title: Familial medullary thyroid carcinoma: not a distinct entity? Genotype-phenotype correlation in a large family.
abstract: BACKGROUND
  Multiple endocrine neoplasia type 2A (MEN 2A) is a hereditary syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism. Familial MTC (FMTC) is characterized by MTC only. Both MEN 2A and FMTC are caused by germline mutations of the RET proto-oncogene.
  
  
  OBJECTIVE
  To assess genotype/phenotype correlations, large families have to be examined periodically over a long period using an extensive screening program.
  
  
  METHODS
  Since 1973, we screened a large family with hereditary C cell carcinoma for MTC, pheochromocytoma, and parathyroid disease by clinical tests and imaging methods. A germline codon Cys618 to Ser mutation in the RET proto-oncogene was recently identified in this family. The disease phenotype associated with this mutation was compared with that of Cys634 mutations in some other large MEN 2A families.
  
  
  RESULTS
  The distinct course of disease in the family described here is similar to that in other FMTC families and MEN 2A families with a Cys618 mutation of the RET gene, but clearly different from that in families with a Cys634 mutation. The frequency of pheochromocytomas and parathyroid disease is clearly lower, whereas cure rates and life expectancy are higher. However, in families with a Cys618 mutation, pheochromocytoma and parathyroid disease do occur.
  
  
  CONCLUSIONS
  In FMTC families with cysteine codon mutations of the RET proto-oncogene, screening for other endocrinopathies is mandatory, since these may not be MTC-only families. Therefore, we suggest that MEN 2A families should not be subclassified into MEN 2A and FMTC, but rather according to their specific mutation in the RET protein (i.e., for this family MEN 2A RET C618S).
authors.affiliation: Department of Internal Medicine, Maasland Hospital, Sittard, The Netherlands.
authors.forename: A M
authors.initials: AM
authors.lastname: Moers
authors.forename: R M
authors.initials: RM
authors.lastname: Landsvater
authors.forename: C
authors.initials: C
authors.lastname: Schaap
authors.forename: J M
authors.initials: JM
authors.lastname: Jansen-Schillhorn van Veen
authors.forename: I A
authors.initials: IA
authors.lastname: de Valk
authors.forename: G H
authors.initials: GH
authors.lastname: Blijham
authors.forename: J W
authors.initials: JW
authors.lastname: Höppener
authors.forename: T M
authors.initials: TM
authors.lastname: Vroom
authors.forename: H K
authors.initials: HK
authors.lastname: van Amstel
authors.forename: C J
authors.initials: CJ
authors.lastname: Lips
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics; D000328:Adult; D000368:Aged; D018276:Carcinoma, Medullary / Q000235:genetics* / Q000473:pathology; D003545:Cysteine / Q000235:genetics*; D015342:DNA Probes; D029721:Drosophila Proteins; D005260:Female; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D006961:Hyperparathyroidism / Q000235:genetics; D008297:Male; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D010673:Pheochromocytoma / Q000235:genetics; 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* / Q000473:pathology
chemical_list: D015342:DNA Probes; 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; D003545:Cysteine