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Primary Acid-Labile Subunit Deficiency due to Recessive IGFALS Mutations Results in Postnatal Growth Deficit Associated with Low Circulating Insulin Growth Factor (IGF)-I, IGF Binding Protein-3 Levels, and Hyperinsulinemia

Departments of Endocrinology (K.E.H., J.A., V.B., J.P., F.D.-G., G.A.M.-M., A.C.-B.), Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, 28009 Madrid, Spain; Centro de Investigación Biomédica En Red (CIBER) Fisiopatología Obesidad y Nutrición (CB06/03) (J.A., V.B., J.P., G.A.M.-M.), Instituto de Salud Carlos III, 28029 Madrid, Spain; Department of Pediatrics (M.C.), Hospital Universitario Son Dureta, Universidad de Palma de Mallorca, 07014 Palma de Mallorca, Spain; and Department of Pediatric Endocrinology (R.G.), Hospital Universitario La Paz, Universidad Autónoma de Madrid, 28049 Madrid, Spain

Address all correspondence and requests for reprints to: Dr. Ángel Campos-Barros, Department of Medical Genetics, Hospital Universitario La Paz, P° Castellana 261, 28046 Madrid, Spain. E-mail: acamposbarros{at}yahoo.org.

Context: Up to 90% of circulating IGF-I and IGF-II are carried bound to either IGF binding protein (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 the bioavailability of IGFs 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 with undetectable ALS, low IGF-I, IGF-II, and IGFBP-3, and hyperinsulinemia, and, in two cases, 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.

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