Genotype-phenotype analysis in multiple endocrine neoplasia type 1.
OBJECTIVE
Multiple endocrine neoplasia type 1 (MEN 1) syndrome is an autosomal dominant disorder caused by germline mutations in the MEN1 gene and characterized by multiple endocrine tumors, most notably in the parathyroid glands, pituitary, and pancreas. The syndrome demonstrates variable expressivity and considerable genetic heterogeneity. Patient data were examined for possible associations between genotype and phenotype.


METHODS
We reviewed recorded medical data from 1975 to 2001 on patients with MEN 1 and compared specific types and locations of MEN1 gene mutations with manifestations of the syndrome.


RESULTS
We identified 109 affected patients from 24 MEN 1 kindreds. The phenotypic expression of MEN 1 in affected individuals included hyperparathyroidism in 74%, pancreatic endocrine tumors in 51%, and pituitary tumors in 35%. Twelve of 14 insulinomas occurred in patients with pituitary tumors. Mutation analysis was completed in 14 of 24 kindreds (80 of the 109 patients). Mutations were most common in exons 2 (31%), 9 (15%), and 10 (23%). All 21 patients with frameshift mutations (and known pancreatic endocrine tumor status) had such tumors. Pituitary tumors were associated with frameshift mutations in exon 2.


CONCLUSIONS
The type and location of MEN1 mutations may be associated with the phenotypic expression of specific tumors. Such information may assist in the genetic counseling and surveillance of at-risk patients. A specific genotype-phenotype correlation is unlikely because of the heterogeneity of the mutations in the MEN1 gene.
Kouvaraki
Maria A
MA
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Lee
Jeffrey E
JE
Shapiro
Suzanne E
SE
Gagel
Robert F
RF
Sherman
Steven I
SI
Sellin
Rena V
RV
Cote
Gilbert J
GJ
Evans
Douglas B
DB
D000328:Adult; D000368:Aged; D005260:Female; D016368:Frameshift Mutation; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D007340:Insulinoma / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics*; D010641:Phenotype; D010911:Pituitary Neoplasms / Q000235:genetics*; D011518:Proto-Oncogene Proteins; D012189:Retrospective Studies
C105373:MEN1 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins