Hereditary Paraganglioma-Pheochromocytoma Panels

Content Review: December 2022 Last Update:

To compare directly to other hereditary cancer panels offered by ARUP Laboratories, refer to the ARUP Hereditary Cancer Panel Comparison table.

Preferred initial test when hereditary PGL/PCC is suspected with no clear biochemical findings

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.



For more detailed information about the genes included on these panels, refer to the Genes Tested table.

Genes Included in ARUP's Hereditary Paraganglioma-Pheochromocytoma Tests
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






















  • Autosomal dominant (AD); some genes may show a parent-of-origin effect.

Test Interpretation


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.

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




None reported



12-20% of HNPGL

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









~40-50% of HNPGL

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



HNPGL, head and neck paraganglioma

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

Analytic Sensitivity/Specificity

Variant Class Analytic Sensitivity (PPA) Estimatea (%) and 95% Credibility Region (%) Analytic Specificity (NPA) Estimate (%)


>99 (96.9-99.4)


Deletions 1-10 bpb

93.8 (84.3-98.2)


Insertions 1-10 bpb

94.8 (86.8-98.5)


Exon-levelc deletions

97.8 (90.3-99.8) [2 exons or larger]

62.5 (38.3-82.6) [single exon]


Exon-levelc duplications

83.3 (56.4-96.4) [3 exons or larger]


Exon-level deletions/duplications (MLPA)



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


Result As Reported in Chart Variant(s) Detected Clinical Significance


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


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.


  • 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
Fumarase deficiency AR
MAX 154950

HPP syndromes

Paraganglioma and pheochromocytoma
MEN1 613733

MEN type 1

Adrenocortical, carcinoid, GEP neuroendocrine tumors, meningioma, parathyroid, pituitary, and thyroid
NF1 613113


Breast, GIST, gliomas, leukemia, malignant peripheral nerve sheath tumors, neurofibromas, and pheochromocytoma
RET 164761


Medullary thyroid carcinoma, parathyroid adenoma or hyperplasia, and pheochromocytoma



HPP syndromes

GIST, paraganglioma, pheochromocytoma, pulmonary chondroma, and renal clear cell carcinoma


SDHAF2 613019

HPP syndromes




HPP syndromes

GIST, paraganglioma, pheochromocytoma, pulmonary chondroma, and renal clear cell carcinoma




HPP syndromes

GIST, paraganglioma, pheochromocytoma, pulmonary chondroma, and renal clear cell carcinoma




GIST, paraganglioma, pheochromocytoma, pulmonary chondroma, and renal clear cell carcinoma


TMEM127 613403

HPP syndromes

Paraganglioma, pheochromocytoma, and renal clear cell carcinoma

VHL 608537

VHL syndrome

Endolymphatic sac tumors, epididymal and broad ligament cystadenomas, hemangioblastoma, neuroendocrine tumors, pheochromocytoma, renal cell carcinoma, and retinal angioma

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