This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gadelha, M. R. Articles by Frohman, L. A. Search for Related Content PubMed PubMed Citation Articles by Gadelha, M. R. Articles by Frohman, L. A.

Loss of Heterozygosity on Chromosome 11q13 in Two Families with Acromegaly/Gigantism Is Independent of Mutations of the Multiple Endocrine Neoplasia Type I Gene¹

Department of Medicine, University of Illinois (M.R.G., S.F.M., R.D.K., L.A.F.), Chicago, Illinois 60612; the Division of Endocrinology and Metabolism, Cedars-Sinai Research Institute, University of California (T.R.P., S.M.), Los Angeles, California 90048; the Department of Medicine, Federal University of Rio de Janeiro (M.R.G., K.N.U., M.V.), Rio de Janeiro, Brazil; and the Department of Neurosurgery, Cook County Hospital and Rush Medical College (R.P.G.), Chicago, Illinois 60612

Address all correspondence and requests for reprints to: Lawrence A. Frohman, M.D., Department of Medicine (M/C 787), University of Illinois, 840 South Wood, Chicago, Illinois 60612. E-mail: frohman{at}uic.edu

Familial acromegaly/gigantism occurring in the absence of multiple endocrine neoplasia type I (MEN-1) or the Carney complex has been reported in 18 families since the biochemical diagnosis of GH excess became available, and the genetic defect is unknown. In the present study we examined 2 unrelated families with isolated acromegaly/gigantism. In family A, 3 of 4 siblings were affected, with ages at diagnosis of 19, 21, and 23 yr. In family B, 5 of 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 associated with high insulin-like growth factor I levels and/or nonsuppressible serum GH levels during an oral glucose tolerance test. GHRH levels were normal in affected members of family A. An invasive macroadenoma was found in 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 was normal. There was no history of consanguinity in either family, and the past medical history and laboratory results excluded MEN-1 and the Carney complex in all affected and unaffected screened subjects. Five of 8 subjects have undergone pituitary surgery to date, and paraffin-embedded pituitary blocks were available for analysis. Loss of heterozygosity on chromosome 11q13 was studied by comparing microsatellite polymorphisms of leukocyte and tumor DNA using PYGM (centromeric) and D11S527 (telomeric), markers closely linked to the MEN-1 tumor suppressor gene. All tumors exhibited a loss of heterozygosity at both markers. Sequencing of the MEN-1 gene revealed no germline 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 messenger ribonucleic acid, as assessed by RT-PCR. These data indicate that loss of heterozygosity in these affected family members appears independent of MEN-1 gene changes and suggest that a novel (tissue-specific?) tumor suppressor gene(s) linked to the PYGM marker and expressed in the pituitary is essential for regulation of somatotrope proliferation.

This article has been cited by other articles:

				C. A. Leontiou, M. Gueorguiev, J. van der Spuy, R. Quinton, F. Lolli, S. Hassan, H. S. Chahal, S. C. Igreja, S. Jordan, J. Rowe, et al. The Role of the Aryl Hydrocarbon Receptor-Interacting Protein Gene in Familial and Sporadic Pituitary Adenomas J. Clin. Endocrinol. Metab., June 1, 2008; 93(6): 2390 - 2401. [Abstract] [Full Text] [PDF]

				R. A. Toledo, D. M. Lourenco Jr., B. Liberman, M. B. C. Cunha-Neto, M. G. Cavalcanti, C. B. Moyses, S. P. A. Toledo, and P. L. M. Dahia Germline Mutation in the Aryl Hydrocarbon Receptor Interacting Protein Gene in Familial Somatotropinoma J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1934 - 1937. [Abstract] [Full Text] [PDF]

				A. F. Daly, M.-L. Jaffrain-Rea, A. Ciccarelli, H. Valdes-Socin, V. Rohmer, G. Tamburrano, C. Borson-Chazot, B. Estour, E. Ciccarelli, T. Brue, et al. Clinical Characterization of Familial Isolated Pituitary Adenomas J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3316 - 3323. [Abstract] [Full Text] [PDF]

				O. Vierimaa, M. Georgitsi, R. Lehtonen, P. Vahteristo, A. Kokko, A. Raitila, K. Tuppurainen, T. M. L. Ebeling, P. I. Salmela, R. Paschke, et al. Pituitary Adenoma Predisposition Caused by Germline Mutations in the AIP Gene. Science, May 26, 2006; 312(5777): 1228 - 1230. [Abstract] [Full Text] [PDF]

				B. S. Soares, K. Eguchi, and L. A. Frohman Tumor Deletion Mapping on Chromosome 11q13 in Eight Families with Isolated Familial Somatotropinoma and in 15 Sporadic Somatotropinomas J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6580 - 6587. [Abstract] [Full Text] [PDF]

				A Cebrian, S Ruiz-Llorente, A Cascon, M Pollan, J J Diez, A Pico, D Telleria, J Benitez, and M Robledo Mutational and gross deletion study of the MEN1 gene and correlation with clinical features in Spanish patients J. Med. Genet., May 1, 2003; 40(5): e72 - 72. [Full Text] [PDF]

				E. J. Lee, T. J. Kotlar, I. Ciric, M. K. Lee, S. K. Lim, H. C. Lee, K. B. Huh, K. E. Mayo, and J. L. Jameson Absence of Constitutively Activating Mutations in the GHRH Receptor in GH-Producing Pituitary Tumors J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3989 - 3995. [Abstract] [Full Text] [PDF]

				B. H. Jorge, S. K. Agarwal, V. S. Lando, R. Salvatori, R. R. Barbero, N. Abelin, M. A. Levine, S. J. Marx, and S. P. A. Toledo Study of the Multiple Endocrine Neoplasia Type 1, Growth Hormone-Releasing Hormone Receptor, Gs{{alpha}}, and Gi2{{alpha}} Genes in Isolated Familial Acromegaly J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 542 - 544. [Abstract] [Full Text]

				C. A. Stratakis and L. S. Kirschner Isolated Familial Somatotropinomas: Does the Disease Map to 11q13 or to 2p16? J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4920 - 4924. [Full Text]

				T. Abe, K. Yoshimoto, M. Taniyama, K. Hanakawa, H. Izumiyama, M. Itakura, and K. Matsumoto An Unusual Kindred of the Multiple Endocrine Neoplasia Type 1 (MEN1) in Japanese J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 1327 - 1330. [Full Text]

				M. R. Gadelha, K. N. Une, K. Rohde, M. Vaisman, R. D. Kineman, and L. A. Frohman Isolated Familial Somatotropinomas: Establishment of Linkage to Chromosome 11q13.1-11q13.3 and Evidence for a Potential Second Locus at Chromosome 2p16-12 J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 707 - 714. [Abstract] [Full Text]