Context: Up to 90% of circulating IGF-I and IGF-II are carried bound to either IGFBP-3 or IGFBP-5, and the acid-labile subunit (ALS) in the form of tertiary complexes that extend their circulating half-life. Three cases of complete ALS deficiency have been recently reported in short stature patients with very low circulating IGF-I and IGFBP-3 levels who presented with homozygous or compound heterozygous mutations in the ALS encoding gene (IGFALS; 16p13.3), thus supporting a role for ALS in the regulation of IGFs bioavailability during postnatal growth.

Objective: We present the molecular and clinical characterization of two novel IGFALS mutations that caused complete ALS deficiency in three unrelated patients with postnatal growth deficit, low IGF-I and IGFBP-3 levels and no GH deficiency.

Results: IGFALS mutation screening identified a novel homozygous IGFALS missense mutation, which altered a conserved residue, N276S, in two of the probands. The third proband presented a novel homozygous nonsense mutation, Q320X, that is predicted to generate a severely truncated ALS protein. The affected probands presented a similar phenotype characterized by a moderate postnatal growth deficit associated to undetectable ALS, low IGF-I, IGF-II, and IGFBP-3, hyperinsulinemia and, in two cases, with delayed puberty.

Conclusions: Primary ALS deficiency due to IGFALS mutations should be considered as a possible cause of postnatal growth deficit in IGF-I deficient patients in the absence of GH deficiency or insensitivity. Determination of serum ALS levels and basal insulinemia can be helpful in the differential diagnosis of patients with idiopathic IGF-I deficiency.