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. DOMENÉ; JESÚS ARGENTE; PETER BANG; WOLFGANG HOGLER; SUSAN KIRSH; CATHERINE PIHOKER; HARVEY K. CHIU; LAURIE COHEN; CHIRSTINA JACOBSEN; HÉCTOR G. JASPER; GABRIELE HAEUSLER; ANGEL CAMPOS-BARROS; ELENA GALLEGO-GOMEZ; RICARDO GRACIA-BOUTHELIER; HERMINE A. DUYVENVOORDE; JESÚS POZO; RON G. ROSENFELD

JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM

ENDOCRINE SOC

Año: 2010 vol. 95 p. 4184 - 4191

0021-972X

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 homozygouswild-type. Within each family, the effect of IGFALS mutationsonstaturewasanalyzed 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 inheight 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 omparison 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. 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 homozygouswild-type. Within each family, the effect of IGFALS mutationsonstaturewasanalyzed 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 inheight 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 omparison 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.