ESPE Abstracts (2014) 82 P-D-2-1-412

ALS Deficiency due to a Novel and Two Already Described IGFALS Gene Mutations in an Unusual Non Consanguineous Family: Two Compound Heterozygous (Father and Son) and Two Heterozygous Carriers (Brother and Mother)

Paula Scaglia, Ana Keselman, Lucía Martucci, Liliana Karabatas, María Gabriela Ballerini, Sabina Domené, Acosta Johanna, Héctor Jasper & Horacio Domené

Centro de Investigaciones Endocrinológicas ‘Dr César Bergadá’ (CEDIE), CONICET – FEI – División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina

Introduction: Complete ALS deficiency (ALS-D), caused by inactivating mutations in both IGFALS gene alleles, presents severe IGF1 and IGFBP3 deficiencies associated to moderate growth retardation.

Aim: To characterize the molecular defect in a family where the index case and his father presented short stature and IGF1 and IGFBP3 deficiencies.

Methods: IGF1, IGFBP3, and GH serum levels were determined by CLIA, ALS by ELISA and western immunoblot (WIB). IGFALS gene was PCR amplified and automatically sequenced.

Results: We studied a short boy (CA 2.4 years, 81.5 cm, −2.9 SDS). He presented normal GH secretion (GHmax: 15.3 ng/ml), undetectable IGF1 (<25 ng/ml), IGFBP3 (<0.5 μg/ml), and ALS (<100 mU/ml) serum levels. IGFALS sequencing revealed he was compound heterozygous for a frameshift mutation (c.103dupG, p.E35Gfs*17) and a novel missense variant (c.1469C>G, p.S490W). His father (156.5 cm, −2.4 SDS) presented IGF1, IGFBP3, and ALS deficiencies (29 ng/ml, <0.5 μg/ml, and <100 mU/ml respectively) and was compound heterozygous for the p.S490W variant and p.L409F.A475V, previously described in an ALS-D family. Patient’s mother (162.3 cm, 0.26 SDS) and his brother (CA 6.0 years, 116.5 cm, 0.41 SDS) were heterozygous for p.E35Gfs*17 and p.S490W variants respectively, with normal levels of IGF1 (128 and 126 ng/ml) and IGFBP3 (2.64 and 2.00 μg/ml). His paternal aunt (153 cm, −1.26 SDS) presented the same genotype as the father and had low IGF1 with undetectable IGFBP3, while the paternal grandmother (156.4 cm, −0.70 SDS) was heterozygous for p.L409F.A475V with normal IGF1 and IGFBP3.

Conclusions: The finding of undiagnosed ALS-D adult subjects, compound heterozygous for IGFALS gene mutations and the appearance of heterozygous carriers in a non consanguineous family, support that these genetic variants are present in the population and are not under a strong negative selection pressure. Remarkably, this is the first report showing fertility is preserved in an ALS-D patient.