title: Impact of heterozygosity for acid-labile subunit (IGFALS) gene mutations on stature: results from the international acid-labile subunit consortium.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Pediatrics, NRC5, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239-3098, USA. ogambetti@yahoo.com
authors.forename: Olga V
authors.initials: OV
authors.lastname: Fofanova-Gambetti
authors.forename: Vivian
authors.initials: V
authors.lastname: Hwa
authors.forename: Jan M
authors.initials: JM
authors.lastname: Wit
authors.forename: Horacio M
authors.initials: HM
authors.lastname: Domene
authors.forename: Jesús
authors.initials: J
authors.lastname: Argente
authors.forename: Peter
authors.initials: P
authors.lastname: Bang
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Högler
authors.forename: Susan
authors.initials: S
authors.lastname: Kirsch
authors.forename: Catherine
authors.initials: C
authors.lastname: Pihoker
authors.forename: Harvey K
authors.initials: HK
authors.lastname: Chiu
authors.forename: Laurie
authors.initials: L
authors.lastname: Cohen
authors.forename: Christina
authors.initials: C
authors.lastname: Jacobsen
authors.forename: Hector G
authors.initials: HG
authors.lastname: Jasper
authors.forename: Gabriele
authors.initials: G
authors.lastname: Haeusler
authors.forename: Angel
authors.initials: A
authors.lastname: Campos-Barros
authors.forename: Elena
authors.initials: E
authors.lastname: Gallego-Gómez
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gracia-Bouthelier
authors.forename: Hermine A
authors.initials: HA
authors.lastname: van Duyvenvoorde
authors.forename: Jesús
authors.initials: J
authors.lastname: Pozo
authors.forename: Ron G
authors.initials: RG
authors.lastname: Rosenfeld
mesh_terms: D000293:Adolescent; D000328:Adult; D001827:Body Height / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003245:Consensus Statements as Topic; D005190:Family; D005260:Female; D006023:Glycoproteins / Q000235:genetics*; D006130:Growth Disorders / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007391:International Cooperation; D019656:Loss of Heterozygosity / Q000235:genetics / Q000502:physiology*; D008297:Male; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; C075944:insulin-like growth factor binding protein, acid labile subunit