title: A NOVEL DOUBLE MUTATION VAL648ILE AND VAL804LEU OF RET PROTO-ONCOGENE IN MULTIPLE ENDOCRINE NEOPLASIA TYPE 2.
abstract: OBJECTIVE
  We report the case of a female patient with multiple endocrine neoplasia type 2A (MEN2A) who was found to have a double mutation in the RET (rearranged during transfection) proto-oncogene.
  
  
  METHODS
  RET mutational analysis was performed by Sanger DNA sequencing.
  
  
  RESULTS
  The proband was a compound heterozygote for the RET germline mutations Val648Ile and Val804Leu on exons 11 and 14, respectively. Genetic analysis of family members showed the presence of the Val648Ile mutation in all except 1 daughter who carried the Val804Leu mutation. However, none of them showed any clinical, biochemical, or histologic signs of neoplastic disease either in the thyroid or adrenal gland. Furthermore, a daughter and the proband's sister who underwent a prophylactic thyroidectomy did not show pathologic evidence of C-cell disease.
  
  
  CONCLUSIONS
  We hypothesize that the combined effect of the 2 mutations may have induced the development of pheochromocytoma (PHEO) in our patient. Thus, in the presence of single RET-induced mild medullary thyroid cancer (MTC) phenotype, the search for additional genetic anomalies may lead to the discovery of rare but potentially more aggressive double mutation genotypes.
authors.forename: Antonella
authors.initials: A
authors.lastname: Verrienti
authors.forename: Antonella
authors.initials: A
authors.lastname: Carbone
authors.forename: Pasquale
authors.initials: P
authors.lastname: Bellitti
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Fabiano
authors.forename: Roberta F
authors.initials: RF
authors.lastname: De Rose
authors.forename: Marianna
authors.initials: M
authors.lastname: Maranghi
authors.forename: Piernatale
authors.initials: P
authors.lastname: Lucia
authors.forename: Cosimo
authors.initials: C
authors.lastname: Durante
authors.forename: Francesca
authors.initials: F
authors.lastname: Rosignolo
authors.forename: Valeria
authors.initials: V
authors.lastname: Pecce
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Sponziello
authors.forename: Cinzia
authors.initials: C
authors.lastname: Puppin
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Costante
authors.forename: Rocco
authors.initials: R
authors.lastname: Bruno
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000473:pathology; D019943:Amino Acid Substitution; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D007930:Leucine / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010673:Pheochromocytoma / Q000235:genetics* / Q000473:pathology; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D014633:Valine / Q000235:genetics
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D007532:Isoleucine; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D007930:Leucine; D014633:Valine