PGL/PCC/GIST Gene Panel
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.
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
- Forceful palpitations
- Excessive sweating
- 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
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.