REVIEWNew genetic causes of pheochromocytoma:
current concepts and the clinical relevanceHartmut P.H. Neumann,1 Markus Cybulla,1 Hirotaka Shibata,2 Mototsugu Oya,3 Mitsuhide Naruse,4Eiji Higashihara,5 Toshiro Terachi,6 Hao Ling,1,7 Hiroshi Takami,8 Taro Shuin9 and Masaru Murai3
1Department of Medicine, Albert-Ludwigs-University, Freiburg, Germany, 2Department of Endocrinology,
Health Center and Department of Internal Medicine, 3Department of Urology, School of Medicine,
Keio University Tokyo, 4Department of Endocrinology, Kyoto Medical Center, Kyoto, 5Department of Urology,
Kyorin University, Tokyo, 6Department of Urology, Tokai University, Kanagawa, Japan, 7Department of Medicine
Tongji Hospital, Tongji University, Shanghai, China, 8Department of Surgery, Teikyo University, Tokyo
9Department of Urology, Kochi Medical School, Kochi, Japan(Received for publication on September 1, 2004)(Revised for publication on December 7, 2004)(Accepted for publication on December 16, 2004)

Abstract. Pheochromocytoma and paraganglioma are tumors of the autonomous nervous system
mainly occurring in the adrenal medulla, but also in the extraadrenal paraganglias of the abdomen,thorax, neck and skull basis. The etiology comprises germline mutations of now 6 genes. About 10
years known are the RET gene susceptible for multiple endocrine neoplasia type 2, the VHL gene forvon Hippel-Lindau Disease, and the NF 1 gene for neuroﬁbromatosis Recklinghausen (neuroﬁbromatosis type 1). Since 2000 the genes for succinatedehydrogenase subunits SDHB, SDHC, andSDHD have been identiﬁed for paraganglioma syndromes type 4, type 3, and type 1 respectively.
Investigations of series of pheochromocytoma patients identiﬁed germline mutations in one of thegenes SDHB, SDHD, VHL and RET in 24% to 50% of the patients. Multifocal tumors, young age andpositive family history, known features associated with inheritence, have not been present in all
patients. Therefore, analyses of blood DNA for mutations in these genes are recommended. Positive
tests provide the patients and their relatives with essential platforms for clinical care. Experiencesin this ﬁeld of medicine have shown that optimal management of patients with pheochromocytomaassociated syndromes is a high challenge. National registries may be instrumental in order to provide
with adequate facilities. (Keio J Med 54 (1): 15–21, March 2005)
Key words: pheochromocytoma, paraganglioma, paraganglioma syndromes, genes of succinatedehydrogenase subunits B, genes of succinatedehydrogenase subunits D

hypertension (17%), mortality rate (15%) and recurrence (6%) are associated with malignancy.3 Thesefeatures are worth to consider reevaluation of patientswith pheochromocytoma under the aspect of risk factors, such as underlying inheritance, germline mutationsof susceptibility genes, and associated disorders.

Introduction
Pheochromocytoma and paragangliomas are theterms for tumors of the autonomous nervous system.
We use the term pheochromocytoma for hormonallyactive tumors mainly located in the adrenals, butsometimes in paraganglias of the retroperitoneum or
thorax. In contrast, paraganglioma is used for nonsecreting tumors, mostly located in paraganglias of theneck and skull basis.1,2
A Japanese study at 2000 revealed that high rates ofSyndromes Associated with Pheochochromocytoma
First, thyroid C cell tumors and pheochromocytoma
form multiple endocrine neoplasia type 2 (MEN 2), a

Presented at the 1351st Meeting of the Keio Medical Society in Tokyo, May 25, 2004
Hartmut P.H. Neumann is supported by grants of the Deutsche Forschungsgemeinschaft (German Research Foundation, Ne 571/5-1 and
571/4-4) and the Deutsche Krebshilfe (German Cancer Aid Foundation 30-3313-Ne 1)
Reprint requests to: Prof. Dr. Hartmut P.H. Neumann, Department of Nephrology and Hypertension, Medical Clinic, Hugstetterstr. 55,
D 79106 Freiburg i.B., Germany, Telephone: þ49 761 270 3578, Facsimile: þ49 761 270 3778, e-mail: Neumann@mm41.ukl.uni-freiburg.de15

16

Neumann HPH, et al: New genetic causes of pheochromocytoma

MEN 2

MTC
+
Pheo

Medullary Thyroid Carcinoma

RETGene#10q11.2
21 Exons

Fig. 1 Multiple endocrine neoplasia type 2 in a 44 year old female patient. Multifocal (bilateral) medullary thyroid carcinoma shown by MIBG
scintigraphy and operation specimen (arrows; arrow heads indicate the tissue bridge). Bilateral adrenal pheochromocytoma shown by MIBG,
CT, and operation specimens (arrows indicate the tumors).

disorder based on germline mutations of the RET gene(Fig. 1). The mutations predisposing to pheochromocytoma are located in exons 10, 11 and 16.4 In Japan,
a large series comprising 48 kindreds with MEN 2revealed a sensitivity of 97% detection rate of thegermline mutations.5
Second, pheochromocytoma is a component of vonHippel-Lindau disease (VHL) together with hemangioblastomas of the eyes, the cerebellum, the brain stemand the spinal cord, as well as tumors and/or cysts of thekidneys and the pancreas6 (Fig. 2). In the kidneys thesetumors are clear cell carcinomas and in the pancreas
islet cell tumors.7 Some VHL patients have only pheochromocytoma. Pathogenetically relevant are mutationsof the VHL gene. More than 300 different VHL mutations have been described, and those associated withpheochromocytoma are nearly all of missense type.8
Experiences from Japan including four VHL patients

Bilateral Pheochromocytoma and Bilateral Renal Carcinomas and Cysts

Other Lesions:
Retinal Angiomas
CNS Hemangioblastomas
Von Hippel-Lindau Disease VHL Gene #3p25-26 3 ExonsFig. 2 Bilateral adrenal pheochromocytoma and bilateral, multifocal,
in part cystic renal cell carcinoma in a 36 year old male patient withvon Hippel-Lindau disease.

Keio J Med 2005; 54 (1): 15–21A

17

33 yr old female
patient with themutation
SDHD R38X

B

C
Fig. 3

Bilateral adrenal pheochromocytoma shown by MRI in coronal and axial projection in a patient with neuroﬁbromatosis type 1.

with pheochromocytoma have been reported in 1995.9
In addition, in 2002 77 families, including 15 withpheochromocytomas have been moleculargeneticallyanalyzed. The overall detection rate was 73%, but infamilies with pheochromocytoma even 93%.10
Third, pheochromocytoma is associated with vonRecklinghausen’s neuroﬁbromatosis in about 1–5% ofsuch patients (Fig. 3). The susceptibility gene is NF
1.11,12Nowadays well recognized are patients with paraganglioma syndrome (PGL) (Fig. 4). The term wascreated on the observation of families with several
patients developing tumors of paraganglias of the neckand skull basis. In 2000 the link of such families witha gene localized in the chromosomal area on chromosome 11q23, the SDHD gene, was elucidated.13,14 The
gene encodes a subunit (subunit D) of succinate dehydrogenase (SDH). The enzyme plays a key role in twoelementary biochemical pathways, the respiratory chain
and the tricarboxylic acid – or Krebs cycle.
SDH consist of subunits A–D, and SDHD was ﬁrst
identiﬁed to be alterated in PGL. This is now named
PGL1. Subsequently we showed that non MEN 2 – non

VHL – non NF 1 pheochromocytoma patients could be
identiﬁed as SDHD mutation carriers.15 Soon later
mutations in the SDHB gene (SDH subunit B) havebeen described in patients with paragangliomas andin such with pheochromocytoma.16 Finally, in a small
subset of paraganglioma patients mutations in the
SDHC gene have been described.17 – 20
Now we distinguish 4 types of PGL, namely type 1(associated with mutations of SDHD), type 4 (SDHB),
type 3 (SDHC ) and type 2 (gene unknown). In contrast
to MEN 2 and VHL, families with SDHx (B, C and D)
mutations are increasingly recognized but still rare.
Therefore, the following data must be handled carefully.
Among all pheochromocytomas more than 25% can
be attributed to one of the 6 syndromes (MEN 2, VHL,
NF 1, PGL 1, 3, and 4) based on mutations of RET,
VHL, SDHB, SDHC and SDHD or clinically to NF 1.
We showed this for the genes RET, VHL, SDHB andSDHD in 271 non related index cases with pheochromocytomas.21 Not included have been the NF 1 cases.
Further, not included have been the relatives of index
cases, a considerable number depending by size of the

18

Neumann HPH, et al: New genetic causes of pheochromocytoma

Neurofibromatosis Type 1 - Morbus Recklinghausen

NF1 Gene #17q11 59 ExonsFig. 4 Paraganglioma syndrome type 1 (associated with a germline
mutation of the SDHD gene) in a 33 year old female patient; rightadrenal pheochromocytoma shown by CT (A), and left sided upper
thoracic paraganglioma in the sympathetic trunc shown by CT (B)and MRT (C).

families and the area where they live. We showed thatmost hereditary pheochromocytoma patients have VHL
mutations followed by RET, SDHD and SDHB. Meanwhile a French series showed a frequency of 50% of
germline mutations in an unselected series of pheochromocytoma patients which also included a priori
familial cases.19
Major Clinical Features of Presentation of
Pheochromocytoma
Age at presentation is much younger in hereditary
than in sporadic pheochromocytoma, with an averageof nearly 20 years difference. Mean age seems to be in
VHL the lowest followed by PGL type 1 and 4, MEN 2
and NF 1. However, patients with germline mutationsof one of the discussed genes may become symptomatic
after the age of 60.21
Location
The adrenals are the preferent location for all
hereditary pheochromocytomas. Nearly exclusively affected, however, are the adrenals in MEN 2.
Extraadrenal paragangliomas are found in about
50% of the PGL 4 patients followed by 45% in thosewith PGL 1 and 22% with VHL. Thus, extraadrenal
location is statistically an attitude of heredity.21
The thorax is a unique area of location of pheochromocytoma. Only 1% of pheochromocytomas are locatedhere. Most thoracic tumors (30%) are associated with
mutations of SDHD followed by VHL (3%).
Paragangliomas of the neck and skull basis are characteristics of carriers of SDHx mutations. Only somevery single cases have been reported in VHL and alsoin MEN 2.22 – 25 Clear differences for affected paraganglia in PGL 1 vs PGL 3 or PGL 4 are unknown.
Multifocal pheochromocytoma is a difﬁcult term,since tumors may be detected simultaneously or arise
as de novo lesions with various time intervals up to
decades. Multifocal location, a striking feature forheredity is absent in many cases associated with any
syndrome. Multifocal pheochromocytoma occur mostoften in MEN 2 followed by VHL, PGL 1 and PGL 4.21
Malignancy has been regarded as a typical biologicalbehaviour of sporadic pheochromocytoma. About 5–
10% of sporadic pheochromocytomas are malignant.
Recently, it was recognized that a considerable percentage of carriers of SDHB mutations have malignant
tumors26 whereas this is very seldom in VHL, exceptional in MEN 2 and not reported in PGL 1.
The knowledge about old and new cases of pheochromocytoma must be discussed in 4 major aspects.
1) How to do genetic analyses?
2) How to diagnose clinically pheochromocytoma/paraganglioma?
3) How to treat patients with pheochromocytomas and/or paragangliomas?
4) How to care for the patient and his family?
Informations regarding these complex features are
given in Tables 1, 2, 3.
Moleculargenetic Analyses
In a given patient, mutations occur only in one
pheochromocytoma susceptibility gene. Therefore, themost likely mutated gene should be analysed ﬁrst. Key
informations can be drawn from family history regarding occurrence of pheochromocytoma and/or paraganglioma and other rare tumors or lesions typical forone of the syndromes. If these are unknown, it would
be wise to do tests for germline mutations neverthelessfor several reasons. 1st: New mutations are well documented in patients with pheochromocytoma for VHLor RET. 2nd: In VHL, mutation carriers may only develop pheochromocytomas. 3rd: The parental generation can carry the mutation, but may not express thedisease. This is possible according to three phenomenons. One is that tumors may be asymptomatic lifelong.

Keio J Med 2005; 54 (1): 15–21
Table 1

19

Classiﬁcation of Pheochromocytoma
VHL Von
Hippel-Lindau
DiseaseMEN 2 Multiple
Endocrine
Neoplasia
Type 2

NF 1
Neuroﬁbromatosis
Recklinghausen(Type 1)

PGL 1

PGL 3

PGL 4

Gene

VHL

RET

NF 1

SDHD

SDHC

SDHB

Chromosomal
Locus

3p25–26

10q11.2

17q11

11q23

1q21–23

1p23–25

Exons

3

21

59

4

6

8

Hot Spotsnoyes

unknownnono

unknown

TypicalTumor
Location

Adrenal andextraadrenal,
abdominal,
seldom thoracic

AdrenalAdrenal andextraadrenal
abdominal

Adrenal,extraadrenal,
abdominal,
thoracic,head and neckparaganglioma

Head andneckparaganglia

Adrenal,extraadrenal,
abdominal,
thoracic

Associated
Lesions

CNS-Hemangioblastoma,Retinal Angioma, Renal
Cell Cancer, Pancreatic
Cysts, Islet Cell tumors,
Endolymphatic Sac
Tumors, Epididymal
Cystadenoma

Medullary Thyroid
Carcinoma,
Hyperparathyreoidism,
Ganglioneuroma

Neuroﬁbromas,
Pigmented Spots,‘‘Lisch-Nodes’’ ofthe Iris Nodulesnono

Head and Neck
Paraganglioma
Renal Cell
Carcinoma(seldom)

Table 2

Table 3

When to consider Pheochromocytoma associated Syndromes?*

Clinical Investigation Programs for Pheochromocytoma associatedSyndroms

Multifocal pheochromocytoma/paraganglioma
Extraadrenal pheochromocytoma/paraganglioma
 Young age
 Family History for pheochromocytoma/paraganglioma Other tumors in the patient of brain, spinal cord, eyes, ears,
thyroid gland, neck, parathyroid gland, kidney, pancreas,
epididymis, skin
 Relatives with tumors of brain, spinal cord, eyes, ears, thyroid
gland, neck, parathyroid gland, kidney, pancreas, epididymis, skin* All patients should be investigated moleculargenetically.

The second feature is reduced penetrance, e.g. somecarriers do not develope tumors at all. As far as weknow, penetrance is high in VHL and MEN 2, but not
100%, whereas such ﬁgures are unknown for the PGLs.
The third mechanism was found in carriers of SDHD
mutations. These develop only tumors, if the mutationis transmitted from the father. The term for this mechanism is maternal imprinting, and it explains, why thedisease can jump over generations.27
Based on the presentation of the tumors it canbe recommended to start for adrenal tumors with RET
and VHL followed by SDHD and SDHB. For extraadrenal tumors RET can be postponed. For neck paraganglioma one should analyze SDHD and SDHB;SDHC may be added. In malignant tumors SDHB andVHL should have preference.

Von Hippel-Lindau Disease
Ophthalmoscopy
MRI of the brain
MRI of the spinal cord
MRI of the abdomen
Catecholamine measurement in 24 h urine of plasma
24 h blood pressure
Audiometry
Ultrasonography of the testes
DOPA or dopamin positron emission tomography (PET)Multiple Endocrine Neoplasia Type 2
Calcitonin measurement at 0 0 , 2 0 and 5 0 after provocation withpentagastrin (pentagastrin test)
Calcium, Parathormon
Paraganglima Syndromes (PGL Types 1, 3, and 4)
MRI of the skull basis and neck
MRI of the thorax
MRI of the abdomen
Catecholamines in 24 h urine or plasma
DOPA or Dopamin PET
Neuroﬁbromatosis type 1
Ophthalmological investigation
Skin investigation

20

Neumann HPH, et al: New genetic causes of pheochromocytoma

Extraadrenal Pheochromocytoma

MRI

modern access.30 – 32 Extensive experience has beengathered thoughout Japan for adrenalectomy usingtransperitoneal and retroperitoneal accesses, resulting
in low complication rates.33 If located in the adrenals,
organ sparing surgery should be attempted.34 Organsparing procedures can also be performed endoscopically and revealed excellent results in experienced
hands.35 – 37 This is a striking argument to estabish thediagnosis of pheochromocytoma/paraganglioma associated syndromes preoperatively.
After Care

DOPA PET

MRI

Tumor between
Aorta andInferior Caval Vein

Fig. 5 Pheochromocytoma shown by MRI in coronal and axial projection (right side) and DOPA PET (left side).

Clinical Diagnosis
Diagnosis and documentation of the tumors shouldbe optimized preoperatively. Biochemistry and radiology are equally important for the diagnosis of pheochromocytoma and paragangliomas. Based on our personal experience and recent studies, documentation of
the tumors should be done using MRI as the ﬁrst line
method. We recommend that the lesion(s) should be
conﬁrmed by nuclear medicine imaging. In this regard,
MIBG scintigraphy is well introduced, but with limited
sensitivity of about 80–85 percent. Nowadays, dopa
positron emission tomography (PET) or dopamin-PET
seems to be the method of choice28,29 (Fig. 5). The useof two imaging methods helps to avoid an overlook ofadditional tumors. In addition, dopamin or dopa PET
enables imaging of all areas, including abdomen, thorax
and neck, and by this method such tumors can bevisualized within only 2–3 hours investigation time.
Preoperatively, the blood pressure must be normalized. International recommendations include use of alpha blockers and beta blockers. Possibly any drug canbe used which achieves normotension. A documentation of preoperative blood pressure for 24 h is advised.
Treatment
Treatment of pheochromocytoma is a high challenge
in all these syndromes. The surgical considerations
must include that these lesions are mostly benign, frequently multifocal, sometimes relapsing, often small
and occur in young age. Endoscopic surgery is theAfter-care depends on the speciﬁc syndrome which
is diagnosed moleculargenetically. An adjusted clinicalprogram has to be performed soon after treatment of
the pheochromocytoma especially for MEN 2 and VHL.
Still an open question is, if and how often and how
extensively the paraganglial system needs controls. The
major question is to anticipate the time when a pheochromocytoma will settle metastases. Carriers of an
SDHB mutation surely need regular controls in thisregard.
In Japan, the yearly detection rate for pheochromocytomas is about 1000 cases.38 Nation-wide projects
need to be well supported in order to establish large
registries, in order to perform moleculargenetic investigations according to the current knowledge, to provide with clinical background informations based on
extensive experience, and to perform the needed regular controls in patients identiﬁed with an inherited,
pheochromocytoma associated condition.
Conclusion
In conclusion, pheochromocytomas and paragangliomas are a high challenge for diagnosis clinicallyand moleculargenetically, for optimal treatment, andfor adequate aftercare which includes the patient and in
mutation positive cases also the family. Experiences inGermany, France and Poland have shown that dedicated, at best national registries should be establishedfor such purposes.
References
1. Neumann HP, Hoegerle S, Manz T, Brenner K, Iliopoulos O:
How many pathways to pheochromocytoma? Semin Nephrol
2002; 22: 89–99
2. Manger WM, Gifford RW. Pheochromocytoma: a clinical overview. Hypertension: Pathophysiology. In: John H. Laragh, Barry
M. Brenner eds, Hypertension: Pathophysiology, Diagnosis, andManagement, 2nd Ed, New York: Raven Press, 1995; 2225–2244
3. Noshiro T, Shimizu K, Watanabe T, Akama H, Shibukawa S,
Miura W, Ito S, Miura Y: Changes in clinical features and longterm prognosis in patients with pheochromocytoma. Am J
Hypertens 2000; 13: 35–43

Keio J Med 2005; 54 (1): 15–21
4. Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel
RF, van Amstel HK, Lips CJ, Nishisho I, Takai SI, et al: The
relationship between speciﬁc RET proto-oncogene mutations
and disease phenotype in multiple endocrine neoplasia type 2.
International RET mutation consortium analysis. JAMA 1996;
276: 1575–1579
5. Egawa S, Futami H, Takasaki K, Iihara M, Okamoto T, Kanbe
M, Ohi T, Saio Y, Miyauchi A, Takiyama Y, et al: Genotypephenotype correlation of patients with multiple endocrine neoplasia type 2 in Japan. Jpn J Clin Oncol 1998; 28: 590–596
6. Neumann HP: Basic criteria for clinical diagnosis and genetic
counselling in von Hippel-Lindau syndrome. Vasa 1987; 16: 220–
226
7. Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK,
Linehan WM, Oldﬁeld EH: von Hippel-Lindau disease. Lancet
2003; 361: 2059–2067
8. Neumann HP, Bender B, Zauner I, Berger DP, Eng C, Brauch
H, Zbar B: Monogenetic hypertension and pheochromocytoma.
Am J Kidney Dis 1996; 28: 329–333
9. Clinical Research Group for VHL in Japan. Germline mutationsin the von Hippel-Lindau disease (VHL) gene in Japanese VHL.
Hum Mol Genet 1995; 4: 2233–2237
10. Yoshida M, Ashida S, Kondo K, Kobayashi K, Kanno H, Shinohara N, Shitara N, Kishida T, Kawakami S, Baba M, et al:
Germ-line mutation analysis in patients with von Hippel-Lindau
disease in Japan: an extended study of 77 families. Jpn J Cancer
Res 2000; 91: 204–212
11. Riccardi VM: Von Recklinghausen neuroﬁbromatosis. N Engl J
Med 1981; 305: 1617–1627
12. Walther MM, Herring J, Enquist E, Keiser HR, Linehan WM:
von Recklinghausen’s disease and pheochromocytomas. J Urol
1999; 162: 1582–1586
13. Hirawake H, Taniwaki M, Tamura A, Amino H, Tomitsuka E,
Kita K: Characterization of the human SDHD gene encoding thesmall subunit of cytochrome b (cybS) in mitochondrial succinateubiquinone oxidoreductase. Biochim Biophys Acta 1999; 1412:
295–300
14. Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der Mey A, Taschner PE, Rubinstein
WS, Myers EN, et al: Mutations in SDHD, a mitochondrialcomplex II gene, in hereditary paraganglioma. Science 2000; 287:
848–851
15. Gimm O, Armanios M, Dziema H, Neumann HP, Eng C: Somatic and occult germ-line mutations in SDHD, a mitochondrialcomplex II gene, in nonfamilial pheochromocytoma. Cancer Res
2000; 60: 6822–6825
16. Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E,
Skoldberg F, Husebye ES, Eng C, Maher ER: Gene mutations inthe succinate dehydrogenase subunit SDHB cause susceptibility
to familial pheochromocytoma and to familial paraganglioma.
Am J Hum Genet 2001; 69: 49–54
17. Niemann S, Becker-Follmann J, Nurnberg G, Ruschendorf F,
Sieweke N, Hugens-Penzel M, Traupe H, Wienker TF, Reis A,
Muller U: Assignment of PGL3 to chromosome 1 (q21–q23) in a
family with autosomal dominant non-chromafﬁn paraganglioma.
Am J Med Genet 2001; 98: 32–36
18. Niemann S, Muller U: Mutations in SDHC cause autosomal
dominant paraganglioma, type 3. Nat Genet 2000; 26: 268–270
19. Bauters C, Vantyghem MC, Leteurtre E, Odou MF, Mouton C,
Porchet N, Wemeau JL, Proye C, Pigny P: Hereditary phaeochromocytomas and paragangliomas: a study of ﬁve susceptibility
genes. J Med Genet 2003; 40: e75
20. Baysal BE, Willett-Brozick JE, Filho PA, Lawrence EC, Myers
EN, Ferrell RE: An Alu-mediated partial SDHC deletion causesfamilial and sporadic paraganglioma. J Med Genet 2004; 41:
703–70921
21. Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O,
Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, et al:
Freiburg-Warsaw-Columbus Pheochromocytoma Study Group:
Germ-line mutations in nonsyndromic pheochromocytoma. N
Engl J Med 2002; 346: 1459–1466
22. Hull MT, Roth LM, Glover JL, Walker PD: Metastatic carotid
body paraganglioma in von Hippel-Lindau disease. An electron
microscopic study. Arch Pathol Lab Med 1982; 106: 235–239
23. Kennedy DW, Nager GT: Glomus tumor and multiple endocrine
neoplasia. Otolaryngol Head Neck Surg 1986; 94: 644–648
24. Schimke RN, Collins DL, Rothberg PG: Functioning carotid
paraganglioma in the von Hippel-Lindau syndrome. Am J Med
Genet 1998; 80: 533–534
25. Zanelli M, van der Walt JD: Carotid body paraganglioma in vonHippel-Lindau disease: a rare association. Histopathology 1996;
29: 178–181
26. Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Crespin M, Nau V, Khau Van Kien P, Corvol P, Plouin PF, et al:
COMETE Network: Mutations in the SDHB gene are associatedwith extra-adrenal and/or malignant phaeochromocytomas.
Cancer Res 2003; 63: 5615–5621
27. van der Mey AG, Maaswinkel-Mooy PD, Cornelisse CJ, Schmidt
PH, van de Kamp JJ: Genomic imprinting in hereditary glomus
tumours: evidence for new genetic theory. Lancet 1989; 2: 1291–
1294
28. Pacak K, Eisenhofer G, Carrasquillo JA, Chen CC, Li ST,
Goldstein DS: 6-[18F]ﬂuorodopamine positron emission tomographic (PET) scanning for diagnostic localization of pheochromocytoma. Hypertension 2001; 38: 6–8
29. Hoegerle S, Nitzsche E, Altehoefer C, Ghanem N, Manz T,
Brink I, Reincke M, Moser E, Neumann HP: Pheochromocytomas: detection with 18F DOPA whole body PET – initial results.
Radiology 2002; 222: 507–512
30. Higashihara E, Tanaka Y, Horie S, Aruga S, Nutahara K,
Homma Y, Minowada S, Aso Y: A case report of laparoscopic
adrenalectomy. Nippon Hinyokika Gakkai Zasshi 1992; 83:1130–1133 (in Japanese)
31. Higashihara E, Tanaka Y, Horie S, Aruga S, Nutahara K, Minowada S, Aso Y: Laparoscopic adrenalectomy: the initial 3 cases.
J Urol 1993; 149: 973–976
32. Higashihara E, Nutahara K, Kato M: Laparoscopic adrenalectomy: alternative or new standard? Curr Urol Rep 2002; 3: 172–178
33. Terachi T, Yoshida O, Matsuda T, Orikasa S, Chiba Y, Takahashi K, Takeda M, Higashihara E, Murai M, Baba S, et al: Complications of laparoscopic and retroperitoneoscopic adrenalectomies in 370 cases in Japan: a multi-institutional study. Biomed
Pharmacother 2000; 54: 211s–214s
34. Neumann HP, Bender BU, Reincke M, Eggstein S, Laubenberger J, Kirste G: Adrenal-sparing surgery for phaeochromocytoma. Br J Surg 1999; 86: 94–97
35. Janetschek G, Finkenstedt G, Gasser R, Waibel UG, Peschel R,
Bartsch G, Neumann HP: Laparoscopic surgery for pheochromocytoma: adrenalectomy, partial resection, excision of paragangliomas. J Urol 1998; 160: 330–334
36. Neumann HP, Reincke M, Bender BU, Elsner R, Janetschek G:
Preserved adrenocortical function after laparoscopic bilateraladrenal sparing surgery for hereditary pheochromocytoma. J
Clin Endocrinol Metab 1999 Aug; 84 (8): 2608–2610
37. Walz MK, Peitgen K, Neumann HP, Janssen OE, Philipp T,
Mann K: Endoscopic treatment of solitary, bilateral, multiple,
and recurrent pheochromocytomas and paragangliomas. World J
Surg 2002; 26: 1005–1012
38. Takayanagi R, Miura K, Nakagawa H, Nawata H: Epidemiologic
study of adrenal gland disorders in Japan. Biomed Pharmacother
2000; 54: 164s–168s