ISSN 1662-4009 (Online)

ESPE Yearbook of Paediatric Endocrinology (2019) 16 4.7 | DOI: 10.1530/ey.16.4.7

Idiopathic short stature and growth hormone sensitivity in prepubertal children

Derraik JGB, Miles HL, Chiavaroli V, Hofman PL & Cutfield WS


Liggins Institute, University of Auckland, Auckland, New Zealand, w.cutfield@auckland.ac.nz.


To read the full abstract: Clin Endocrinol. 2019;91:110–117.

Idiopathic short stature (ISS) refers to a heterogeneous population of children with a height more than 2 SDS below the mean for age, sex, and population, in presence of normal birth size and body proportions, and without evidence of any identifiable cause. The use of next generation sequencing (NGS) has shown that a high proportion of subjects with ISS have specific genetic variants. The majority of these variants are in genes related to the growth plate cartilage and in the GH/IGF-I axis. Affected patients may have mild forms of skeletal dysplasia, or subtle hormonal abnormalities suggesting hormone insensitivity.

ISS subjects show normal GH responses to pharmacological stimulation tests. The finding of subnormal levels of IGF-I [1–3] associated with reduced serum GH binding protein (GHBP), the circulating fragment of the GH receptor encompassing its extracellular domain [4], has raised the suspicion of mild forms GH resistance in some of these children.

This study evaluated a cohort of 23 ISS and 23 sex and age-matched normal stature (NS) children. All patients underwent IGF-I generation test, as an index GH sensitivity, and a wide range of biochemical parameters was analyzed. ISS and NS children showed no differences in IGF-I generation. Among ISS children, a lower birth weight was associated with a lower percentage of IGF-I increase in the generation test. After four days of rhGH administration, GHBP levels decreased in ISS subjects but increased in NS children, whereas leptin levels increased in NS but did not change in ISS subjects. A higher response of insulin to rhGH administration was noted in ISS children.

Collectively these results show no reduction in GH induced IGF-I generation in ISS compared to normal children. The correlation between lower birth size and lower response to IGF-I generation test in ISS children, indicating lower GH sensitivity, is puzzling. Fetal growth is independent of GH as the fetal liver does not express GH receptors which start to be massively expressed only after birth.

References: 1. Ranke MB, Schweizer R, Elmlinger MW, Weber K, Binder G, Schwarze CP, Wollmann HA. Significance of basal IGF-I, IGFBP-3 and IGFBP-2 measurements in the diagnostics of short stature in children. Horm Res 2000;54:60–68.

2. Blair JC, Camacho-Hubner C, Miraki Moud F, Rosberg S, Burren C, Lim S, Clayton PE, Bjarnason R, Albertsson-Wikland K, Savage MO. Standard and low-dose IGF-I generation tests and spontaneous growth hormone secretion in children with idiopathic short stature. Clin Endocrinol 2004;60:163–168.

3. Clayton P, Bonnemaire M, Dutailly P, Maisonobe P, Naudin L, Pham E, Zhang Z, Grupe A, Thiagalingam A, Denefle P. Characterizing short stature by insulin-like growth factor axis status and genetic associations: results from the prospective, cross-sectional, epidemiogenetic EPIGROW study. J Clin Endocrinol Metab 2013;98:E1122–1130.

4. El Kholy M, Mella P, Rashad M, Buzi F, Meazza C, Zahra S, Elsedfy HH. Growth hormone/IGF-I axis and growth hormone receptor mutations in idiopathic short stature. Horm Res Paediatr 2011;76:300–306.

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