Growth hormone secretion and immunological function of a male patient with a homozygous STAT5b mutation

Abstract

Objective: STAT5b is a component of the GH signaling pathway. Recently, we described a 31-year-old male patient (height, K5.9 SDS) with a novel homozygous inactivating mutation in the STAT5b gene. The purpose of this study is to describe the phenotype in detail, including GH secretion and immunological function. In addition, we report four family members of this patient, all heterozygous carriers of the mutation. Design and methods: Twenty-four hour GH and prolactin secretion characteristics were assessed by blood sampling at 10-min intervals. An IGF-I generation test was performed. Monocyte function was tested by stimulation of whole blood with lipopolysaccharide (LPS) in the presence or absence of Interferon-g (IFN-g). In addition, T cell function was determined by measuring proliferative responses of peripheral blood mononuclear cells (PBMC) after stimulation by various polyclonal activators and Interleukin-2 (IL-2). Clinical and biochemical characteristics were determined in the carriers of the mutation. Results: GH secretory parameters were comparable with that of healthy male controls (mean fat percentage 25), but likely increased in relation to the patient's 40% body fat. The regularity of GH secretion was diminished. Prolactin secretion was increased by sixfold. The IGF-I generation test showed a small increase in IGF-I and IGF-binding protein-3 on lower GH doses and an increase in IGF-I to K2.4 SDS on the highest dose of GH. In vitro, IL-12p40, IL 10, and tumour necrosis factor-a (TNF-a) production rates by PBMC increased to values within the normal range upon stimulation of LPS. Heterozygous carriers of the mutation did not show abnormalities, although the height of the males was below the normal range. Conclusions: This report shows that GH and prolactin secretion were increased in this patient homozygous for a new STAT5b mutation. Although STAT5b plays a role in signaling within immune cells, clinical immunodeficiency is not an obligatory phenomenon of STAT5b deficiency per se. Heterozygous carriers of a STAT5b mutation show no signs of GH insensitivity. 156 155-165 European Journal of Endocrinology

Genetic disorders in the GH–IGF-I axis in mouse and man

“…One patient suffers from juvenile idiopathic arthritis (53). The 30-year-old male patient has no history or signs of immune deficiency (120). Thus, in the human, an intact STAT5b is not obligatory for a normal immune phenotype.…”

A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings

“…Considering that this mutation was found in heterozygous state and that it did not segregate with the disease in this family, along with the fact that in silico analysis predicted this variant to be benign, we considered that p.D137N is not the cause of the GHI in our patients. The involvement of STAT5B in GHI patients without mutations in GHR has been recently described in six patients (3)(4)(5)(6)(7)(8)(9). A major characteristic of patients with GHI due to STAT5B defects is the presence of immunological dysfunction.…”

“…Recently, homozygous mutations in the signal transducer and activator of transcription 5B gene (STAT5B; OMIM: *604260) were described in patients with GHI (3)(4)(5)(6)(7)(8)(9). Besides the clinical and hormonal phenotype of GHI, the majority of these patients also had severe immune dysfunction and elevated prolactin (PRL) levels (3)(4)(5)(6)(7)(8)(9).…”

“…Besides the clinical and hormonal phenotype of GHI, the majority of these patients also had severe immune dysfunction and elevated prolactin (PRL) levels (3)(4)(5)(6)(7)(8)(9). STAT5B is a critical molecule involved in GHR signal transduction, mediating the growth-promoting actions of the GHR.…”

“…Although lymphoid interstitial pneumonia, chronic diarrhea, severe eczema, herpes keratitis, herpes zoster, severe varicella, and juvenile arthritis were described in female patients with STAT5B mutations (15), the only male patient reported did not have a clear evidence of immunological defects (7,8). It was conjectured that the immune-dysfunction phenotype associated with STAT5B deficiency could be sex dependent (8).…”