Pheochromocytoma in Genetic Disorders

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Pheochromocytoma in genetic disorders

AUTHOR: William F Young, Jr, MD, MSc
SECTION EDITORS: André Lacroix, MD, Benjamin A Raby, MD, MPH
DEPUTY EDITOR: Katya Rubinow, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2024.

This topic last updated: Jan 22, 2024.
INTRODUCTION
Pheochromocytoma is a rare neoplasm, probably occurring in less than 0.2 percent of patients with hypertension [1,2].
Pheochromocytoma in genetic disorders will be reviewed here. The diagnosis and treatment of pheochromocytoma are
discussed separately. (See "Clinical presentation and diagnosis of pheochromocytoma" and "Treatment of
pheochromocytoma in adults".)
PHEOCHROMOCYTOMA IN GENETIC DISORDERS
Most catecholamine-secreting tumors are sporadic. However, approximately 40 percent of patients have the disease as
part of a familial disorder [3,4].
Hereditary catecholamine-secreting tumors typically present at a younger age than sporadic neoplasms [4,5]. Sporadic
pheochromocytoma is usually diagnosed on the basis of symptoms or an incidental discovery on computed imaging,
whereas syndromic pheochromocytoma is frequently diagnosed earlier in the course of disease because of biochemical
surveillance or genetic testing [6]. Familial pheochromocytoma is also diagnosed at a younger age because of much
earlier symptomatic tumor development [4].
Familial pheochromocytoma — There are several familial syndromic disorders associated with adrenal
pheochromocytoma, all of which have autosomal dominant inheritance: von Hippel-Lindau (VHL) syndrome, multiple
endocrine neoplasia type 2 (MEN2) and, less commonly, neurofibromatosis type 1 (NF1).
The approximate frequency of pheochromocytoma in these disorders is 10 to 20 percent in VHL syndrome, 50 percent in
MEN2, and 3 percent with NF1 [7-9]. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease"
and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2" and "Neurofibromatosis type 1 (NF1):
Pathogenesis, clinical features, and diagnosis".)
VHL syndrome — The von Hippel-Lindau (VHL) phenotype includes pheochromocytoma (frequently bilateral),
paraganglioma (mediastinal, abdominal, pelvic, neck, and skull base), hemangioblastoma (involving the cerebellum,
spinal cord, or brainstem), retinal angioma, clear cell renal cell carcinoma, pancreatic neuroendocrine tumors,
endolymphatic sac tumors of the middle ear, serous cystadenomas of the pancreas, and papillary cystadenomas of the
epididymis and broad ligament.
The VHL tumor suppressor gene, located on chromosome 3p25-26, encodes a protein that regulates hypoxia-induced
proteins. More than 300 germline VHL pathogenic variants have been identified that lead to loss of function of the VHL
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protein.
Patients with VHL syndrome may be divided into two groups: type I and type II. Patients from kindreds with type I
syndrome do not develop pheochromocytoma, whereas patients with kindreds with type II syndrome are at high risk for
developing pheochromocytoma. In addition, kindreds with type II VHL syndrome are subdivided into type IIA (low risk for
renal cell carcinoma), type IIB (high risk for renal cell carcinoma), and type IIC (pheochromocytomas only). Genotype-
phenotype correlations have been documented for this disorder, and specific pathogenic variants are associated with
particular patterns of tumor formation. In up to 98 percent of cases, pheochromocytoma is associated with missense
pathogenic variants (rather than truncating or null pathogenic variants) in the VHL gene. Certain missense pathogenic
variants appear to be associated with the type IIC presentation of VHL (pheochromocytomas only). (See "Clinical features,
diagnosis, and management of von Hippel-Lindau disease", section on 'Pheochromocytomas'.)
MEN2 — Multiple endocrine neoplasia type 2A (MEN2A) is characterized by medullary thyroid cancer (MTC) in all
patients, pheochromocytoma in 50 percent, primary hyperparathyroidism in 20 percent, and cutaneous lichen
amyloidosis in 5 percent [10-13].
Most pathogenic variants in MEN2A kindreds (93 to 98 percent) involve one of six cysteine residues in the cysteine-rich
region of the RET protein's extracellular domain encoded in RET exons 10 (codons 609, 611, 618, and 620) or 11 (codons
630 or 634). Eighty-five percent of individuals with MEN2A have a pathogenic variant in codon 634, particularly
p.Cys634Arg. Aganglionic megacolon (Hirschsprung disease) may occur in families with MEN2A who have a "Janus"
pathogenic variant (a pathogenic variant that acts simultaneously as both a gain-in-function and a loss-of-function
pathogenic variant) in the RET proto-oncogene (exon 10: codons 609, 611, 618, 620). (See "Classification and genetics of
multiple endocrine neoplasia type 2".)
MEN type 2B represents approximately 5 percent of all MEN2 cases, and the phenotype is characterized by MTC in all
patients, pheochromocytoma in 50 percent, mucocutaneous neuromas (typically involving the tongue, lips, and eyelids) in
most patients, skeletal deformities (eg, kyphoscoliosis or lordosis), joint laxity, myelinated corneal nerves, and intestinal
ganglioneuromas (hyperganglionic megacolon).
MEN2B-associated tumors are caused by pathogenic variants in the RET protein's intracellular domain. A single
methionine to threonine missense pathogenic variant in exon 16 (p.Met918Thr) is responsible for more than 95 percent of
MEN2B cases. Another pathogenic variant, alanine to phenylalanine at codon 883 in exon 15, has been found in 4 percent
of MEN2B kindreds. (See "Classification and genetics of multiple endocrine neoplasia type 2".)
Phenotype of MEN2 versus VHL syndrome — The clinical and biochemical characteristics of pheochromocytomas in
multiple endocrine neoplasia type 2 (MEN2) versus the von Hippel-Lindau (VHL) syndrome were investigated in a study of
19 and 30 patients with these disorders, respectively; the following findings were noted [14]:
● MEN2 patients were more symptomatic with a higher incidence of hypertension (primarily paroxysmal).
● MEN2 patients all had elevated serum concentrations of metanephrine (the epinephrine metabolite), while all VHL
patients had elevated serum normetanephrine concentrations (the norepinephrine metabolite).
● Compared with MEN2 tumors, VHL tumors had lower total tissue contents of catecholamines and expression of
tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. They also had much lower
expression of phenylethanolamine N-methyltransferase (PNMT, the enzyme that converts norepinephrine to
epinephrine) and tissue stores of epinephrine.
Thus, the difference in clinical phenotype (MEN2 patients are more symptomatic) can be explained by the differences in
biochemical phenotype (MEN2 patients, due to the higher PNMT and TH expression, have an adrenergic phenotype with
higher rates of catecholamine biosynthesis).
Neurofibromatosis type 1 — There is also an association with NF1 [7], an autosomal dominant disorder characterized
by neurofibromas, multiple cafe au lait spots, axillary and inguinal freckling, iris hamartomas (Lisch nodules), bony
abnormalities, central nervous system gliomas, pheochromocytoma and paraganglioma, macrocephaly, and cognitive
deficits. The expression of these features is variable. Approximately 3 percent of patients with NF1 develop
catecholamine-secreting tumors [9]. In these patients, the catecholamine-secreting tumor is usually a solitary benign
adrenal pheochromocytoma, occasionally bilateral adrenal pheochromocytoma, and rarely a peri adrenal abdominal
paraganglioma.
Genetic testing for NF1 is available, but it is not routinely performed, as the diagnosis is made based upon clinical
phenotype. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)
Other pathogenic variants — Since 1990, at least 20 different pheochromocytoma/paraganglioma susceptibility genes
have been reported [4,15]. Susceptibility (or driver) genes where genetic variants predispose to pheochromocytoma and
paraganglioma have three general transcription signatures: cluster 1, genes encoding proteins that function in the
cellular response to hypoxia; cluster 2, genes encoding proteins that activate kinase signaling; and cluster 3, genes
encoding proteins that are involved in Wnt signaling ( table 1). Cluster 1 tumors are mostly extra-adrenal
paragangliomas (except in VHL where most tumors are localized to the adrenal), and nearly all have a noradrenergic
biochemical phenotype, whereas cluster 2 tumors are usually adrenal pheochromocytomas with an adrenergic
biochemical phenotype. Cluster 3 tumors can have a noradrenergic or adrenergic biochemical phenotype. Cluster 1
germline driver genes include: SDHD, SDHC, SDHB, SDHAF2, SDHA, VHL, HIF2A (EPAS1), FH gene encoding fumarate
hydratase, EGLN1 (PHD2), EGLN2 (PHD1), KIF1B, SLC25A11, IDH1, MDH2, DLST, and DNMT3A. Cluster 2 germline driver genes
include: RET, NF1, MAX, and TMEM127 ( table 1) [16-20]. Cluster 3 germline driver genes include: CSDE1, MAML3, and
UBTF::MAML3 fusions.
Familial paraganglioma — Familial paraganglioma is an autosomal dominant disorder characterized by paragangliomas

that are located most often in the skull base and neck but also in the mediastinum, abdomen, pelvis, and urinary bladder
[16].
The occurrence of catecholamine hypersecretion in a patient with familial paraganglioma depends upon tumor location;
approximately 5 percent of skull base and neck paragangliomas and more than 50 percent of abdominal paragangliomas
hypersecrete catecholamines and metanephrines [21]. (See "Paragangliomas: Epidemiology, clinical presentation,
diagnosis, and histology".)
Most cases of familial paraganglioma are caused by pathogenic variants in the succinate dehydrogenase (SDH;
succinate:ubiquinone oxidoreductase) subunit genes (SDHB, SDHC, SDHD, SDHAF2, SDHA), which compose portions of
mitochondrial complex II [22-28]. Mitochondrial complex II is a tumor suppressor gene involved in the electron transport
chain and the tricarboxylic-acid (TCA) cycle. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and
histology", section on 'Familial paraganglioma and SDH pathogenic variants'.)
● Most germline pathogenic variants in SDHD, SDHAF2, and SDHC have been identified in multigenerational families
with biochemically silent skull base and neck paragangliomas [29,30]. In patients with SDHD and SDHAF2 pathogenic
variants, penetrance depends on the pathogenic variant's parent of origin [25,26,29]. Hence, the disease is not
manifested when the pathogenic variant is inherited from the mother but is highly penetrant when inherited from
the father. This phenomenon is known as maternal imprinting.
● In a prospective study, 445 patients with skull base and neck and/or thoracic-abdominal or pelvic paragangliomas
were recruited over 5 years in 20 referral centers [31]. SDH germline pathogenic variants were found 242 patients
(54.4 percent): 130 in SDHD, 96 in SDHB, and 16 in SDHC. A skull base and neck paraganglioma was present in 97.7
percent of the SDHD and 87.5 percent of the SDHC pathogenic variant carriers, but in only 42.7 percent of the SDHB
carriers. A thoracic-abdominal or pelvic location was present in 63.5 percent of the SDHB, 16.1 percent of the SDHD,
and in 12.5 percent of the SDHC pathogenic variant carriers. Multiple paragangliomas were diagnosed in 66.9
percent of the SDHD pathogenic variant carriers. A malignant paraganglioma was documented in 37.5 percent of the
SDHB, 3.1 percent of the SDHD, and none of the SDHC pathogenic variant carriers.
● SDHD, SDHC, SDHAF2, SDHA, and SDHB germline pathogenic variant screening is commercially available and staged
testing (eg, starting with SDHD, SDHC, and SDHAF2 pathogenic variant analysis in patients with skull base and neck
paragangliomas and SDHB pathogenic variant analysis in patients with paragangliomas below the neck) should be
considered in all patients with paraganglioma [28]. (See 'Genetic screening' below.)
Sporadic pheochromocytoma
Frequency of genetic abnormalities — In an early series of 271 patients with apparent sporadic pheochromocytoma
from population-based registries in Germany and Poland who were tested for germline pathogenic variants in the four
genes described above that have been associated with pheochromocytoma (VHL, RET, SDHD, and SDHB [5]), the following
findings were noted:
● A pathogenic variant was identified in 66 patients (24 percent): 30 VHL (11 percent of patients overall), 13 RET (4.8
percent), 12 SDHB (4.4 percent), and 11 SDHD (4 percent). All but four of the patients had no signs or symptoms of
the diseases associated with the specific pathogenic variant. Possible explanations for sporadic and frequently
localized disease in these patients include spontaneous pathogenic variant, decreased penetrance, maternal
imprinting, and gene-gene or gene-environment interactions.
● Although all had a negative family history at entry, the family history became positive at last follow-up in 12 of 30
with a VHL pathogenic variant, 6 of 13 with a RET pathogenic variant, and none of 23 with a SDH complex pathogenic
variants.
A retrospective study from France reported on molecular genetic testing over a decade (2001 to 2010) [32]. A genetic test
for paraganglioma/pheochromocytoma was assessed for 2499 subjects, of which 1620 were index cases. Germline
pathogenic variants were found in 363 index cases (22.4 percent): 269 in SDHx genes (137 in SDHB, 100 in SDHD, 30 in
SDHC, 2 in SDHA), 64 in VHL, 23 in RET, and 7 in TMEM127. Overall, a germline pathogenic variant was identified in 44.7
percent of patients with a suspected hereditary pheochromocytoma/paraganglioma and in 8 percent of patients with an
apparently sporadic paraganglioma/pheochromocytoma.
More recently, a prospective observational study from the United Kingdom National Health Service included a total of 501
probands with pheochromocytoma/paraganglioma: 31 percent of patients had a pathogenic variant in SDHB, SDHD, or
VHL [33]. Pathogenic variant detection rates were highest in those with a positive family history (62 percent), malignancy
(53 percent), multiple tumors (33 percent), or paraganglioma (44 percent). Twenty-eight percent of individuals with a
single sporadic adrenal pheochromocytoma had a disease-causing pathogenic variant.
Implications for genetic screening — Based upon the above data, it appears that the yield of routine genetic
testing in patients with apparently sporadic adrenal pheochromocytoma (defined by unilateral disease, a negative family
history, and no syndromic signs of symptoms) ranges from 8 to 28 percent.
All patients should be monitored for findings of a genetic syndrome, some of which can be detected on physical
examination [8,34], including:
● Retinal angiomas in VHL syndrome

● A thyroid mass in MEN2
● Cafe au lait spots, axillary and inguinal freckling, Lisch nodules on the iris, and subcutaneous neurofibromas in NF1
● A neck mass in paraganglioma syndromes
Evaluation and monitoring of first-degree relatives is also important since each of these disorders is transmitted as an
autosomal dominant trait.
GENETIC SCREENING
Genetic testing should be considered in all patients with documented pheochromocytoma or paraganglioma [4]. Genetic
testing can be complex; testing one family member has implications for related individuals. Genetic counseling is
recommended to help families understand the implications of genetic test results; to coordinate testing of at-risk
individuals; and to help families work through the psychosocial issues that may arise before, during, or after the testing
process.
An asymptomatic person at risk for disease on the basis of family history of pheochromocytoma/paraganglioma should
have genetic testing only if an affected family member has a known disease-causing pathogenic variant.
Suggested approach — The clinician may obtain a list of clinically approved molecular genetic diagnostic laboratories at
Genetic Testing Registry. The field of genetic testing is rapidly evolving, and at many clinical laboratories, sequential
genetic testing is no longer done, as it is less expensive to utilize next-generation sequencing technology for all clinically
available mutations as a package. However, in those patients with neck and skull base paragangliomas, a case can be
made for obtaining an SDHx panel.
Genetic testing for neurofibromatosis type 1 (NF1) is available but is not routinely performed, as the diagnosis is made
based upon clinical phenotype.
Bilateral adrenal pheochromocytoma — If a patient presents with bilateral adrenal pheochromocytoma, it will always
be caused by germline pathogenic variant, primarily in RET or VHL [35]. However, approximately 7 percent of patients will
have germline pathogenic variants in TMEM127, NF1, SDHx, or MAX [35]. The biochemical phenotype (eg, adrenergic
[multiple endocrine neoplasia type 2 (MEN2)] or noradrenergic [von Hippel-Lindau (VHL) syndrome]) can also be used to
predict the results of genetic testing.
Known pathogenic variant — Additional evaluation for patients with an identified pathogenic variant or syndrome (VHL
syndrome, MEN2, NF1) is discussed separately. (See "Clinical features, diagnosis, and management of von Hippel-Lindau
disease" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2" and "Neurofibromatosis type
1 (NF1): Pathogenesis, clinical features, and diagnosis".)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around the world are
provided separately. (See "Society guideline links: Pheochromocytoma and paraganglioma".)
SUMMARY AND RECOMMENDATIONS
● Familial pheochromocytoma – Most catecholamine-secreting tumors are sporadic. However, some patients
(approximately 40 percent) have the disease as part of a familial disorder; in these patients, the catecholamine-
secreting tumors are more likely to be bilateral adrenal pheochromocytomas or paragangliomas. Several familial
syndromic disorders are associated with pheochromocytoma, all of which have autosomal dominant inheritance:
• Von Hippel-Lindau (VHL) syndrome, associated with pathogenic variants in the VHL tumor suppressor gene. (See
'VHL syndrome' above.)
• Multiple endocrine neoplasia type 2 (MEN2), which is associated with pathogenic variants in the RET proto-
oncogene. (See 'MEN2' above.)
• Pheochromocytoma is also seen, albeit infrequently, with neurofibromatosis type 1 (NF1), due to pathogenic
variants in the NF1 gene. (See 'Neurofibromatosis type 1' above.)
• The approximate frequency of pheochromocytoma in these disorders is 10 to 20 percent in VHL syndrome, 50

percent in MEN2, and 3 percent with NF1.
● Familial paraganglioma – Most cases of familial paraganglioma are caused by pathogenic variants in the succinate
dehydrogenase (SDH; succinate:ubiquinone oxidoreductase) subunit genes (SDHB, SDHC, SDHD, SDHAF2, SDHA). (See
'Familial paraganglioma' above.)
● Genetic testing – Genetic testing should be considered in all patients with pheochromocytoma or paraganglioma.
(See 'Genetic screening' above.)
An asymptomatic person at risk for disease on the basis of family history of pheochromocytoma/paraganglioma
should have genetic testing only if an affected family member has a known disease-causing pathogenic variant. (See
'Suggested approach' above.)
ACKNOWLEDGMENT
The UpToDate editorial staff acknowledges Norman M Kaplan, MD, who contributed to earlier versions of this topic
review.
Use of UpToDate is subject to the Terms of Use.
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Topic 133 Version 27.0
GRAPHICS
Germline mutations associated with pheochromocytoma and paraganglioma
Typical tumor location and other

Syndrome/name Gene
associations
Pseudo-hypoxic – Cluster 1 *
SDHD mutation (familial paraganglioma type 1) ¶ SDHD Primarily skull base and neck; occasionally adrenal
medulla, mediastinum, abdomen, pelvis; GIST;
possible pituitary adenoma
SDHAF2 mutation (familial paraganglioma type SDHAF2 Primarily skull base and neck; occasionally abdomen
2) ¶ and pelvis
SDHC mutation (familial paraganglioma type 3) SDHC Primarily skull base and neck; occasionally abdomen
and pelvis; GIST; possible pituitary adenoma
SDHB mutation (familial paraganglioma type 4) SDHB Abdomen, pelvis and mediastinum; rarely adrenal
medulla, skull base, and neck; GIST; possible
pituitary adenoma
SDHA mutation SDHA Primarily skull base and neck; occasionally abdomen
and pelvis; GIST; possible pituitary adenoma
VHL disease VHL Adrenal medulla, frequently bilateral; occasionally

paraganglioma that may be localized from skull base
to pelvis
Hereditary leiomyomatosis and renal cell FH Multifocal and metastatic; associated with hereditary
carcinoma (Reed syndrome) – Fumarate leiomyomatosis, uterine fibroids, and renal cell
hydratase mutation cancer
Hypoxia inducible factor 2-alpha EPAS1 (HIF2A) Paraganglioma, polycythemia, and rarely
somastostatinoma
Familial erythrocytosis associated with mutation EGLN2 Polycythemia associated with pheochromocytoma
in prolyl hydroxylase isoform 1 (PDH1) and paraganglioma
Familial erythrocytosis associated with mutation EGLN1 Polycythemia associated with pheochromocytoma
in prolyl hydroxylase isoform 2 (PDH2) and paraganglioma
Kinesin Family Member 1B gene KIF1B Neuroblastoma
DNA methyltransferase 3-alpha gene DNMT3A Skull base and neck paraganglioma
Dihydrolipoamide S-succinyltransferase gene DLST PGL7 tumor predisposition syndrome;

pheochromocytoma and thoraco-abdominal
paragangliomas
Succinate-CoA ligase GDP-forming subunit beta SUCLG2 Paraganglioma

gene
Kinase signaling pathway – Cluster 2 Δ
MEN2A and MEN2B RET Adrenal medulla, frequently bilateral
Neurofibromatosis type 1 NF1 Adrenal or peri-adrenal
MAX ¶ MAX Adrenal medulla
Familial pheochromocytoma TMEM127 Adrenal medulla; possible renal cell carcinoma
HRAS proto-oncogene, GTPase HRAS
Wnt signaling pathway – Cluster 3 ◊
Cold shock domain E1 CSDE1 Sporadic, aggressive disease with frequent

recurrence and metastases
UBTF (Upstream Binding Transcription Factor) UBTF::MAML3 fusion Sporadic, aggressive disease with frequent
fusion with MAML3 (mastermind like recurrence and metastases
transcriptional coactivator 3)
GIST: gastrointestinal stromal tumor; MEN2: multiple endocrine neoplasia type 2; SDH: succinate dehydrogenase; VHL: von Hippel-
Lindau.
* Cluster 1 tumors are mostly extra-adrenal paragangliomas (except in VHL, where most tumors are localized to the adrenal), and
nearly all have a noradrenergic biochemical phenotype.
¶ Associated with maternal imprinting.
Δ Cluster 2 tumors are usually adrenal pheochromocytomas with an adrenergic biochemical phenotype.
◊ Cluster 3 tumors can have a noradrenergic or adrenergic biochemical phenotype.
Original figure modified for this publication. Young WF. Endocrine hypertension. In: Williams Textbook of Endocrinology, Melmed S, Polonsky KS, Larsen PR,
Kronenberg HM (Eds), 13th ed, Elsevier Inc, Philadelphia 2015. p.556. Table used with the permission of Elsevier Inc. All rights reserved.
Graphic 106549 Version 3.0
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Contributor Disclosures
William F Young, Jr, MD, MSc Consultant/Advisory Boards: AstraZeneca Pharmaceuticals [Biologic effects of aldosterone synthase
inhibitors]; Crinetics Pharmaceuticals - Scientific advisory board [Discovery drugs for rare endocrine diseases]; Roche Diagnostics
Corporation [Laboratory assays for detection of catecholamine-secreting tumors and primary aldosteronism]. All of the relevant
financial relationships listed have been mitigated. André Lacroix, MD Patent Holder: Université Paris-Saclay [Endocrine diseases
related to KDM1A]. Grant/Research/Clinical Trial Support: Corcept Therapeutics [Cushing's syndrome]. Consultant/Advisory Boards:
Ipsen [Pituitary tumors]; Pfizer [Pituitary tumors]; Recordati [Cushing's syndrome]. Speaker's Bureau: Recordati [Cushing's syndrome].
All of the relevant financial relationships listed have been mitigated. Benjamin A Raby, MD, MPH No relevant financial relationship(s)
with ineligible companies to disclose. Katya Rubinow, MD No relevant financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting
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Pheochromocytoma in Genetic Disorders - UpToDate

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Pheochromocytoma in Genetic Disorders - UpToDate

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3/4/24, 8:57 PM Pheochromocytoma in genetic disorders - UpToDate

Official reprint from UpToDate®

Literature review current through: Feb 2024.

PHEOCHROMOCYTOMA IN GENETIC DISORDERS

Familial paraganglioma — Familial paraganglioma is an autosomal dominant disorder characterized by paragangliomas

● Retinal angiomas in VHL syndrome

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

• The approximate frequency of pheochromocytoma in these disorders is 10 to 20 percent in VHL syndrome, 50

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20. Mannelli M, Rapizzi E, Fucci R, et al. 15 YEARS OF PARAGANGLIOMA: Metabolism and

Germline mutations associated with pheochromocytoma and paraganglioma

Typical tumor location and other

VHL disease VHL Adrenal medulla, frequently bilateral; occasionally

Kinesin Family Member 1B gene KIF1B Neuroblastoma

Dihydrolipoamide S-succinyltransferase gene DLST PGL7 tumor predisposition syndrome;

Succinate-CoA ligase GDP-forming subunit beta SUCLG2 Paraganglioma

Kinase signaling pathway – Cluster 2 Δ

MEN2A and MEN2B RET Adrenal medulla, frequently bilateral

Neurofibromatosis type 1 NF1 Adrenal or peri-adrenal

MAX ¶ MAX Adrenal medulla

Familial pheochromocytoma TMEM127 Adrenal medulla; possible renal cell carcinoma

HRAS proto-oncogene, GTPase HRAS

Wnt signaling pathway – Cluster 3 ◊

Cold shock domain E1 CSDE1 Sporadic, aggressive disease with frequent

¶ Associated with maternal imprinting.

◊ Cluster 3 tumors can have a noradrenergic or adrenergic biochemical phenotype.

Graphic 106549 Version 3.0

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