Contribution of genetic analysis in screening for MEN1 among patients with sporadic disease and one or more typical manifestation

Ann Endocrinol (Paris). 2006 Dec;67(6):581-7. doi: 10.1016/s0003-4266(06)73010-4.

Abstract

Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant hereditary syndrome (OMIM 131100) due to MEN1 gene mutations, predisposing to the development of hyperplasic and tumoral lesions of neuroendocrine tissues. Since the identification of the gene in 1997, more than 400 different mutations of MEN1 have been registered. Genotypic analysis of MEN1 remains fastidious and must be reserved to targeted situations. If the lesions appear in a familial assessed context, there is a strong argument to search for MEN1 mutation. This is not the case in a sporadic context. With experience acquired in our laboratory, we evaluated the frequency of MEN1 mutations in patients with sporadic presentations. Our aim was to better define criteria for MEN1 genotypic analysis. One hundred and twenty four blood samples from unrelated patients, who gave their written informed consent, were analyzed. These patients exhibited 1 to 4 manifestations of MEN1 without any familial context. After DNA extraction, the analysis was undertaken by PCR-sequencing of all the MEN1 coding exons and exon/intron boundaries or by PCR of the pre-screened fragments alone, a technique made possible by indirect screening mutation methods. Mutations were identified by comparing the sequences to the reference MEN1 sequence available from GENBANK (U93237.1). Mutations were identified in 19 patients, with variable prevalence according to clinical manifestations: 100% for patients with 4 manifestations, 45.5% for patients with 3 manifestations, 19% for patients with 2 manifestations and 2% for patients with only one manifestation. Mutations were: 11 point variations (58%), including 2 splicing sites and 8 frameshift mutations (42%) including 5 deletions, 2 insertions and 1 insertion/deletion; one mutation was identified twice. We showed a relationship between clinical presentation and MEN1 mutation identification, especially with the number of clinical manifestations but also with the type of manifestation. Pancreatic manifestations were significantly linked with probability of mutation. In a sporadic context with at least two established manifestations of MEN1, the overall probability of identifying a mutation was 26%, warranting MEN1 genotypic analysis.

MeSH terms

  • Adult
  • Chromosomes, Human, Pair 11*
  • DNA / blood
  • DNA / genetics
  • DNA / isolation & purification
  • Diagnosis, Differential
  • Gene Frequency
  • Genetic Testing*
  • Humans
  • Middle Aged
  • Molecular Sequence Data
  • Multiple Endocrine Neoplasia Type 1 / classification
  • Multiple Endocrine Neoplasia Type 1 / diagnosis
  • Multiple Endocrine Neoplasia Type 1 / genetics*
  • Mutation

Substances

  • DNA

Associated data

  • GENBANK/U93237
  • OMIM/131100