1. PGL/PCC/GIST Gene Panel


July 11, 2018

Disease summary:

Paragangliomas (PGL) are tumors that arise from neuroendocrine tissues along the vertebrae. They can hypersecrete catecholamines or be non-secretory. Pheochromocytomas (PCC) are PGL tumors confined to the adrenal glands and usually secrete catecholamines.  Gastrointestinal stromal tumors (GIST) are soft tissue sarcomas that can arise throughout the GI tract.

PGL, PCC and GIST may occur sporadically or as part of  various syndromes, namely multiple endocrine neoplasia type 2 (MEN2), neurofibromatosis type 1 (NF1), Von Hippel-Lindau syndrome (VHL), and hereditary PGL/PCC syndromes 1, 2.

Genetic pathogenic variants in the genes, GDNF, KIF1B, MAX, MEN1, NF1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53, VHL (Table 1)6-21account for approximately 60% of PCC/PGL cases1, 7. GIST are associated with pathogenic variants in the SDHA, SDHB, SDHC and SDHD genes.

Autosomal dominant

1/100,000-300,000 in general population 1, 2.

  • Due to hypersecretion of catecholamines in PGL and PCC1, 3:

    • Elevations in blood pressure and pulse
    • Headaches
    • Forceful palpitations
    • Excessive sweating
    • Anxiety

  • Due to the presence of enlarging non-secretory PGL masses 1, 3:

    • Unilateral hearing loss,
    • Pulsatile tinnitus,
    • Swallowing difficulty,
    • Pain and/or problems with tongue motion

  • Due to GIST

    • Abdominal pain
    • Nausea and vomiting
    • Blood in stool and vomit
    • Fatigue due to anemia
    • Skin hyperpigmentation

PGL/PCC syndrome should be considered in all individuals with the following findings 3, 4:

  • Multiple tumors (i.e. >1 paraganglioma or pheochromocytoma), including bilateral adrenal pheochromocytoma
  • Multifocal with multiple primary tumors at the same time or consequently
  • Recurrent tumors and early onset tumors (i.e., age <45 years)
  • Positive family history of similar tumors
  • Identification of a heterozygous pathogenic variant in one of the following genes (Table 1): GDNF, KIF1B, MAX, MEN1, NF1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53, VHL 6-21

There is no cure for PGL/PCC/GIST-related disorders to date, but following treatments and management can relieve symptoms 1, 2, 4.

  • For secretory tumors, alpha-blockers to regulate blood pressure and surgery if possible
  • For non-secretory head and neck PGL, surgery or radiotherapy
  • Targeted therapy such as imatinib in GIST

The differential diagnosis of PGL/PCC/GIST-related disorders – depending on the major symptoms in the initial case – includes the following diseases 1, 2, 4:

  • Neurofibromatosis type I (NF1)
  • Von Hippel-Lindau disease (VHL)
  • Multiple endocrine neoplasia type 2 (MEN2),
  • Carney triad
  • Carney-Stratakis dyad (Carney-Stratakis syndrome)

Differential diagnosis for isolated catecholamine-secreting PCC include the following conditions 1, 2, 4:

  • Paroxysmal supraventricular tachycardia
  • Angina pectoris
  • Anxiety disorders, Munchausen's syndrome
  • Hyperthyroidism, thyrotoxicosis
  • Hypoglycemia, insulinoma
  • Intestinal carcinoid tumor
  • Menopause

To confirm/establish the diagnosis, CENTOGENE offers the following tests:

  • PGL/PCC/GIST panel, targeted NGS Panel which includes sequencing of the genes GDNF, KIF1B, MAX, MEN1, NF1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53, VHL
  • PGL/PCC/GIST panel, targeted NGS Panel + CNV which includes sequencing and additionally detection of large deletions and duplications from the NGS data
  • Individuals with a positive family history of PGL/PCC/GIST
  • Individuals with most common symptoms of PGL/PCC/GIST (regardless of family history)

Confirmation of a clinical diagnosis through genetic testing of PGL/PCC/GIST can allow for genetic counseling and may direct medical management.

Table 1. Overview of the genes in PGL/PCC/GIST panel:

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
GDNF 600837 pheochromocytoma; congenital central hypoventilation syndrome; Hirschsprung Disease, Susceptibility To, 3 AD 0
KIF1B 605995 type 2A1 Charcot-Marie-Tooth disease; pheochromocytoma AD 62
MAX 154950 pheochromocytoma AD 6
MEN1 613733 multiple endocrine neoplasia type 1 AD 7
NF1 613113 neurofibromatosis type 1; Leukemia, juvenile myelomonocytic AD 139
RET 164761 Hirschsprung disease; familial medullary thyroid carcinoma; multiple endocrine neoplasia 2B; pheochromocytoma; multiple endocrine neoplasia 2A; congenital central hypoventilation syndrome AD 17
SDHA 600857 mitochondrial complex II deficiency; Leigh syndrome; dilated cardiomyopathy-1GG; paragangliomas type 5 AD, AR, M 39
SDHAF2 613019 paragangliomas type 2 AD 4
SDHB 185470 paragangliomas type 4; pheochromocytoma; gastrointestinal stromal tumor; paraganglioma and gastric stromal sarcoma AD 2
SDHC 602413 Paragangliomas 3; gastrointestinal stromal tumor; paraganglioma and gastric stromal sarcoma AD 11
SDHD 602690 paragangliomas 1; pheochromocytoma; mitochondrial complex II deficiency; paraganglioma and gastric stromal sarcoma AD, AR 7
TMEM127 613403 pheochromocytoma AD 2
TP53 191170 familial breast cancer; colorectal cancer; Hepatocellular Carcinoma; Li-Fraumeni syndrome 1; Osteogenic Sarcoma; Pancreatic Cancer AD 14
VHL 608537 Renal carcinoma, chromophobe, somatic; pheochromocytoma; von Hippel-Lindau disease; Erythrocytosis, familial, 2 AD, AR 12