BACKGROUND AND OBJECTIVES: Medullary thyroid carcinoma (MTC) occurs both 
sporadically and in the autosomal dominantly inherited multiple endocrine 
neoplasia (MEN) type 2 syndromes. The distinction between true sporadic MTC and 
a new mutation familial case is important for future clinical management of both 
the patient and family. The susceptibility gene for MEN 2 is the RET 
proto-oncogene. Systematic analysis for germline mutations of the RET 
proto-oncogene was performed in a series of 67 patients with apparently sporadic 
MTC to determine whether they were true sporadic cases or unsuspected de novo 
MEN 2 cases.
DESIGN AND PATIENTS: Sixty-seven unselected patients with sporadic MTC were 
randomly ascertained from clinic patients from four centres. The diagnosis of 
MTC was confirmed by histopathology. Germline DNA was extracted from peripheral 
blood leucocytes or from paraffin-embedded tissue and subsequently used for 
polymerase chain reaction amplification.
MEASUREMENTS: Polymerase chain reaction based RET mutation analysis was 
performed by direct double-stranded cycle sequencing of exons 10, 11, 13 and 16, 
within which the majority of MEN2 mutations have been shown to occur.
RESULTS: In this series, there was one proven case of germline mutation in RET 
codon 620, which previously has been shown to be responsible for MEN 2, thus 
indicating heritable disease. No germline mutation in codon 918, typical of MEN 
2B, was found.
CONCLUSIONS: A figure of 1.5% germline mutations in 67 apparently sporadic MTC 
is lower than the incidence of familial disease reported in previous series 
involving clinical and biochemical screening. The presence of a germline 
mutation in the RET proto-oncogene in a patient with MTC indicates heritable 
disease. The absence of germline RET exon 10, 11, 13 or 16 mutation appears to 
rule out MEN 2A to a high probability, although the presence of a familial form 
of MTC other than classical MEN 2A cannot be excluded conclusively.