title: RET mutation profile and variable clinical manifestations in a family with multiple endocrine neoplasia type 2A and Hirschsprung's disease.
abstract: BACKGROUND
  RET proto-oncogene germ line mutations are associated with the inherited multiple endocrine neoplasia type 2 syndromes (MEN 2), as well as with familial and sporadic Hirschsprung's disease (HSCR). In this study, we report a family in which the MEN 2A and the HSCR phenotypes are associated with a single point mutation in exon 10 of the RET proto-oncogene. Furthermore, we have investigated polymorphic sequence variants of the RET proto-oncogene.
  
  
  METHODS
  Family members were tested for RET proto-oncogene mutations in exons 10, 11, 13, 14, 15, and 16 by double-gradient denaturing-gradient gel electrophoresis, nucleotide sequence analysis, and restriction endonuclease digestion of polymerase chain reaction products. The status of exon 2 and 13 polymorphic sites was investigated by EagI and TaqI digestion in 12 selected patients.
  
  
  RESULTS
  A heterozygous C618R mutation of RET exon 10 was identified in 12 family members. Five out of 7 children with mildly elevated pentagastrin-stimulated calcitonin levels who carried the mutation underwent prophylactic thyroidectomy before the age of 12. C-cell hyperplasia (CCH) was found in 4 children and a microscopic medullary thyroid carcinoma (MTC) in an 8-year-old female. Neither CCH nor MTC was found in the only family member affected with HSCR, an 8-year-old male. This patient inherited the mutated RET allele from his mother, who had MTC but not HSCR, together with a rare allelic variant at codon 45 of RET exon 2.
  
  
  CONCLUSIONS
  This report of a newly-described kindred with the infrequent clinical association between MEN 2A and HSCR confirms the risk of the latter phenotype among carriers of RET exon 10 cysteine codon mutations. Nevertheless, the influence of other genetic or environmental factors cannot be excluded.
authors.affiliation: Department of Biomedical Sciences and Advanced Therapies, Section of Endocrinology, University of Ferrara, Via Savonarola 9, I-44100 Ferrara, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pasini
authors.forename: Roberta
authors.initials: R
authors.lastname: Rossi
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Ambrosio
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Zatelli
authors.forename: Maria
authors.initials: M
authors.lastname: Gullo
authors.forename: Morena
authors.initials: M
authors.lastname: Gobbo
authors.forename: Paola
authors.initials: P
authors.lastname: Collini
authors.forename: Antonella
authors.initials: A
authors.lastname: Aiello
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Pansini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Trasforini
authors.forename: Ettore Ciro
authors.initials: EC
authors.lastname: degli Uberti
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D029721:Drosophila Proteins; D005091:Exons / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D011315:Preventive Medicine / Q000379:methods; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; D013965:Thyroidectomy
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