A novel heterozygous STAT5B variant in a patient with short stature and partial growth hormone insensitivity (GHI)

RAMIREZ LAURA; SANGUINETI N; SCAGLIA P; ANA KESELMAN; BALLERINI MG; KARABATAS L; ESTEFANIA LANDI; CASTRO JULIA; DOMENÉ S; PENNISI PATRICIA A; JASPER HG; DR. RODOLFO REY; DOMENÉ HM; BERGADA, I; GUTIERREZ M

GROWTH HORMONE & IGF RESEARCH : OFFICIAL JOURNAL OF THE GROWTH HORMONE RESEARCH SOCIETY AND THE INTERNATIONAL IGF RESEARCH SOCIETY.

CHURCHILL LIVINGSTONE

Lugar: ESCOCIA; Año: 2019 vol. 50 p. 61 - 70

1096-6374

Abstract: Background: The most frequent monogenic causes of growthhormone insensitivity (GHI) include defects in genes encoding the GHreceptor itself (GHR), the signal transducer and activator oftranscription (STAT5B), the insulin like-growth factor type I (IGF1) andthe acid-labile subunit (IGFALS). GHI is characterized by a continuum ofmild to severe post-natal growth failure. Objective: To characterize themolecular defect in a patient with short stature and partial GHI. Patientand Methods: The boy was born at term adequate for gestational age fromnon-consanguineous normal-stature parents. At 2.2 years, he presentedproportionate short stature (height -2.77 SDS), wide forehead and normalmental development. Whole-exome analysis and functional characterization(site-directed mutagenesis, dual luciferase reporter assay,immunofluorescence and, western immunoblot) were performed. Results:Biochemical and endocrinological evaluation revealed partial GHinsensitivity with normal stimulated GH peak (7.8 ng/ml), undetectableIGF1 and low IGFBP3 levels. Two heterozygous variants in the GH-signalingpathway were found: a novel heterozygous STAT5B variant (c.1896G>T,p.K632N) and a hypomorphic IGFALS variant (c.1642C>T, p.R548W).Functional in vitro characterization demonstrated that p.K632N-STAT5b isan inactivating variant that impairs STAT5b activity through abolishedphosphorylation. Remarkably, the patient´s immunological evaluationdisplayed only a mild hypogammaglobulinemia, while a major characteristicof STAT5b deficient patients is severe immunodeficiency. Conclusions: Wereported a novel pathogenic inactivating STAT5b variant, which may beassociated with partial GH insensitivity and can present without severeimmunological complications in heterozygous state. Our results contributeto expand the spectrum of phenotypes associated to GHI.