title: 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.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Heath
authors.forename: Jesús
authors.initials: J
authors.lastname: Argente
authors.forename: Vicente
authors.initials: V
authors.lastname: Barrios
authors.forename: Jesús
authors.initials: J
authors.lastname: Pozo
authors.forename: Francisca
authors.initials: F
authors.lastname: Díaz-González
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Martos-Moreno
authors.forename: María
authors.initials: M
authors.lastname: Caimari
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gracia
authors.forename: Angel
authors.initials: A
authors.lastname: Campos-Barros
mesh_terms: D000293:Adolescent; D015153:Blotting, Western; D001827:Body Height; D015519:Bone Density; D002352:Carrier Proteins / Q000097:blood / Q000235:genetics*; D002675:Child, Preschool; D005808:Genes, Recessive; D006023:Glycoproteins / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D006130:Growth Disorders / Q000209:etiology / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D006946:Hyperinsulinism / Q000209:etiology*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000032:analysis*; D008297:Male; D009154:Mutation; D011627:Puberty
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D018972:Insulin-Like Growth Factor Binding Protein 3; C075944:insulin-like growth factor binding protein, acid labile subunit; D007334:Insulin-Like Growth Factor I