Clinical and Biochemical Response to rhGH Treatment in Children with Idiopathic Short Stature (ISS): Impact of Heterozygous Variants in the IGFALS Gene

SCAGLIA, PAULA; KESELMAN, ANA; MARTUCCI, LUCIA; KARABATAS, LILIANA; MARTINEZ, ALICIA; GUTIERREZ, MARIANA; DOMENE, HORACIO; ROPELATO, MARIA GABRIELA; JASPER, HECTOR; BRASLAVSKY, DEBORA; BALLERINI, MARIA GABRIELA; DOMENÉ SABINA; BERGADA, IGNACIO

Buenos Aires

Congreso; XXVI Congreso de la Sociedad Latinoamericana de Endocrinología Pediátrica; 2016

Sociedad Latinoamericana de Endocrinología Pediátrica

Background:Acid-labile subunit (ALS) is crucial to stabilize IGF-I in circulating ternary complexes. Complete ALS deficiency is characterized by short stature, severe reduction of serum IGF-I and IGFBP-3 levels and poor response to rhGH treatment. Less information is available on the response to rhGH treatment in children heterozygous carriers for IGFALS gene variants.Aim: Evaluate auxological and biochemical responses to one year of rhGH treatment in short children either homozygous wild-type (WT) or heterozygous carriers (HC) for non-synonymous IGFALS variants. Patients: Short children (height ≤ -2.5 SDS) presenting normal stimulated GH levels (GH max ≥ 4.7 ng/ml) were recruited. Six patients (5 boys, aged 6.7±2.2) had heterozygous IGFALS gene variants: 4 probably pathogenic by in silico or in vitro assessment: p.E35Gfs*17 (n=2), p.G506R (n=1), p.H128R (n=1), and 2 probably benign: p.R548W (n=1) and p.P22L (n=1). Other 6 ISS children (4 boys, aged 6.5±2.0) were homozygous WT. Height and IGF-I, IGFBP-3 levels were evaluated before and after one-year of rhGH treatment (dose of 0.33 mg/kg/week). ALS levels were evaluated only before treatment [HC: -1.95±-0.15 (n=6); WT: 1.57±2.00 (n=4); NS).Results: Auxological and biochemical data are shown in the Table.Conclusions: Short children HC for IGFALS variants showed a satisfactory and similar response to one year rhGH treatment compared to WT-ISS children, although with a lower increase in IGF-I levels. This suggests that short children, carriers for IGFALS variants, could be more sensitive to IGF-I, that paracrine action of locally produced IGF-I has a more important effect on linear growth, or a combination of both. The impact of rhGH treatment on adult height in carriers for IGFALS variants remains to be determined.Auxological and biochemical data HC(mean±SDS) WT(mean±SDS) T-test Height SDS -2.90±0.15-2.82±0.53NS IGF-I SDS -2.25±0.44-0.44±0.95 p=0.0018IGFBP-3 SDS -2.05±0.98 0.00±0.55 p=0.0012 IGF-I SDS on rhGH 0.32±1.48 2.21±0.94 p=0.025 IGFBP-3 SDS on rhGH 0.16±0.92 1.14±0.82 NS HV (cm/year) 9.93±1.49 10.72±1.53 NS Delta height SDS 1.21±0.43 1.15±0.26 NS