Genetic causes of growth hormone insensitivity beyond GHR
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Genetic causes of growth hormone insensitivity beyond GHR Vivian Hwa 1 & Masanobu Fujimoto 1,2 Ron G. Rosenfeld 4
&
Gaohui Zhu 1,3 & Wen Gao 1 & Corinne Foley 1 & Meenasri Kumbaji 1 &
Accepted: 1 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Growth hormone insensitivity (GHI) syndrome, first described in 1966, is classically associated with monogenic defects in the GH receptor (GHR) gene which result in severe post-natal growth failure as consequences of insulin-like growth factor I (IGF-I) deficiency. Over the years, recognition of other monogenic defects downstream of GHR has greatly expanded understanding of primary causes of GHI and growth retardation, with either IGF-I deficiency or IGF-I insensitivity as clinical outcomes. Mutations in IGF1 and signaling component STAT5B disrupt IGF-I production, while defects in IGFALS and PAPPA2, disrupt transport and release of circulating IGF-I, respectively, affecting bioavailability of the growth-promoting IGF-I. Defects in IGF1R, cognate cell-surface receptor for IGF-I, disrupt not only IGF-I actions, but actions of the related IGF-II peptides. The importance of IGF-II for normal developmental growth is emphasized with recent identification of defects in the maternally imprinted IGF2 gene. Current application of next-generation genomic sequencing has expedited the pace of identifying new molecular defects in known genes or in new genes, thereby expanding the spectrum of GH and IGF insensitivity. This review discusses insights gained and future directions from patient-based molecular and functional studies. Keywords GH insensitivity . IGF-I deficiency . IGF-I insensitivity . GH-IGF-I axis
1 Growth hormone insensitivity, GHI: Historical perspective The development of human pituitary growth hormone (hGH), followed by the manufacture of recombinant-DNA-derived GH, revolutionized therapy for children with GH deficiency (GHD). To date, tens of thousands of children worldwide have been treated with GH. The diagnosis and management of GHD has been hampered significantly by recognized limitations in our ability to establish a
* Vivian Hwa [email protected] * Ron G. Rosenfeld [email protected] 1
Department of Pediatrics, Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati OH, 45229 USA
2
Division of Pediatrics and Perinatology, Faculty of Medicine, Tottori University, 36-1 Nishi-Cho Yonago 683-8504 Japan
3
Department of Endocrinology, Children’s Hospital of Chongqing Medical University, Chongqing 40014 China
4
Department of Pediatrics, Oregon Health & Science University, Portland OR, 97239 USA
firm diagnosis in many cases. Major problems include: 1) nonphysiologic nature of GH stimulation tests; 2) lack of a satisfactory methodology for resolving conflicting data from two or more stimulation tests; 3) arbitrary definitions of what constitutes a subnormal response to provocative testing; 4) insufficient attention to effects of age, pub
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