Genetic Testing for Hereditary Paraganglioma/Pheochromocytoma

Preferred initial test when hereditary PGL/PCC is suspected

Disease Overview

Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are familial cancer syndromes characterized by benign or malignant neuroendocrine tumors: paragangliomas (neuroendocrine tumors of the autonomic nervous system) and pheochromocytomas (paragangliomas of the adrenal medulla). PGL/PCC tumors can affect both the sympathetic nervous system and the parasympathetic nervous system.

Clinical presentation varies but can include:

  • Hypertension
  • Paroxysmal tachycardia
  • Heart palpitations
  • Pallor/weight loss
  • Hyperglycemia
  • Metastatic disease

Pathogenic germline variants in SDHA, SDHB, SDHC, and SDHD, among other genes, predispose individuals to PGL/PCC tumors with an increased risk for malignancy. Whereas malignancy risk is low in tumors associated with pathogenic variants in the SDHA, SDHC, and SDHD genes, malignancy risk is high (34-97%) in tumors associated with variants in the SDHB gene.  

Testing Strategy

Biochemical Testing

Often utilized in conjunction with computed tomography (CT) radiography, biochemical testing 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.

Pathogenic variants in the SDHA, SDHB, SDHC, and SDHD genes are associated with the following biochemical phenotypes  :

  • SDHA: mixed
  • SDHB: norepinephrine/normetanephrine
  • SDHC: norepinephrine/normetanephrine
  • SDHD: norepinephrine/normetanephrine, often silent

Genetic Testing

Genetic testing should be considered in individuals who have 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 at <45 years of age

Offer targeted testing for a known familial variant (see Related Tests below). If no familial variant has been previously identified, order a multigene sequencing panel that includes deletion/duplication analysis.

For detailed information on the testing strategy for PGL/PCC tumors, refer to the ARUP Consult Pheochromocytoma - Paraganglioma topic.

Genetics

Genes Tested

Gene Symbol MIM # Disorders Inheritance

SDHA

600857

Paragangliomas 5

Neurodegeneration with ataxia and late-onset optic atrophy

AD

Dilated cardiomyopathy 1GG

Mitochondrial complex II deficiency, nuclear type 1

AR

SDHB

185470

Paragangliomas 4

Gastrointestinal stromal tumor

Pheochromocytoma

Paraganglioma and gastric stromal sarcoma

AD

Mitochondrial complex II deficiency, nuclear type 4

AR

SDHC

602413

Paragangliomas 3

Paraganglioma and gastric stromal sarcoma

Gastrointestinal stromal tumor

AD

SDHD

602690

Paragangliomas 1, with or without deafness

Paraganglioma and gastric stromal sarcoma

Pheochromocytoma

AD, with parent-of-origin effecta

Mitochondrial complex II deficiency, nuclear type 3

AR

aTumor predisposition generally occurs only when variants are inherited paternally.

AD, autosomal dominant; AR, autosomal recessive

For information regarding other rare genes associated with hereditary PGL/PCC (eg, MAX, SDHAF2, or TMEM127), see the ARUP Consult Pheochromocytoma - Paraganglioma topic. See Related Tests for additional testing options.

Inheritance

  • Primarily autosomal dominant
    • Parent-of-origin effect for SDHD: tumor predisposition generally occurs only when variants are inherited paternally
  • Rarely autosomal recessive (see Genes Tested for additional details)

Penetrance

Penetrance varies by gene and is incomplete and age dependent.     

  • SDHA: 10-50% by age 70
  • SDHB: ~22-58% by age 60
  • SDHC: 25% by age 60
  • SDHD: ~43% by age 60

Test Interpretation

Sensitivity/Specificity

Clinical sensitivity: 22-45%

  • Approximately 30% of individuals diagnosed with PGL/PCC have a detectable germline variant in one of the genes associated with PGL/PCC susceptibility.
Gene Proportion of Hereditary PGL/PCC Syndromes Attributed to Pathogenic Variants in Gene Proportion of Variants Detectable by Sequence Analysis (%) Proportion of Variants Detectable by Deletion/Duplication Analysis (%)

SDHA

0.6-3%

~100

None reported

SDHB

10-25%

12-20% of HNPGL

24-44% of chest, abdomen, and pelvic PGL/PCC

~85-95

~5-15

SDHC

2-8%

~85

~15

SDHD

~8-9%

~40-50% of HNPGL

~15% of chest, abdomen, and pelvic PGL/PCC

~95

~5

HNPGL, head and neck paraganglioma

Sources: Else, 2018 ; Bausch, 2017 ; Baysal, 2002 ; Berends, 2018 ; Burnichon, 2009 

Analytical Sensitivity

  • For MLPA: >99%
  • For massively parallel sequencing:
Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

99.9

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

99.9

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; 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 variant is disease causing or benign

Negative

No pathogenic variants detected

Diagnosis of hereditary PGL/PCC less likely, though not excluded

aFor pathogenic and likely pathogenic SDHD variants, clinical manifestations generally only occur when inherited paternally.

Limitations

  • A negative result does not exclude a diagnosis of hereditary paraganglioma-pheochromocytoma.
  • Diagnostic errors can occur due to rare sequence variations
  • 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 targeted genes
    • Regulatory region and deep intronic variants
    • Noncoding transcripts
  • The following exons are not sequenced due to technical limitations of the assay:
    • SDHA (NM_004168) exon 14
    • Breakpoints of large deletions/duplications
    • Deletions/duplications in the SDHA gene
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Certain variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants

References

Additional Resources