1. PGL/PCC/GIST gene panel

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, modifier of; Central hypoventilation syndrome; Hirschsprung disease, susceptibility to, 3 AD 0
KIF1B 605995 ?Charcot-Marie-Tooth disease, type 2A1; Pheochromocytoma; Neuroblastoma, susceptibility to, 1 AD, Isolated cases 61
MAX 154950 Pheochromocytoma, susceptibility to AD 6
MEN1 613733 Multiple endocrine neoplasia 1 AD 7
NF1 613113 Neurofibromatosis, type 1; Neurofibromatosis, familial spinal; Watson syndrome; Neurofibromatosis-Noonan syndrome; Leukemia, juvenile myelomonocytic AD, Somatic mutation 149
RET 164761 Hirschsprung disease, protection against; Hirschsprung disease, susceptibility to, 1; Medullary thyroid carcinoma; Multiple endocrine neoplasia IIB; Pheochromocytoma; Multiple endocrine neoplasia IIA; Central hypoventilation syndrome, congenital AD 15
SDHA 600857 Mitochondrial respiratory chain complex II deficiency; Leigh syndrome; Cardiomyopathy, dilated, 1GG; Paragangliomas 5 AD, AR, M 39
SDHAF2 613019 Paragangliomas 2 AD 4
SDHB 185470 Paragangliomas 4; Pheochromocytoma; Gastrointestinal stromal tumor; Paraganglioma and gastric stromal sarcoma; Cowden syndrome 2 AD, Isolated cases 2
SDHC 602413 Paragangliomas 3; Gastrointestinal stromal tumor; Paraganglioma and gastric stromal sarcoma AD, Isolated cases 10
SDHD 602690 Carcinoid tumors, intestinal; Paragangliomas 1, with or without deafness; Pheochromocytoma; Mitochondrial complex II deficiency; Paraganglioma and gastric stromal sarcoma; Cowden syndrome 3 AD, AR 5
TMEM127 613403 Pheochromocytoma, susceptibility to AD 2
TP53 191170 Breast cancer; Colorectal cancer; Hepatocellular carcinoma; Glioma susceptibility 1; Li-Fraumeni syndrome; Adrenal cortical carcinoma; Osteosarcoma; Pancreatic cancer; Choroid plexus papilloma; Nasopharyngeal carcinoma; Basal cell carcinoma 7 AD, AR, MF, Somatic mutation 12
VHL 608537 Renal cell carcinoma, somatic; Pheochromocytoma; von Hippel-Lindau syndrome; Erythrocytosis, familial, 2 AD, AR 12