Loss of heterozygosity on chromosome 11q13 in two families with acromegaly/gigantism is independent of mutations of the multiple endocrine neoplasia type I gene

Familial acromegaly/gigantism occurring in the absence of multiple endocrin e neoplasia type I (MEN-1) or the Carney complex has been reported in 18 fa milies since the biochemical diagnosis of GH excess became available, and t he genetic defect is unknown. In the present study we examined 2 unrelated families with isolated acromegaly/gigantism. In family A, 3 of 4 siblings w ere affected, with ages at diagnosis of 19, 21, and 23 yr. In family B, 5 o f 13 siblings exhibited the phenotype and were diagnosed at 13, 15, 17, 17, and 24 yr of age. All 8 affected patients had elevated basal GH levels ass ociated with high insulin-like growth factor I levels and/or nonsuppressibl e serum GH levels during an oral glucose tolerance test. GHRH levels were n ormal in affected members of family A. An invasive macroadenoma was found i n 6 subjects, and a microadenoma was found in 1 subject from family B. The sequence of the GHRH receptor complementary DNA in 1 tumor from family A wa s normal. There was no history of consanguinity in either family, and the p ast medical history and laboratory results excluded MEN-1 and the Carney co mplex in all affected and unaffected screened subjects. Five of 8 subjects have undergone pituitary surgery to date, and paraffin-embedded pituitary b locks were available for analysis. Loss of heterozygosity on chromosome 11q 13 was studied by comparing microsatellite polymorphisms of leukocyte and t umor DNA using PYGM (centromeric) and D11S527 (telomeric), markers closely Linked to the MEN-1 tumor suppressor gene. All tumors exhibited a loss of h eterozygosity at both markers. Sequencing of the MEN-1 gene revealed no ger mline mutations in either family, nor was a somatic mutation found in tumor DNA from one subject in family A. The integrity of the MEN-1 gene in this subject was further supported by demonstration of the presence of MEN-1 mes senger ribonucleic acid, as assessed by RT-PCR. These data indicate that lo ss of heterozygosity in these affected family members appears independent o f MEN-1 gene changes and suggest that a novel (tissue-specific?) tumor supp ressor gene(s) linked to the PYGM marker and expressed in the pituitary is essential for regulation of somatotrope proliferation.