Severe growth hormone insensitivity resulting from total absence of signal transducer and activator of transcription 5b.
BACKGROUND
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.


METHODS
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 microg/ml; normal, 5.6-16) levels were abnormally low and failed to increase during an IGF-I generation test.


METHODS
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.


CONCLUSIONS
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.
Hwa
Vivian
V
Department of Pediatrics, NRC5, Oregon Health & Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239-3098, USA. hwav@ohsu.edu
Little
Brian
B
Adiyaman
Pelin
P
Kofoed
Eric M
EM
Pratt
Katherine L
KL
Ocal
Gonul
G
Berberoglu
Merih
M
Rosenfeld
Ron G
RG
D000293:Adolescent; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005260:Female; D016368:Frameshift Mutation; D005786:Gene Expression Regulation / Q000187:drug effects; D006130:Growth Disorders / Q000209:etiology* / Q000235:genetics; D013006:Growth Hormone / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008894:Milk Proteins / Q000235:genetics*; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D015534:Trans-Activators; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone