A de novo mutation of the RET proto-oncogene in a patient with MEN 2A

Multiple endocrine neoplasia type 2A (MEN 2A) is an inherited cancer syndrome characterised by medullary thyroid carcinoma (MTC), phaeochromocytoma and parathyroid hyperplasia. Recently, germline missense mutations of the RET protooncogene have been identified in patients with MEN 2A but not in unaffected individuals or normal controls, suggesting a causal relationship between these RET mutations and the MEN 2A phenotype. In 97% of MEN 2A families, point mutations in exon 10 or 11 result in the replacement of one of five cysteine residues in the RET extracellular domain with any of several alternative amino acids. The most frequently detected mutation is a TGC arrow right CGC conversion at codon 634, resulting in a Cys arrow right Arg amino acid substitution which is observed in 54% of MEN 2A families. We report a multi-generation family in which an apparently novel MEN 2A mutation has occurred. Sequence analyses of RET exons 10 and 11 in the founder MEN 2A patient, her offspring and unaffected parents indicate that a de novo mutation of RET codon 634 is associated with the appearance of the MEN 2A phenotype in this family.