Head and Neck Paragangliomas in Von Hippel-Lindau Disease and ...

Head and Neck Paragangliomas in Von Hippel-Lindau Disease and Multiple Endocrine
Neoplasia Type 2
Short title: Head and Neck Paragangliomas in VHL and MEN 2
Carsten C Boedeker, MD 1 *, Zoran Erlic, MD 2 *, Stéphane Richard, MD, PhD 3 , Udo Kontny, MD 4 ,
Anne-Paule Gimenez-Roqueplo, MD 5 , Alberto Cascon, PhD 6 , Mercedes Robledo, MD 6 , José M de
Campos, MD 7 , Francien H van Nederveen, MD 8 , Ronald R de Krijger, MD, PhD 8 , Nelly Burnichon,
MD 5 , José Gaal, MD 8 , Martin A. Walter, MD 9 , Kirsten Reschke, MD 10 , Thorsten Wiech, MD 11 ,
Johannes Weber, MD 12 , Klaus Rückauer, MD 13 , Pierre Francois Plouin, MD 14 , Vincent Darrouzet,
MD 15 , Sophie Giraud, MD, PhD 16 , Charis Eng, MD, PhD 17,18 , Hartmut PH Neumann, MD 2
1 Department of Otorhinolaryngology, Albert-Ludwigs-University, Freiburg, Germany
2 Department of Nephrology, Section of Preventive Medicine, Albert-Ludwigs-University, Freiburg,
Germany
3 Génétique Oncologique EPHE-CNRS FRE 2939, Faculté de Médecine Paris Sud; Réseau National
INCa and Centre Pilote Tumeurs Rares INCa/AP-HP, Service d’Urologie, Hôpital de Kremlin-Bicêtre,
France
J Clin Endocrin Metab. First published ahead of print March 31, 2009 as doi:10.1210/jc.2009-0354
4 Division of Pediatric Hematology and Oncology, Albert-Ludwigs-University, Freiburg, Germany
5 Assistance Publique-Hôpitaux de Paris, Service de Génétique, Hôpital Européen Georges Pompidou,
and Université Paris Descartes, Paris, France
6 Hereditary Endocrine Cancer Group, Spanish National Cancer Center, Madrid and ISCIII Center for
Biomedical Research on Rare Diseases (CIBERER), Spain
7 Neurosurgery Department, Fundación Jiménez Díaz, Autonomous University, Madrid, Spain
8 Department of Pathology, Josephine Nefkens Institute, Erasmus MC-University Medical Centre
Rotterdam, Rotterdam, The Netherlands
9 Department of Nuclear Medicine, University Hospital Basel, Switzerland
10 Division of Nephrology and Endocrinology, Otto von Guericke University, Magdeburg, Germany
1
Copyright (C) 2009 by The Endocrine Society

11 Department of Pathology, Albert-Ludwigs-University, Freiburg, Germany
12 Department of Neuroradiology, Albert-Ludwigs-University, Freiburg, Germany
13 Department of Surgery, University of Freiburg, Germany
14 Assistance Publique-Hôpitaux de Paris, Unité d'Hypertension artérielle, Hôpital Européen Georges
Pompidou, and Université Paris Descartes, Paris, France
15 ENT Department, Skull Base Surgery Department, Hôpital Pellegrin, University Victor Segalen
Bordeaux 2, Bordeaux, France 33000F
16 Laboratoire de Génétique & Réseau National INCa, Hôpital Edouard Herriot, Lyon, France
17 Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
18 Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
*These authors contributed equally to the study.
Correspondence
Prof. Dr. Hartmut P.H. Neumann, MD
Department of Nephrology and General Medicine, University of Freiburg
Hugstetter Str. 55, D-79106 Freiburg, Germany
phone: +49-761/270-3363, fax: +49-761/270-3778
e-mail: hartmut.neumann @uniklinik-freiburg.de
Disclosure summary: The authors have nothing to disclose.
NIH Statement: "This is an un-copyedited author manuscript copyrighted by The Endocrine Society.
This may not be duplicated or reproduced, other than for personal use or within the rule of “Fair Use
of Copyrighted Materials” (section 107, Title 17, U.S. Code) without permission of the copyright
owner, The Endocrine Society. From the time of acceptance following peer review, the full text of this
manuscript is made freely available by The Endocrine Society at http://www.endojournals.org/. The
final copy edited article can be found at http://www.endojournals.org/. The Endocrine Society
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disclaims any responsibility or liability for errors or omissions in this version of the manuscript or in
any version derived from it by the National Institutes of Health or other parties. The citation of this
article must include the following information: author(s), article title, journal title, year of publication
and DOI.”
Precise: Head and neck paragangliomas represent a very rare feature in von Hippel-Lindau
disease, multiple endocrine neoplasia type 2 and neurofibromatosis type 1.
Key words: Head and neck paraganglioma, paraganglioma syndromes, pheochromocytoma, von
Hippel-Lindau disease, multiple endocrine neoplasia type 2, neurofibromatosis type 1, germline
mutations
Word count: Manuscript Text 3535; Abstract 249; Number of Tables: 1.
Reprint requests should be addressed Prof. Dr. Hartmut P.H. Neumann, MD
Sources of funding and support:
Hartmut P.H. Neumann is supported by grants from the Deutsche Krebshilfe (107995 to HPHN), the
Deutsche Forschungsgemeinschaft (NE 571/5-3 to HPHN), and the European Union (LSHC-CT-2005-
518200 to HPHN).
Anne-Paule Gimenez-Roqueplo is supported by Institut National de la Santé et de la Recherche
Médicale, by PHRC grant COMETE 3 for the COMETE Network (AOM 06 179) and by GIS-
Maladies Rares for the PGL.NET network.
Mercedes Robledo is supported by a grant from FIS (PI080883) and CIBERER.
Stéphane Richard and Sophie Giraud are supported by grants from the Institut National du Cancer
(INCa) and the Ligue Nationale contre le Cancer (Comités du Cher et de l’Indre).
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Charis Eng is the recipient of a Doris Duke Distinguished Clinical Scientist Award, is the Sondra J.
and Stephen R. Hardis Endowed Chair of Cancer Genomic Medicine at the Cleveland Clinic and is a
NIH funded investigator.
Francien van Nederveen is supported by a grant from The Netherlands Organisation for Health
Research and Development and The Dutch Cancer Society.
Ronald de Krijger is supported by a grant from the “Vanderes” Foundation.
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ABSTRACT
Background
Head and neck paragangliomas (HNPs) occur as sporadic or familial entities, the latter mostly in
association with germline mutations of the SDHB, SDHC or SDHD (SDHx) genes. Heritable non-
SDHx HNP might occur in von Hippel-Lindau disease (VHL, VHL gene), multiple endocrine
neoplasia type 2 (MEN2, RET gene) and neurofibromatosis type 1 (NF1, NF1 gene). Reports of non-
SDHx HNP presentations are scarce and guidance for genetic testing non-existent.
Material and Methods
An international consortium registered patients with HNPs and performed mutation analyses of the
SDHx, VHL and RET genes. Those with SDHx germline mutations were excluded for purposes of this
study. Personal and family histories were evaluated for paraganglial tumors, for the major tumor
manifestations and for family history of VHL, MEN2 or NF1.
Results
Twelve patients were found to have hereditary non-SDHx HNPs out of a total of 809 HNP and 2084
VHL registrants, 11 in the setting of germline VHL mutations and 1 of a RET mutation. The
prevalence of hereditary HNP is 5/1,000 VHL patients and 9/1,000 non-SDHx HNP patients.
Comprehensive literature review revealed previous reports of HNPs in 5 VHL, 2 MEN2 and in 1 NF1
patients. Overall, 11 here presented HNP cases and 4 previously reported VHL-HNPs had lesions
characteristic for VHL and/or a positive family history for VHL.
Conclusions
Our observations provide evidence that molecular genetic testing for VHL or RET germline mutations
in patients with HNP should only be done, if personal and/or family history shows evidence for one of
these syndromes.
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INTRODUCTION
Head and neck paragangliomas (HNPs) are highly vascularized tumors of the autonomic nervous
system, mainly arising from the carotid body or the glomus jugulare, tympanicum or vagale. HNPs
occur as sporadic as well as hereditary entities (1, 2). Hereditary HNPs have attracted interest in
particular from 2000, when a first susceptibility gene for the so called ”paraganglioma syndromes”
(PGL) was detected (PGL 1) (3). This gene, SDHD, located on 11q23, encodes subunit D of the
enzyme succinate dehydrogenase or mitochondrial complex II. Subsequently, two other PGL
susceptibility genes, encoding the B and C subunits of SDH, were described, SDHB (PGL4) and
SDHC (PGL3) (4, 5). A fourth susceptibility gene, for PGL 2, has been mapped to 11q13, but has not
yet been identified (6). These three known PGL susceptibility genes will be collectively referred to
here as SDHx. In contrast, SDHA gene mutations do not predispose to PGL (7).
Because of intense clinical investigation subsequent to 2000, we know that HNP is a major component
tumor of the syndromes characterized by germline SDHx mutations (1, 2, 8, 9). Studies from us and
others have shown that patients with SDHx mutations are not only at risk for HNPs, but also for other
tumors of the paraganglial system including adrenal pheochromocytoma and extraadrenal
pheochromocytoma of the retroperitoneum, pelvis and thorax (1, 2, 8, 10, 11). However, HNPs
occurring in the non-SDHx heritable disorders have been anecdotal. In order to examine the clinical
context of non-SDHx heritable HNPs, we adopted and updated the European Australian American
HNP Registry in which we previously studied the characteristics and prevalence of HNPs (12) and
proposed to different groups to join us. As the Non-SDHx HNP Consortium, we then proceeded to
study the prevalence of HNPs and other salient clinical features and family histories in registrants
found to have von Hippel-Lindau disease (VHL), multiple endocrine neoplasia type 2 (MEN 2) and
type 1 neurofibromatosis (NF 1).
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MATERIAL AND METHODS
Subjects
The international Non-SDHx-HNP-Consortium was constituted in 2008 in order to identify and to
clinically and genetically characterize patients with HNP with heritable syndromes in the absence of
germline SDHx mutations. We paid particular attention to additional component tumors suggestive of
VHL, MEN 2 or NF 1. We adopted and updated the registrants from the European Australian
American HNP Registry including symptomatic and asymptomatic HNPs as of March 1, 2009 which
included a total of 513 subjects. In particular, centers dedicated to clinical care and molecular genetic
diagnosis of HNPs in 26 countries including Germany, Spain, The Netherlands, Italy, Hungary,
Ukraine, Serbia, Greece, Poland, Sweden, Finland, Denmark, Belgium, France, Switzerland, Austria,
Turkey, Iran, China, Japan, the USA, Brazil, Chile, Argentina, Australia and New Zealand were
recontacted. Separately to the European Australian American HNP Registry, the Netherlands and
France have national HNP registries with 147 and 149 registrants in whom SDHx mutations have been
excluded, respectively. This aimed to identify unrecognized patients with HNP for case registration
and for updating the HNP registry for prevalence estimations.
For prevalence estimations in VHL, we used the national population-based registries for Germany,
France, Spain, and the Netherlands.
Genetic Analysis
All registrants provided 10 ml EDTA-anticoagulated blood for molecular genetic analyses. The
analyses comprised testing of the VHL (RefSeq:NM_000551.2) and RET (RefSeq:NM_020975.4)
genes for germline mutations. DNA extraction, primers, PCR conditions and sequencing methods
followed published protocols of international standards (1, 2, 10, 11). Of note, analyses also included
screening for large deletions or rearrangements of the VHL gene, since such mutations have been
described in VHL patients with pheochromocytoma (13, 14). Overall, 809 HNP patients
(513+147+149) of the European Australian American HNP Registry, the French HNP Registry and
the Rotterdam HNP Registry combined were subjected to the above described analyses.
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Criteria for Diagnosis of Non-SDHx Heritable Neoplasia Syndromes
The criteria for non-SDHx heritable HNPs are absence of germline mutations in the genes SDHB,
SDHC and SDHC analyzed as shown above and presence of clinical or molecular genetic evidence for
MEN 2, VHL or NF 1. VHL was diagnosed, if the patient was found to have a germline VHL mutation
and/or had at least one of the tumors of the VHL component spectrum of hemangioblastoma of the eye
or central nervous system (CNS), renal cell carcinoma (RCC) or pheochromocytoma. MEN 2 was
diagnosed if the patient was found to carry a germline RET mutation or a first degree relative had a
medullary thyroid carcinoma and a pheochromocytoma. NF 1 was diagnosed, if the patient had at least
two of the following clinical features: multiple neurofibromas, plexiform neurofibroma, axillary
freckling, café au lait spots and Lisch nodules of the iris and/or a first degree relative with confirmed
NF 1 (8, 15-17).
Approval and Consent
The study design was approved by the ethical committee of the University of Freiburg and all
participating centers accordingly. All participants gave written informed consent. The study was
performed in accordance with the guidelines of the Helsinki Declaration of 1975, as revised in 1983.
RESULTS
By March 1, 2009, the International Non-SDHx HNP Consortium registered 12 patients with HNPs
who showed characteristics suggesting a non-SDHx-related heritable tumor syndrome. Eleven of the
12 patients were found to carry germline mutations in the VHL gene, and one in the RET gene. Six of
the patients originate from France, two from Germany, two from Spain and one each from The
Netherlands and Switzerland.
To estimate the prevalence of HNP in VHL individuals, we used the country-specific registries to
provide a denominator. For VHL, the French VHL registry comprises 886 registrants, the German
VHL Registry based in Freiburg 844, the Spanish VHL registry 296, and the Dutch VHL registry 58
registrants respectively as of January 1, 2009.
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Regarding VHL, the prevalence of HNP in the national registries was 2/844 or 2/1,000 in Germany,
2/296 or 7/1,000 in Spain, and 6/886 or 7/1,000 in France, respectively. In the Netherlands, the VHL
registry comprises 58 cases, but none of the registrants had HNP (18). In total, prevalence of HNP
amongst VHL cases was 10/2085 or 5/1,000.
Regarding HNP, the European Australian American Head and Neck Paraganglioma Registry counts
513 registrants, the Rotterdam HNP registry 147 registrants and the French HNP registry 149
registrants in whom SDHx mutations have been excluded.
Regarding HNP prevalence in the European Australian American HNP Registry, which includes
Germany, Spain and Switzerland among other countries but not the Netherlands and France, was
5/513 or 10/1,000 registrants in whom SDHx mutations have been excluded. In the Netherlands and
France, the prevalence of hereditary non-SDHx HNP was 1/147 or 7/1,000 and 1/149 or 7/1,000,
respectively. In total, among all 809 registrants, prevalence was 9/1,000.
Case reports:
Case 1
In 1997, a 7-year old boy was diagnosed with a malignant extraadrenal pheochromocytoma of the left
retroperitoneum with regional lymph node metastases. These were treated with resection of the
primary tumor, lymphadenectomy and chemotherapy according to the protocol GPOH-MET 97 (19).
At age 9, there was a local recurrence, which was treated with resection and external radiotherapy of
20 Gy. At age 13, a right adrenal pheochromocytoma was resected. At age 15, a left carotid body
tumor was clinically detected and removed, but this recurred at age 16 and again resected. At age 17, a
pheochromocytoma at the renal pelvis was diagnosed on a routine MRI and resected. At age 18, he is
disease-free except for a lesion in the L1 vertebral body suggestive of hemangioma or
pheochromocytoma, a lesion first diagnosed in 2004 but unchanged over the last 5 years. The family
history was initially negative for VHL. Molecular genetic testing revealed the mutation VHL
p.Tyr98His. Predictive testing was offered to the patient’s family and revealed that the mother and
other relatives were positive. Clinical investigations of these relatives showed retinal
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hemangioblastomas in the aunt and a pheochromocytoma in a cousin whereas the mother had no
abnormalities at all.
Case 2
An asymptomatic 29-year old man was offered VHL-specific clinical surveillance due to a family
history of known VHL and genetic testing which revealed carriership for the family-specific VHL
mutation. MRI of the brain showed surprisingly a pituitary tumor. Further work up showed
hyperprolactinemia and thus biochemical evidence for a prolactinoma. He was treated with
bromocriptine for five years. At age 34, he reported a painful swelling on his left neck where a mass
was palpable. CT disclosed a left carotid body tumor which was resected. At age 41, multiple
pancreatic cysts and a left kidney cancer were detected which was resected and showed histologically
a clear cell carcinoma. The father and two brothers have been treated for multiple retinal, cerebellar
and spinal cord hemangioblastomas. Molecular genetic testing of the patient detected the family-
specific VHL mutation p.Leu135X.
Case 3
A 23-year old female was initially diagnosed with hypertension and elevated platelets. Because of the
young age and hypertension, 24-hour urine catecholamines were measured and found to be elevated.
Abdominal CT scan disclosed bilateral adrenal pheochromocytomas, confirmed by 123-iodine-MIBG
scintigraphy. The MIBG scan, however, did not only show uptake in the adrenal glands, but also in the
right neck area. Subsequently, an MRI of the neck disclosed a 2.5 cm carotid body tumor. The tumor
was resected and histologically confirmed. The family history was negative for tumors of the VHL
spectrum. Genetic testing revealed a germline mutation of the VHL gene p.Phe119Leu.
Case 4
A 23-year old asymptomatic female presented with a palpable mass on the left side of the neck during
a routine check-up for her VHL p.Arg64Pro family-specific mutation, already previously identified in
this patient’s family. No other clinical manifestations had been detected until then. Somatostatin
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eceptor scintigraphy revealed a hotspot near the left carotid artery, indicating a paraganglioma. No
hypertension or increase in catecholamines was observed. The removed 2.5 cm tumor was
histopathologically a paraganglioma. At age 33, there was no recurrence, nor did the patient have other
tumors. Interestingly, the VHL disease had a heterogeneous presentation in the family, with bilateral
pheochromocytomas and clear cell renal carcinoma as the initial presentation in the father. In addition,
the patient´s son underwent a unilateral adrenalectomy for pheochromocytoma at age of 7.
Case 5
A 37-year old female noticed a mass at the left side of her neck. MRI disclosed a 3 cm carotid body
tumor. The mass was removed, and histopathology revealed a paraganglioma. At age 50, the patient
was operated for a left adrenal pheochromocytoma. Clinical screening for VHL showed asymptomatic
retinal and spinal hemangioblastomas. Her mother suffered from blindness of one eye potentially due
to retinal angiomatosis and was operated for a left adrenal pheochromocytoma. Her uncle died due to
renal cell carcinoma and had spinal hemangioblastomas. Molecular genetic analysis revealed the
mutation VHL p.Arg107His. All her three sons are also carriers, one of whom was operated for a right
adrenal pheochromocytoma at age 24 and a left adrenal pheochromocytoma at age 32. Screening of
the 27-year old son revealed asymptomatic retinal and spinal hemangioblastomas.
Case 6
A 42-year old male with a history of thyroidectomy for medullary thyroid carcinoma and removal of
an adrenal cortical adenoma (not pheochromocytoma) presented with chronic headaches, tinnitus and
progressive hearing loss. Diagnostic whole-body work-up revealed a 4 cm jugular paraganglioma with
partial destruction of the labyrinth and without further tumor manifestations. The jugular tumor was
treated with selective arterial embolization and stereotactic external-beam radiation. During follow-up,
new metastases from the medullary thyroid carcinoma were diagnosed and the patient was transferred
for systemic radio-peptide treatment with DOTATOC. Both malignancies showed distinct radiotracer
uptake and the treatment resulted in partial response. Molecular genetic analysis revealed a
p.Cys620Arg RET mutation.
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Case 7
In 1980, a 15-year old girl with a familial history of VHL presented with loss of visual acuity leading
to the diagnosis of bilateral retinal hemangioblastomas followed by laser and cryotherapy. However,
outcome was unilateral blindness. Further, the patient was then operated three times for CNS
hemangioblastomas between age 18 and 24. At age 26 she presented with a palpable lateral neck mass.
CT of the head and neck revealed a 3 cm carotid body tumor. The tumor was removed, and histology
showed a paraganglioma. Molecular genetics identified the VHL germline mutation p.Thr105Pro.
Case 8
In 1997, a 19-year old man with a familial history for VHL presented with headaches. MRI of the
CNS was normal, but ophthalmologic examination showed a right retinal hemangioblastoma that was
treated by laser. In 2002, he had right nephrectomy and left nephron-sparing surgery for renal cell
carcinoma. At age 27, a palpable mass on the left side of the neck was diagnosed during dental care.
CT and MRI revealed a 4 cm carotid body tumor which was removed after selective embolization.
Histology revealed a paraganglioma. The patient has also pancreatic cysts. Molecular genetics
identified the deletion of exons 2 and 3 of the VHL gene.
Case 9
In 1990, a 26-year old woman from a VHL family presented with lumbar pain. CT showed a right
adrenal pheochromocytoma which was removed. Two years later she had left nephrectomy for
multiple renal cell carcinoma. At age 33, she presented with a lateral cervical mass associated with
Horner’s syndrome and pain in the right ear. CT showed a 6 cm carotid paraganglioma which was
removed and histologically confirmed. At age 42 a cerebellar hemangioblastoma was removed.
Molecular analysis identified the VHL germline mutation p.Ser139fs.
Case 10
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In 1994, a 34-year old woman without personal and familial history for VHL was referred to the
hospital because of persistent pharyngeal discomfort. MRI demonstrated a 4 cm tumor in the
parapharyngeal space suggestive of a schwannoma or a carotid paraganglioma. The tumor was
removed and histology revealed a paraganglioma. Postoperatively, she had Horner’s syndrome and a
transitory hypoglossal paresis. At age 46, bilateral adrenal pheochromocytoma and a paraaortic
paraganglioma were removed. Later, her niece has been diagnosed with a pheochromocytoma, and her
brother suffered from pheochromocytoma, renal cell carcinoma and retinal hemangioblastomas. The
proband’s mother was then found to have pheochromocytoma. Molecular analysis identified the VHL
mutation p.Tyr98His.
Case 11
In 1978, an 8-year old girl without familial history of VHL was operated for a right
pheochromocytoma, and at age 13, for a contralateral pheochromocytoma. At age 15, a 4 cm mass at
the neck was diagnosed by selective arteriography as a carotid paraganglioma which was removed and
histologically confirmed. The patient was then operated twice for cerebellar hemangioblastoma at age
22, leading to the diagnosis of VHL disease. At age 27, the patient was operated again for a retrocaval
pheochromocytoma and for islet cell tumors. The patient was also repeatedly treated for bilateral
retinal hemangioblastomas leading to blindness at age 32. At age 36, again a pheochromocytoma was
removed. Molecular genetic analysis identified the p.Thr157Ile VHL germline mutation. So far, there
are no affected relatives.
Case 12
In 1993, a 39-year old female with recent onset of hypertension was diagnosed with a right
pheochromocytoma. At age 36, a suspected left pheochromocytoma was noted by CT and increased
urinary metanephrines was confirmed at age 39 by 123 iodine MIBG scintigraphy. This imaging
showed in addition an uptake located in the neck. MRI confirmed a left adrenal tumor and a left 2 cm
vagal paraganglioma which was removed and confirmed histopathologically. Genetic testing identified
the VHL p.Tyr156Cys mutation. No other tumor of the VHL spectrum was discovered. Three of her
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four sons were found to carry the mutation. Clinical screening of all 3 disclosed a 2.4 cm abdominal
paraganglioma in one of them, but no lesion in the other brothers.
Summary of Case Reports
In summary, of the 12 non-SDHx HNP arising in VHL and MEN 2 patients, 8 are female and 4 are
male, with ages at diagnosis 15-42 (mean 28). Eleven had an VHL mutations and one an RET
mutations. Eight of the 11 VHL mutations and also the RET mutation were missense mutations. Three
cases were identified at an asymptomatic stage, whereas nine had symptoms of a local mass or due to
dysfunction of the vestibular-cochlear nerve. All but one of the VHL cases had carotid body tumors.
The other VHL case had a vagal paraganglioma and the case with the RET mutation had a jugular
paraganglioma. All cases had a single HNP. Family history was suggestive for VHL in 6 cases.
Additional tumors have been previously diagnosed in 8 cases. Thus, all cases with VHL had clinical
manifestations and/or a suggestive family history for VHL.
In addition to those meeting the criteria for heritable non-SDHx-HNP for this study, there are 31 out of
809 registrants who have the stigmata of inherited HNP. Eight had a family history for paraganglial
tumors in relatives, and 5 HNP patients also had abdominal paraganglial tumors. Furthermore is note
worthy that 20 of the HNP patients had multiple tumors. All these patients had no germline mutation
in the genes SDHB, SDHC, SDHD, RET and VHL, and no clinical signs for NF1.
DISCUSSION
Paraganglial tumors can be divided into nearly always vasoactive abdominal, pelvic and thoracic
pheochromocytomas (here all classified as pheochromocytomas) and nearly always non-vasoactive but
space-occupying tumors of the head and neck paraganglia (here all classified as paragangliomas or
HNPs). Several studies over the last 7 years have shown that approximately one third of symptomatic
presentations of pheochromocytomas, even in the absence of other syndromic features or family
history, are caused by germline mutations.(1, 2, 8, 10, 11, 16) The prevalence of susceptibility genes
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involved in a pheochromocytoma presentation, in decreasing order of frequency, of VHL, SDHB, RET,
NF1 and SDHD is 41%, 18%, 17%, 13%, and 11% respectively.(16) Given the data that even
apparently sporadic pheochromocytomas have a relatively high frequency of germline mutations, most
clinicians would offer gene testing, in the setting of genetic counselling, to all patients presenting with
a pheochromocytoma irrespective of other features or family history. Knowledge of the relative
prevalence of a specific gene involved associated with certain clinical features allows some type of
prioritisation of which gene(s) to begin testing with. In contrast to relatively high prevalences of VHL,
RET and NF1 involved in pheochromocytoma presentations, our recent international molecular genetic
study on nearly 600 unrelated patients with symptomatic HNPs showed that virtually all patients with
HNPs due to germline mutations have the mutation in one of the following genes: SDHB, SDHC and
SDHD (12). Additionally, certain clinical features in HNP patients can accurately help prioritize which
gene to begin testing (12). The occurrence of HNP in the non-SDHx PGL syndromes, mainly VHL and
MEN 2, has been anecdotal (20-27). The literature provides little guidance as to the prevalence of
VHL, MEN 2 and NF 1 in HNP presentations. It also provides little guidance in regard to associated
clinical features and family history in patients with non-SDHx-related heritable HNP.
Our present study addresses these issues relevant to clinical practice in several subspecialties. First,
among all symptomatic HNP presentations, we were able, after exclusion of SDHx germline mutation-
associated cases, to estimate that 5/1,000 actually have VHL. Second, we could estimate that among
individuals with VHL, 8/1,000 will have HNP. Third, VHL has the highest prevalence among non-
SDHx hereditary HNP with 11 out of 12 cases in our study. In the literature, 5 of 8 cases had VHL,
and 2 had MEN 2 (20-25, 27). All but three VHL patients showed germline VHL missense mutations.
NF 1 was the etiology of non SDHx heritable HNP in one case in the literature, but not in our series
(26).
Sixteen out of 20 patients, 10 from our study and 6 in the literature, presented with a carotid body
tumor (20-23, 25, 27). One of our patients and one from literature had a glomus jugulare, one of our
patients a glomus vagale tumor and one from the literature a glomus tympanicum tumor (Table 1) (24,
26). Remarkably, 15 of the 16 VHL-HNP patients had clinical features suggestive of VHL, with
classical VHL lesions or a family history diagnostic for VHL. All but one of the HNPs were benign. In
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one case with HNP and adrenal pheochromocytoma, lung metastases were found by biopsy (20). Most
patients were diagnosed with HNP in their 3 rd to 5 th decades of life. Of note, 3 of the 16 VHL cases, 1
from France, 1 from Germany and 1 from America (23) share the identical mutation VHL p.Tyr98His
which has been shown as a founder effect in the Blackforest with emigrants to Pennsylvania and Ohio
(28).
In summary, VHL is the dominant syndrome in Non-SDHx mutation-associated inherited HNP. Since
the majority of our and the reported patients with HNP have clinical features suggesting VHL, MEN 2
or NF 1, our data provide evidence that genetic testing for VHL, RET and NF1 mutations are not
necessary unless other syndromic component tumors occur in the patient or there is at least one family
member with known VHL, MEN 2 or NF 1. If the data continue to hold, then NF 1 needs not to be
considered in HNP presentations. In pursuing this exercise, it also became obvious that there exists
an additional set of individuals who have at least one “red flag” likewise multiple HNPs, additional
pheochromocytoma and/or a family history for paraganglial tumors denoting genetic contribution but
are without any mutation in the known PGL/pheochromocytoma-predisposing genes. These will serve
to guide the search for novel predisposition genes.
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ACKNOWLEDGMENTS
We thank the members of the French VHL Study Group and specially Prof. Françoise Archambeault-
Mouveroux, Prof. Bernard Baranger, Prof. Jean-Paul Becquemin, Prof. Gérard Benoît, Prof. Xavier
Bertagna, Prof. Jean-Luc Poncet, and Prof. Jacques Young.
We acknowledge the exellent assistance of Aurelia Winter for the European Australian American
HNP Registry.
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Table 1. Demographic and clinical data summary of the 12 cases of this study and reported hereditary head and neck paragangliomas in von Hippel-
Lindau disease (VHL), multiple endocrine neoplasia type 2 (MEN 2) and neurofibromatosis type 1 (NF 1)
Case/ Age Sex Disorder Mutation Sympt- Cause of Admission HNP Location Family Previous Tumors Tumors Later
(Reference)
omatic
History
1 15 m VHL VHL p.Tyr98His no Routine VHL check Carotid Body negative Pheo no
2 34 m VHL VHL p.Leu135X yes Painful lateral neck mass Carotid Body positive Prolactinoma RCC, PcCy
3 23 f VHL VHL p.Phe119Leu no High Platelet Count Carotid Body negative Pheo no
4 23 f VHL VHL p.Arg64Pro yes Lateral neck mass Carotid Body positive no no
5 37 f VHL VHL p.Arg107His yes Lateral neck mass Carotid Body positive no CNS and retinal hbl,
Pheo
6 42 m MEN 2 RET p.Cys620Arg yes Tinnitus; hearing loss Gl jugulare negative no MTC
7 26 f VHL VHL p.Thr105Pro yes Lateral neck mass Carotid Body positive CNS and retinal hbl no
8 27 m VHL VHL del ex 2 and 3 yes Lateral neck mass Carotid Body positive Retinal hbl, RCC,
Pheo, PcCy
no
9 33 f VHL VHL p.Ser139fs yes Lateral neck mass, Horner's Carotid Body positive Retinal hbl, RCC, CNS hbl, RCC, Abd
syndrome, ear pain
PcCy
Pgl
10 34 f VHL VHL p.Tyr98His yes Pharyngeal discomfort Carotid Body negative no Pheos, Thoracic Pgl
11 15 f VHL VHL p.Thr157Ile yes Lateral neck mass Carotid Body negative Pheos, retinal hbl CNS hbl, ICT, Pheo
12 39 f VHL VHL p.Tyr156Cys no Routine VHL check Gl vagale negative Bilateral Pheo no
(20) 18 m VHL not reported yes Lateral neck mass Carotid Body positive no Pheo
(21) 32 m VHL not reported yes Lateral neck mass Carotid Body negative CNS hbl no
(22) nr m VHL VHL p.Val166Phe nr not reported Carotid Body negative Pheo, CNS hbl no
(23) nr f VHL VHL p.Tyr98His nr not reported Carotid Body positive Retinal hbl, Pheo,
PcCy
no
(24) 37 f MEN 2 not reported yes Tinnitus; hearing loss Gl tympanicum positive no MTC, Pheo
(25) 29 f MEN 2 not reported yes not reported Carotid Body nr no MTC
(26) 20 f NF 1 not reported yes Ear noise, tinnitus, hearing Gl jugulare positive Neurofibromas, Cafe Not reported
loss
au lait spots, Pheo
(27) 24 f VHL VHL p.Tyr152Ile Not
reported
not reported Carotid Body negative no no
22

Abbreviations: HNP, head and neck paraganglioma; Age, age at HNP manifestation; nr, not reported; Gl, glomus; Pheo, pheochromocytoma; CNS, central
nervous system; hbl, hemangioblastoma;RCC, renal cell carcinoma; PcCy, multiple pancreatic cysts; Pgl, paraganglioma; ICT islet cell tumor; MTC, medullary
thyroid carcinoma
23