This Article Full Text Full Text (PDF) All Versions of this Article: 90/7/4260    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart 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 Hwa, V. Articles by Rosenfeld, R. G. Search for Related Content PubMed PubMed Citation Articles by Hwa, V. Articles by Rosenfeld, R. G. Related Collections Neuroendocrinology and Pituitary Pediatric Endocrinology

Severe Growth Hormone Insensitivity Resulting from Total Absence of Signal Transducer and Activator of Transcription 5b

Department of Pediatrics, Oregon Health & Sciences University (V.H., B.L., E.M.K., K.L.P., R.G.R.), Portland, Oregon 97239; Faculty of Medicine, Department of Pediatric Endocrinology, Ankara University (P.A., G.O., M.B.), Ankara, Turkey; Department of Pediatrics, Stanford University (R.G.R.), Palo Alto, California 94304; and Lucile Packard Foundation for Children’s Health (R.G.R.), Palo Alto, California 94304

Address all correspondence and requests for reprints to: Dr. Vivian Hwa, Department of Pediatrics, NRC5, Oregon Health & Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239-3098. E-mail: hwav{at}ohsu.edu.

Context: The central clinical feature of GH insensitivity (GHI) is severe growth failure associated with elevated serum concentrations of GH and abnormally low serum levels of IGF-I. GHI can be the result of an abnormality in the GH receptor or aberrancies downstream of the GH receptor.

Objective: We investigated the GH-IGF-I axis in a young female GHI subject who presented with a height of 114 cm (–7.8 SD score) at age 16.4 yr.

Patient: The subject, from a consanguineous pedigree, had circulating levels of GH and GH-binding protein that were normal to elevated, whereas IGF-I (7.2 ng/ml; normal, 242–600), IGF-binding protein-3 (543 ng/ml; normal, 2500–4800), and acid-labile subunit (1.22 µg/ml; normal, 5.6–16) levels were abnormally low and failed to increase during an IGF-I generation test.

Design: Dermal fibroblast cultures were established with the consent of the patient and family. Immunoblot analysis of cell lysates and DNA sequencing of her signal transducer and activator of transcription 5b (STAT5b), a critical intermediate of the GH-IGF-I axis, were performed.

Results: Sequencing of the STAT5b gene revealed a novel homozygous insertion of a single nucleotide in exon 10. The insertion resulted in a frame shift, leading to early protein termination and consequent lack of immunodetectable STAT5b protein.

Conclusion: The identification of a second case of severe growth failure associated with STAT5b mutation implicates a unique and critical role for STAT5b in GH stimulation of IGF-I gene expression and statural growth.

This article has been cited by other articles:

				G. Kenth, J. A M. Mergelas, and C. G. Goodyer Developmental changes in the human GH receptor and its signal transduction pathways J. Endocrinol., July 1, 2008; 198(1): 71 - 82. [Abstract] [Full Text] [PDF]

				C. Nielsen, L. C. Gormsen, N. Jessen, S. B. Pedersen, N. Moller, S. Lund, and J. O. L. Jorgensen Growth Hormone Signaling in Vivo in Human Muscle and Adipose Tissue: Impact of Insulin, Substrate Background, and Growth Hormone Receptor Blockade J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2842 - 2850. [Abstract] [Full Text] [PDF]

				L. Hennighausen and G. W. Robinson Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B Genes & Dev., March 15, 2008; 22(6): 711 - 721. [Abstract] [Full Text] [PDF]

				M J E Walenkamp and J M Wit Genetic disorders in the GH IGF-I axis in mouse and man Eur. J. Endocrinol., August 1, 2007; 157(suppl_1): S15 - S26. [Abstract] [Full Text] [PDF]

				P. Fang, S. Riedl, S. Amselem, K. L. Pratt, B. M. Little, G. Haeusler, V. Hwa, H. Frisch, and R. G. Rosenfeld Primary Growth Hormone (GH) Insensitivity and Insulin-Like Growth Factor Deficiency Caused by Novel Compound Heterozygous Mutations of the GH Receptor Gene: Genetic and Functional Studies of Simple and Compound Heterozygous States J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2223 - 2231. [Abstract] [Full Text] [PDF]

				M. Ono, D. J. Chia, R. Merino-Martinez, A. Flores-Morales, T. G. Unterman, and P. Rotwein Signal Transducer and Activator of Transcription (Stat) 5b-Mediated Inhibition of Insulin-Like Growth Factor Binding Protein-1 Gene Transcription: A Mechanism for Repression of Gene Expression by Growth Hormone Mol. Endocrinol., June 1, 2007; 21(6): 1443 - 1457. [Abstract] [Full Text] [PDF]

				M. G. Holloway, Y. Cui, E. V. Laz, A. Hosui, L. Hennighausen, and D. J. Waxman Loss of Sexually Dimorphic Liver Gene Expression upon Hepatocyte-Specific Deletion of Stat5a-Stat5b Locus Endocrinology, May 1, 2007; 148(5): 1977 - 1986. [Abstract] [Full Text] [PDF]

				M. J E Walenkamp, S. Vidarsdottir, A. M Pereira, M. Karperien, J. van Doorn, H. A van Duyvenvoorde, M. H Breuning, F. Roelfsema, M F. Kruithof, J. van Dissel, et al. Growth hormone secretion and immunological function of a male patient with a homozygous STAT5b mutation Eur. J. Endocrinol., February 1, 2007; 156(2): 155 - 165. [Abstract] [Full Text] [PDF]

				O. M. Vidal, R. Merino, E. Rico-Bautista, L. Fernandez-Perez, D. J. Chia, J. Woelfle, M. Ono, B. Lenhard, G. Norstedt, P. Rotwein, et al. In Vivo Transcript Profiling and Phylogenetic Analysis Identifies Suppressor of Cytokine Signaling 2 as a Direct Signal Transducer and Activator of Transcription 5b Target in Liver Mol. Endocrinol., January 1, 2007; 21(1): 293 - 311. [Abstract] [Full Text] [PDF]

				M. H. Vickers, P. L. Hofman, P. D. Gluckman, P. E. Lobie, and W. S. Cutfield Combination therapy with acipimox enhances the effect of growth hormone treatment on linear body growth in the normal and small-for-gestational-age rat Am J Physiol Endocrinol Metab, December 1, 2006; 291(6): E1212 - E1219. [Abstract] [Full Text] [PDF]

				A. L. Rosenbloom and J. Guevara-Aguirre Reclassification of Insulin-Like Growth Factor I Production and Action Disorders J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4232 - 4234. [Abstract] [Full Text] [PDF]

				R. Pfaffle Genetics of growth in the normal child Eur. J. Endocrinol., November 1, 2006; 155(suppl_1): S27 - S33. [Abstract] [Full Text] [PDF]

				J. O. L. Jorgensen, N. Jessen, S. B. Pedersen, E. Vestergaard, L. Gormsen, S. A. Lund, and N. Billestrup GH receptor signaling in skeletal muscle and adipose tissue in human subjects following exposure to an intravenous GH bolus Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E899 - E905. [Abstract] [Full Text] [PDF]

				A. Bernasconi, R. Marino, A. Ribas, J. Rossi, M. Ciaccio, M. Oleastro, A. Ornani, R. Paz, M. A. Rivarola, M. Zelazko, et al. Characterization of Immunodeficiency in a Patient With Growth Hormone Insensitivity Secondary to a Novel STAT5b Gene Mutation Pediatrics, November 1, 2006; 118(5): e1584 - e1592. [Abstract] [Full Text] [PDF]

				S. Vidarsdottir, M. J. E. Walenkamp, A. M. Pereira, M. Karperien, J. van Doorn, H. A. van Duyvenvoorde, S. White, M. H. Breuning, F. Roelfsema, M. F. Kruithof, et al. Clinical and Biochemical Characteristics of a Male Patient with a Novel Homozygous STAT5b Mutation J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3482 - 3485. [Abstract] [Full Text] [PDF]

				V. Hwa, G. Haeusler, K. L. Pratt, B. M. Little, H. Frisch, D. Koller, and R. G. Rosenfeld Total Absence of Functional Acid Labile Subunit, Resulting in Severe Insulin-Like Growth Factor Deficiency and Moderate Growth Failure J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1826 - 1831. [Abstract] [Full Text] [PDF]

				P. Fang, E. M. Kofoed, B. M. Little, X. Wang, R. J. M. Ross, S. J. Frank, V. Hwa, and R. G. Rosenfeld A Mutant Signal Transducer and Activator of Transcription 5b, Associated with Growth Hormone Insensitivity and Insulin-Like Growth Factor-I Deficiency, Cannot Function as a Signal Transducer or Transcription Factor J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1526 - 1534. [Abstract] [Full Text] [PDF]

				D. J. Chia, E. Subbian, T. M. Buck, V. Hwa, R. G. Rosenfeld, W. R. Skach, U. Shinde, and P. Rotwein Aberrant Folding of a Mutant Stat5b Causes Growth Hormone Insensitivity and Proteasomal Dysfunction J. Biol. Chem., March 10, 2006; 281(10): 6552 - 6558. [Abstract] [Full Text] [PDF]