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

BACKGROUND: The most frequent 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). GHI is characterized by a continuum of mild to severe post-natal growth failure. OBJECTIVE: 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 (site-directed mutagenesis, dual luciferase reporter assay, immunofluorescence and western immunoblot) were performed. RESULTS: 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 (c.1896G>T, p.K632N) and a hypomorphic IGFALS variant (c.1642C>T, p.R548W). Functional in vitro characterization demonstrated that p.K632N-STAT5b is an inactivating variant that impairs STAT5b activity through abolished phosphorylation. Remarkably, the patient's immunological evaluation displayed only a mild hypogammaglobulinemia, while a major characteristic of STAT5b deficient patients is severe immunodeficiency. CONCLUSIONS: We reported a novel pathogenic inactivating STAT5b variant, which may be associated with partial GH insensitivity and can present without severe immunological complications in heterozygous state. Our results contribute to expand the spectrum of phenotypes associated to GHI.

A mosaic de novo duplication of 17q21-25 is associated with GH insensitivity, disturbed in vitro CD28-mediated signaling, and decreased STAT5B, PI3K, and NF-κB activation.

OBJECTIVE: The established causes of GH insensitivity include defects of the GH receptor and STAT5B. The latter condition is also characterized by severe immunodeficiency. A recent case with short stature, GH resistance, and immunodeficiency due to an IκB mutation suggests that the NF-κB pathway may interact with STAT5B signaling. DESIGN: Here, we present a case of a short child with several congenital anomalies as well as GH insensitivity and mild immunodeficiency associated with a mosaic de novo duplication of chromosome 17q21-25, suggesting that overexpression of one of the duplicated genes may be implicated in GH resistance. METHODS AND RESULTS: In vitro studies on blood lymphocytes showed disturbed signaling of the CD28 pathway, involving NF-κB and related proteins. Functional studies on cultured skin fibroblasts revealed that NF-κB activation, PI3K activity, and STAT5 phosphorylation in response to GH were suppressed, while the sensitivity to GH in terms of MAPK phosphorylation was increased. An in silico analysis of the duplicated genes showed that MAP3K3 and PRKCA are associated with the NF-κB pathway. Baseline MAP3K3 expression in T-cell blasts (TCBs) was normal, but PRKCA expression in TCBs and fibroblasts was significantly higher than that in control cells. CONCLUSIONS: We conclude that the 17q21-25 duplication is associated with GH insensitivity and disturbed STAT5B, PI3K, and NF-κB signaling, possibly due to PRKCA mRNA overexpression.

STAT5b deficiency: lessons from STAT5b gene mutations.

Growth hormone (GH) regulates insulin-like growth factor (IGF)-I production primarily through activation of the GH receptor (GHR)-signal transducer and activator of transcription (STAT)-5b signaling cascade. One of four STAT proteins (STAT1, -3, -5a and -5b) activated by the GH-GHR system, the critical importance of STAT5b in IGF-I production became evident with the identification of homozygous, autosomal recessive STAT5b mutations in patients who presented with severe postnatal growth failure, growth hormone insensitivity syndrome (GHIS) and marked IGF-I deficiency. Unlike GHIS due to GHR mutations, patients carrying STAT5b mutations also presented with chronic pulmonary disease and evidence of perturbations of T-cell homeostasis. At present, no single treatment(s) is available to improve both poor statural growth and immune deficiency. Continued clinical evaluations of patients with STAT5b mutations and elucidating the impact of the mutation on STAT5b structure and function, are important to understanding the pathophysiology of this rare, complex, disease (MIM 245590).

Effects of growth hormone (GH) and insulin-like growth factor-I therapy in patients with gene defects in the GH axis.

We report on four patients (3 F) who were diagnosed as having either a 6.7 kb GH1 gene deletion, a GH1 signalling peptide mutation, or a GH receptor mutation, with particular regard to treatment modalities (GH, rhIGF-I) and final height. Patients with GH1 gene defects developed anti-GH antibodies (GH-Ab) following GH treatment. Surprisingly, growth response to GH was unrestricted in one girl, who reached a final height within her target height range, whereas her cousin with the identical genetic defect responded far less favourably. Variability in the growth inhibiting potency of GH-Ab may therefore depend on genetic disposition, specific epitopes, or induction of immunological tolerance. Growth response during rhIGF-I treatment carried out in three of the patients was moderate, but pubertal development and bone age acceleration occurred in the two patients treated at pubertal age. GH resistance, either caused by GH-Ab or GH receptor mutations, is still difficult to treat and results in a heterogeneous outcome.