Significance of Direct Confirmation of Growth Hormone Insensitivity for the Diagnosis of Primary IGF-I Deficiency.

Joanna Smyczyńska,Andrzej Lewiński,Maciej Hilczer,Urszula Smyczyńska,Renata Stawerska

doi:10.3390/jcm9010240

Abstract

Primary insulin-like growth factor-I (IGF-I) deficiency is a synonym of growth hormone (GH) insensitivity (GHI), however the necessity of direct confirmation of GH resistance by IGF-I generation test (IGF-GT) is discussed. GHI may disturb intrauterine growth, nevertheless short children born small for gestational age (SGA) are treated with GH. We tested the hypothesis that children with appropriate birth size (AGA), height standard deviation score (SDS) <−3.0, GH peak in stimulation tests (stimGH) ≥10.0 µg/L, IGF-I <2.5 centile, and excluded GHI may benefit during GH therapy. The analysis comprised 21 AGA children compared with 6 SGA and 20 GH-deficient ones, with height SDS and IGF-I as in the studied group. All patients were treated with GH up to final height (FH). Height velocity, IGF-I, and IGF binding protein-3 (IGFBP-3) concentrations before and during first year of treatment were assessed. Effectiveness of therapy was better in GHD than in IGF-I deficiency (IGFD), with no significant difference between SGA and AGA groups. All but two AGA children responded well to GH. Pretreatment IGF-I and increase of height velocity (HV) during therapy but not the result of IGF-GT correlated with FH. As most AGA children with apparent severe IGFD benefit during GH therapy, direct confirmation of GHI seems necessary to diagnose true primary IGFD in them.

Highlights

In 1966, Laron et al [1] published the first report concerning consanguineous children with extremely short stature despite high growth hormone (GH) secretion
As the main laboratory findings in this disease include insulin-like growth factor-I (IGF-I) deficiency (IGFD) and normal GH levels, in current classifications it is labelled as primary IGFD, which is considered to be synonymous of GH insensitivity (GHI), while secondary IGFD is equivalent to GH deficiency (GHD) [4]
In a database containing more than 1000 patients treated with recombinant human GH (rhGH) in our center during the last 20 years, 27 children fulfilling the inclusion criteria to the studied group were found, among them there were 21 AGA and 6 small for gestational age (SGA) ones as well as 20 children with GHD, fulfilling the inclusion criteria to the comparative group

Summary

Introduction

In 1966, Laron et al [1] published the first report concerning consanguineous children with extremely short stature despite high growth hormone (GH) secretion. It turned out that disorders of GH–IGF-I axis should be considered as a continuum from severe GHD to complete GHI, including a wide range of less severe impairments of GH secretion or GH sensitivity, with different phenotypic and biochemical features, related to a variety of genetic defects [5,6]. Except for the classic form of GH receptor resistance, currently known as Laron syndrome, other molecular defects leading to reduced GH sensitivity have been described, including ones in the intracellular GH signaling pathway (STAT5B, STAT3, IKBKB, IL2RG, PIK3R1), synthesis of insulin-like growth factors (IGFs) and disorders of IGF-I – insulin-like binding protein-3 – acid-labile subunit (IGFALS) complex [8,9,10]. Despite the fact that in Laron’s first studies defects of GH molecule were excluded [3], the possibility of bioinactive GH secretion (Kowarski syndrome) has been included in “ESPE classification of pediatric endocrine diagnoses”, as a relatively rare condition [4]

Methods

Results

Conclusion