title: Coexistence of multiple endocrine neoplasia type 1 and type 2 in a large Italian family.
abstract: To describe the coexistence of mutations of both the multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2) genes in a large Italian family and evaluate if it could be associated with more aggressive clinical manifestations of the two syndromes. Blood samples were obtained for genetic and biochemical analyses. The RET gene exons (8, 10, 11, 13, 14, 15, 16, 18) and the MEN1 coding regions, including the exon-intron boundaries, were amplified by PCR and directly sequenced. We identified two germline mutations in the proband: the first one, K666M, located at the exon 11 of RET proto-oncogene and the second one, IVS4+1G>T, located in the MEN1 gene. The functional characterization of IVS4+1G>T variation, located in the splicing donor site of exon 4 of MEN1 gene, caused the in-frame junction of exon 3 to exon 5, thus obtaining a shorter protein. The same proband's germline mutations were found in 16 relatives out of 21 screened subjects: 8 carried IVS4+1G>T, 4 RET K666M, and 4 both the mutations. This is the second report in literature of coexistence in the same family of germline mutations of both RET proto-oncogene and MEN1 gene. The simultaneous presence of the two mutations was not apparently associated with more aggressive diseases, since at last follow-up all patients appeared to be disease-free or well compensated by medical therapy; finally, no one exhibited metastatic diseases.
authors.affiliation: Unit of Cardiology, Scientific Institute Casa Sollievo della Sofferenza, 71013, San Giovanni Rotondo, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Mastroianno
authors.forename: Massimo
authors.initials: M
authors.lastname: Torlontano
authors.forename: Alfredo
authors.initials: A
authors.lastname: Scillitani
authors.forename: Leonardo
authors.initials: L
authors.lastname: D'Aloiso
authors.forename: Antonella
authors.initials: A
authors.lastname: Verrienti
authors.forename: Nazario
authors.initials: N
authors.lastname: Bonfitto
authors.forename: Antonio
authors.initials: A
authors.lastname: De Bonis
authors.forename: Leonardo
authors.initials: L
authors.lastname: D'Agruma
authors.forename: Lucia Anna
authors.initials: LA
authors.lastname: Muscarella
authors.forename: Vito
authors.initials: V
authors.lastname: Guarnieri
authors.forename: Franca
authors.initials: F
authors.lastname: Dicembrino
authors.forename: Marianna
authors.initials: M
authors.lastname: Maranghi
authors.forename: Cosimo
authors.initials: C
authors.lastname: Durante
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Filetti
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005190:Family; D005260:Female; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D018761:Multiple Endocrine Neoplasia Type 1 / Q000150:complications / Q000235:genetics*; D018813:Multiple Endocrine Neoplasia Type 2a / Q000150:complications / Q000235:genetics*; D010375:Pedigree; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: C000715470:MAS1 protein, human; C105373:MEN1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human