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Impact of heterozygosity for acid-labile subunit (IGFALS) gene mutations on stature: results from the international acid-labile subunit consortium Fofanova-Gambetti OV; Hwa V; Wit JM; Domene HM; Argente J; Bang P; Hogler W; Kirsch S; Pihoker C; Chiu HK; Cohen L; Jacobsen C; Jasper HG; Haeusler G; Campos-Barros A; Gallego-Gomez E; Gracia-Bouthelier R; van Duyvenvoorde HA; Pozo J; Rosenfeld RGJ Clin Endocrinol Metab 2010[Sep]; 95 (9): 4184-91CONTEXT: 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.|Adolescent[MESH]|Adult[MESH]|Body Height/*genetics[MESH]|Carrier Proteins/*genetics[MESH]|Case-Control Studies[MESH]|Child[MESH]|Child, Preschool[MESH]|Consensus Development Conferences as Topic[MESH]|Family[MESH]|Female[MESH]|Glycoproteins/*genetics[MESH]|Growth Disorders/genetics[MESH]|Heterozygote[MESH]|Humans[MESH]|International Cooperation[MESH]|Loss of Heterozygosity/genetics/*physiology[MESH]|Male[MESH]|Models, Biological[MESH]|Mutation/physiology[MESH]|Young Adult[MESH] |
