the patients who
revealed their pheochromocytoma before 50 or/and had
a bilateral tumour. This approach thus required a more
detailed clinical survey to select the patients who will be
eligible for genetic testing. Applying this algorithm would
using this approach, and based on our experience, no
patients with a germ line mutation would be missed.
Could we propose guidelines for
performing genetic predisposition tests?
Our aim is to propose guidelines that could be easily
implanted in order to optimize our financial support. We
believe that an intermediate statement could be
proposed between the ‘European’ systematic screening
and the ‘American’ restrictive screening. According
to us, a genetic predisposition test for hereditary
– should be performed in all patients with an age of
onset less than 20 (prevalence of hereditary forms:
33.3%) or with a bilateral pheochromocytoma
– is strongly recommended in patients with an age of
onset less than 50 (cumulative prevalence: 10.4%);
– is not recommended in patients with a unilateral
Figure 1 Cost analysis of the two algorithms, systematic genetic analysis (upper part) and clinically guided genetic analysis (lower part)
meaning that only patients with an age of onset less than 50 or a bilateral pheochromocytoma will be eligible for genetic testing. For easier
calculations, the costs were calculated for a sample of 100 patients. The clinically guided genetic testing would lead to a 42.700 euros cost
reduction for 100 patients attending the outpatient visit. *Cost of abdominal CT-scan excluded.
P Pigny and others
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160
pheochromocytoma diagnosed after 50 for whom
imaging data (performed as recommended in Table 3
and in (12)) are in favour of a familial disease. The
occurrence of one new event during the patient’s
follow-up (that is systematic in our medical centre for
every patient with a pheochromocytoma) would lead
to reconsideration of the necessity of genetic testing.
In conclusion, genetic testing may help to predict for
a patient the risk of multifocal tumours and/or
malignancy, and to identify at risk relatives early.
Nevertheless, we believe that the best strategy in
terms of efficiency and cost has to modulate the use of
genetic testing by clinical experience.
Declaration of interest
The contributing authors declare that there is no conflict of interest
that could be perceived as prejudicing the impartiality of the research
This research did not receive any specific grant from any funding
agency in the public, commercial or not-for-profit sector.
We thank the following clinicians for their support and for providing
clinical information: Drs O Verier-Mine, V Degros, M Ladsous (CH
Valenciennes), Y Reznik, M Joubert (CHU Caen), R Desailloud (CHU
Amiens), R Leroy, C Siame & J P Cappoen (Lille).
1 Lewis CE & Yeh MW. Molecular Genetics and Metabolism 2008 94
2 Dahia PL. Evolving concepts in pheochromocytoma and para-
ganglioma. Current Opinion in Oncology 2006 18 1–8.
3 Schlisio S, Kenchappa RS, Vredeveld LCW, George RE, Stewart R,
Maris JM, Look T, Meyerson M, Peeper DS, Carter BD & Kaelin WG.
The kinesin KIFB acts downstream from EglN3 to induce apoptosis
and is a potential 1p36 tumor suppressor. Genes and Development
2008 22 884–893.
4 Neumann HP, Bausch B, McWhinney SR, Bender B, Gimm O,
Januszewic A & Eng C. Germline mutations in nonsyndromic
pheochromocytoma. New England Journal of Medicine 2002 346
5 Bauters C, Vantyghem MC, Leteurtre E, Odou MF, Mouton C,
Porchet N, Wemeau JL, Proye C & Pigny P. Hereditary phaeochro-
mocytomas and paragangliomas: a studyoffive susceptibilitygenes.
Journal of Medical Genetics 2003 40 e75.
6 Gimenez-Roqueplo AP, Lehnert H, Mannelli M, Neumann H,
Opocher G, Maher ER & Plouin PF. Phaeochromocytoma, new
genes and screening strategies. Clinical Endocrinology 2006 65
7 Bayley JP, Deville P & Taschner PE. The SDH mutation database:
an online resource for succinate dehydrogenase sequence
variants involved in pheochromocytoma, paraganglioma and
mitochondrial complex II deficiency. BMC Medical Genetics 2005
8 Patocs A, Gergics P, Balogh K, Toth M, Fazakas F, Liko O & Racz K.
Ser80Ile mutation and a concurrent Pro25Leu variant of the VHL
gene in an extented Hungarian von Hippel–Lindau family. BMC
Medical Genetics 2008 9 29.
9 Synthe `se Nationale de L’e ´volution de L’activite ´ D’oncoge ´ne ´tique
2003–2006. Institut National du Cancer, Mars 2008.
10 Jimenez C, Cote G, Arnold A & Gagel RF. Should patients with
apparently sporadic pheochromocytomas or paragangliomas be
screened for hereditary syndromes? Journal of Clinical Endo-
crinology and Metabolism 2006 91 2851–2858.
11 Pacak K, Eisenhofer G, Ahlman H, Bornstein SR, Gimenez
McNicol AM & Tischler AS. Pheochromocytoma: recommen-
dations for clinical practice from the first International Sym-
posium. Nature Clinical Practice. Endocrinology & Metabolism 2007
12 Pawlu C, Bausch B, Reisch N & Neumann HPH. Genetic testing for
pheochromocytoma-associated syndromes. Annales d’Endocrinologie
2005 66 178–185.
Received 17 November 2008
Accepted 19 November 2008
Genetic testing in pheochromocytoma
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160