Improvement of diagnostic criteria in growth hormone insensitivity syndrome: solutions and pitfalls

Abstract

A survey to identify children and adolescents with primary growth hormone insensitivity syndrome (GHIS) yielded 38 patients who were positively identified using a scoring system that included five criteria: height, basal growth hormone (GH), GH binding protein, basal insulin‐like growth factor 1 (1GF‐I) and the increase of IGF‐I after 4 days of GH administration (IGF generation test). Because of an overlap of the accepted and excluded groups with respect to points scored, an attempt was made to improve the scoring system. The new criteria were: height below –3 SDS, basal GH 4 mU/I or above, GH binding below 10%, basal IGF‐I and basal IGF binding protein‐3 (IGFBP‐3) below the 0.1 centile for age, an increase of IGF‐I in the IGF generation test less than 15 μg/1, and the increase of IGFBP‐3 less than 0.4 mg/1. With this scoring system, a clear separation between the accepted and the excluded groups was obtained. IGFBP‐3 was included to give the GH‐dependent parameters of the IGF system more weight and because the accuracy of IGFBP‐3 in the IGF generation tests was greater than the accuracy of IGF‐I, when the group of patients with GHIS was compared with a group of patients with GH deficiency. Unexpectedly, the IGF generation test was unable to segregate both cohorts completely. In the GHIS‐positive group, a significant correlation was found between basal IGF‐I or IGFBP‐3 levels corrected for age (SDS) and height SDS (r= 0.49, p < 0.002 and r= 0.61, p < 0.0001, respectively). There was also a significant correlation between the changes of IGF‐I or IGFBP‐3 in the IGF generation test and height SDS. That is, the patients with a slight response to GH were those with the least growth retardation, suggesting the existence of partial GH insensitivity.

Pharmacokinetic and pharmacodynamic profile of a new sustained-release GH formulation, LB03002, in children with GH deficiency

“…Although based on a limited number of patients, this difference in response of IGF1 and IGFBP3 seems to support observations reported in GH-deficient and SGA children during the IGF1 generation test (13)(14)(15)(16)(17)(18). For GH-deficient and SGA children, it was shown that IGF1 levels do not plateau after 1 week of GH treatment and that close to normal IGF1 levels are reached after 3 months of GH administration, while IGFBP3 increased into the normal range much earlier (17,18); a comparable pattern for IGF1 and IGFBP3 is seen in the present study with LB03002.…”

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

“…In a child with the clinical and biological features of Laron syndrome, including high basal GH and low basal IGF1 and IGFBP3, the response to the IGFGT has been proposed as a step towards the diagnosis (3,29).…”

“…One of the most widely used is the 'standard IGFGT', which is performed over 5 days and requires four rhGH injections (33 mg/kg per day; total dose of 132 mg/kg) (3,29,30). In several studies in the 1990s, the diagnosis of severe GHIS was based presumptively on a scoring system that included the standard IGFGT (Table 2) (3,29). As the molecular diagnosis of Laron syndrome was not available in most of the patients, it was impossible to draw any firm conclusions about the sensitivity of the test (3,29).…”

“…In several studies in the 1990s, the diagnosis of severe GHIS was based presumptively on a scoring system that included the standard IGFGT (Table 2) (3,29). As the molecular diagnosis of Laron syndrome was not available in most of the patients, it was impossible to draw any firm conclusions about the sensitivity of the test (3,29). However, from these initial studies, cut-off values were arbitrarily defined as twice the intra-assay coefficient of variation (3), or an absolute IGF1 increment of 15 ng/ml (29).…”

“…As the molecular diagnosis of Laron syndrome was not available in most of the patients, it was impossible to draw any firm conclusions about the sensitivity of the test (3,29). However, from these initial studies, cut-off values were arbitrarily defined as twice the intra-assay coefficient of variation (3), or an absolute IGF1 increment of 15 ng/ml (29). Blum et al (29) also suggested that measuring IGFBP3 levels may improve the significance of the test, with an arbitrary cut-off of 0.4 mg/l for the absolute IGFBP3 increment.…”