A Homozygous RET K666N Genotype With an MEN2A Phenotype

Area of Science:

• Endocrinology
• Genetics
• Oncology

Background:

• Germline RET K666N mutations are linked to medullary thyroid cancer (MTC) but usually exhibit low disease penetrance.
• Multiple Endocrine Neoplasia type 2A (MEN2A) is typically associated with RET mutations, but isolated MTC can occur.

Observation:

• A 59-year-old woman presented with MTC and bilateral pheochromocytoma (PHEO).
• Genetic testing revealed a homozygous RET K666N mutation in the patient.
• Her adult children carried a heterozygous K666N mutation; one developed MTC, the other had C-cell hyperplasia.

Findings:

• The homozygous RET K666N mutation was associated with both MTC and bilateral PHEO.
• Heterozygous carriers of the RET K666N mutation showed variable penetrance, including MTC and C-cell hyperplasia, but not PHEO.
• No additional mutations were found to explain the PHEO in the proband.

Implications:

• Homozygosity for the RET K666N mutation may increase disease penetrance and lead to a broader spectrum of endocrine tumors, including PHEO.
• This case highlights the importance of considering gene dosage effects in hereditary cancer syndromes.
• Further research is needed to understand the full clinical spectrum and genetic modifiers of RET mutations.