Heterozygous IGFALS gene mutations are present in both idiopathic short stature (ISS) and in normal children: impact on height and acid-labile subunit (ALS) levels

SCAGLIA P; DOMENÉ H; MARTÍNEZ A; KESELMAN A; PIPMAN V; BENGOLEA V; KARABATAS L; LESCANO E; ROPELATO MG; BALLERINI MG; HEINRICH JJ; JASPER HG

New York, N.Y., USA

Congreso; LWPES / ESPE 8th Joint Meeting; 2009

ESPE / LWPES / SLEP / APEG / APPES / JSPE

PO2-125 Genetics of Growth IIGenetics of Growth II Heterozygous IGFALS gene mutations are present in both idiopathic short stature (ISS) and in normal children: impact on height and acid-labile subunit (ALS) levelsIGFALS gene mutations are present in both idiopathic short stature (ISS) and in normal children: impact on height and acid-labile subunit (ALS) levels Paula A Scaglia1; Horacio M Domené1; Alicia S Martínez1; Ana C Keselman1; Viviana R Pipman2; Sonia V Bengolea3; Liliana M Karabatas1; Eva M Lescano4; María G Ropelato1; María G Ballerini1; Juan J Heinrich1; Héctor G Jasper1 1Centro de Investigaciones Endocrinológicas (CEDIE-CONICET), Hospital de Niños R. Gutiérrez, Buenos Aires, Argentina; 2Pediatría, Hospital Tornú, Buenos Aires, Argentina; 3Pediatría, Hospital J.A. Fernández, Buenos Aires, Argentina; 4Pediatría, Hospital de Niños Eva Perón, Santiago del Estero, Argentina 1; Horacio M Domené1; Alicia S Martínez1; Ana C Keselman1; Viviana R Pipman2; Sonia V Bengolea3; Liliana M Karabatas1; Eva M Lescano4; María G Ropelato1; María G Ballerini1; Juan J Heinrich1; Héctor G Jasper1 1Centro de Investigaciones Endocrinológicas (CEDIE-CONICET), Hospital de Niños R. Gutiérrez, Buenos Aires, Argentina; 2Pediatría, Hospital Tornú, Buenos Aires, Argentina; 3Pediatría, Hospital J.A. Fernández, Buenos Aires, Argentina; 4Pediatría, Hospital de Niños Eva Perón, Santiago del Estero, Argentina Background: Human ALS deficiency, caused by inactivating mutations in the IGFALS gene, is characterized by moderate growth retardation and marked reduction of IGF-I and IGFBP-3 levels that remain low after GH treatment. Heterozygous (HZ) carriers for IGFALS gene mutations are frequently shorter than their wild type (WT) first degree relatives. Likely, milder cases of ALS deficiency having less detrimental gene mutations in one or both IGFALS alleles may be present in a subgroup of ISS children. Objectives: The aim of this study was to search for IGFALS gene mutations in unselected ISS children and in control children selected by low normal levels of ALS, and to determine the impact of these mutations on height and ALS levels. Subjects and Methods: We studied 46 normal children (ages 5.0-16.3 y) out of 190, presenting ALS levels <-0.5 SDS and 87 ISS children (ages 1.8-8.9 y). Serum levels of ALS were determined by RIA and expressed as SDS in relation to normal controls. The IGFALS gene was PCR amplified and entirely sequenced. Results: Non-synonymous HZ IGFALS gene mutations were found in 6 ISS patients: E35GfsX16, G83S, R277H, A330D and A546V; as well as in 3 normal controls: V239M, N276S and R277H. Height SDS in HZ controls were: -0.35; 1.09; and -1.10, respectively. By extending this study to first degree relatives of ISS children, auxological, genetic and biochemical data were obtained from 11 siblings (1 HZ) and 8 parents (3 HZ). In HZ carriers (parents + children), height and ALS levels (mean SDS}SD) were lower than WT: -2.05}0.88 (n=10) vs. -0.08}0.83 (n=15), p<0.0001 for height; and -2.02}1.74 vs. –0.70}1.10, p=0.029 for ALS levels. When height deficit was evaluated within each family, the D height SDS in HZ (HZ HSDS - mean WT HSDS) was significantly lower than the hypothetical value 0 (median -1.71; range -0.61 to -2.32, p=0.002). Non-synonymous HZ IGFALS gene mutations were found in 6 ISS patients: E35GfsX16, G83S, R277H, A330D and A546V; as well as in 3 normal controls: V239M, N276S and R277H. Height SDS in HZ controls were: -0.35; 1.09; and -1.10, respectively. By extending this study to first degree relatives of ISS children, auxological, genetic and biochemical data were obtained from 11 siblings (1 HZ) and 8 parents (3 HZ). In HZ carriers (parents + children), height and ALS levels (mean SDS}SD) were lower than WT: -2.05}0.88 (n=10) vs. -0.08}0.83 (n=15), p<0.0001 for height; and -2.02}1.74 vs. –0.70}1.10, p=0.029 for ALS levels. When height deficit was evaluated within each family, the D height SDS in HZ (HZ HSDS - mean WT HSDS) was significantly lower than the hypothetical value 0 (median -1.71; range -0.61 to -2.32, p=0.002). Conclusions: In families of ISS children, both height and ALS levels were lower in HZ carriers for IGFALS mutations compared to WT, suggesting that both gene alleles are required to express maximal ALS levels and to fulfill growth potential. Although the role of ALS on growth is not completely understood, HZ IGFALS gene mutations could be involved in the etiology of short stature in a subset of ISS children. The finding of IGFALS gene mutations in normal control children reveals that these mutations are also present in the normal population and could be the source of ALS deficient subjects in nonconsanguineous families.