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

KESELMAN, A.; BRASLAVSKY, D.; SCAGLIA, P.A.; KARABATAS, L.; BALLERINI, M.G.; MARTUCCI, L. ; GUTIÉRREZ, M.; DOMENÉ, S.; MARTÍNEZ, A.; ROPELATO, M.G.; BERGADÁ, I.; DOMENÉ, H.; JASPER, H.

Buenos Aires

Congreso; XXVI Reunion Anual de la Sociedad Latinoamericana de Endocrinología Pediatrica; 2016

Background: Acid-labile subunit (ALS) is crucial to stabilizeIGF-I in circulating ternary complexes. Complete ALS deficiencyis characterized by short stature, severe reduction of serum IGF-Iand IGFBP-3 levels and poor response to rhGH treatment. Lessinformation is available on the response to rhGH treatment in childrenheterozygous carriers for IGFALS gene variants.Aim: Evaluate auxological and biochemical responses to oneyear of rhGH treatment in short children either homozygous wildtype(WT) or heterozygous carriers (HC) for non-synonymousIGFALS variants.Patients: Short children (height " ?2.5 SDS) presenting normalstimulated 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 probablybenign: p.R548W (n!= 1) and p.P22L (n!= 1). Other 6 ISS children(4 boys, aged 6.5!± 2.0) were homozygous WT. Height andIGF-I, IGFBP-3 levels were evaluated before and after one-year ofrhGH treatment (dose of 0.33 mg/kg/week). ALS levels were evaluatedonly 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 thetable 1.Conclusions: Short children HC for IGFALS variants showeda satisfactory and similar response to one year rhGH treatmentcompared to WT-ISS children, although with a lower increase inIGF-I levels. This suggests that short children, carriers for IGFALSvariants, could be more sensitive to IGF-I, that paracrine action oflocally produced IGF-I has a more important effect on lineargrowth, or a combination of both. The impact of rhGH treatmenton adult height in carriers for IGFALS variants remains to be determined.