Consequences of direct genetic testing for germline mutations in the clinical management of families with multiple endocrine neoplasia, type II

JAMA. 1995 Oct 11;274(14):1149-51.


Objective: Multiple endocrine neoplasia, type II (MEN-II) is an autosomal dominant disorder characterized by tumors of thyroid C cells and pheochromocytoma. Recently, germline mutations in the RET proto-oncogene have been identified in patients with MEN-II. The aims of this study were (1) to define the mutations in clinically diagnosed MEN-II families, (2) to compare the results of genetic and biochemical testing, and (3) to evaluate the impact of mutation analyses for the members of these families.

Design: Register-based survey study of clinically affected and unaffected members of MEN-II families.

Setting: Register of families from Germany and Spain with pheochromocytomas. Two research laboratories at Cambridge University in the United Kingdom.

Patients: We investigated consenting affected and unaffected members belonging to a series of 10 families who met the clinical criteria for MEN-II.

Main outcome measures: (1) Presence or absence of germline mutation in the RET proto-oncogene in affected and unaffected members of the 10 families, and (2) in the absence of RET mutation in a given family, presence or absence of germline mutation in the von Hippel-Lindau (VHL) gene, which is the susceptibility gene involved in a closely related syndrome, von Hippel-Lindau disease.

Results: In eight of these families, RET mutations were identified. The specific mutations were detected in all affected members. The remaining two families without RET mutations were subsequently shown to have a mutation within the VHL gene. The VHL mutations were identified in both families and represent a previously undescribed base change. After identification of the mutation, premorbid genetic testing was performed in all MEN-II and VHL families, resulting in detection of asymptomatic carriers in the MEN-II families. Clinically, the two VHL families differed from the eight MEN-II families by the presence of a C-cell tumor in only one individual from each family and extra-adrenal pheochromocytoma in three of nine affected individuals in the two families combined.

Conclusions: The diagnosis of MEN-II should be confirmed by molecular genetic analysis and the diagnosis of VHL syndrome should be considered for families with an absence of RET mutations and a preponderance of pheochromocytomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Gland Neoplasms / genetics
  • Chromosomes, Human, Pair 3
  • DNA / isolation & purification*
  • DNA Mutational Analysis
  • Drosophila Proteins*
  • Female
  • Genetic Testing*
  • Germ-Line Mutation*
  • Humans
  • Ligases*
  • Male
  • Multiple Endocrine Neoplasia Type 2a / genetics*
  • Nuclear Proteins / genetics*
  • Pedigree
  • Pheochromocytoma / genetics*
  • Polymerase Chain Reaction
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Thyroid Neoplasms / genetics
  • Tumor Suppressor Proteins*
  • Ubiquitin-Protein Ligases*
  • Von Hippel-Lindau Tumor Suppressor Protein
  • von Hippel-Lindau Disease / genetics


  • Drosophila Proteins
  • MAS1 protein, human
  • Nuclear Proteins
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins
  • DNA
  • Ubiquitin-Protein Ligases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, Drosophila
  • Ligases
  • VHL protein, human