title: A ten-year clinical update of a large RET p.Gly533Cys kindred with medullary thyroid carcinoma emphasizes the need for an individualized assessment of affected relatives.
abstract: OBJECTIVE
  Reviewing the clinical outcomes of a large kindred with a RET p.Gly533Cys mutation, 10 years after the first description of this kindred, has provided an important set of clinical data for healthcare decision-making.
  
  
  METHODS
  We identified 728 RET533 Brazilian relatives, spread out over 7 generations. We performed clinical examination, biochemical and imaging analyses in the proband and in 103 carriers.
  
  
  RESULTS
  The proband has been followed without evidence of structural disease in the last 10 years but with elevated calcitonin. The clinical and surgical features of 60 thyroidectomized RET533 relatives were also described. Forty-six patients had MTC (21-72 years), and 11 patients had C-cell hyperplasia (CCH) (5-42 years). Twelve MTC patients with lymph node metastases had a tumour size of 0·7-2·8 cm. Calcitonin level and CEA were correlated with disease stage, and none of the patients presented with an altered PTH or metanephrine. A 63-year-old woman developed pheochromocytoma and breast cancer. Two other RET533 relatives developed lung squamous cell carcinoma and melanoma.
  
  
  CONCLUSIONS
  A vast clinical variability in RET533 presentation was observed, ranging from only an elevated calcitonin level (3%) to local metastatic disease (25%). Many individuals were cured (42%) and the majority had controlled chronic disease (56%), reinforcing the need for individualized ongoing risk stratification assessment. The importance of this update relies on the fact that it allows us to delineate the natural history of RET 533 MEN2A 10 years after its first description.
authors.affiliation: Department of Medicine, Laboratory of Molecular and Translational Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Priscila S
authors.initials: PS
authors.lastname: Signorini
authors.forename: Maria Inez C
authors.initials: MI
authors.lastname: França
authors.forename: Cleber P
authors.initials: CP
authors.lastname: Camacho
authors.forename: Susan C
authors.initials: SC
authors.lastname: Lindsey
authors.forename: Flávia O F
authors.initials: FO
authors.lastname: Valente
authors.forename: Teresa S
authors.initials: TS
authors.lastname: Kasamatsu
authors.forename: Alberto L
authors.initials: AL
authors.lastname: Machado
authors.forename: Camila P
authors.initials: CP
authors.lastname: Salim
authors.forename: Rosana
authors.initials: R
authors.lastname: Delcelo
authors.forename: Ana O
authors.initials: AO
authors.lastname: Hoff
authors.forename: Janete M
authors.initials: JM
authors.lastname: Cerutti
authors.forename: Magnus R
authors.initials: MR
authors.lastname: Dias-da-Silva
authors.forename: Rui M B
authors.initials: RM
authors.lastname: Maciel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D002116:Calcitonin / Q000097:blood; D002272:Carcinoembryonic Antigen / Q000097:blood; D018278:Carcinoma, Neuroendocrine; D002648:Child; D002675:Child, Preschool; D003545:Cysteine / Q000235:genetics; D005192:Family Health; D005260:Female; D005500:Follow-Up Studies; D005998:Glycine / Q000235:genetics; D006801:Humans; D008297:Male; D008676:Metanephrine / Q000652:urine; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics* / Q000601:surgery; D009154:Mutation; D010375:Pedigree; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000601:surgery; D013965:Thyroidectomy; D013997:Time Factors; D055815:Young Adult
chemical_list: D002272:Carcinoembryonic Antigen; D008676:Metanephrine; D002116:Calcitonin; D051096:Proto-Oncogene Proteins c-ret; D003545:Cysteine; D005998:Glycine