Impact of heterozygosity for acid-labile subunit (IGFALS) gene mutations on stature: Results from the International Acid-Labile Subunit Consortium

Olga V. Fofanova-Gambetti, Vivian Hwa, Jan M. Wit, Horacio M. Domene, Jesús Argente, Peter Bang, Wolfgang Högler, Susan Kirsch, Catherine Pihoker, Harvey K. Chiu, Laurie Cohen, Christina Jacobsen, Hector G. Jasper, Gabriele Haeusler, Angel Campos-Barros, Elena Gallego-Gómez, Ricardo Gracia-Bouthelier, Hermine A. Van Duyvenvoorde, Jesús Pozo, Ron G. Rosenfeld

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


Context: To date, 16 IGFALS mutations in 21 patients with acid-labile subunit (ALS) deficiency have been reported. The impact of heterozygosity for IGFALS mutations on growth is unknown. Objective: The study evaluates the impact of heterozygous expression of IGFALS mutations on phenotype based on data collected by the International ALS Consortium. Subjects/Methods: Patient information was derived from the IGFALS Registry, which includes patients with IGFALS mutations and family members who were either heterozygous carriers or homozygous wild-type. Within each family, the effect of IGFALS mutations on stature was analyzed as follows: 1) effect of two mutant alleles (2ALS) vs. wild-type (WT); 2) effect of two mutant alleles vs. one mutant allele (1ALS); and 3) effect of one mutant allele vs. wild-type. The differences in height SD score (HtSDS) were then pooled and evaluated. Results: Mean HtSDS in 2ALS was -2.31 ± 0.87 (less than -2 SDS in 62%); in 1ALS, -0.83 ± 1.34 (less than -2 SDS in 26%); and in WT, -1.02 ± 1.04 (less than -2 SDS in 12.5%). When analyses were performed within individual families and pooled, the difference in mean HtSDS between 2ALS and WT was -1.93 ± 0.79; between 1ALS and WT, -0.90 ± 1.53; and between 2ALS and 1ALS, -1.48 ± 0.83. Conclusions: Heterozygosity for IGFALS mutations results in approximately 1.0 SD height loss in comparison with wild type, whereas homozygosity or compound heterozygosity gives a further loss of 1.0 to 1.5 SD, suggestive of a gene-dose effect. Further studies involving a larger cohort are needed to evaluate the impact of heterozygous IGFALS mutations not only on auxology, but also on other aspects of the GH/IGF system.

Original languageEnglish (US)
Pages (from-to)4184-4191
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Issue number9
StatePublished - Sep 2010
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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