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The Journal of Clinical Endocrinology & Metabolism 92(3):779 –786
Copyright © 2007 by The Endocrine Society
doi: 10.1210/jc.2006-2315
EXTENSIVE CLINICAL EXPERIENCE
Clinical Presentations, Biochemical Phenotypes, and
Genotype-Phenotype Correlations in Patients with
Succinate Dehydrogenase Subunit B-Associated
Pheochromocytomas and Paragangliomas
Henri J. L. M. Timmers, Anna Kozupa, Graeme Eisenhofer, Margarita Raygada, Karen T. Adams,
Daniel Solis, Jacques W. M. Lenders, and Karel Pacak
Reproductive Biology and Medicine Branch (H.J.L.M.T., A.K., K.T.A., D.S., K.P.), National Institute of Child Health and
Human Development, Clinical Neurocardiology Section (G.E.), National Institute of Neurological Disorders and Stroke, and
Laboratory of Clinical Genetics (M.R.), National Institutes of Health, Bethesda, Maryland 20892-1109; and Department of
Internal Medicine (J.W.M.L.), Division of General Internal Medicine, and Department of Endocrinology (H.J.L.M.T.),
Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands
Context: Mutations of the gene encoding succinate dehydrogenase
subunit B (SDHB) predispose to malignant paraganglioma (PGL).
Recognition of the SDHB phenotype in apparently sporadic PGL directs appropriate treatment and family screening.
and was the sole symptom in 14%. Seventy-six percent had hypertension, and 90% lacked a family history of PGL. All primary tumors
but one originated from extraadrenal locations. Mean ⫾ SD tumor size
was 7.8 ⫾ 3.7 cm. In this referral-based study, 28% presented with
metastatic disease and all but one eventually developed metastases
after 2.7 ⫾ 4.1 yr. Ten percent had additional head and neck PGLs.
The biochemical phenotype was consistent with hypersecretion of
both norepinephrine and dopamine in 46%, norepinephrine only in
41%, and dopamine only in 3%. Ten percent had normal catecholamine (metabolite) levels, consistent with biochemically silent PGL.
No obvious genotype-phenotype correlations were identified.
Objective: The objective of the study was to assess mutation-specific
clinical and biochemical characteristics of SDHB-related PGL.
Design: The study design was retrospective descriptive.
Patients: Patients included 29 patients (16 males) with SDHB-related abdominal or thoracic PGL.
Conclusions: SDHB-related PGL often presents as apparently sporadic PGL with symptoms related to tumor mass effect rather than
to catecholamine excess. The predominant biochemical phenotype
consists of hypersecretion of norepinephrine and/or dopamine,
whereas 10% of tumors are biochemically silent. The clinical expression of these tumors cannot be predicted by the genotype. (J Clin
Endocrinol Metab 92: 779 –786, 2007)
Intervention: There was no intervention.
Main Outcome Measures: Clinical presentations, plasma and urine
concentrations of catecholamines and O-methylated metabolites, and
genotype-phenotype correlations were measured.
Results: Mean ⫾ SD age at diagnosis was 33.7 ⫾ 15.7 yr. Tumorrelated pain was among the presenting symptoms in 54% of patients
P
ARAGANGLIOMAS (PGLS) are tumors that derive
from either sympathetic tissue in adrenal and extraadrenal locations or parasympathetic tissue of the head and
neck (1). The majority of sympathetic tissue-derived PGLs
produce catecholamines, whereas parasympathetic PGLs
usually do not. A PGL arising from catecholamine-producing cells of the adrenal medulla is also referred to as pheochromocytoma (PHEO) (2, 3). The three genes involved in the
pathogenesis of familial PGL syndrome described to date
(4 – 6) include those encoding the B, C, and D subunits of
mitochondrial complex II enzyme succinate dehydrogenase
(SDH). Mutations of these genes result in distinct clinical
syndromes. SDHC mutation carriers typically present with
benign solitary head and neck PGL (7), whereas SDHD mutations are most frequently associated with multifocal head
and neck PGL and less frequently with adrenal and extraadrenal PGL (8, 9). The typical PGL associated with SDHB
mutations originates from extraadrenal abdominal or thoracic locations (8 –11). In contrast to predominantly benign
SDHC and D-associated tumors, up to 70% of SDHB-related
abdominal and thoracic PGLs develop into metastatic disease (12).
Recognizing SDHB-related disease in individual patients
can be delayed due to several factors. Despite an autosomal
dominant pattern of inheritance, penetrance of the disease is
incomplete and age dependent (8). Many patients with
SDHB-related tumors have no family history of PGL. Of
First Published Online January 2, 2007
Abbreviations: CT, Computed tomography; MRI, magnetic resonance imaging; PGL, paraganglioma; PHEO, pheochromocytoma; SDH,
succinate dehydrogenase.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.
779
780
J Clin Endocrinol Metab, March 2007, 92(3):779 –786
Timmers et al. • SDHB-Related Paraganglioma
patients with apparently sporadic PHEO or abdominal/thoracic PGL, 4 –7% have been identified as carriers of pathogenic SDHB mutations (12, 13). Furthermore, the diagnosis
may be delayed by lack of symptoms related to catecholamine excess. Such clinically silent PGLs either do not produce catecholamines or produce and metabolize but do not
secrete catecholamines or produce dopamine but not other
catecholamines (14 –17).
The aim of this study was to gain detailed insight into the
clinical and biochemical characteristics of SDHB-associated
tumors. In this single-center, referral-based study of patients
with SDHB-associated PHEO or abdominal/thoracic PGL,
clinical presentation, biochemical phenotype, tumor localization and pathology, and additional diagnoses were evaluated for evidence of genotype-phenotype correlations.
Timely recognition of the SDHB phenotype in apparently
nonfamilial cases direct an appropriate strategy for treatment, follow-up, and family screening.
Patients and Methods
Patients
This study included 29 patients (16 males, 13 females) with histological proof PHEO or of extraadrenal abdominal (including intrapelvic)
or thoracic PGL. There was no evidence of any family relationships
among patients. Eighteen patients were also included in a previous
study by our group (18). The patients represent all consecutive carriers
of an allelic variant of the SDHB gene among a large group of patients
who underwent genetic testing as part of evaluation of benign or malignant PGL at the National Institutes of Health (NIH). Genetic testing
for mutations in the SDHB gene was performed at the Department of
Human Genetics of the Pittsburgh University Medical Center as described elsewhere (19). Patients were included between November 2000
and May 2006. The protocol for this study was approved by the Institutional Review Board of the National Institutes of Child Health and
Human Development at the NIH. All patients provided written informed consent. The reason for referral to the NIH was to outline an
optimal treatment plan for (suspected) metastatic PGL. The mean ⫾ sd
interval between the initial diagnosis and referral to NIH was 5.0 ⫾ 8.5
yr. Clinical evaluation included a standardized inventory of symptoms
and signs. Information on individual patients is summarized in Table 1.
Laboratory tests and imaging
Blood samples were collected into heparin-containing tubes by use of
a forearm venous cannula, with patients supine for at least 20 min before
sampling. Patients were instructed to fast and abstain from caffeinated
and decaffeinated beverages overnight and avoid taking acetaminophen
for 5 d before blood sampling. All samples were collected on ice, and
plasma was separated and stored at ⫺80 C before analysis according to
recommended procedures (20). Plasma was assayed by HPLC for concentrations of free metanephrines and catecholamines, as described previously (21, 22), with further details and modifications as listed on the
Clinical Neurochemistry Laboratory web site (http://www.catecholamine.org/labprocedures). The 24-h urinary outputs of catecholamines and deconjugated (free plus conjugated) fractionated metanephrines for patients seen at the NIH were measured by HPLC or liquid
chromatography with tandem mass spectroscopy, under a contract between the NIH Clinical Center and an outside commercial laboratory
(Mayo Medical Laboratories, Rochester, MN). HPLC procedures were
also used for urinary measurements in patients seen elsewhere, as described previously. Biochemical profiles were determined during the
initial evaluation at the NIH. Hypersecretion of catecholamines was
defined as elevation of plasma and/or urine levels of the catecholamines
TABLE 1. Characteristics of individual patients
No.
Sex,
age at SDHB sequence
diagnosis variant protein
(yr)
cDNA
Ref.
Primary tumor
location,
size (cm)
Metastases,
years since
diagnosis
Metastases,
location
Family
history
of PGL
0.0
8.4
0.9
a/p, li, b
a/p, lu, li, b, n
lu, li, b
Neg
Neg
Neg
a/p, li, b
a/p, lu
b
a/p, b
a/p, lu, li, n
a/p, lu, b, n
a/p, b
a/p, li
a/p, lu, b, me
a/p, lu, b, me
a/p, li, b
1
2
3
F, 38
M, 10
F, 51
p.Pro130HisfsX5
IVS1–9A⬎G
IVS3⫹1G⬎A
c.391_392delC
c.73–9A⬎G
c.286⫹1G⬎A
28
18
18
l (juxta-)adrenal, ⬎5
r paraadrenal, 10
r paraaortic abd, 7.5
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
M, 35
F, 34
M, 52
F, 23
F, 49
M, 28
M, 8
F, 37
M, 10
M, 39
F, 39
F, 25
M, 35
M, 29
M, 60
IVS3–1G⬎C
p.Arg115X
p.Cys196Tyr
p.Val124SerfsX39
p.Ile127Ser
p.Cys196Tyr
p.Val140Phe
p.Val140Phe
p.Arg46X
p.Gln214His
IVS3⫹2T⬎A
p.Cys192Arg
IVS1⫹1G⬎T
p.Gly96Asp
p.Trp200Cys
c.287–1G⬎C
c.343C⬎T
c.587G⬎A
c.369_370insA
c.380T⬎G
c.587G⬎A
c.418G⬎T
c.418G⬎T
c.136C⬎T
c.642G⬎C
c.286⫹2T⬎A
c.574T⬎C
c.72⫹1G⬎T
c.287G⬎A
c.600G⬎T
New
8, 23
8, 9
New
18
8, 9, 12
18
18
8, 23, 25
18
18
9, 12
8, 26
18
New
l pararenal, 14.5
bladder, 5
l paraaortic abd, 6.0
Paraaortic abd, 3.0
r paraadrenal, 5.5
Bladder/chest wall
l parailiac art, ⬎5.0
Pelvic, 13.5
l paraadrenal, 5.0
l paraadrenal, 9.0
l extraadrenal abd, 7.0
r paraaortic abd, 4.0
Aortic bifurcation, 7.7
l pararenal, 18.0
Aortic bifurcation, 6.0
0.5
2.5
0.2
0.3
4.3
0.0
0.0
0.8
17.1
4.1
4.5
0.0
1.7
0.2
a/p, b, me
b
a/p, lu, b
Pos
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
19
20
21
M, 23
F, 24
M, 47
p.Arg46X
c.136C⬎T
8, 23
p.Ile127Ser
c.380T⬎G
18
p.Glu228GlyfsX27 c.683_684delAG 18
Aortic bifurcation, 7.5
l juxtaadrenal, 5.5
l para-(ad)renal, 10.0
0.0
0.0
3.5
b
b
a/p, b, me
Neg
Neg
Pos
22
23
24
F, 72
F, 35
F, 45
IVS1⫹1G⬎T
p.Arg46X
p.Val140Phe
Aortic bifurcation, 10.0
Bladder, 3.5
r paraaortic abd, 5.5
0.2
1.5
0.0
a/p, b
a/p, me
a/p
Neg
Neg
Neg
c.72⫹1G⬎T
c.136C⬎T
c.418G⬎T
8, 26
8, 23
18
25
F, 51
IVS5–2A⬎G
c.541–2A⬎G
18
r adrenal, 5.5
3.4
a/p, me, n
Pos
26
M, 11
p.Val140Phe
c.418G⬎T
18
Paraaortic abd, 8.0
1.1
a/p, lu, b
Neg
27
28
29
M, 39
M, 7
M, 35
p.Arg46Gln
p.Arg230His
p.Val140Phe
c.137G⬎A
c.689G⬎A
c.418G⬎T
27
10
18
l extraadrenal abd, 15.0
l pararenal, 4.0
l pararenal, 8.0
0.0
7.1
13.3
a/p, me, b
a/p, lu, b
b
Neg
Neg
Neg
Additional diagnosis
Hypercholesterolemia, obesity,
depression
Sinusitis, appendicitis
Hypothyroidism
Dyspepsia
Uterus myoma, cholelithiasis
Miscarriage
Varicocele
Cholelithiasis, deep venous
trombosis
Hiatus hernia
Hernia nuclei pulposi,
depression
Uterus myoma, hypothyroidism
Uterus/bladder prolaps,
cholelithiasis
Benign breast tumor, colon
polyps, melanoma, goiter
Myocardial hypertrophy, hernia
nuclei pulposi
Asthma, acid reflux, nodule l
upper thyroid
Pos, Positive; Neg, negative; M, male; F, female; l, left; r, right; art, artery; abd, abdomen; a/p, abdominal/pelvic; lu, lung; li, liver; me,
mediastinum; n, neck.
Timmers et al. • SDHB-Related Paraganglioma
J Clin Endocrinol Metab, March 2007, 92(3):779 –786
781
tases of a large, 16 cm extra-adrenal PGL located in the left
retroperitoneum. These 3 patients lacked symptoms of catecholamine excess, which is consistent with the findings of
normal levels of plasma and urine catecholamines and catecholamine metabolites. Also, during progression of metastatic lesions during follow-up, their plasma and urine levels
of catecholamines and their metabolites remained normal.
The fourth patient (no. 21) who had pain as an isolated initial
symptom presented with abdominal pain and nausea due to
an invasive 10 cm retroperitoneal tumor. Laboratory findings
in this particular patient indicated isolated hypersecretion of
dopamine and not of other catecholamines. Later on he developed metastatic lesions to the bone and mediastinum. At
this point he did experience occasional palpitations, diaphoresis and bouts of hypertension in addition to therapyresistant bone pain. Another patient (no. 11) was completely
free of symptoms and signs, when a 9-cm intrapelvic tumor
was incidentally discovered on ultrasound during pregnancy. Her laboratory findings were consistent with both
norepinephrine and dopamine production.
In 3 of 29 (10%) patients, family history was positive for
PGL. The father of one patient (no. 4) was a carrier of the same
SDHB mutation as was his son (IVS3–1G⬎C), and had a neck
PGL removed at age 30. The father of another patient (no. 21)
had multiple head and neck PGL and was being treated for
malignant abdominal PGL with multiple bone lesions elsewhere. The mother of another patient (no. 25) had a mediastinal PGL removed in her fifties and was doing well. Information on the genotype of the latter two relatives is
lacking. A sister of another (no. 23), who was also carrier of
the p.Arg46X mutation, had no history of PGL, but was
treated for papillary thyroid cancer.
and/or the O-methylated metabolites metanephrine and normetanephrine above the upper range of normal.
Anatomic localization of PGL was performed by whole-body CT
and/or whole-body MRI, which included the head and neck area in
search of (additional) parasympathetic PGL.
Results
Initial clinical presentation
Age at presentation of first symptoms was 30.6 ⫾ 16.0
(range 6 –70) yr. The initial clinical presentation included
one or more symptoms relating to catecholamine excess in
23 of 28 (82%) of patients (Table 2). Nine of 28 (32%)
patients had a classic triad of headache, palpitations and
diaphoresis. These symptoms occurred episodically in 14
of 16 (88%) patients, were related to exercise in three
patients (no. 5, 20, and 26) and to micturition in two
patients (no. 10, 24). The latter two had intrapelvic tumors.
Three patients presented with hypertensive crisis, either
during pregnancy (no. 5) or during anesthesia for stomach
surgery (no. 19), one coinciding with stroke (no. 28). Twenty-two of 29 (76%) patients had a history of hypertension,
including one (no. 1) who became blind due to hypertensive retinopathy.
Tumor-related pain was among the initial presenting
symptoms in 15 of 28 (54%) patients, and was the sole presenting symptom in 4 patients (no. 17, 18, 21, 27). One of these
patients (no. 17) presented with upper abdominal discomfort
caused by a large 18 cm retroperitoneal mass. Another (no.
18) had experienced pelvic pain, hematuria and weight loss
before presenting with deep venous thrombosis of the left leg
due to intrapelvic metastases. Another (no. 27) presented
with back pain related to multiple metastatic lesions of the
lumbar spine that were pathologically proven to be metasTABLE 2. Signs and symptoms at presentation
Anxiety/
panic
attacks
Hypertension
Dizziness
Nausea
Chest
pain
Tumorrelated
pain
⫹
⫺
⫹
⫺
⫺
⫺
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫺
⫺
⫺
⫹
⫺
⫹
⫹
⫹
⫺
⫹
⫹
⫺
⫺
⫺
⫺
⫹
⫹
⫹
⫹
⫹
⫹
⫺
⫺
⫺
⫺
⫹
⫹
⫺
⫹
⫺
⫺
⫹
⫺
⫺
⫺
⫹
⫺
⫺
⫹
⫺
⫺
⫹
⫹
⫺
⫹
⫺
⫹
⫺
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫹
⫹
⫹
⫹
Headache
Tachycardia/
palpitations
Diaphoresis
Flushing
1
2
3
4
5
⫹
⫹
⫺
⫺
⫹
⫹
⫺
⫹
⫹
⫹
⫹
⫹
⫹
⫺
⫹
⫺
⫺
6
7
8
9
10
11
⫺
⫹
⫹
⫹
⫹
⫺
⫹
⫹
⫹
⫹
⫹
⫹
⫺
⫹
⫺
⫺
⫹
⫺
⫺
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫺
12
13
14
15
16
⫹
⫹
⫹
⫹
⫹
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫹
⫺
⫹
⫺
⫹
⫹
17
18
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
19
20
21
22
⫹
⫺
⫺
⫺
⫹
⫺
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫹
⫺
⫺
⫹
⫹
⫹
⫹
⫺
⫹
⫹
⫹
⫹
⫺
⫹
⫹
62
⫹
⫹
⫹
⫹
⫺
⫹
⫹
68
⫺
⫹
⫹
⫹
⫺
⫹
⫹
56
Patient no.
23
24
25
26
27
28
29
Percent
of total
⫹
⫹
⫹
Pallor
Tremor
⫹
⫹
⫹
⫹
⫺
⫺
⫹
44
⫹
⫺
⫹
⫺
⫹
⫺
20
⫺
⫺
⫺
⫹
⫹
29
⫹
⫹
⫺
⫹
⫺
62
⫹
⫹
⫹
⫺
⫹
⫹
⫹
⫹
⫺
⫹
⫺
75
⫺
⫹
⫺
⫺
⫺
32
⫹
⫺
⫹
⫺
⫹
⫹
57
⫺
⫹
⫺
⫹
⫺
⫺
⫹
53
⫹
⫹
⫹
⫹
⫹
⫺
⫹
⫺
⫺
⫹
⫹
⫹
⫹
54
Additional
comments
Severe hypertensive retinopathy, fatigue
Recent diabetes mellitus, weight loss
Exercise-related symptoms, hypertensive crisis
during pregnancy
Weight loss
Constipation, dyspnea
Fatigue
Tachycardia upon voiding, fatigue, weight loss
No symptoms (incidentaloma on ultrasound
for pregnancy)
Fatigue
Presenting symptoms unknown, patient diseased
Fatigue, orthostatic tachycardia, dizziness
Erectile dysfunction, deep venous thrombosis,
weight loss
Fatigue, dyspnea
Deep venous trombosis, hematuria, fatigue,
weight loss
Fatigue, weakness
Exercise-related nausea/vomiting, abdominal pain
Fatigue, weight loss, blurred vision, constipation,
weakness
Sympoms related to voiding
Dizziness
Dyspnea
Exercise-related symptoms, fatigue, weakness
Hypertensive crisis including stroke
Numbness in hands, fatigue
782
J Clin Endocrinol Metab, March 2007, 92(3):779 –786
Timmers et al. • SDHB-Related Paraganglioma
Diagnosis and follow-up
Mean ⫾ sd age at diagnosis of PHEO or PGL was 33.7 ⫾
15.7 yr. The delay until the diagnosis was 4.5 ⫾ 4.6 (range
1–19) years. Primary tumors, detected by either computed
tomography (CT) or magnetic resonance imaging (MRI),
were in extraadrenal locations in all but one patient (no. 25).
The maximal diameter of the primary tumors from either
pathology or radiology reports was 7.8 ⫾ 3.7 cm. In eight of
29 (28%) patients, metastatic disease was already apparent at
initial presentation. Malignant PHEO and PGL was defined
as the presence of metastatic lesions at sites in which chromaffin tissue is normally absent (23). Pathology reports of all
resected (n ⫽ 21) and biopsied (n ⫽ 8) primary tumors were
consistent with PHEO or PGL. In 14 of 29 (48%) patients,
tumor invasion of blood/lymphatic vessels or adjacent organs was mentioned in the pathology report. Head and neck
PGLs had been diagnosed before referral in three of 2930
(10%) patients (no. 12, 21: left glomus caroticum, and no. 24:
left glomus jugulare). No additional head and neck tumors
were identified during evaluation at the NIH. Additional
diagnoses from medical history are indicated in Table 1.
In this referral-based study, all patients except one developed metastatic lesions. One patient (no. 15) had no radiological or biochemical evidence of malignant PGL. Mean
interval between diagnosis of PGL and metastatic disease
was 2.7 ⫾ 4.1 (range 0 –17) yr. Metastatic locations included
the abdominal/intrapelvic compartment (outside the liver)
in 89% of patients, bone in 75%, lung in 36%, liver in 25%,
mediastinum in 29%, and head or neck in 14% (Table 1).
Metastatic lesions were detected by CT and/or MRI in 27 of
28 (96%) patients. In one patient (no. 20), CT and MRI were
negative, whereas [123I]-metaiodobenzylguanidine scintigraphy showed multiple bone lesions as well as pathological
activity in the right abdominal paraaortic region. Four patients died of widespread metastatic disease (no. 8, 13, 22,
and 25).
Biochemical phenotype
Data available from outside centers on laboratory findings
at diagnosis of primary nonmetastatic PHEO were limited.
At diagnosis of the primary tumor, plasma concentrations of
norepinephrine were elevated in five of five patients, free
normetanephrine in five of six, and plasma dopamine in
three of six, whereas none had elevated plasma concentrations of epinephrine or free metanephrine. At this point, 24-h
urinary output of norepinephrine was elevated in six of
seven patients, deconjugated normetanephrine in four of six,
vanillylmandelic acid in nine of 10, dopamine in one of one,
and epinephrine and metanephrine in none. At evaluation of
metastatic disease at the NIH, the profile of catecholamine
hypersecretion was distributed as follows: both norepinephrine and dopamine in 13, norepinephrine only in 12, dopamine only in one, and no hypersecretion of catecholamines
in the three (Table 3). Two patients (no. 9, 22) with wide-
TABLE 3. Biochemical phenotype
Plasma
Urine
Patient no.
NE
E
DA
NMN
MN
CgA
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Percent of total
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫺
⫺
⫹
⫹
⫺
⫹
⫹
⫹
⫹
⫹
⫺
⫹
⫹
86
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
3
⫹
⫹
⫺
⫹
⫺
⫺
⫺
⫹
⫹
⫹
⫹
⫹
⫹
⫺
⫺
⫹
⫺
⫺
⫹
⫺
⫹
⫹
⫹
⫺
⫺
⫺
⫺
⫺
⫺
48
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫺
⫹
⫹
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫹
⫹
⫹
⫹
⫺
⫺
⫹
⫹
⫺
⫹
⫹
⫹
⫹
⫹
⫺
⫹
⫹
82
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
7
⫹
⫺
⫺
⫺
⫺
⫺
⫹
⫹
⫺
⫹
⫺
⫹
⫺
⫹
⫹
⫹
⫹
⫹
81
NE
E
DA
NMN
MN
⫹
⫺
⫹
⫺
⫺
⫹
⫹
⫹
⫹
⫹
⫹
⫺
⫹
⫹
⫹
⫹
⫺
⫺
⫹
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫹
⫹
⫺
⫹
⫹
⫺
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫹
⫺
⫹
⫹
⫹
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫺
⫺
⫺
⫹
⫺
⫹
⫹
⫺
⫺
⫹
⫺
⫺
⫺
⫹
⫹
⫺
⫺
⫺
⫺
⫺
⫹
⫹
⫹
⫹
⫺
⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫹
⫹
⫹
⫺
⫹
⫺
⫹
⫺
⫺
⫺
⫹
75
0
33
84
20
Biochemical phenotype
NE⫹DA
NE⫹DA
NE
NE⫹DA
NE
NE
NE
NE⫹DA
NE⫹DA (⫹E)
NE⫹DA
NE⫹DA
NE⫹DA
NE⫹DA
NE
NE
NE⫹DA
none
none
NE⫹DA
NE
DA
NE⫹DA (⫹E)
NE⫹DA
NE
NE
NE
none
NE
NE
Elevated (marked as ⫹) and normal (marked as ⫺) concentrations of catecholamines and their metabolites at evaluation of metastatic disease
(all but no. 16) and primary nonmetastatic PHEO (no. 16). Patients 8 and 14 were evaluated after chemotherapy. NE, Norepinephrine; E,
epinephrine; DA, dopamine; NMN, normetanephrine; MN, metanephrine; CgA, chromogranin A.
Timmers et al. • SDHB-Related Paraganglioma
spread metastatic disease from extraadrenal PGL and largely
elevated levels of norepinephrine and dopamine had additional elevation of plasma epinephrine and/or metanephrine. In the first patient (no. 9), plasma norepinephrine and
dopamine were increased to 55 and 4 times the upper reference limit of normal, respectively, whereas plasma epinephrine was normal and plasma metanephrine was elevated to twice the upper limit, respectively. The second
patient (no. 22) with largely increased plasma norepinephrine (40 times the upper limit) and dopamine (25 times the
upper limit) also had mildly elevated plasma levels of epinephrine and metanephrine (both two times the upper limit)
on one occasion. Plasma concentrations of chromogranin A
were elevated in 13 of 16 patients (81%) and 10 of 13 patients
(77%) with metastatic disease (Table 3).
Genotype-phenotype correlation
In 29 index patients, 20 different sequence variants of the
SDHB gene were found (Table 1), nine of which had been
previously reported as disease-causing mutations by others
(8, 9, 12, 13, 24 –29). Eleven allelic variants were identified by
our group, eight of which were published previously (18). Of
these 11 variants, nine are very likely to represent diseasecausing mutations for the following reasons: five were also
found in other patients with PGL (no. 4, 8, 11, 14, 18, 20, 24,
26, 29), two resulted in a frameshift causing a premature stop
codon and a truncated protein (no. 7, 21), one was located in
a splice site donor site (no. 3), and one in a splice site acceptor
site (no. 25). The latter two splice site mutations are likely to
interfere with RNA processing. In addition, the p.Val140Phe
allelic variant, which was present in five patients (Table 1),
was absent in 100 control subjects. Whether the missense
mutations observed in the remaining two patients (no. 2 and
13) with new variants represent disease-causing mutations
remains to be confirmed. In the first patient (no. 2) the variant
was located close to a splice acceptor consensus region,
whereas the variant in second patient (no. 13) causes substitution of an amino acid in a strongly conserved region of
the protein. Family history of both patients was negative for
PGL. Additional genetic testing for additional mutations of
SDHD, RET, and VHL genes was performed in 21, 20, and 19
patients, respectively. All results were negative.
Genotype-phenotype correlations among patients with
SDHB mutations in different exons did not reveal obvious
differences for age at presentation, biochemical phenotype,
primary tumor size and location, distribution of metastatic
lesions, or presence of additional head and neck PGLs (Fig.
1).
Discussion
Important information on the clinical characteristics and
penetrance of different SDH-related PGL syndromes among
index cases and their family members was gathered by large
multinational PGL study consortia (8, 9, 12). In these reports,
a particularly severe clinical phenotype of tumors with high
malignant potential was observed in carriers of a mutation
in the SDHB gene. We present the first single-center evaluation of genetic, clinical, and biochemical characteristics of a
large group of patients with SDHB-related PGL. Early rec-
J Clin Endocrinol Metab, March 2007, 92(3):779 –786
783
ognition of features pointing toward SDHB-related disease is
important because this diagnosis warrants aggressive therapy and intensive follow-up.
Clinical presentation
The majority of patients had one or more symptoms related to catecholamine excess in addition to hypertension.
However, only one third had the classical triad of headache,
palpitations, and diaphoresis. In more than half of the patients, the clinical picture at initial presentation was dominated by problems caused by space-occupying effects of the
tumor, including pain or discomfort, deep venous thrombosis, urological problems, and weight loss. These symptoms
and signs are unusual in benign PHEO and PGL and probably relate to a high prevalence of large invasive tumors and
metastatic disease at presentation. Space-occupying complications in patients with suspected PGL should trigger clinicians to think of an SDHB-related malignant tumor. An atypical presentation may account for the observed mean delay
between the onset of symptoms and the diagnosis of 4.5 yr.
The majority of the currently investigated patients presented in their early 30s, which is similar to earlier observations for index cases (8). We confirm, however, that SDHBrelated tumors may also occur in young children before 10
yr of age or not until after age 65 yr (11, 27). The age-related
penetrance among SDHB mutation carriers was found to be
29% by 30 yr of age and 45% by age 40 yr (8). Genetic and/or
environmental factors responsible for this large variability in
penetrance are unknown.
Only 10% of the currently investigated patients had a
family history of PGL, compared with 37% of patients in a
previous report (8). In the same study, screening of asymptomatic SDHB-positive relatives identified tumors in 11% (8).
We agree with the notion that all first-degree family members of patients with SDHB-associated PGL should be offered
genetic testing (30). We are currently extending our genetic,
clinical, and biochemical studies to the patients’ relatives.
Our findings emphasize that a negative family history of
PHEO and PGL by no means rules out the presence of an
SDHB mutation. The prevalence of SDHB mutations in apparently sporadic nonsyndromic PHEO is 4 –7% (12, 13, 31).
It is in the patients lacking a positive family history that
clinicians depend on other clinical, biochemical, and radiological clues for SDHB mutations. Familial PGL syndrome
may be expected from the finding of additional head and
neck PGL, which are present in up to 31% of SDHB mutation
carriers (8, 9). In addition, 80% of SDHB-associated PGL are
located in extraadrenal abdominal, intrapelvic, or thoracic
locations (12). Tumors are more often multifocal and are
usually large, with diameters of around 9 cm (12). Among the
patients in the current study, only 10% had an additional
head or neck PGL and as many as 97% of the primary tumors
were in extra-adrenal locations, with a mean diameter of
nearly 8 cm.
Biochemical phenotype
Evaluation of the biochemical phenotype of PGL mainly
revealed hypersecretion of norepinephrine and/or dopamine. Our findings of predominant hypersecretion of nor-
784
J Clin Endocrinol Metab, March 2007, 92(3):779 –786
Timmers et al. • SDHB-Related Paraganglioma
FIG. 1. Phenotype of index patients with PHEO according to SDHB mutation. The eight exons of SDHB are represented diagrammatically.
Missense mutations are shown in the upper portion of the figure, and truncating or splice site mutations are shown in the lower portion. The
phenotype observed in each patient is represented by a unit of four boxes, with the patient number shown above. DA producing, Hypersecretion
of dopamine (⫾ other catecholamines).
epinephrine are consistent with the notion that extraadrenal
PGL rarely secrete epinephrine (32). This probably reflects a
decreased expression of phenylethanolamine-N-methyltransferase, the enzyme that converts norepinephrine to epinephrine (33). According to limited information on the biochemical phenotype of SDHB-related PGL in a previous
report (8), six of 30 patients showed elevated urinary excretion of both epinephrine and norepinephrine, whereas one of
30 patients showed elevations confined to urinary epinephrine. It is not mentioned whether elevated urinary epinephrine levels were found in adrenal or extraadrenal tumors.
Cosecretion of dopamine, which was present in half of the
patients with norepinephrine hypersecretion, is mainly
found in multifocal or metastatic extraadrenal PGL (14). In
addition, increased excretion of dopamine was shown to
predict malignant potential in preoperative patients with
apparently nonmetastatic PGL (34). Exclusive overproduction of dopamine, as found in one patient, is rare and mainly
occurs in extraadrenal PGL (14, 16, 17). As observed in the
case we present here, these patients have an atypical presentation, lacking symptoms of catecholamine excess and
hypertension (16). In clinical practice, measurement of
plasma levels of dopamine or its O-methylated metabolite
methoxytyramine should be considered for identification of
tumors that predominantly produce dopamine but only in
patients with an atypical presentation in whom PGL is
strongly suspected despite normal plasma and urinary levels
of other catecholamines, and the catecholamine O-methylated metabolites, normetanephrine, and metanephrine (14).
Patients with PGL who lack symptoms of catecholamine
excess pose a significant diagnostic challenge (15). Such clinically silent tumors may occur in PGLs that do not produce
catecholamines, in those that produce and metabolize, but do
not secrete catecholamines, and those that produce dopamine but not other catecholamines (14 –16). The diagnosis of
biochemically silent tumors, i.e. tumors that either do not
Timmers et al. • SDHB-Related Paraganglioma
produce or do not secrete catecholamines, is usually delayed
until advanced metastatic disease, when complications of
space-occupying lesions occur. This was also the case in the
three patients with biochemically silent tumors in the current
study. In this respect, these SDHB-related extraadrenal abdominal PGLs appear to share features with parasympathetic head and neck PGLs, which are also usually biochemically silent (35). These tumors may arise from subsets of cells
that lack the ability to produce, metabolize, and secrete catecholamines. Alternatively, tumor cells may lose this ability
due to dedifferentiation before the tumor is big enough to
secrete significant amounts of catecholamines. For the monitoring of these biochemically silent PGLs, plasma levels of
chromogranin A may provide an alternative biochemical
parameter (36). Plasma chromogranin was positive in two of
the three patients’ tumors that did not produce
catecholamines.
SDHB mutations and malignant disease
Of the patients described in our study, all but one (97%)
developed metastatic lesions of PGL at a mean interval of 2.7
yr after the diagnosis. The finding of a very high rate of
malignant PGL among SDHB mutation carriers is due to
selection bias of this referral-based study. In the majority of
cases, the actual reason for referral to the NIH was evaluation
and treatment of metastatic disease. However, among previously described patients with SDHB-associated PHEO or
abdominal/thoracic PGL, the rates of malignancy were also
high: 11 of 32 (34%) (9), 15 of 21 (71%) (12), and 18 of 48
(37.5%) (8). In nearly one third of cases, though, malignant
disease was already evident at the initial diagnosis of PHEO/
PGL, which is similar to the previous finding of 22% (8).
Apart from malignant PGL, SDHB mutations have been
suggested to be associated with malignant tumors of the
extraparaganglial system. Among 53 SDHB mutation carriers, two patients from the same family had renal clear cell
carcinoma at young age and one patient with a different
mutation had a papillary thyroid carcinoma at age 14 yr (9,
37). These associations, however, were not confirmed by
more recent studies (8, 12) including the present one.
Previously, genotype-phenotype correlations failed to distinguish differences in tumor location and malignant potency of SDHB-related PGL between different mutations (8).
In addition, clinical phenotypes may largely differ between
family members with the same mutation. In the present
study, features that are associated with aggressive tumor
behavior, including young age at presentation, large tumor
size, metastatic disease at presentation, and hypersecretion
of dopamine, were equally distributed among patients with
missense vs. truncating mutations and were independent of
exon locations.
Apart from intragenic mutations, there are two reports on
five patients with extraadrenal PGL related to large deletions
of the SDHB gene (38, 39). These whole gene or partial deletions, with a possible hot spot in the first exon, remain
undetected by conventional SDHB gene analysis. Because
data on such deletion families are still limited, it remains to
be elucidated whether this genotype is associated with a
phenotype distinct from intragenic SDHB mutations.
J Clin Endocrinol Metab, March 2007, 92(3):779 –786
785
Conclusions
SDHB-associated PHEO and PGL is characterized by a
high malignant potency, warranting aggressive therapy,
strict follow-up, and family screening. The diagnosis may be
delayed by a negative family history and an atypical clinical
presentation with signs and symptoms that are predominantly related to tumor growth rather than to catecholamine
excess. The biochemical phenotype usually consists of hypersecretion of norepinephrine and/or dopamine, but 10%
of tumors are biochemically silent. The clinical expression of
these tumors in individual patients cannot be predicted by
the type and location of the SDHB gene mutation.
Acknowledgments
We thank Diana Benn for helpful discussions and feedback to the
manuscript. We thank Thanh-Truc Huynh for her technical assistance.
Received October 24, 2006. Accepted December 21, 2006.
Address all correspondence and requests for reprints to: Karel Pacak,
M.D., Ph.D., D.Sc., Head, Section on Medical Neuroendocrinology, Reproductive Biology and Medicine Branch, National Institute of Child
Health and Human Development, 10 Center Drive, Building 10, CRC,
Room 1-E 3140, MSC 1109, Bethesda, Maryland 20892-1109. E-mail:
karel@mail.nih.gov.
This work was supported by the Intramural Research Program of the
National Institute of Child Health and Human Development/National
Institutes of Health.
Disclosure Statement: The authors have nothing to disclose.
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