Short Stature Associated to Partial Growth Hormone Insensitivity (GHI) Due to a Digenic Disorder with a Hypomorphic Variant in IGFALS Combined to a Novel Heterozygous STAT5B Missense Variant

LAURA RAMIREZ; NORA SANGUINETTI; ANA KESELMAN; PAULA SCAGLIA; ARIEL BERENSTEIN; MARIA GABRIELA ROPELATO; MARIA GABRIELA BALLERINI; LILIANA KARABATAS; SABINA DOMENE; LUCIA MARTUCCI; DEBORA BRASLAVSKY; HAMILTON CASSINELLI; BARBARA CASALI; GRACIELA DEL REY; PATRICIA PENNISI; HECTOR JASPER; MARTIN VAZQUEZ; RODOLFO REY; HORACIO DOMENE; IGNACIO BERGADA; MARIANA GUTIERREZ

Congreso; Congreso Latinoamericano de Endocrinología pediátrica (SLEP); 2018

Background: GHI is characterized by growth failure, elevated GH, and low IGF-I and IGFBP-3 serum levels. GHI has been associated to monogenic defects in several genes including GHR, STAT5B, IGF1, IGFALS.Aim: To characterize the molecular defect in a patient with short stature and GHI.Case: The boy was born at term AGA from non-consanguineous parents. His parents and siblings had normal height. At 2.1 years, patient´s height was 73.5 cm (-3.23 SD), weight 8.28 kg (-2.5 SD), and head circumference 48.5 cm (0 SD). He presented proportionate short stature, wide forehead and normal mental development.Results: Biochemical and endocrinological evaluation were normal, including stimulated GH peak (7.8 ng/ml), with undetectable IGF-I and low IGFBP3 levels (1.34 µg/ml; -2.01 SD). IGF-I generation test (rhGH 33 µg/kg.day for 7 days) showed a poor response (IGF-I T, p.Arg548Trp) and a novel heterozygous missense variant in STAT5b (c.1896G>T, p.Lys632Asn) were found by candidate gene approach and WES, respectively. In vitro transfected CHO cells secreted significantly less R548W-ALS compared to WT-ALS (1). Studies using K632N-STAT5b transfected into HEK293-T cells showed impaired STAT5b phosphorylation upon GH stimulation. Also, its transcriptional activity determined by luciferase reporter assay, was diminished under basal and GH-stimulated conditions. Co-transfection of K632N- and WT-STAT5b resulted in decreased transcriptional activity compared to WT-STAT5b, suggesting a dominant negative effect for K632N-STAT5b. Interestingly, this effect was reversed under GH stimulation (200 ng/ml). Conclusion: The combined effect of a hypomorphic ALS variant (p.Arg548Trp) and a novel heterozygous STAT5b variant (p.Lys632Asn) with dominant-negative properties could be responsible for the patient?s partial GHI phenotype.