This Article Full Text Full Text (PDF) All Versions of this Article: 93/5/1616    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Google Scholar Articles by Heath, K. E. Articles by Campos-Barros, A. PubMed PubMed Citation Articles by Heath, K. E. Articles by Campos-Barros, A. Related Collections Metabolism Pediatric Endocrinology

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.