A KINDRED WITH A RET CODON Y791 F MUTATION PRESENTING WITH HIRSCHSPRUNG\’S DISEASE.

Background: Activating mutations in the RET gene underlie hereditary medullary thyroid carcinoma (MTC), a prominent featu re of MEN2, with a strong genotype/phenotype correlation. Inactivating mutations in the RET gene may be found in 35-75% of Hirschsprung's disease (HD). Co-occurrence of MTC and HD is rare, usually associated with mutations in exon 10. Recently, new missense mutations in exon 13, codons 790 & 791 have been described. Penetrance for MTC with Y791 F is apparently low. This mutation has been previously described in one patient with HD and several patients with sporadic MTC, but there is no report of a Y791 F patient or kindred with both diseases.

Methods and Results: We report a kindred identified after the diagnosis of a 3 months old baby with HD. RET protooncogene genotyping revealed a Y791 F mutation. There was no family history suggestive of MTC or MEN2 Five other family members were found to be carriers of the same mutation (ages 0.5 to 75 years). None had palpable thyroid nodules. All mutation carriers had a neck US; one had a multinodular goiter and one had a 7 mm nodule with gross calcifications-FNA was not informative. Two other patients had several <1 cm nodules which did not require an FNA. Basal calcitonin levels were normal in all carriers. Calcium infusion tests were preformed in 5/6 mutation carriers: two had calcitonin levels consistent with C cell hyperplasia and 3 others had a normal response; 4/6 had urinary catecholamines performed with normal results.

Discussion: In this kindred we have shown that despite the presence of RETY791 F mutation and advanced age in some of the carriers, none of the carriers displayed signs of MTC. This finding is compatible with other reports in the literature which point to a low penetrance of this mutation for the development of MTC, especially in families in which there is no MTC in the index patient as is the case in our kindred. Therefore, a conservative strategy with repeat neck US and Ca stimulation testing appears to be appropriate in these selected cases.