GeneDx, Inc.
Test Information Sheet
207 Perry Parkway
Gaithersburg, MD 20877
Phone: 301-519-2100
Fax: 301-519-2892
E-mail: [email protected]
www.genedx.com
Hereditary Paraganglioma-Pheochromocytoma Syndrome (PGL/PCC)
Including SDHB, SDHC, SDHD, SDHA, SDHAF2, and TMEM127 Gene Analysis
Mendelian Inheritance in Man Number: 168000 Paragangliomas 1; PGL1; 601650 Paragangliomas 2; PGL2; 605373
Paragangliomas 3; PGL3; 115310 Paragangliomas 4; PGL4; 185470 Succinate Dehydrogenase Complex, Subunit B,
SDHB; 602413 Succinate Dehydrogenase Complex, Subunit C; SDHC; 602690 Succinate Dehydrogenase Complex,
Subunit D; SDHD; 613019 Succinate Dehydrogenase Complex Assembly Factor 2; SDHAF2 (also known as SDH5);
613403 Transmembrane Protein 127; TMEM127
Clinical features:
Hereditary Paraganglioma-Pheochromocytoma Syndrome (PGL/PCC) is an inherited autosomal dominant cancer
predisposition syndrome. Individuals with a germline mutation in any of the disease susceptibility genes are
considered to be at an increased risk of developing paraganglioma(s), pheochromocytoma(s), or both. These tumors
stem from neural crest cells and hence are considered neuro-endocrine tumors. The clinical presentation of PGL/PCC
syndrome is variable and depends on the size and anatomic location of tumors. PGLs are clinically categorized into
head and neck paragangliomas (HNP) and extra-adrenal paragangliomas. Paragangliomas of the head and neck arise
from paraganglia that are aligned along the parasympathetic nervous system. They are usually non-secreting, benign
and asymptomatic tumors. The most common is the carotid body paraganglioma. The extra-adrenal paragangliomas
are distributed along the sides of the spine and aorta anywhere from the upper neck to the pelvic floor, paralleling the
distribution of the sympathetic nervous system. They may be functionally active and secrete hormones
(catecholamines), thus leading to hypertension, tachycardia, sweating, and diarrhea. Extra-adrenal paragangliomas
also have a greater tendency for malignancy. Paragangliomas occurring within the adrenal glands are referred to as
pheochromocytomas and are functionally active. They are usually benign, although malignant pheochromocytomas
are well reported.
Inheritance pattern:
Autosomal dominant with incomplete penetrance. Due to a parent-of-origin effect, mutations in SDHD and SDHAF2
genes generally cause PGL/PCC syndrome only when the pathogenic variant is inherited from the father.
Genetics:
Paraganglioma and pheochromocytoma may occur in patients with several different inherited cancer susceptibility
syndromes, including PGL/PCC syndrome, multiple endocrine neoplasia type 2 (MEN 2), von Hippel–Lindau
disease (VHL), and neurofibromatosis type 1 (NF 1). The PGL/PCC syndrome is due to germline mutations in
subunits of the mitochondrial complex II, also known as succinate dehydrogenase (SDH). This protein complex
comprises four subunits, which are encoded by four different genes: SDHA (5p15), SDHB (1p36), SDHC (1q23),
and SDHD (11q23). SDHAF2 (11q13.1) is responsible for the flavination of the SDHA protein, which is essential
for a fully functional succinate dehydrogenase complex. Autosomal recessive pathogenic variants in the SDHA gene
are primarily associated with Leigh encephalopathy; however, there have been case reports of individuals with
paraganglioma and a heterozygous, dominant mutation in the SDHA gene.1,2 Pathogenic variants in the SDHB,
SDHC, and SDHD genes are commonly associated with PGL/PCC syndrome. These genes are categorized as tumor
suppressor genes, as it was demonstrated that a heterozygous germline mutation is generally associated with somatic
loss of the wild-type allele in the tumor tissue.2 Approximately 70% of familial cases of head and neck
paragangliomas are caused by pathogenic germline variants in SDHD or SDHB, while pathogenic SDHC, SDHA,
and SDHAF2 variants are rare.3,5 The detection rate of pathogenic variants in SDHD, SDHB and SDHC in patients
with sporadic PGL/PCC is much lower, ranging between 8-17%.4,6
Information Sheet for Hereditary Pheochoromocytoma/Paraganglioma Page 1 of 4
© GeneDx
5/2016
Pathogenic germline variants of SDHD, SDHB, and SDHC have been detected in a subset of patients with gastrointestinal stromal tumors (GIST) in association with paragangliomas (aka “Carney-Stratakis syndrome”) 7, as well as
in a small subset of PTEN-negative patients with Cowden and Cowden-like syndromes. 8 Pathogenic SDHB variants
also have been found in patients with inherited renal cell carcinoma. 9
Most recently, pathogenic variants in the TMEM127 gene, located on chromosome 2q11, have been identified in
individuals with isolated pheochromocytoma; isolated paraganglioma has also been observed.10,11
Reasons for referral:
 Confirmation of a clinical diagnosis
 Differentiation of PGL/PCC syndrome from other hereditary cancer predisposition syndromes, such as MEN2,
VHL and NF1
 Identification of family members at-risk for paraganglioma/pheochromocytoma
 Genetic counseling and recurrence risk assessment
 Prenatal diagnosis in families with a known mutation
Some loose genotype-phenotype correlations have been established, which may help in devising a suitable testing
strategy:
SDHB
 Pathogenic variants should be considered first in patients with malignant PGL/PCC.
 Pathogenic varaints are often found in sporadic cases and are usually associated with abdominal
PGLs, which may or may not secrete catecholamines.
SDHD
 Pathogenic variants are most frequently identified in families with non-secreting head and neck
PGLs (although PCC or functional, secreting PGL may also occur).
 This gene is maternally imprinted, thus there is often a paternal family history of PGL/PCC
syndrome.
 Pathogenic variants are often found in association with head and neck paragangliomas.
SDHAF2
 Pathogenic variants are rare and have been reported mainly in families with head and neck
paragangliomas and an early age of onset.
 This gene is maternally imprinted, thus there is often a paternal family history of PGL.
TMEM127
 Pathogenic variants are found most commonly in individuals with isolated pheochromocytoma,
frequently bilateral.
The following chart of syndromic, metastatic, and nonmetastatic cases may serve as a reference guide for molecular
testing in patients with PGL/PCC syndrome.12
Information Sheet for Hereditary Pheochromocytoma/Paraganglioma Page 2 of 4
© GeneDx
5/2016
Test method:
GeneDx offers sequential tiered testing for five SDH genes (SDHD, SDHB, SDHC, SDHA, and SDHAF2) and
TMEM127. The clinical phenotype and family history of a patient should dictate the order in which testing
proceeds (see flow chart above). Using genomic DNA from the submitted specimen, bi-directional DNA
sequence of the coding exons and splice sites of the SDHD (exons 1-4), SDHB (exons 1-8), SDHC (exons 1-6),
SDHA (exons 1-15), SDHAF2 (exons 1-4), and/or TMEM127 (exons 1-4, including the splice junction of
noncoding exon 1) genes is obtained and analyzed. In addition, targeted array CGH analysis with exon-level
resolution (ExonArrayDx) is available to evaluate for a deletion or duplication of one or more exons of the
SDHB, SDHC, and SDHD genes. Deletion/duplication testing is performed for the SDHB, SDHC, and SDHD
genes concurrently.
Variant spectrum
The vast majority of pathogenic variants in the SDHB, SDHC, and SDHD genes are nonsense variants, small
insertions/deletions, and splice variants, although missense variants and large deletions have also been
reported.13,14,15 Several pathogenic founder variants have been reported in patients from the Netherlands, including
p.Asp92Tyr and p.Leu139Pro in SDHD and a deletion of exon 3 of the SDHB gene. In the United States, the P81L
variant in the SDHD gene has been reported in numerous unrelated patients with head and neck paragangliomas.4
A database of normal and pathogenic variants for the SDH subunit genes is maintained by the Leiden University
Medical Center (http://chromium.liacs.nl/lovd_sdh/home.php).
While the majority of the pathogenic TMEM127 variants lead to truncation of the TMEM127 protein (small
insertions/deletions, nonsense, slice site mutations), missense variants affecting conserved amino acid positions
have also been observed.23
Test sensitivity
The likelihood of identifying a pathogenic variant in individuals with familial HNP is estimated to be 70%. 4
Overall, approximately 30% of patients with HNP, regardless of family history, have an identifiable pathogenic
variant in the SDHB, SDHC, or SDHD genes.16,17,18 Specifically, pathogenic SDHB variants are identified in 711%, pathogenic SDHC variants are identified in ~4%, and pathogenic SDHD variants are identified in 15-17% of
patients with HNP.16,18 Although the majority of pathogenic variants are identified by sequence analysis,
approximately 3% of patients with HNP have a deletion or duplication of an exon or larger in SDHB, SDHC, or
SDHD that would not be detected by sequencing.16 A single nucleotide duplication has been reported in the
SDHAF2 gene, but no deletions have yet been reported.24
Approximately 37% of individuals with familial pheochromocytoma have an identifiable pathogenic variant in the
SDHB or SDHD genes. 19 Among individuals with an apparently sporadic pheochromocytoma or secreting
paraganglioma, pathogenic variants are identified in the SDHB or SDHD genes in an estimated 3-10%. 17,19, 20
Specifically, pathogenic SDHB variants are identified in 2-7% and pathogenic SDHD variants are identified in 14% of patients. 17,19,20 To date, pathogenic variants in the SDHC gene have not been detected in patients with
isolated pheochromocytoma. The sensitivity of testing for whole and partial deletions or duplications in this
population is currently not well established.
Pathogenic variants in the TMEM127 gene have been identified in approximately 2% of individuals with isolated
pheochromocytoma or paraganglioma.21,22 The vast majority of individuals with pathogenic TMEM127 variants
have pheochromocytoma, frequently bilateral. However, pathogenic variants have also been identified in
individuals with paraganglioma.22 To date, no large deletions or duplications have been identified in the
TMEM127 gene.
Information Sheet for Hereditary Pheochromocytoma/Paraganglioma Page 3 of 4
© GeneDx
5/2016
Specimen Requirements and Shipping/Handling:
 Blood: A single tube with 1-5 mL whole blood in EDTA. Ship overnight at ambient temperature, using a cool
pack in hot weather. Specimens may be refrigerated for 7 days prior to shipping.
 Buccal Brushes: Cannot be accepted.
 Prenatal Diagnosis: For prenatal testing for a known mutation in the SDHB, SDHC, SDHD, SDHAF2, or
TMEM127 genes, please refer to the specimen requirements table on our website at:
http://www.genedx.com/test-catalog/prenatal/. Ship specimen overnight at ambient temperature, using a cool
pack in hot weather.
Required Forms:
 Sample Submission (Requisition) Form – complete all pages
 Payment Options Form or Institutional Billing Instructions
For test codes, prices, CPT codes, and turn-around-times, please refer to the “Hereditary ParagangliomaPheochromocytoma Syndrome” page on our website: www.genedx.com
References cited:
1. Burnichon et al. (2010) Hum Mol Genet 19(15):3011-20, 2. Korpershoek et al., (2011) J Clini Endocrin Metab 96(9):Epub, 3.
Gimenez-Roqueplo AP. (2006) Ann N Y Acad Sci 1073:112-21, 4. Baysal et al. (2002) J Med Genet 39(3):178-83, 5. Bayley et al.
(2010) Lancet Oncol 11:366-72, 6. Badenhop et al. (2004) J Med Genet 41:e99, 7. Pasini et al. (2008) Eur J Hum Genet 16:79-88, 8.
Ni et al. (2008) Am J Hum Genet 83:261-8, 9. Ricketts et al. (2008) J Natl Cancer Inst 100:1260-2, 10. Yao et al., (2010) JAMA
304(23):2611-2619, 11. Neumann et al., (2011) J Clin Endocrinol Metab 96(8):Epub, 12. Lenders et al. (2014) J. Clin. Endocrinol.
Metab. 99 (6):1915-42 (PMID: 24893135), 13. Baysal et al. (2004) J Med Genet 41(9):703-9, 14. Cascon et al. (2006) Genes
Chromosomes Cancer 45(3):213-9, 15. McWhinney et al. (2004) J Clin Endocrinol Metab 89(11):5694-9, 16. Neumann et al.
(2009) Cancer Res 69:3650-6, 17. Mannelli et al. (2009) J Clin Endocrinol Metab 94(5):1541-7, 18. Schiavi et al. (2005) JAMA
294:2057-63, 19. Amar et al. (2005) J Clin Oncol 23:8812-8, 20. Jimenez et al. (2006) J Clin Endocrinol Metab 91:2851-8, 21. Yao
et al., (2010) JAMA 304(23):2611-2619, 22. Neumann et al., (2011) J Clin Endocrinol Metab 96(8):Epub, 23. Jiang and Dahia,
(2011) Endocrinol 152(6):Epub, 24. Piccini et al. (2012) Endocrine Related Cancer 19 (2):149-55 (PMID: 22241717).
Information Sheet for Hereditary Pheochromocytoma/Paraganglioma Page 4 of 4
© GeneDx
5/2016