ESPE Abstracts

Background: Certain genetic defects in the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis are associated with severe primary IGF-1 deficiency (SPIGFD) and short stature. Detection of genetic defects may confirm short stature aetiology alongside clinical/biochemical features. Increlex^® is a recombinant human IGF-1 (rhIGF-1) approved for children/adolescents with SPIGFD.

Methods: The Increlex^® registry is an ongoing, multicentre, open-label, observational study monitoring safety and effectiveness of rhIGF-1 in children/adolescents with growth deficiencies (NCT00903110). Eligible individuals: aged 2-18 years, receiving rhIGF-1. This complementary analysis describes reported genetic testing in patients enrolled in 10 European countries from Dec2008-May2019. Details of genetic testing methodology and/or functional analyses are not reported in the registry.

Results: At the time of analysis, 281 patients (missing=3) were enrolled at 118 sites. At least one genetic test was reported in 57.9% (161/278) patients; ≥1 abnormality was detected in 34.8% (56/161), of whom 96.4% (54/56) had ≥1 gene abnormality classically associated with SPIGFD (GHR[n = 42/54, all with Laron syndrome diagnoses]; GH[n = 7/54]; IGF 1[n = 4/54]; STAT5B[n = 2/54]; IGFALS[n = 1/54]). Genetic testing of 2/54 patients showed ≥2 abnormalities including mutation/deletion in GH and IGF-1 genes and mutation/deletion in GHR, GH and SHOX genes. 2/56 patients had a mutation/deletion in PTPN11 only. Patients with ≥1 reported genetic abnormality had shorter mean height standard deviation score at rhIGF-1 commencement (n = 48; mean: ¬4.68; 95%CI: ¬5.18, ¬4.17) versus patients without abnormalities (n = 98; mean: ¬3.78; 95%CI: ¬4.01, -3.55; t-test: P = 0.002) and patients not reported to have had genetic testing (n = 102; mean: -3.37; 95%CI: ¬3.58, ¬3.16; t-test: P < 0.001). No other differences in baseline characteristics were found; proportions of patients with SPIGFD at Baseline were 91.1% (51/56) in those with reported genetic abnormalities, 81.9% (86/105) in those without and 89.7% (105/117) in those not reported to have had genetic testing. Some patients (49.1% [27/55]) with reported genetic abnormalities were naïve to rhIGF-1 treatment and prepubertal at rhIGF-1 commencement. Incidences of targeted treatment-emergent adverse events (TEAEs) in patients with reported genetic abnormalities, without reported abnormalities and not reported to have had genetic testing were 66.1% (37/56), 49.5% (51/103) and 43.5% (50/115) (Chi-square test: genetic abnormality versus none, P = 0.045; genetic abnormality versus no testing, P = 0.006). The most common TEAE was hypoglycaemia.

Conclusions: Genetic testing was reported for >50% patients. Patients with versus without reported genetic abnormalities had shorter stature at first rhIGF-1 dose and more TEAEs. Further work is required to understand the role of genetic testing in clinical practice.