Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Original Paper Horm Res 2009;71:100–110 DOI: 10.1159/000183899 Three Novel IGFALS Gene Mutations Resulting in Total ALS and Severe Circulating IGF-I/IGFBP-3 Deficiency in Children of Different Ethnic Origins Olga V. Fofanova-Gambetti a Vivian Hwa a Susan Kirsch b Catherine Pihoker c Harvey K. Chiu c Wolfgang Högler d Laurie E. Cohen e Christina Jacobsen e Michael A. Derr a Ron G. Rosenfeld a, f, g a Department of Pediatrics, NRC5, Oregon Health and Science University, Portland, Oreg., USA; b Hospital for Sick Children, Toronto, Ont., Canada; c Children’s Hospital & Regional Medical Center, Seattle, Wash., USA; d Diana, Princess of Wales Children’s Hospital, Birmingham, UK; e Division of Endocrinology, Children’s Hospital Boston, Boston, Mass., f Lucile Packard Foundation for Children’s Health, Palo Alto, Calif., and g Department of Pediatrics, Stanford University, Stanford, Calif., USA C60S/L244F mutation in exon 2, located within a highly con- served LRR 1 and LRR 9, respectively. Conclusions: The iden- tification of additional novel IGFALS mutations, resulting in severe IGF-I/IGFBP-3 and ALS deficiencies, supports IGFALS as a candidate gene of the GH/IGF system, implicated in the pathogenesis of primary IGF deficiency, and represents an important part of its differential diagnosis. Copyright © 2009 S. Karger AG, Basel Introduction GH-1 gene expression and secretion of growth hor- mone (GH) into the systemic circulation are the contrib- utors to key mammalian postnatal growth. Following its secretion by the anterior pituitary gland, GH associates with the cell surface GH receptor (GHR) to induce its metabolic effects. The growth-promoting effects of GH Key Words Primary IGF deficiency  IGFALS gene mutations  Acid-labile subunit deficiency Abstract Background/Aims: To date, four mutations in the IGFALS gene have been reported. We now describe two children of different ethnic background with total acid-labile subunit (ALS) and severe circulating IGF-I/IGFBP-3 deficiencies re- sulting from three novel mutations in the IGFALS gene. Pa- tients/Methods: Serum and DNA of patients were analyzed. Results: Case 1 is a 12-year-old boy of Mayan origin. Case 2 is a 5-year-old girl of Jewish/Eastern European (Polish, Rus- sian, Austrian-Hungarian)/Icelandic/European (French, Eng- lish) ancestry. The reported cases had moderate short stat- ure (–2.91 and –2.14 SDS, respectively), nondetectable serum ALS and extremely low serum concentrations of IGF-I and IGFBP-3. Case 1 harbored a novel homozygous 1308_1316 dup9 mutation in a highly conserved leucine-rich repeat (LRR) 17 motif of exon 2, representing an in-frame insertion of 3 amino acids, LEL. Case 2 harbored a novel heterozygous Received: February 2, 2008 Accepted: July 9, 2008 Published online: January 8, 2009 HORMONE RESEARCH Olga V. Fofanova-Gambetti, MD, PhD Department of Pediatrics, NRC5, Oregon Health and Science University 3181 SW Sam Jackson Park Rd Portland OR 97239 (USA) Tel. +1 503 494 1932, Fax +1 503 494 0428, E-Mail ogambetti@yahoo.com © 2009 S. Karger AG, Basel 0301–0163/09/0712–0100$26.00/0 Accessible online at: www.karger.com/hre O.V. F.-G. and R.G.R. have been members of the European Society for Paediatric Endocrinology (ESPE) since 1998.