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Background. The clinical association of multiple endocrine neoplasia type 2A (MEN 2A) and Hirschsprung's
disease (HD), although rare, has been previously observed. Recently, germline mutations
in the RET proto-oncogene, a transmembrane receptor with tyrosine kinase activity,
have been detected in patients with familial HD. RET is also the predisposition gene
for the inherited cancer syndrome MEN 2A.
Methods. We describe a DNA sequence variation within the coding region of RET in two large
unrelated kindreds with MEN 2A (with 83 and 42 persons affected) in which HD cosegregated
with MEN 2A in seven patients. Mutational analysis was performed with a highly sensitive
polymerase chain reaction-based denaturing gradient gel electrophoresis technique
followed by direct sequencing of mutants.
Results. Genetic analysis by denaturing gradient gel electrophoresis detected mutant bands
in RET exon 10 in patients with MEN 2A from both kindreds. Direct DNA sequencing of
mutants revealed a thymine-to-adenine base change in codon 618, resulting in a cysteine-to-serine
substitution. The identical mutation was present in all seven children with HD. Of
these children five underwent thyroidectomy for C-cell abnormalities; one 3-year-old
child is awaiting thyroid surgery, and the remaining patient died at age of 12 weeks.
Conclusions. The RET codon 618 Ser mutation could predispose patients with MEN 2A to HD. RET may
assume a critical role in embryologic enteric nerve migration and tumorigenesis of
cells from neural crest lineage.
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Article info
Publication history
Accepted:
August 15,
1994
Footnotes
†Supported by grants from the National Institutes of Health (1K08DK02176-02), American Cancer Society (VM-73), and the John and Suzanne Munn Endowed Research Fund of the University of Michigan Comprehensive Cancer Center (R.A.D.)
Identification
Copyright
© 1995 Mosby-Year Book, Inc. Published by Elsevier Inc.
