A novel (p.Leu213Phe) and 2 recurrent (p.E35Gfs*17 and p.Asn276Ser) IGFALS gene mutations in two children presenting IGF-I and IGFBP-3 deficiencies

ANGELA SPINOLA-CASTRO; PAULA A SCAGLIA; ADRIANA SILVIERO-MIACHON; JULIANA SAITO TARTUCI; HÉCTOR G JASPER; HORACIO M DOMENÉ

Milan

Congreso; 9th Joint Meeting of Paediatric Endocrinology (ESPE, PES, APEG, APPES, ASPAE, JSPE, SLEP); 2013

ESPE

Background: ALS deficiency (ALS-D) resulting from IGFALS gene defects has been characterized in children with severe IGF-I and IGFBP-3 deficiencies associated to mild growth retardation. Objective and hypotheses: To characterize the molecular defect in two children with normal height and severe IGF-I and IGFBP-3 deficiencies. Methods: We studied 2 unrelated children (1 girl, 1 boy) born at term (weight 2890 and 2710 g; length 49 and 48 cm, respectively). At 4.7 years of age, although presenting normal height (-1.28 and -1.73 SDS), they both underwent GH stimulation test and IGF-I and IGFBP-3 measurements, because of phenotypic features suggestive of GH deficiency and adjusted target heights -0.73 and -1.41 SDS. Serum GH, IGF-I and IGFBP-3 levels were determined by ICMA. IGFALS gene was PCR amplified and automatically sequenced.Results: Both children had normal GH response to stimulation tests (7.6 and 15.3 ng/ml) and low levels of IGF-I (< 25 and 38 ng/ml; reference range, RR: 49-289) and IGFBP-3 (< 0.5 and 0.80 µg/ml; RR: 1.0-4.7). IGFALS gene sequencing revealed: the girl was compound heterozygous for 2 already described mutations (c.103dupG; p.E35GfsX17 and c.827A>G; p.Asn276Ser), while the boy was homozygous for a novel missense mutation (c.637C>T; p.Leu213Phe). This mutation, affecting a highly conserved leucine residue, was not found in 196 controls and is predicted to be probably damaging by in silico analysis. Conclusions: These two cases illustrate the broad spectrum of clinical presentation in ALS-D patients, despite the consistent finding of severe IGF-I and IGFBP-3 deficiencies. Interestingly, features of GH deficiency have not been previously reported in ALS-deficient patients, and they are diagnosed later, probably because linear growth remains almost normal during the first years of life. Careful follow-up of these patients will clarify if they are able to remain growing within normal limits or alternatively they further deteriorate their heights.