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

LAURA RAMÍREZ URREA, ; PAULA SCAGLIA, ; MARÍA GABRIELA BALLERINI, ; NORA SANGUINETI, ; ARIEL BERENSTEIN, ; LILIANA KARABATAS, SABINA DOMENÉ1, LUCÍA MARTUCCI1,; ANA KESELMAN, ; MARÍA GABRIELA ROPELATO, MARÍA GABRIELA BALLERINI1, LILIANA KARABATAS1, SABINA DOMENÉ1, LUCÍA MARTUCCI1,; SABINA DOMENÉ, LUCÍA MARTUCCI Y COLS,

Cusco

Congreso; XXVII Latin American Meeting of Pediatric Endocrinology; 2018

Soc. Latinoam. Endoc. Pediat.

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 the 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 K632NSTAT5b 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.