title: V804M RET mutation and familial medullary thyroid carcinoma: report of a large family with expression of the disease only in the homozygous gene carriers.
abstract: BACKGROUND
  Only 9 families with familial medullary thyroid carcinoma due to V804M mutation have been reported until now. We describe a large kindred with not only heterozygous but also homozygous members with the V804M mutation. This is, to our knowledge, the first report of a homozygous RET mutation.
  
  
  METHODS
  Fifty-three members from 4 successive generations of a family with a high level of consanguinity underwent genetic analysis. The pentagastrin provocative test and biochemical screening to rule out either hyperparathyroidism or pheochromocytoma were performed only on gene carriers of the mutation.
  
  
  RESULTS
  Twenty-six gene carriers for V804M mutation were identified (4 homozygous and 22 heterozygous). Three of 4 homozygous patients underwent total thyroidectomy. In 1 patient neither medullary thyroid carcinoma nor C-cell hyperplasia was detected, and in another patient only 3 small foci of C-cell hyperplasia were found on the histologic examination. The pentagastrin stimulation test result was within the normal range in all the heterozygous gene carriers and, consequently, thyroidectomy was not indicated. The screening for both hyperparathyroidism and pheochromocytoma was negative in all patients.
  
  
  CONCLUSIONS
  In the family reported, the V804M mutation in heterozygous patients seems not to be enough to express the full disease. This finding strongly supports the concept of the indolent behavior of V804M RET proto-oncogene mutation. In addition, our results suggest that when counseling for preventive total thyroidectomy, the specific mutation of RET proto-oncogene and also the natural history of the disease within a particular family should be considered.
authors.affiliation: Department of Endocrinology, Hospital Vall d'Hebron, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Lecube
authors.forename: Cristina
authors.initials: C
authors.lastname: Hernandez
authors.forename: Josep
authors.initials: J
authors.lastname: Oriola
authors.forename: Rosa
authors.initials: R
authors.lastname: Galard
authors.forename: Enrique
authors.initials: E
authors.lastname: Gémar
authors.forename: Jorge
authors.initials: J
authors.lastname: Mesa
authors.forename: Rafael
authors.initials: R
authors.lastname: Simó
mesh_terms: D000293:Adolescent; D000328:Adult; D018276:Carcinoma, Medullary / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D029721:Drosophila Proteins; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: D029721:Drosophila Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila