Paraganglioma syndrome

• Overview
  • Genes include SDH A, SDH B, SDH C, and SDH D
    • Tumour suppressor genes
  • Typically autosomal dominant mutations
• Manifestations
  • Phaeochromocytomas
  • Paragangliomas
  • Also at risk of developing GIST
    • SDH deficient GISTs are less likely to respond to imatinib.
• Types
  • SDH-A
    • Very rare
  • SDH-B
    • About 80% of patients will develop a tumour by age of 50
    • Usually paraganglionomas
    • Higher likelihood of being malignant
  • SDH-C
    • Rare
    • Usually develop paraganglionomas
    • Low chance of malignancy.
  • SDH-D
    • 90% of patients develop tumour by age of 50
    • Usually para-ganglionomas
    • Higher likelihood of being malignant

SDH-B and D are the bad subtypes with high rates of tumours by aged 50 and also higher rates of the tumours being malignant

• Pathogenic variants in the genes encoding different subunits of the SDH enzyme complex
• Linked to hereditary pheochromocytoma/paraganglioma
• SDHx genes
  • SDHA, SDHB, SDHC, and SDHD, SDHAF2
• Paraganglioma syndrome 1-5
  • PGL1
    • Paraganglioma syndrome 1 (PGL1) is associated with pathogenic variants in SDHD at gene locus 11q23
    • Most common
  • PGL2
    • Paraganglioma syndrome 2 (PGL2) is associated with pathogenic variants in the gene for SDH complex assembly factor 2 (SDHAF2), which is located at gene locus 11q12.2
    • To date, PGL2 has been diagnosed only in patients with an affected father, which may indicate maternal imprinting
  • PGL3
    • Paraganglioma syndrome 3 (PGL3) is associated with pathogenic variants in SDHC at locus 1q21
  • PGL4
    • Paraganglioma syndrome 4 (PGL4) is associated with pathogenic variants in SDHB at gene locus 1p36.1-35
    • Second most common type
  • PGL5
    • Paraganglioma syndrome 5 (PGL5) is associated with pathogenic variants in SDHA, which comprises 15 exons and encodes a 2390-bp transcript.