Clinical Endocrinology (2008)
68
, 762–768 doi: 10.1111/j.1365-2265.2007.03131.x
© 2008 The Authors
762
Journal compilation © 2008 Blackwell Publishing Ltd
O R I G I N A L A R T I C L E
Blackwell Publishing Ltd
Uncommon clinical presentations of pheochromocytoma and paraganglioma in two different patients affected by two distinct novel VHL germline mutations
Tonino Ercolino*, Lucia Becherini*, Andrea Valeri¶, Michele Maiello*, Maria Sole Gaglianò*, Gabriele Parenti*, Matteo Ramazzotti‡, Elisa Piscitelli*, Lisa Simi†, Pamela Pinzani†, Gabriella Nesi§, Donatella Degl’Innocenti‡, Nico Console¶, Carlo Bergamini¶ and Massimo Mannelli*
*
Department of Clinical Physiopathology, Division of Endocrinology,
†
Division of Clinical Biochemistry,
‡
Department of Biochemistry,
§
Department of Human Pathology and Oncology, University of Florence, Florence, Italy and
¶
General and Vascular Surgical Unit, Azienda Ospadaliera Universitaria Careggi, Florence, Italy
Summary
Context
The von Hippel-Lindau (VHL) syndrome is an inherited
multitumour disorder characterized by clinical heterogeneity and
high penetrance. Pheochromocytoma (Pheo) is present in 10%–15%
of cases and can be isolated or associated with other lesions such as
haemangioblastomas, kidney cysts or cancer and pancreatic lesions.
In VHL patients, Pheos generally secrete norepinephrine and are
located in the adrenals. Extra-adrenal Pheos (paragangliomas, PGLs)
are rare.
Objective
While performing genetic testing in patients affected by
apparently sporadic Pheos or PGLs, we found two novel different
VHL germline mutations in two females who presented with two
distinct very uncommon clinical pictures. One patient was studied
for the presence of an adrenal incidentaloma and the other for the
presence of a neck tumour.
Methods and results
Patients coding regions and exon–intron
boundaries of RET (exons 10, 11, 13–15), VHL, SDHD, SDHB and
SDHC genes were amplified and sequenced. We identified two novel
VHL point mutations: a
L198V
missense mutation in a 32-year-old
female affected by a right adrenal compound and mixed tumour
constituted by an epinephrine secreting Pheo, a ganglioneuroma and
an adrenocortical adenoma, and a
T152I
missense mutation in a 24-
year-old female affected by a left carotid body tumour. No other
lesions were found in the patients or in the VHL mutation positive
relatives.
Conclusions
These cases enlarge the list of VHL mutations and
add new insights in the clinical variability of VHL disease, thus
confirming the importance of genetic testing in patients affected by
apparently sporadic Pheos or PGLs.
(Received 12 July 2007; returned for revision 7 August 2007; finally
revised 27 September 2007; accepted 16 October 2007)
Introduction
von Hippel-Lindau (VHL) disease is an autosomal dominant-
inherited tumour syndrome
1
related to mutations in the VHL
tumour suppressor gene, located on chromosome 3p25-26.
2
The major features of VHL disease are retinal and central nervous
system (CNS) haemangioblastomas, clear cell renal carcinomas and
pheochromocytomas (Pheo).
1–3
The overall frequency of Pheo in
VHL is about 10%–15%,
1–3
but Pheo is often the most frequent
feature in type 2A and 2B families while it is the sole manifestation
in type 2C and typically absent in type 1 kindreds.
1,3,4
All type 2A and 2C families and the vast majority of 2B families
are affected by VHL missense mutations.
4–8
In VHL patients, Pheos
are generally intra-adrenal, often bilateral
1,3,9
and are typically
noradrenaline secreting.
10
Extra-adrenal locations are rare.
We report two patients affected by two distinct novel germline
VHL missense mutations, who present with two very uncommon
clinical pictures.
Patients and methods
Mutation analysis
After obtaining informed consent, DNA was extracted from peri-
pheral blood leucocytes using the commercial kit NucleoSpin Blood
L (Macherey-Nagel, Düren, Germany) following the manufacturer’s
instructions.
Searching for germline mutations of the susceptibility genes in
patients affected by Pheo, we analysed RET (exons 10, 11, 13–15),
VHL (all exons), SDHD (all exons), SDHB (all exons) and SDHC
(all exons) genes.
All the gene coding regions and exon–intron boundaries were
amplified by PCR using the appropriate primers. For exons
Correspondence: Massimo Mannelli, Department of Clinical Physiopathology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy. Tel.: +39 0554271428; Fax: +39 0554271413; E-mail: [email protected]
VHL and clinical presentations
763
© 2008 The AuthorsJournal compilation © 2008 Blackwell Publishing Ltd,
Clinical Endocrinology
,
68
, 762–768
amplification, genomic DNA (200 ng) was denaturated at 95
°
C for
5 min, mixed with 10
×
buffer, 1·5 m
m
MgCl
2
, 0·4 m
m
primers,
200 m
m
dNTP, 1 U Taq polymerase in a final volume of 25
μ
l, and
cycled 30
×
at 95
°
C for 1 min, 58
°
C for 30 s, 72
°
C for 30 s and final
extention at 72
°
C for 7 min. Total PCR products were then purified
using a PCR purification kit (Qiagen, Milan, Italy) following the
protocol instructions and semiquantified in a 2% agarose ethidium
bromide gel using DNA molecular weight (Roche, Indianapolis, IN).
To perform the cycle-sequencing reaction, 5 ng of DNA were then
blended with each primer (0·8
μ
m
) in a Terminator Ready Reaction
Mix containing Big Dye Terminators (Applied Biosystems, Milan,
Italy) and submitted to 1 min at 96
°
C and 25 cycles at 96
°
C for 10 s,
50
°
C for 5 s, 60
°
C for 4 min. A second purification step was
necessary for the Big Dye removal with DyeEx 2·0 Spin Kit (Qiagen).
A 5-
μ
l of marked and purified DNA were submitted to sequencing
analysis with ABI PRISM 310 Genetic Analyser (Applied Biosystems).
Loss of heterozigosity (LOH) analysis
LOH was only determined in DNA extracted from laser microdissected
cells of tumour obtained at surgery from patient 1. For microdissec-
tion of frozen tissue sections, we used the PALM Laser – Microbeam
System (P.A.L.M. Microlaser Technologies AG, Bernried, Germany)
which enables the contact-free isolation of single cells or group of
cells. The sections were mounted onto a polyethylene membrane
slide according to the manufacturer’s instructions. Frozen sections
were fixed with ethanol immediately after cutting in a cryostat,
stained with Haematoxylin/Eosin followed by increasing ethanol
series and air-dried. The microdissected cells were catapulted into
the lid of a 0·5-ml reaction tube using the laser pressure catapulting
technique of the instrument. For the isolation of DNA, 30
μ
l of RLT
Buffer (Qiagen) were applied into the lid. Subsequently the tubes
were centrifuged and the samples extracted by using the DNA micro
kit (Qiagen) following manufacturer’s instructions. An aliquot of
this DNA was used for subsequent PCR and sequencing analysis as
previously reported.
11
Moreover, microsatellite analysis was per-
formed in two different loci according to the consensus physical map
of chromosome 3p. We choose the microsatellites D3S1038 in the
locus 3p26.1-3p25.2 and D3S1297 in the locus 3pter-3p25. The PCR
and sequencing of the microsatellite D3S1038 and D3S1297 were
carried out in a final volume of 25
μ
l containing 50 ng of genomic
DNA. The amplification was performed denaturing at 95
°
C for
5 min, mixed with 10
×
buffer, 1·5 m
m
MgCl
2
, 0·4 m
m
of fluorescent
primers, 200 m
m
dNTP, 1 U Taq polymerase and cycled 25
×
at 95
°
C
for 1 min, 58
°
C for 30 s, 72
°
C for 30 s and final extention at 72
°
C for
7 min. A 2-ul of the fluorescent PCR was added to 12·5
μ
l of formamide
and 0·5
μ
l of ROX size standard and then submitted to sequencing
analysis with ABI PRISM 310 Genetic Analyser (Applied Biosystems).
The analysis was performed by using the Genscan software and
analysed by Genotyper software.
Structural analysis
Three-dimensional analysis of the wild-type and the mutated VHL
proteins was performed by SWISS-PROT <http://www.expasy.ch/
cgi-bin/sprot-search-ful>.
Case reports
Patient 1.
A 32-year-old female presented a right adrenal mass at
sonography performed for gallbladder’s stones. An abdominal
computed tomography (CT) confirmed the presence of a solid
hypodense lesion of the right adrenal gland, 3
×
2·5 cm in size, that
showed an inhomogeneous enhancement after contrast injection
and was associated with a cystic lesion. In spite of a completely silent
clinical history, the hormonal analysis revealed elevated levels of
urinary metanephrine (2275
μ
g/24 h, n.v. 52–341) (11·54
μ
mol/24 h,
n.v. 0·26–1·7), normal levels of urinary normetanephrine (407
μ
g/
24 h, v.n. 88–440) (2·26
μ
mol/24 h, n.v. 0·48–2·4) and vanillylmandelic
acid (4·6 mg/24 h, v.n. 1·8–6·7) (23·0
μ
mol/24 h, n.v. 9·0–34·0),
normal levels of basal plasma catecholamines (adrenaline 40 pg/ml,
n.v. 5–125; noradrenaline 90 pg/ml, n.v. 65–400) (adrenaline
218 pmol/l n.v. 27–683; noradrenaline 532 pmol/l, n.v. 355–2185),
elevated level of plasma cortisol (1150 nmol/l, v.n.160–690) and
urinary free cortisol (486 nmol/l, v.n. < 275), normal levels of
androgens and ACTH in the low normal range (11·6 ng/l, v.n. 9–
52). Dexamethasone suppression test showed suppression of plasma
cortisol (76 nmol/l). A
123
I-MIBG scintigraphy showed a high tracer
uptake in the region of the right adrenal gland. The patient was
asymptomatic and the physical examination was negative. Blood
pressure measurement was always normal. After 7 days of doxazosine
treatment, the patient underwent laparoscopic removal of the
right adrenal gland and of the gallbladder. The postsurgical period
was uneventful and all hormonal parameters were normal 2 weeks
after surgery.
Patient 2.
A 24-year-old female was referred to our out-patient
clinic after having been operated for a 2·8-cm left carotid body
tumour. No relevant diseases were present in her past medical
history. Her family history was negative for the presence of neural
crest-derived tumours. Being a student in medicine, she asked for
genetic testing. After having sequenced all the exons of SDHD, SDHB
and SDHC genes, we then analysed the VHL gene.
Patients’ families.
Clinical, laboratory and genetic studies were later
on extended to all the family members who consented to be studied.
Results
Mutation analysis
In patient 1, no mutations were found in RET, SDHD, SDHB and
SDHC genes. In contrast, we identified a novel VHL point mutation
constituted by an heterozygous missense mutation,
L198V
(
594C >
G
), a C to G nucleotide substitution leading to a Leucine to Valine
amino acid change in exon 3 (Fig. 1a).
In patient 2, the analysis of SDHD, SDHB and SDHC genes
showed a normal sequence in all the exons. In contrast, we found
an heterozygous missense mutation
T152I
(
455C > T
), a C to T
nucleotide substitution, leading to a Threonine to Isoleucine amino
acid change in exon 2 of VHL gene (Fig. 2a). Both VHL codons at
the mutated sites are highly conserved through the species and were
not detected in 100 control subjects.
764
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et al.
© 2008 The AuthorsJournal compilation © 2008 Blackwell Publishing Ltd,
Clinical Endocrinology
,
68
, 762–768
The genetic test performed in the family members, the brother
and the father, of patient 1 showed no mutations (Fig. 1b), while in
patient 2 family, the sister and the mother, were found to carry the
VHL mutation (Fig. 2b).
LOH analysis
We did not find LOH in any of the components of the mixed tumour.
Clinical evaluation
Consequently to the finding of a VHL mutation, patient 1 was
extensively evaluated for the presence of other VHL-linked lesions.
Ophthalmoscopy as well as brain, thoracic and abdominal Nuclear
Magnetic Resonance (NMR) did not show any of the typically VHL-
associated lesions (retinal or CNS angiomas; endolymphatic sac
tumours; pancreatic or renal cysts; renal carcinoma; cystoadenoma
of the broad ligament).
Patient 2 as well as her mother and sister, both carriers of
the mutation, underwent a complete clinical evaluation,
which included an extensive physical examination, laboratory
tests (urinary metanephrine and normetanephrine, plasma
chromogranin A), an ophthalmoscopic examination and radio-
logical exams (NMR of the brain, CT scan of the thorax and
the abdomen). In each of the three subjects, the clinical examina-
tion, the laboratory tests and the radiological evaluations were
normal.
Histological characterization of the tumours
The histological examination of tumour in patient 1 showed a com-
pound adrenal medullary neoplasm, Pheo and ganglioneuroma,
associated to a cortical adenoma (Fig. 1c) appearing as a distinct
nodule in the context of the mass.
Histological characteristics of tumour in patient 2 showed a
glomus tumour and are shown in Fig. 2.
Fig. 1 (a) Electropherogram of wild-type (upper) and patient 1 (lower) showing the germline mutation L198V in exon 3 of the VHL gene. (b) Pedigree of patient 1 family. (c) Anatomical and histological characteristics of the compound and mixed tumour. S1: areas of pheochromocytoma containing large, polygonal chief cells which exhibit nuclear pleomorphism (Haematoxylin and Eosin stain; original magnification, × 25) S2: Ganglioneuromatous areas in which ganglion cells are admixed with abundant Schwann cells (Haematoxylin and Eosin stain; original magnification, ×60). S3: Adrenal cortical adenoma composed of alveolar clusters of lipid-rich cells (Haematoxylin and Eosin stain; original magnification, ×60).
VHL and clinical presentations
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© 2008 The AuthorsJournal compilation © 2008 Blackwell Publishing Ltd,
Clinical Endocrinology
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, 762–768
Structural analysis of missense mutations
Structural modelling of the two mutations is shown in Fig. 3.
Discussion
These two VHL mutation positive patients presented with a clinical
picture which, although associated to the presence of a Pheo and a
paraganglioma (PGL), by no way resembled the typical phenotype
of VHL disease. In fact, none of the patients presented with the
typically associated lesions in the CNS, retina, kidney and pancreas,
and although the type 2C form is characterized by the sole presence
of Pheo, the tumours diagnosed in our patients showed very unusual
or unique characteristics.
In patient 1, the adrenal mass was a compound and mixed tumour
presenting not only the association of chromaffin tissue with a
ganglioneuroma but also a distinct adrenocortical adenoma. The
adenoma was probably cortisol secreting, as suggested by the
increased urinary free cortisol, although dexamethasone suppressed
plasma cortisol and signs of chronic hypercortisolism were absent.
Compound
12–18
and/or mixed
19,20
adrenal tumours, although rare,
have been reported in the literature but, to our knowledge, this is
the first report on the association of three different tumours in the
same adrenal in a patient presenting a missense mutation of VHL
gene. Interestingly, recently we reported on a patient affected by a
compound Pheo/ganglioneuroma and an adrenal adenoma in the
contralateral gland, presenting an intronic variant in the VHL gene.
21
In VHL disease, Pheos are characterized by a noradrenergic
phenotype.
10,22
Therefore, an additional surprising finding in patient
1 was the pure adrenergic phenotype of the tumour. Urinary
adrenaline was about seven times higher than the upper limit of
normal while urinary noradrenaline was normal, thus demonstrating
the intratumoural synthesis of adrenaline.
It is impossible to establish whether adrenaline production might
depend on phenyl-ethanol-amine-
N
-methyltransferase (PNMT)
activation by cortisol secreted by the cortical adenoma, but the very
low or even absent PNMT gene expression in VHL Pheos
10
makes
the hypothesis unlikely. Moreover, in normal adrenal medulla
PNMT is maximally activated by adrenal cortisol as demonstrated
by the unchanged adrenaline : noradrenaline ratio in adrenal venous
blood of patients with Cushing’s disease.
23
The finding of normal adrenaline plasma levels suggests an intense
intratumoural conversion of adrenaline into metanephrine and
explains the silent clinical picture. Moreover, the finding that
metanephrine was the only abnormal marker of chromaffin pathology
reaffirms that the differential measurement of plasma or urinary
metanephrines is the laboratory test to be used in the diagnosis of
Pheo.
24
Fig. 2 (a) Electropherogram of wild-type (upper) and patient 2 (lower) showing the germline mutation T152I in exon 2 of the VHL gene. (b) Pedigree of patient 2 family. (c) Histological characterization of the glomus tumour: S1: Glomus tumour showing the nested growth (‘zellballen’) with delicate fibrovascular septae (Haematoxylin and Eosin stain; original magnification, ×60) S2: The chief cells react strongly and diffusely with chromogranin (immunoperoxidase and Haematoxylin counterstain; original magnification, ×120). S3: The sustentacular cells are highlighted by S-100 protein (immunoperoxidase and Haematoxylin counterstain; original magnification, ×120).
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Clinical Endocrinology
,
68
, 762–768
As no other living member of the family tested positive for the
mutation, it is impossible to determine whether patient 1 presented
with a
de novo
mutation. Her mother died at the age of 51 years of
a lung carcinoma.
Patient 2 was studied 1 year after the removal of a left carotid body
tumour. Head/neck PGLs are typically found in SDHx-mutated
patients,
11,25,26
but the genetic analysis of SDHD, SDHB and SDHC
were negative. To exclude the presence of large deletions in
SDHx
genes we also performed MLPA analysis which gave negative results
(data not shown).
Abdominal PGLs are rarely found in VHL disease and head/neck
PGLs are even rarer.
1
One peculiarity of this patient is that the
glomus tumour was the only lesion present. An additional peculiarity
is the absence of any VHL lesions in the two family members who
are positive for the same VHL mutation. In fact, VHL disease is
characterized by a high penetrance,
27
but the sister and the mother,
who is 48-years-old, were disease free. The patient and her mutated
relatives are regularly evaluated once a year by ophtalmoscopy, head,
neck and abdominal NMR as well as urinary metanephrines and
plasma chromogranin A measurement. The result was disease free
at the last evaluation. These findings might suggest that the VHL
T152I
mutation is characterized by a low penetrance.
We have no functional data to assess that these novel mutations
are responsible for the development of these tumours. The LOH
analysis did not help us in clarifying this issue. In fact, we did not
find LOH in any of the components of the mixed tumour, but it is
known that not all the VHL-linked tumours show LOH.
28
Other
events, such as hypermethylation or point mutations of the promoter
might cause allelic loss of function as well as additional somatic
heterozygous mutations occurring in the tumour cells.
However, structural analysis of the VHL protein suggests that
the mutations might indeed have functional relevance. Both the
missense mutations,
L198V
and
T152I
, are located in the
β
domain
of the VHL gene. The
β
domain consists of seven-stranded
β
sandwich,
residues 63–154, and an
α
helix, residues 193–204. The T152 is
located in the loop connecting the
β
and
α
domains, and could be
important for the alteration of the protein conformation, while the
L198 is located in a very important region for the elongin C binding
(Fig. 3). Moreover, both VHL codons at the mutated sites are highly
conserved through the species, the mutations were not detected in
more than 100 control subjects and amino acid changes in VHL
codon 198 (
L198Q
and
L198R
) have been described. Specifically, the
L198Q mutation has been associated with Pheo.
29,30
The clinical diagnosis of VHL disease stems on the recognition of
the disease-linked lesions which drive to the genetic analysis. Our
study started from the analysis of the susceptibility genes in patients
affected by apparently sporadic Pheos or PGLs and thus permitted
us to detect some uncommon VHL-related clinical presentations
which otherwise would have been gone unrecognized.
In conclusion, the present paper enlarges the list of VHL mutations
and adds new insights in the clinical variability of VHL disease, thus
confirming the importance of genetic testing in patients affected by
apparently sporadic Pheos or PGLs.
Acknowledgements
This work was supported by grants from MIUR (Ministero
dell’Istruzione, dell’Università e della Ricerca) (prot. 2004069534),
from the Department of Pathophysiology, University of Florence and
by an unrestricted grant from Villa Gisella (Florence, Italy).
M. Mannelli is member of the ENS@T (European Network for the
Study of Adrenal Tumours).
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