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FeedbackMassively Parallel Sequencing
Preferred initial test when hereditary PGL/PCC is suspected with no clear biochemical findings
Massively Parallel Sequencing/Multiplex Ligation-Dependent Probe Amplification (MLPA)
Preferred initial test when hereditary PGL/PCC is suspected and characteristic biochemical findings are present
If a familial sequence variant has been previously identified, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information.
Disease Overview
Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are familial cancer syndromes characterized by benign or malignant neuroendocrine tumors. PGL/PCC tumors can affect both the sympathetic nervous system and the parasympathetic nervous system. Pathogenic germline variants in multiple genes have been implicated in hereditary PGL/PCC syndromes. PGL/PCC syndromes are characterized by the presence of paragangliomas (neuroendocrine tissue-derived tumors) and pheochromocytomas (paragangliomas confined to the adrenal medulla). Hereditary PGL/PCC is often characterized by an early age of disease onset, the presence of multiple (or recurrent) paragangliomas/pheochromocytomas, and family history.
Clinical presentation varies but may include:
- Hypertension
- Paroxysmal tachycardia
- Heart palpitations
- Pallor/weight loss
- Hyperglycemia
- Metastatic disease
Testing Strategy
Biochemical Testing
Biochemical testing is often utilized in conjunction with computed tomography (CT) radiography and aids in characterizing the clinical and phenotypic features of PGL and PCC. Initial biochemical testing for hereditary PGL/PCC syndromes includes measurement of plasma-free metanephrines and/or urine metanephrines, dopamine (in plasma or urine), homovanillic acid, methoxytyramine, and fractionated catecholamines.
The following biochemical phenotypes are observed in the presence of pathogenic variants in the associated genes :
- MAX: mixed
- SDHA: mixed
- SDHAF2: unclear
- SDHB: norepinephrine/normetanephrine
- SDHC: norepinephrine/normetanephrine
- SDHD: norepinephrine/normetanephrine, often silent
- TMEM127: mixed
Genetic Testing
Genetic testing should be considered in individuals who have either PGL/PCC tumors or a relative with a hereditary PGL/PCC syndrome, and in individuals who meet any of the following criteria :
- Clinical evidence of a PGL/PCC syndrome
- Confirmed family history of PGL/PCC tumors
- Multiple, multifocal, or extra-adrenal tumors
- Malignancy associated with a PGL/PCC tumor
- Onset occurs at <45 years of age
Offer targeted testing for a known familial variant. If no familial variant has been previously identified, order a multigene sequencing panel that includes a deletion/duplication analysis.
For detailed information on the testing strategy for PGL/PCC tumors, refer to the ARUP Consult Pheochromocytoma - Paraganglioma topic.
Genetics
Genes
For more detailed information about the genes included on these panels, refer to the Genes Tested table.
| Genes Included | Hereditary Paraganglioma-Pheochromocytoma (SDHA, SDHB, SDHC, and SDHD) Sequencing and Deletion/Duplication 3004480 | Hereditary Paraganglioma-Pheochromocytoma Expanded Panel, Sequencing and Deletion/Duplication 3005912 |
|---|---|---|
|
FH |
|
✔ |
|
MAX |
|
✔ |
|
MEN1 |
|
✔ |
|
NF1 |
|
✔ |
|
RET |
|
✔ |
|
SDHA |
✔ |
✔ |
|
SDHAF2 |
|
✔ |
|
SDHB |
✔ |
✔ |
|
SDHC |
✔ |
✔ |
|
SDHD |
✔ |
✔ |
|
TMEM127 |
|
✔ |
|
VHL |
|
✔ |
Inheritance
- Autosomal dominant (AD); some genes may show a parent-of-origin effect.
Test Interpretation
Sensitivity/Specificity
Clinical Sensitivity
Variable, based on phenotype.
Approximately 30% of individuals diagnosed with PGL/PCC have a detectable germline variant in one of the genes associated with PGL/PCC susceptibility.
Analytic Sensitivity/Specificity
| Variant Class | Analytic Sensitivity (PPA) Estimatea (%) and 95% Credibility Region (%) | Analytic Specificity (NPA) Estimate (%) |
|---|---|---|
|
SNVs |
>99 (96.9-99.4) |
>99.9 |
|
Deletions 1-10 bpb |
93.8 (84.3-98.2) |
>99.9 |
|
Insertions 1-10 bpb |
94.8 (86.8-98.5) |
>99.9 |
|
Exon-levelc deletions |
97.8 (90.3-99.8) [2 exons or larger] 62.5 (38.3-82.6) [single exon] |
>99.9 |
|
Exon-levelc duplications |
83.3 (56.4-96.4) [3 exons or larger] |
>99.9 |
|
Exon-level deletions/duplications (MLPA) |
>99 |
>99 |
|
aPPA values are derived from larger methods-based MPS and/or Sanger validations. These values do not apply to testing performed by MLPA unless otherwise indicated. bVariants greater than 10 bp may be detected, but the analytic sensitivity may be reduced. cIn most cases, a single exon deletion or duplication is less than 450 bp and 3 exons span a genomic region larger than 700 bp. bp, base pairs; MLPA, multiplex ligation-dependent probe amplification; MPS, massively parallel sequencing; NPA, negative percent agreement; PPA, positive percent agreement; SNVs, single nucleotide variants |
||
Results
| Result As Reported in Chart | Variant(s) Detected | Clinical Significance |
|---|---|---|
|
Positive |
One pathogenic or likely pathogenic variant detected |
Confirms or predicts a diagnosis of a hereditary PGL/PCC syndromea |
|
See note |
One variant of uncertain significance detected |
Unknown if the variant is disease-causing or benign |
|
Negative |
No pathogenic variants detected |
Diagnosis of hereditary PGL/PCC is less likely, though not excluded |
|
aFor pathogenic and likely pathogenic MAX, SDHAF2, and SDHD variants, clinical manifestations generally only occur when inherited paternally. |
||
Limitations
- A negative result does not exclude a diagnosis of hereditary PGL/PCC or another cancer syndrome.
- Diagnostic errors can occur due to rare sequence variations
- The interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
- The following will not be evaluated:
- Variants outside the coding regions and intron-exon boundaries of the targeted genes
- Regulatory region and deep intronic variants
- Breakpoints of large deletions/duplications
- The following exons are not sequenced due to the technical limitations of the assay:
- MEN1 (NM_001370251) 8
- SDHA (NM_004168) 14; (NM_001294332) 13; (NM_001330758) 12
- SDHC (NM_001035511) partial exon 5 (Chr1:161332225-161332330); (NM_001278172) partial exon 4 (Chr1:161332225-161332330)
- SDHD (NM_001276506) 4
- VHL (NM_001354723) 2
- The following may not be detected:
- Deletions/duplications/insertions of any size by MPS
- Large duplications fewer than 3 exons in size
- Noncoding transcripts
- Single exon deletions/duplications may not be detected based on the breakpoints of the rearrangement.
- Some variants may not be detected due to technical limitations in the presence of pseudogenes and/or repetitive/homologous regions.
- Low-level somatic variants
- Deletions/duplications in the following exons:
- MEN1 (NM_001370251) 8
- SDHA (NM_004168) 1,10-15; (NM_001294332) 1,9-14; (NM_001330758) 1,10-13
- VHL (NM_001354723) 2
Genes Tested
To compare directly to other hereditary cancer panels offered by ARUP Laboratories, refer to the ARUP Hereditary Cancer Panel Comparison table.
| Gene Symbol | MIM # | Disorders | Inheritance |
|---|---|---|---|
| FH | 136850 |
FH tumor predisposition syndrome/HLRCC Cutaneous and uterine leiomyomata, papillary type 2 renal cancer, paraganglioma, and pheochromocytoma |
AD |
| Fumarase deficiency | AR | ||
| MAX | 154950 |
HPP syndromes Paraganglioma and pheochromocytoma |
ADa |
| MEN1 | 613733 |
MEN type 1 Adrenocortical, carcinoid, GEP neuroendocrine tumors, meningioma, parathyroid, pituitary, and thyroid |
AD |
| NF1 | 613113 |
NF1 Breast, GIST, gliomas, leukemia, malignant peripheral nerve sheath tumors, neurofibromas, and pheochromocytoma |
AD |
| RET | 164761 |
MEN2 Medullary thyroid carcinoma, parathyroid adenoma or hyperplasia, and pheochromocytoma |
AD |
|
SDHA |
600857 |
HPP syndromes GIST, paraganglioma, pheochromocytoma, pulmonary chondroma, and renal clear cell carcinoma |
AD |
| SDHAF2 | 613019 |
HPP syndromes Paraganglioma |
ADb |
|
SDHB |
185470 |
HPP syndromes GIST, paraganglioma, pheochromocytoma, pulmonary chondroma, and renal clear cell carcinoma |
AD |
|
SDHC |
602413 |
HPP syndromes GIST, paraganglioma, pheochromocytoma, pulmonary chondroma, and renal clear cell carcinoma |
AD |
|
SDHD |
602690 |
GIST, paraganglioma, pheochromocytoma, pulmonary chondroma, and renal clear cell carcinoma |
ADb |
| TMEM127 | 613403 |
HPP syndromes Paraganglioma, pheochromocytoma, and renal clear cell carcinoma |
AD |
| VHL | 608537 |
VHL syndrome Endolymphatic sac tumors, epididymal and broad ligament cystadenomas, hemangioblastoma, neuroendocrine tumors, pheochromocytoma, renal cell carcinoma, and retinal angioma |
AD |
|
aPossible paternal parent-of-origin effect. bPaternal parent-of-origin effect. AR, autosomal recessive; GEP, gastro-entero-pancreatic; GIST, gastrointestinal stromal tumor; HLRCC, hereditary leiomyomatosis and renal cell cancer; HPP, hereditary paraganglioma-pheochromocytoma; MEN, multiple endocrine neoplasia; NF1, neurofibromatosis type 1; VHL, Von Hippel-Lindau |
|||
References
-
GeneReviews - Hereditary Paraganglioma-Pheochromocytoma Syndromes
Else T, Greenberg S, Fishbein L. Hereditary paraganglioma-pheochromocytoma syndromes. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington, Seattle. Last update Oct 2018; accessed Feb 2020.
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Lenders JWM, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915-1942.
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Hampel H, Bennett RL, Buchanan A, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17(1):70-87. Reaffirmed with Addendum: Genet Med. 2019;21(12):2844.
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NCCN - Neuroendocrine and adrenal tumors, version 3.2021
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: neuroendocrine and adrenal tumors. Version 3.2021. Updated Aug 2021; accessed Dec 2021.
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29177515
van der Tuin K, Mensenkamp AR, Tops CMJ, et al. Clinical aspects of SDHA-related pheochromocytoma and paraganglioma: a nationwide study [published correction appears in J Clin Endocrinol Metab. 2018;103(5):2077]. J Clin Endocrinol Metab. 2018;103(2):438-445.
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28374168
Jochmanova I, Wolf KI, King KS, et al. SDHB-related pheochromocytoma and paraganglioma penetrance and genotype-phenotype correlations. J Cancer Res Clin Oncol. 2017;143(8):1421-1435.
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Bausch B, Schiavi F, Ni Y, et al. Clinical characterization of the pheochromocytoma and paraganglioma susceptibility genes SDHA, TMEM127, MAX, and SDHAF2 for gene-informed prevention. JAMA Oncol. 2017;3(9):1204-1212.
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Baysal BE, Willett-Brozick JE, Lawrence EC, et al. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet. 2002;39(3):178-183.
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Berends AMA, Buitenwerf E, de Krijger RR, et al. Incidence of pheochromocytoma and sympathetic paraganglioma in the Netherlands: a nationwide study and systematic review. Eur J Intern Med. 2018;51:68-73.
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Burnichon N, Rohmer V, Amar L, et al. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab. 2009;94(8):2817-2827.
To compare directly to other hereditary cancer panels offered by ARUP Laboratories, refer to the ARUP Hereditary Cancer Panel Comparison table.