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  • Author: M J E Walenkamp x
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M J E Walenkamp and J M Wit

Animal knockout experiments have offered the opportunity to study genes that play a role in growth and development. In the last few years, reports of patients with genetic defects in GH–IGF-I axis have greatly increased our knowledge of genetically determined causes of short stature. We will present the animal data and human reports of genetic disorders in the GH–IGF-I axis in order to describe the role of the GH–IGF-I axis in intrauterine and postnatal growth. In addition, the effects of the GH–IGF-I axis on the development and function of different organ systems such as brain, inner ear, eye, skeleton, glucose homeostasis, gonadal function, and immune system will be discussed. The number of patients with genetic defects in the GH–IGF-I axis is small, and a systematic diagnostic approach and selective genetic analysis in a patient with short stature are essential to identify more patients. Finally, the implications of a genetic defect in the GH–IGF-I axis for the patient and the therapeutic options will be discussed.

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Marie J E Walenkamp, Solrun Vidarsdottir, Alberto M Pereira, Marcel Karperien, Jaap van Doorn, Hermine A van Duyvenvoorde, Martijn H Breuning, Ferdinand Roelfsema, M Femke Kruithof, Jaap van Dissel, Riny Janssen, Jan M Wit and Johannes A Romijn

Objective: STAT5b is a component of the GH signaling pathway. Recently, we described a 31-year-old male patient (height, −5.9 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-γ (IFN-γ). 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 −2.4 SDS on the highest dose of GH. In vitro, IL-12p40, IL 10, and tumour necrosis factor-α (TNF-α) 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.