Germline FH mutations presenting with pheochromocytoma

Area of Science:

• Endocrinology
• Oncology
• Genetics

Background:

• Germline mutations in succinate dehydrogenase (SDH) genes are common causes of inherited pheochromocytoma (PCC) and paraganglioma (PGL).
• Fumarate hydratase (FH) gene mutations are typically associated with hereditary leiomyomatosis and renal cell carcinoma, but a rare link to PCC/PGL has emerged.
• Cellular metabolism abnormalities due to SDH or FH inactivation can activate hypoxic response pathways and epigenetic alterations.

Purpose of the Study:

• To identify novel genes predisposing to PCC and PGL.
• To investigate the role of the fumarate hydratase (FH) gene in PCC and PGL development.
• To expand the known clinical spectrum of FH mutations.

Main Methods:

• Exome resequencing was performed on a childhood PCC case to identify candidate genes.
• FH mutation analysis was conducted in 71 additional patients with PCC, PGL, or head and neck PGL.
• In vitro studies were used to assess the functional impact of identified FH mutations.

Main Results:

• Two candidate FH missense mutations (p.Cys434Tyr and p.Glu53Lys) were identified.
• In vitro analyses confirmed that both identified FH mutations rendered the enzyme catalytically inactive.
• The findings suggest FH mutations can be a rare cause of PCC/PGL.

Conclusions:

• Germline FH mutations can, rarely, manifest as PCC or PGL.
• The clinical phenotype associated with FH mutations is extended to include pediatric PCC.
• This study highlights the importance of considering FH in the genetic workup of PCC/PGL, especially in younger patients.