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Molecular Analysis of the ret and GDNF Genes in a Family with Multiple Endocrine Neoplasia Type 2A and Hirschsprung Disease¹

Unidad de Genética Médica y Diagnóstico Prenatal (S.B., B.S., M.E.S., G.A.) and Servicio de Endocrinología (E.N.), Hospital Universitario Virgen del Rocío, 41013 Sevilla, Spain; Translational Research Laboratory, Charles A. Dana Human Cancer Genetics Unit, Department of Adult Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115; and Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge (C.E.), Cambridge, United Kingdom

Address all correspondence and requests for reprints to: Salud Borrego M.D., Ph.D., Unidad de Genética Médica y Diagnóstico Prenatal, Hospital Universitario Virgen del Rocío, Avenida M.Siurot s/n, 41013 Sevilla, Spain.

The clinical association between multiple endocrine neoplasia type 2 (MEN2) and Hirschsprung disease (HSCR) is infrequent. Germline mutations of the ret protooncogene are the underlying cause of the MEN2 syndromes and a proportion of cases of HSCR. In this report, we describe a new kindred in which the MEN2 and HSCR phenotypes are associated with a single C620S point mutation at one of the cysteine codons of the extracellular domain of the ret protooncogene. We also speculate about the role of a silent mutation in exon 2 of this same gene (A45A), present in a homozygous state in the patient with both MEN2A and HSCR. To investigate the contribution of GDNF to the phenotype observed in this kindred, we scanned the coding region of GDNF in the patient with MEN2/HSCR, but no mutation was found.

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