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.


Overview of the genes in CENTOGENE´s PGL/PCC/GIST panel:

Gene OMIMChr. Locus Allelic disorders OMIM
GDNF
600837
5p13.2 Pheochromocytoma, PCC (171300); Central hypoventilation syndrome (209880); Hirschsprung disease 3 , HSCR (613711)
KIF1B
605995
1p36.22 Pheochromocytoma (171300); Charcot-Marie-Tooth disease, type 2A1 (118210); Neuroblastoma 1 (256700)
MAX
154950
14q23.3 Pheochromocytoma (171300)
MEN1
613733
11q13.1 Multiple endocrine neoplasia 1, MEN1 (131100); Adrenal adenoma, Angiofibroma, Carcinoid tumor of lung, Lipoma, Parathyroid adenoma (unknown OMIM)
NF1
613113
17q11.2 Neurofibromatosis spinal (162210); Neurofibromatosis type 1, NF1 (162200); Neurofibromatosis-Noonan syndrome (601321); Watson syndrome (193520); Leukemia juvenile myelomonocytic (607785)
RET
164761
10q11.21 PCC (171300); Central hypoventilation syndrome, congenital (209880); Medullary thyroid carcinoma (155240); MEN IIA (171400); MEN IIB (162300); HSCR 1 (142623)
SDHA
600857
5p15.33 Paragangliomas 5, PGL5 (614165); Cardiomyopathy, dilated, 1GG (613642); Leigh syndrome (256000); Mitochondrial respiratory chain complex II deficiency (252011) 
SDHAF2
613019
11q12.2 PGL2 (601650)
SDHB
185470
1p36.13 PCC (171300); Cowden syndrome 2 (612359); Gastrointestinal stromal tumor (606764); PGL and gastric stromal sarcoma (606864); PGL4 (115310)
SDHC
602413
1q23.3 PGL3 (605373)
SDHD
602690
11q23.1 PGL1, with or without deafness, PGL1 (168000); PCC (171300)
TMEM127
613403
2q11.2 PCC (171300)
TP53
191170
17p13.1 Adrenal cortical carcinoma (202300); Breast cancer (114480); Choroid plexus papilloma (260500); Colorectal cancer (114500); Hepatocellular carcinoma (114550); Li-Fraumeni syndrome (151623); Nasopharyngeal carcinoma (607107); Osteosarcoma (259500); Pancreatic cancer (260350); Basal cell carcinoma 7 (614740); Glioma susceptibility 1 (137800)
VHL
608537
3p25.3 PCC (171300); Erythrocytosis 2 (263400); Renal cell carcinoma (144700); von Hippel-Lindau syndrome (193300)