Introduction: Although the majority of growth hormone insensitivity syndrome (GHIS) cases are classical, the spectrum of clinical phenotypes has expanded to include “atypical” GHIS subjects with milder phenotypes due to very rare heterozygous growth hormone receptor (GHR) mutations with dominant negative effects. Case Presentation: A 13-year-old pubertal boy presented with short stature (−1.7 SDS) and delayed bone age (11.5 years). His serum IGF-1 was low (16 ng/mL; reference range: 179–540). IGFBP-3 (1.3 mg/L; 3.1–9.5) and ALS (565 mU/mL; 1,500–3,500) were also low. GH stimulation test was normal, and GHBP was markedly elevated (6,300 pmol/L; 240–3,000). Additionally, the boy had insulin resistance and liver steatosis. His final height reached −1.8 SDS, which was 3.0 SDS below his mid-parental height. GHR gene from genomic DNA and established primary fibroblast culture was analyzed and a synonymous heterozygous GHR: c.945G>A variant, in the last nucleotide of exon 9 (encoding intracellular domain of GHR) was identified. In vitro analysis of the GHR cDNA demonstrated a splicing defect, leading to the heterozygous excision of exon 9. The final predicted product was a truncated GHR protein which explained the elevated GHBP levels. Conclusion: We describe the first synonymous heterozygous GHR splicing variant in the exon 9-encoding part of the intracellular domain of GHR identified in a patient with mild short stature, thus supporting the continuum of genotype-phenotype of GHIS.

Journal Section:
Novel Insights from Clinical Practice / Case Report
Keywords:
Growth hormone insensitivity syndrome, Growth hormone receptor defect, IGF-1, Insulin resistance
1.
Storr HL, Chatterjee S, Metherell LA, Foley C, Rosenfeld RG, Backeljauw PF, et al. Nonclassical GH insensitivity: characterization of mild abnormalities of GH action. Endocr Rev. 2019;40(2):476–505.
2.
Laron Z, Pertzelan A, Mannheimer S. Genetic pituitary dwarfism with high serum concentation of growth hormone--a new inborn error of metabolism?Isr J Med Sci. 1966;2(2):152–5.
3.
Rughani A, Zhang D, Vairamani K, Dauber A, Hwa V, Krishnan S. Severe growth failure associated with a novel heterozygous nonsense mutation in the GHR transmembrane domain leading to elevated growth hormone binding protein. Clin Endocrinol. 2020;92(4):331–7.
4.
Vairamani K, Merjaneh L, Casano-Sancho P, Sanli ME, David A, Metherell LA, et al. Novel dominant-negative GH receptor mutations expands the spectrum of GHI and IGF-I deficiency. J Endocr Soc. 2017;1(4):345–58.
5.
Aalbers AM, Chin D, Pratt KL, Little BM, Frank SJ, Hwa V, et al. Extreme elevation of serum growth hormone-binding protein concentrations resulting from a novel heterozygous splice site mutation of the growth hormone receptor gene. Horm Res. 2009;71(5):276–84.
6.
Iida K, Takahashi Y, Kaji H, Nose O, Okimura Y, Abe H, et al. Growth hormone (GH) insensitivity syndrome with high serum GH-binding protein levels caused by a heterozygous splice site mutation of the GH receptor gene producing a lack of intracellular domain. J Clin Endocrinol Metab. 1998;83(2):531–7.
7.
Derr MA, Aisenberg J, Fang P, Tenenbaum-Rakover Y, Rosenfeld RG, Hwa V. The growth hormone receptor (GHR) c.899dupC mutation functions as a dominant negative: Insights into the pathophysiology of intracellular GHR defects. J Clin Endocrinol Metab. 2011;96(11):E1896–904.
8.
Takagi M, Shinohara H, Nagashima Y, Hasegawa Y, Narumi S, Hasegawa T. A novel dominant negative mutation in the intracellular domain of GHR is associated with growth hormone insensitivity. Clin Endocrinol. 2016;85(4):669–71.
9.
Ayling RM, Ross R, Towner P, Von Laue S, Finidori J, Moutoussamy S, et al. A dominant-negative mutation of the growth hormone receptor causes familial short stature. Nat Genet. 1997;16(1):13–4.
10.
Andrews A, Cottrell E, Maharaj A, Ladha T, Williams J, Schilbach K, et al. Characterization of dominant-negative growth hormone receptor variants reveals a potential therapeutic target for short stature. Eur J Endocrinol. 2023;188(4):353–65.
11.
Leung DW, Spencer SA, Cachianes G, Hammonds RG, Collins C, Henzel WJ, et al. Growth hormone receptor and serum binding protein: purification, cloning and expression. Nature. 1987;330(6148):537–43.
12.
Fisker S. Physiology and pathophysiology of growth hormone-binding protein: methodological and clinical aspects. Growth Horm Igf Res. 2006;16(1):1–28.
13.
Savage MO, Attie KM, David A, Metherell LA, Clark AJ, Camacho-Hübner C. Endocrine assessment, molecular characterization and treatment of growth hormone insensitivity disorders. Nat Clin Pract Endoc. 2006;2(7):395–407.
14.
Burren CP, Woods KA, Rose SJ, Tauber M, Price DA, Heinrich U, et al. Clinical and endocrine characteristics in atypical and classical growth hormone insensitivity syndrome. Horm Res. 2001;55(3):125–30.
15.
Woods KA, Fraser NC, Postel-Vinay MC, Savage MO, Clark AJ. A homozygous splice site mutation affecting the intracellular domain of the growth hormone (GH) receptor resulting in Laron syndrome with elevated GH-binding protein. J Clin Endocrinol Metab. 1996;81(5):1686–90.
16.
Hermanussen M, Cole J. The calculation of target height reconsidered. Horm Res. 2003;59(4):180–3.
17.
Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. GH Research Society. J Clin Endocrinol Metab. 2000;85(11):3990–3.
18.
Aisenberg J, Auyeung V, Pedro HF, Sugalski R, Chartoff A, Rothenberg R, et al. Atypical GH insensitivity syndrome and severe insulin-like growth factor-I deficiency resulting from compound heterozygous mutations of the GH receptor, including a novel frameshift mutation affecting the intracellular domain. Horm Res Paediat. 2010;74(6):406–11.
19.
Takashima A. Establishment of fibroblast cultures. Curr Protoc Cell Biol. 1998;00(1):2–12.
20.
Reese MG, Eeckman FH, Kulp D, Haussler D. Improved splice site detection in genie. J Comput Biol. 1997;4(3):311–23.
21.
Dastot F, Sobrier ML, Duquesnoy P, Duriez B, Goossens M, Amselem S. Alternatively spliced forms in the cytoplasmic domain of the human growth hormone (GH) receptor regulate its ability to generate a soluble GH-binding protein. Proc Natl Acad Sci. 1996;93(20):10723–8.
22.
Ross RJM, Esposito N, Shen XY, Von Laue S, Chew SL, Dobson PRM, et al. A short isoform of the human growth hormone receptor functions as a dominant negative inhibitor of the full-length receptor and generates large amounts of binding protein. Mol Endocrinol. 1997;11(3):265–73.
23.
Laron Z, Ginsberg S, Webb M. Nonalcoholic fatty liver in patients with Laron syndrome and GH gene deletion – preliminary report. Growth Horm Igf Res. 2008;18(5):434–8.
24.
Guevara-Aguirre J, Procel P, Guevara C, Guevara-Aguirre M, Rosado V, Teran E. Despite higher body fat content, Ecuadorian subjects with Laron syndrome have less insulin resistance and lower incidence of diabetes than their relatives. Growth Horm Igf Res. 2016;28:76–8.
25.
Sharma R, Kopchick JJ, Puri V, Sharma VM. Effect of growth hormone on insulin signaling. Mol Cell Endocrinol. 2020;518:111038.
© 2023 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2023
You do not currently have access to this content.