DIAGNOSIS OF ENDOCRINE DISEASE: Limitations of the IGF1 generation test in children with short stature

Abstract

The IGF1 generation test (IGFGT) is often used during the assessment of suspected GH insensitivity (GHI). We report the results of a survey undertaken in 2010 to determine the use of IGFGT amongst members of the European Society for Paediatric Endocrinology to evaluate suspected GHI. The literature surrounding the usefulness and limitations of IGFGT are reviewed, and recommendations provided for its use. Of 112 paediatric endocrinologists from 30 countries who responded to the survey, 91 (81%) reported that they had used the IGFGT in the previous 2 years; O10 IGFGT protocols were used. The IGFGT impacted treatment decisions for 97% of the respondents and was a prerequisite for recombinant human IGF1 treatment for 45% of respondents. From a literature review, sensitivity of the IGFGT was evaluated as 77-91% in molecularly proven cases of GHI; specificity was %97%, depending on the protocol. The positive predictive value of the IGFGT is likely to be low, as the frequency of normality is predictably higher than that of abnormality in GH signalling. Given the limitations of the IGFGT in the most severe cases of GHI syndrome (GHIS), the ability of the IGFGT to detect less severe GHIS is doubtful. In a pragmatic approach, the IGFGT may not be useful for the diagnosis of GHIS.

Short Stature in a Boy with Multiple Early-Onset Autoimmune Conditions due to a <b><i>STAT3</i></b> Activating Mutation: Could Intracellular Growth Hormone Signalling Be Compromised?

“…At 2.5 years of age, the patient’s bone age corresponded with his calendar age, but his bone age became slightly retarded at 5.5 years, when he underwent endocrine assessment for short stature. His height was 103 cm (–2.60 SD); his peak GH concentration following insulin-induced hypoglycaemia was 27.7 µg/L, although his IGF-I level was low (37 µg/L; –2.22 SD) and his IGF-BP3 level was low normal (2.27 mg/L; –0.85 SD) [20, 21]. Because these results were suggestive of decreased sensitivity to GH, we performed a standard IGF-I generation test (GH 0.033 mg/kg/day sc for 4 consecutive days) that led to an insufficient increase in IGF-I from 37 to 46 µg/L [20, 21].…”

“…Because these results were suggestive of decreased sensitivity to GH, we performed a standard IGF-I generation test (GH 0.033 mg/kg/day sc for 4 consecutive days) that led to an insufficient increase in IGF-I from 37 to 46 µg/L [20, 21]. We proceeded with a high-dose prolonged IGF-I generation test (GH 0.067 mg/kg/day sc for 14 consecutive days), which also led to an insufficient increase in IGF-I from 72 µg/L (–1.67 SD) to 87 µg/L (–1.43 SD) and only a partial rise in IGF-BP3 from 2.70 mg/L (–0.69 SD) to 3.29 mg/L (–0.15 SD) [20, 21]. …”

Clinical Features of a New Acid-Labile Subunit <b><i>(IGFALS)</i></b> Heterozygous Mutation: Anthropometric and Biochemical Characterization and Response to Growth Hormone Administration

“…To differentiate between low serum levels of IGF1 that are responsive or partially responsive to GH, and low serum levels of IGF1 that do not respond to GH administration, appears as an important goal. In this context an IGF1 generation test could be helpful but the modality of execution of such tests is still a matter of debate because it is probably of utility only in the diagnosis of severe GH insensitivity [18]. …”

Personalized Approach to Growth Hormone Treatment: Clinical Use of Growth Prediction Models

“…However, this test has not yet been adequately standardized, and, more importantly, studies of GH-induced production of IGF-I and IGFBP-3 in children with GHD showed considerable variability in responsiveness and overlapping responses between patients with GHD and GH insensitivity [54,55]. …”