The continuum between GH deficiency and GH insensitivity in children
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The continuum between GH deficiency and GH insensitivity in children Martin O. Savage 1,2
&
Helen L. Storr 1
&
Philippe F. Backeljauw 3
Accepted: 8 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract The continuum of growth hormone (GH)-IGF-I axis defects extends from severe to mild GH deficiency, through short stature disorders of undefined aetiology, to GH insensitivity disorders which can also be mild or severe. This group of defects comprises a spectrum of endocrine, biochemical, phenotypic and genetic abnormalities. The extreme cases are generally easily diagnosed because they conform to well-studied phenotypes with recognised biochemical features. The milder cases of both GH deficiency and GH insensitivity are less well defined and also overlap with the group of short stature conditions, labelled as idiopathic short stature (ISS). In this review the continuum model, which plots GH sensitivity against GH secretion, will be discussed. Defects causing GH deficiency and GH insensitivity will be described, together with the use of a diagnostic algorithm, designed to aid investigation and categorisation of these defects. The continuum will also be discussed in the context of growth-promoting endocrine therapy. Keywords Growth hormone deficiency . Growth hormone insensitivity . Idiopathic short stature . Insulin-like growth factor I
1 Introduction Growth hormone (GH) deficiency and GH insensitivity are recognised endocrine abnormalities which present clinically as defects of linear growth in children. In their severe or ‘classical’ forms, both are easily recognised and their clinical and biochemical characteristics conform to well-established phenotypes, presenting little challenge for diagnosis. However, both disorders comprise a wide range of pathogenetic defects, are by definition heterogeneous, encompassing a broad range of severe and mild abnormalities [1, 2]. The mild forms of each diagnosis may present the clinician with challenges of diagnosis and effective therapeutic management. The concept of a continuum of GH-IGF-1 axis defects was first proposed by Pinchas Cohen in 2006 [3]. This endocrine axis plays a fundamental role in the regulation of linear growth
* Martin O. Savage [email protected]
in children [4]. Defects in GH secretion cause deficiency of IGF-1 production and defects of GH action (GH insensitivity) also result in so-called ‘primary’ IGF-1 deficiency. Both GH deficiency and insensitivity are associated, in their untreated states, with significant growth failure and impaired adult height. Although molecular discoveries during the past 30 years have enabled both GH deficiency and GH insensitivity to be classified in more detail, as will be described below, the continuum model allows defects of the GH-IGF-1 axis to be divided into three fundamental groups, GH deficiency, short stature of unknown origin also known as idiopathic short stature (ISS), and GH insensitivity (Fig. 1a, b) [3, 5]. The common factor in these three groups is IGF-1 defici
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