Loss of heterozygosity on chromosome 11q13 in two families with acromegaly/gigantism is independent of mutations of the multiple endocrine neoplasia type I gene
Mr. Gadelha et al., Loss of heterozygosity on chromosome 11q13 in two families with acromegaly/gigantism is independent of mutations of the multiple endocrine neoplasia type I gene, J CLIN END, 84(1), 1999, pp. 249-256
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.