Download SDHB

Journal Club 2006.9.21
Diabetes and Endocrine Department,
Kameda medical center
Masahiro Masuzawa
REVIEW ARTICLE
Should Patients with Apparently Sporadic Pheochromocytomas or
Paragangliomas be Screened for Hereditary Syndromes?
Camilo Jiménez, Gilbert Cote, Andrew Arnold and Robert F. Gagel
Instituto Nacional de Cancerología/Fundación Santafé de Bogotá (C.J.), Colombia, South America, Joint
Baylor College of Medicine/The University of Texas M. D. Anderson Cancer Center Training Program in
Endocrinology, Houston, Texas 77030; Department of Endocrine Neoplasia and Hormonal Disorders (G.C.,
R.F.G.), The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; and Center for
Molecular Medicine (A.A.), University of Connecticut School of Medicine, Farmington, Connecticut 06030
Address all correspondence and requests for reprints to: Robert F. Gagel, M.D., Unit 433, M. D. Anderson
Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030. E-mail: rgagel{at}mdanderson.org.
The Journal of Clinical Endocrinology & Metabolism, 2006, 91(8):2851-2878
ABSTRACT
Background The group of susceptibility genes for pheochromocytoma that included the protooncogene RET (associated with multiple endocrine neoplasia type 2 [MEN-2]) and the tumorsuppressor gene VHL (associated with von Hippel–Lindau disease) now also encompasses the
newly identified genes for succinate dehydrogenase subunit D (SDHD) and succinate
dehydrogenase subunit B (SDHB), which predispose carriers to pheochromocytomas and glomus
tumors. We used molecular tools to classify a large cohort of patients with pheochromocytoma with
respect to the presence or absence of mutations of one of these four genes and to investigate the
relevance of genetic analyses to clinical practice.
Methods Peripheral blood from unrelated, consenting registry patients with pheochromocytoma was
tested for mutations of RET, VHL, SDHD, and SDHB. Clinical data at first presentation and follow-up
were evaluated.
Results Among 271 patients who presented with nonsyndromic pheochromocytoma and without a
family history of the disease, 66 (24 percent) were found to have mutations (mean age, 25 years;
32 men and 34 women). Of these 66, 30 had mutations of VHL, 13 of RET, 11 of SDHD, and 12 of
SDHB. Younger age, multifocal tumors, and extraadrenal tumors were significantly associated with
the presence of a mutation. However, among the 66 patients who were positive for mutations, only
21 had multifocal pheochromocytoma. Twenty-three (35 percent) presented after the age of 30
years, and 17 (8 percent) after the age of 40. Sixty-one (92 percent) of the patients with mutations
were identified solely by molecular testing of VHL, RET, SDHD, and SDHB; these patients had no
associated signs and symptoms at presentation.
Conclusions Almost one fourth of patients with apparently sporadic pheochromocytoma may be
carriers of mutations; routine analysis for mutations of RET, VHL, SDHD, and SDHB is indicated to
identify pheochromocytoma-associated syndromes that would otherwise be missed.
N Engl J Med, 2002, 346:1459-1466
The Hereditary Pheochromocytoma
or
Paraganglioma Syndrome
NF1
NF1 is an autosomal-dominant disorder, occurring in one of 3000–4000 people and characterized by
neurofibromas, lightly pigmented birthmarks (café au lait spots), iris hamartomas (Lish nodules), and skinfold freckling. NF1 is caused by inactivating mutations of neurofibromin, a tumor suppressor gene that
encodes a GTPase-activating protein involved in the inhibition of Ras activity. Pheochromocytomas are rare,
with frequency estimates of 0.1–5.7% but elevated to 20–50% in hypertensive patients with NF1 . In most
reported NF1 catecholamine-producing tumors, single pheochromocytomas are the most common
presentation (84%), followed by bilateral pheochromocytomas (10%) and sympathetic paragangliomas (6%) .
Most are benign tumors (90%), although malignant pheochromocytomas and sympathetic paragangliomas
have also been found . These tumors have a presentation and course similar to those of the sporadic ones.
Most of them occur in adults (mean age, 42 yr), with rare examples of multigenerational pheochromocytomas
. Most pheochromocytomas produce a predominance of norepinephrine and therefore most commonly present
with hypertension and adrenergic symptomatology. However, 22% of pheochromocytomas have no symptoms
related to excessive catecholamine secretion . NF1 can be diagnosed simultaneously with
pheochromocytoma; however, the typical skin lesions lead to the diagnosis of NF1 during childhood , making
NF1 unlikely to present as apparently sporadic pheochromocytoma.
VHL
VHL is an autosomal-dominant syndrome with an incidence of one in 36,000 births . VHL is caused by
mutations of the VHL gene, a tumor suppressor gene that encodes a protein (pVHL) that regulates hypoxiainducible genes, the fibronectin matrix assembly, and angiogenesis . This protein inhibits the accumulation of
hypoxia-induced proteins through ubiquitin-mediated degradation of hypoxia-inducible factor-1 subunits
under conditions of normoxemia . In carriers of VHL gene germline mutations, the regulation of genes such as
the vascular endothelial growth factor and other genes involved in cellular growth seems to be lost,
predisposing the VHL carriers to both benign and malignant tumors in multiple organs (i.e. renal, testicular,
and pancreatic cysts, renal cell cancer, islet cell tumors, central nervous system hemangioblastomas,
endolymphatic sac tumors, and adrenal tumors) . Pheochromocytomas occur in 10–34% of patients with VHL
with a mean age at presentation of 18.3 yr. The prevalence is 6–9% in people with mutations caused by partial
or complete deletions of the VHL gene (VHL type 1), whereas those with missense mutations have a
prevalence of 40–59% (VHL type 2), exhibiting genotype-phenotype correlation . These catecholamineproducing tumors could present as the first or only manifestation of VHL (VHL type 2C) . Consequently,
VHL carriers can present as apparently sporadic pheochromocytoma. VHL catecholamine-producing tumors
are most commonly pheochromocytomas (90%), although sympathetic paragangliomas have been described
(abdomen 8%, chest 2%, and neck 0.1%) . Approximately half of pheochromocytomas are bilateral , and most
produce norepinephrine . There are uncommon examples of malignant catecholamine-producing tumors in
VHL (<10%), frequently sympathetic paragangliomas .
Figure 1. The ubiquitination of the HIF-1 by the pVHL. (Modified with permission from S. Richard: Atlas of Genetics and
Cytogenetics in Oncology and Haematology, VHL, January 2002;
http://www.infobiogen.fr/services/chromcancer/Genes/VHLID132.html.) HIF-1 heterodimerizes with HIF-1ß to form HIF
that functions as a transcription factor. HIF activates the expression of genes involved in angiogenesis, erythropoiesis, energy
metabolism, apoptosis, and/or proliferation in response to low-oxygen tension (hypoxia) conditions. pVHL inhibits HIF
activity under normal oxygen conditions (normoxia) by targeting the HIF-1 subunits for ubiquitination and proteasomal
degradation (left). pVHL binds to HIF only when a conserved proline (Pro 564) in HIF is hydroxylated, a modification that is
oxygen-dependent (27 ). Under hypoxic conditions (right), the nonhydroxylated HIF-1 subunits are not recognized by
pVHL; HIF consequently accumulates and thereby restores normoxia. Among the possible target genes activated by HIF are
the genes encoding the following: VEGF, erythropoietin (Epo), glucose transporter-1 (Glut-1), platelet-derived growth factorß (PDGF), plasminogen activator inhibitor 1 (PAI-1), and TGF- . EloB, Elongin B; EloC, Elongin C; Cul2, Cullin2; Rbx1,
RBx1-protein; E2, ubiquitin conjugating enzyme.
MEN1
MEN1 is an autosomal-dominant syndrome characterized by primary hyperparathyroidism, pancreatic islet
cell neoplasms, and pituitary adenomas caused by inactivating mutations of the MEN1 locus coding for the
suppressor protein menin. MEN1 may be associated with pheochromocytomas. Fewer than 10 cases of
pheochromocytoma have been identified in MEN1, all unilateral, rarely malignant, and most characterized by
hypertension and predominant norepinephrine production . None presented as apparently sporadic
pheochromocytomas. Given the extremely rare association between MEN1 and pheochromocytomas, and the
much higher prevalence of parathyroid, pancreatic, and pituitary diseases in this syndrome, it is not surprising
that MEN1 has not yet been reported to present clinically as apparently sporadic pheochromocytoma.
MEN2
MEN2 is an autosomal-dominant syndrome caused by activating mutations in the RET protooncogene, which
encodes a transmembrane receptor tyrosine kinase involved in the regulation of cell proliferation and
apoptosis. MEN2A is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and
hyperparathyroidism. MEN2B is characterized by MTC, mucosal ganglioneuromas, and pheochromocytoma.
Pheochromocytoma occurs in approximately half of gene carriers and is almost always located within the
adrenal glands. There have been rare reports of sympathetic paragangliomas , although most of these have
been found in the adrenal region and may represent a tumor that has developed in an adrenal rest , recurrence
of a previously excised adrenal medullary tumor , or seeding from a malignant pheochromocytoma . Bilateral
pheochromocytomas occur in approximately half of patients with MEN2 who have pheochromocytomas;
their development is frequently asynchronous, with separation by as much as 15 yr . Pheochromocytomas
tend to develop after MTC is identified; however, there are well-documented examples of MEN2-related
pheochromocytomas presenting before MTC is found as the initial manifestation of this syndrome . Even so,
most such cases do not present clinically as apparently sporadic pheochromocytoma, given that the MEN2
family history or nonsolitary tumor focus is known or suspected. Thus, whereas MEN2 has been reported to
present as an apparently sporadic pheochromocytoma, such cases are rare.
Pheochromocytomas occur most commonly with codon 634 (MEN2A) or 918 (MEN2B) RET protooncogene
mutations and with lesser frequency in kindreds with mutations of codons 609, 611, 618, 620, 768, 790, 791,
V804L, V804M, 883, and 891. Pheochromocytomas have not been found in kindreds with mutations of
codons 532–534, 630, and 912. Malignant pheochromocytomas are uncommon and are generally found in
patients with large tumors. The pattern of catecholamine production in MEN2 pheochromocytoma differs
from that seen in other hereditary forms of pheochromocytoma. Epinephrine is produced in
disproportionately large amounts, resulting in an early clinical phenotype characterized by attacks of
palpitations, nervousness, anxiety, and headaches, rather than the more common pattern of hypertension seen
with sporadic or other hereditary tumors.
Fig 2. The RET receptor tyrosine kinase is positioned in the cell
membrane. It is activated when its ligand binds a co-receptor and
the complex in turn interacts with RET.
Fig 3. Schematic representation of the RET gene showing the codons
involved in germline mutation in MEN 2.
PGL1
PGL1 is an autosomal-dominant syndrome with maternal imprinting, characterized by familial and isolated
head and neck parasympathetic paragangliomas and less frequently by sympathetic paragangliomas and
pheochromocytomas. PGL1 is caused by inactivating mutations in the mitochondrial complex II SDHD gene,
a tumor suppressor gene involved in the electron transport chain and the tricarboxylic acid cycle. SDHD
mutations result in destabilization and loss of structural integrity of the complex II. Consequently, oxygen
free radical production increases, stabilizing the hypoxia-inducible factor-1 with subsequent activation of
TGF-ß, platelet-derived growth factor receptor-ß, and a ligand for the epidermal growth factor receptor,
predisposing to tumor formation. SDHD mutations represent 97% of total germline mutations observed in
pheochromocytoma/paraganglioma kindreds found with succinate dehydrogenase mutations. However, this
percentage must be certainly an overstatement; more recent literature indicates that mutations of other
subunits of the succinate dehydrogenase complex, mainly SDHB, account for at least one half of the
mutations. These mutations exhibit a genotype-phenotype correlation. Approximately 75% of
pheochromocytomas and sympathetic paragangliomas occur when mutations are localized in the 5' portion of
SDHD. Most of these tumors exhibit a benign behavior; however, they can also be malignant.
Pheochromocytomas can be unilateral or bilateral. The mean age at diagnosis is 43 yr, with rare cases
reported in people younger than 20 yr. SDHD mutations can present as apparently sporadic
pheochromocytoma because of the maternal imprinting and the lack of more clearly defined manifestations.
PGL2
PGL2 is an autosomal-dominant syndrome defined by familial head and neck parasympathetic
paragangliomas. Hereditary transmission occurs exclusively in children of fathers carrying the gene, pointing
to the importance of maternal imprinting. The causative gene has been mapped to chromosome 11q13.1 but
has not yet been identified. It is unlikely that people with this syndrome will present with an apparently
sporadic pheochromocytoma because of its rarity and parasympathetic lineage. So far, no cases of PGL2
presenting as pheochromocytoma have been described.
PGL3
PGL3 is an autosomal-dominant syndrome without maternal imprinting, characterized by benign and seldom
multifocal head and neck parasympathetic paragangliomas. PGL3 was initially reported in only one family.
The investigators who evaluated this single kindred identified a missense mutation of SDHC, another
component of the mitochondrial complex II. None of these family members had a catecholamine-producing
tumor. Recently, an international registry of 121 individuals with head and neck paragangliomas and 371
individuals with pheochromocytomas described a prevalence of germline SDHC mutations in 4% of patients
with head and neck parasympathetic paragangliomas; no SDHC mutations were identified in sympathetic
paragangliomas or pheochromocytomas. Therefore, at present, it is unnecessary to consider this genetic
disorder in patients with apparently sporadic pheochromocytomas.
PGL4
PGL4 is an autosomal-dominant syndrome, characterized by parasympathetic paragangliomas and frequently
by sympathetic paragangliomas and/or pheochromocytomas. Inactivating mutations in the tumor suppressor
SDHB gene are responsible for PGL4 syndrome. These mutations cause mitochondrial complex II
destabilization and may activate the hypoxic/angiogenic pathway predisposing to tumor formation, with a
very strong association with a malignant intra- or extraadrenal phenotype. Apparently sporadic
pheochromocytoma has been found in carriers of SDHB mutations, with a mean age of presentation at 34 yr.
Although SDHB mutations have been recently described in association with renal cell carcinomas and
papillary thyroid carcinomas, the lack of a frequent association with these disorders, a possible low
penetrance, and a risk for new-onset SDHB mutations may explain the subset presenting as apparently
sporadic pheochromocytoma.
Figure ４. The proposed model of WT and mutant SDHC containing complex II with the
proposed site of superoxide production. Proposed normal complex II existing in B1 cells (A)
and the proposed SDHC mutant complex II present in B9 cells (B). Arrows, flow of electrons
as they are passed from succinate through the flavin to the FeS groups and then to the CoQbinding site or the heme b site.
TABLE 1. Hereditary tumor syndromes that include paraganglioma or pheochromocytoma
Syndrome,
OMIM
classification
Caus
ative
gene
NF1
NF1
VHL
Gen
e
locu
s
Catecholamine
production by
tumors
Maternal
imprintin
g
Protein
product
17q
11.2
–
Neurofibromin
GTP hydrolysis
Tumor
suppre
ssor
+
Pheochromocytoma/sympatheti
c paraganglioma
VHL
3p2
5–
26
–
VHL
Suppressor of
transcription
elongation
Tumor
suppre
ssor
+
Pheochromocytoma/sympatheti
c paraganglioma
MEN1
MENI
N
11q
13
–
Menin
Transcription
regulation
Tumor
suppre
ssor
+
Pheochromocytoma
MEN2
RET
10q
11.2
–
RET
Tyrosine kinase
receptor
Protooncog
ene
+
Pheochromocytoma
PGL1
SDH
D
11q
23
±
Succinate
dehydrogenase
subunit D
Regulation of
mitochondrial ATP
production
Tumor
suppre
ssor
+
Pheochromocytoma/sympatheti
c and parasympathetic1
paragangliomas
PGL2
Unkn
own
11q
13.1
±
Unknown
Unknown
Unkno
wn
–
Parasympathetic1
paragangliomas
PGL3
SDHC
1q2
1
–
Succinate
dehydrogenase
subunit C
Regulation of
mitochondrial ATP
production
Tumor
Suppre
ssor
–
Parasympathetic1
paragangliomas
PGL4
SDHB
1p3
6.1–
35
–
Succinate
dehydrogenase
subunit B
Regulation of
mitochondrial ATP
production
Tumor
suppre
ssor
+
Pheochromocytomas/sympathet
ic and parasympathetic1
paragangliomas
Protein function
Mecha
nism
Phenotype
TABLE 2. Reported frequencies of germline mutations in specific endocrine syndromes associated with apparently sporadic
pheochromocytomas
Investigator (first author/year)
Location
MEN2, RET
VHL, VHL
Eng/1995
United States/England/Canada
1/46
0/46
Lindor/1995
United States
0/29
Beldjord/1995
France
0/28
Brauch/1997
Germany
0/62
2/62
Bar/1997
Israel
0/26
0/26
Rodien/1997
France
1/120
Van der Harst/1998
The Netherlands
Gimm/2000
Germany
1/16
Astuti/2001
England
0/24
1/24
Neumann/2002
Poland and Germany
8/250
18/250
7/250
12/250
Gimenez/2003
France
0/84
2/84
6/84
8/84
Benn/2003
Australia
0/2
2/2
14/376 = 3.72%
23/360 = 6.38%
Totals
PGL1, SDHD
PGL4, SDHB
5/67
10/645 = 1.55%
27/535 = 5.04%
TABLE 3. Clinical features suggestive of hereditary pheochromocytoma
Clinical features
Pheochromocytoma
Sudden death, particularly at a young age
Hypertension or stroke, particularly at a young age or during pregnancy
Hypertensive response to anesthesia
VHL
Kidney or pancreatic cysts or cancer
Testicular mass or cyst in children
Early onset of deafness
Early onset of blindness
Central nervous system tumors
MEN2
Thyroid cancer, goiter
High blood calcium or kidney stones
PGL1 and PGL4
Head and neck tumors with signs and symptoms mainly related to their location (dysphonia, dysphagia, etc.) more than excessive
production of catecholamines
Abdominal tumors
TABLE 4. When should genetic testing be considered?
Rank of order1
When to do genetic testing
Unilateral pheochromocytomas in individuals < 20 yr2
VHL > RET > SDHB =
SDHD
Bilateral pheochromocytomas2
VHL > RET > SDHB =
SDHD
Sympathetic paragangliomas < 20 yr
VHL > SDHB > SDHD
Sympathetic paragangliomas >20 yr
SDHB > VHL > SDHD
When not to do genetic testing
Age > 50 yr
Genetic testing is optional (not routinely recommended)
Patients with unilateral pheochromocytomas, ages 20–50 yr, and no suspicious clinical findings
or family history for hereditary disease2
1
2
SDHB > VHL > SDHD
>>> RET
The rank of order may vary if there is a clinical individual or familiar suspicion for a specific hereditary disease.
If the biochemical profile indicates an increased production of epinephrine/metanephrines, RET should be tested first.
Conclusion: We recommend genetic testing for patients with an apparently sporadic
pheochromocytoma under the age of 20 yr with family history or features suggestive of
hereditary pheochromocytoma or for patients with sympathetic paragangliomas. For
individuals who do not meet these criteria, genetic testing is optional.