Idiopathic short stature is essentially a diagnosis of exclusion made after physical examination and biochemical assessment ruled out other causes of short stature. Different molecular defects have been characterized in ISS. Complete ALS deficiency (ACLSD), characterized by severe deficiencies of IGF-I, IGFBP-3, and ALS, is caused by mutations in the IGFALS gene. Milder cases of ACLSD, heterozygous carriers of IGFALS gene variants, may be present in a subgroup of ISS children. By studding 218 normal and 117 ISS children, we determined that non-synonymous IGFALS variants were more frequent in ISS (15.5% vs. 4.8%; P=0.0039). From 16 ISS children with non-synonymous variants, one presented ACLSD (compound heterozygous for p.Glu35Glyfs*17/p.Ser490Trp) and other five presented partial ACLSD (heterozygous carriers for p.Glu35Glyfs*17, p.Arg277His, p.Pro287Leu, and 2 p.Arg548Trp). One variant affected ALS synthesis (p.Glu35Glyfs*17) and other two, with normal synthesis and secretion, albeit to lower ALS concentrations (p.Ala330Asp, p.Arg548Trp). Complete ACLSD represented 1%, and partial ACLSD 5% of ISS children, presenting IGALS pathogenic or still no classified variants. Identification of partial ACLSD may have practical implications, considering that these children, different to what was reported in complete ACLSD, retain their ability to respond to rhGH treatment. To prove the efficacy of this treatment requires large follow-up until adult height.

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