Original Paper

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<sup>a, f, g

a</sup>Department of Pediatrics, NRC5, Oregon Health and Science University, Portland, Oreg., USA;
^bHospital for Sick Children, Toronto, Ont., Canada;
^cChildren's Hospital & Regional Medical Center, Seattle, Wash., USA;
^dDiana, Princess of Wales Children's Hospital, Birmingham, UK;
^eDivision of Endocrinology, Children's Hospital Boston, Boston, Mass.,
^fLucile Packard Foundation for Children's Health, Palo Alto, Calif., and
^gDepartment of Pediatrics, Stanford University, Stanford, Calif., USA

Address of Corresponding Author

Horm Res 2009;71:100-110 (DOI: 10.1159/000183899)

  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 resulting from three novel mutations in the IGFALS gene. Patients/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, Russian, Austrian-Hungarian)/Icelandic/European (French, English) ancestry. The reported cases had moderate short stature (-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 C60S/L244F mutation in exon 2, located within a highly conserved LRR 1 and LRR 9, respectively. Conclusions: The identification 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

  Author Contacts

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

  Article Information

O.V. F.-G. and R.G.R. have been members of the European Society for Paediatric Endocrinology (ESPE) since 1998.

Received: February 2, 2008
Accepted: July 9, 2008
Published online: January 8, 2009
Number of Print Pages : 11
Number of Figures : 4, Number of Tables : 3, Number of References : 11