OR11,62 The effect of genotype on molecular mechanisms leading to the 3-M primordial growth disorder

Abstract

patients who fit the height and IGF-I criteria of severe primary IGFD, i.e. both height and IGF-I standard deviation scores (SDS) ≤−3 with normal or elevated concentrations of growth hormone (GH). rhIGF-I is also approved for patients who have GH gene deletions and who have developed GH neutralizing antibodies to GH. In Europe the indication is slightly different, as severe primary IGFD is defined there as a height SDS ≤−3, but with basal IGF-I concentration of <2.5th percentile. With the availability of rhIGF-I to treat short stature associated with severe primary IGFD, pediatric endocrinologists must identify the correct patients for such therapy, and do so based both on clinical presentation in addition to information gathered from molecular testing. Because the latter is not yet widely available, clinicians still mainly rely upon auxology, and measurements of IGF-I and stimulated GH concentrations. Therapeutic decision-making is made more difficult because of several reasons: some patients appear to have milder deficiency of IGF-I, but are clearly showing sub-normal growth – they may not fit the criteria completely. Some patients have been treated previously with GH and are considered to be poor responders. Finally, after the initial description of distinct single-gene defects leading to severe primary IGFD, more and more patients are being documented with milder forms of IGFD. It has become apparent that there is a continuum of clinically relevant abnormalities affecting not only GH secretion, but also GH sensitivity, influencing the GH/IGF-I axis at different levels. The information gathered from the aforementioned long-term IGF-I studies was confined to a rather narrow population of patients with severe GH insensitivity leading to severe IGFD. Treatment data from patients who may have milder IGFD has only become available during the last couple of years. More information on efficacy and safety are thus needed in this group of patients, both for IGF-I monotherapy and GH/IGF-I combination therapy as well. This presentation will review the efficacy and safety information on IGF-I therapy, both for patients with severe primary IGFD and for patients with milder forms of IGFD, and address how therapeutic intervention for such patients should be approached using the available evidence for a clinical patient continuum, as well as the present knowledge on efficacy and safety of IGF-I.