A novel Leu409Phe IGFALS gene mutation results in complete ALS deficiency in a boy presenting short stature, pubertal delay and severe IGF-I and IGFBP-3 deficiencies

DOMENE H M; BERGADA IGNACIO; SCAGLIA PA; KARABATAS L; BRASLAVSKY D; JASPER HG

Montevideo

Congreso; 51st Annual Meeting of the ESPE(European Society for Pediatric Endocrinology); 2012

European Society for Pediatric Endocrinology

A novel Leu409Phe IGFALS gene mutation results in complete ALS deficiency in a boy presenting short stature, pubertal delay and severe IGF-I and IGFBP-3 deficiencies Horacio Domené1; Ignacio Bergadá2; Paula Scaglia1; Liliana Karabatas1; Débora Braslavsky2; Héctor Jasper1 1Centro de Investigaciones Endocrinológicas (CEDIE), CONICET, Buenos Aires, Argentina; 2División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina Background: GH insensitivity has been associated to GHR, STAT5b, IGF1 and IGFALS gene defects. Despite similar degrees of IGF-I deficiency only IGFALS gene defects result in mild growth deficit. To date, at least 24 ALS-deficient patients have been characterized at the molecular level. Objective and hypotheses: To characterize the molecular defect in a short boy presenting IGF-I and IGFBP-3 deficiencies. Methods: The proband is a 13 10/12 year old prepubertal boy, born at term with 2800 g (father 160 cm, -1.88 SDS; mother 157 cm, -0.6 SDS). He is the fourth of nine siblings, weight 28.3 kg, height 134.7 cm (-2.65 SDS), BA 12 9/12 years for CA 13 5/12. Serum GH, IGF-I and IGFBP-3 levels were de­termined by ICMA, ALS by Western immunoblot (WIB) and in vitro ternary complex (TC) formation by size exclusion chromatography. Results: Clinical and biochemical evaluation excluded blood, renal and thy­roid disorders and celiac disease. He presented a normal GH response (22.0 ng/ml) to an arginine-clonidine test and low IGF-I (29 and 33 ng/ml; -3.29 and -2.90 SDS) and IGFBP-3 (<0.25 μg/ml) levels. ALS was undetectable by WIB and serum from the patient was unable to form TC, even after spiking with rhIGFBP-3. IGFALS gene sequencing revealed two homozygous novel mis­sense mutations (c.1225C>T; p.Leu409Phe and c.1424C>T; p.Ala475Val). Whilst the p.Leu409Phe affects a highly conserved leucine residue located within consensus LRR β-strand motif (LxxLxLxxN/CxL) in the 15th LRR domain and is predicted to be probably damaging by in silico analysis (Poly­Phen 2), the p.Ala475Val mutation changes a non conserved residue being probably a benign variant. These mutations were not found in 380 alleles from local controls. Conclusions: As shown by this case, the association of severe IGF-I and IGFBP-3 deficiencies to mild growth retardation is suggestive of ALS defi­ciency, particularly when associated to pubertal delay. The increasing number of ALS deficient reported patients indicates that this condition may be more prevalent that previously suspected.