Combined STAT5B and igfals heterozygous genetic variants in a patient with partial growth hormone insensitivity

Abstract

Monogenic causes of growth hormone insensitivity (GHI) include defects in genes encoding the GH receptor itself (GHR), the signal transducer and activator of transcription (STAT5B), the insulin like-growth factor type I (IGF1) and the acid-labile subunit (IGFALS). Affected children could be severely growth retarded, although mutations in heterozygous state in some of these genes were associated to a milder clinical phenotype. We aimed to characterize the molecular defect in a patient with short stature and partial GHI. Patient and methods: The boy was born at term adequate for gestational age from non-consanguineous normal-stature parents. At 2.2 years, he presented proportionate short stature (height -2.77 SDS), wide forehead and normal mental development. Whole-exome analysis and functional characterization (dual luciferase reporter assays, immunofluorescence and, western immunoblot) were performed. Biochemical and endocrinological evaluation revealed partial GH insensitivity with normal stimulated GH peak (7.8 ng/ml), undetectable IGF1, and low IGFBP3 levels. Two heterozygous variants in the GH-signaling pathway were found: a novel heterozygous STAT5B variant (p.K632N) and a hypomorphic IGFALS variant (p.R548W). In vitro studies demonstrated that mutation p.K632N impairs STAT5b phosphorylation, nuclear translocation and transcriptional activity. Conclusions: In short children with GHI, genetic testing is recommended. We present compelling evidence to support p.K632N as a novel inactivating STAT5b variant. The combination of heterozygous IGFALS and STAT5B variants contributes to the patient’s partial GHI phenotype.