Characterization of Immunodeficiency in a Patient With Growth Hormone Insensitivity Secondary to a Novel STAT5b Gene Mutation

Abstract

STAT5 proteins are components of the common growth hormone and interleukin 2 family of cytokines' signaling pathway. Mutations in the STAT5b gene, described in 2 patients, lead to growth hormone insensitivity that resembles Laron syndrome. Clinical immunodeficiency was also present, although immunologic defects have not been well characterized thus far. Here we describe a 16-year-old girl who suffered generalized eczema and recurrent infections of the skin and respiratory tract since birth. She also suffered severe chronic lung disease and multiple episodes of herpetic keratitis. Clinical features of congenital growth hormone deficiency were observed, such as persistently low growth rate, severely delayed bone age, and postnatal growth failure resulting from growth hormone resistance. This combined phenotype of growth hormone insensitivity and immunodeficiency was attributable to a homozygous C-->T transition that resulted in a nonsense mutation at codon 152 in exon 5 of the STAT5b gene. This novel mutation determined a complete absence of protein expression. The main immunologic findings were moderate T-cell lymphopenia (1274/mm3), normal CD4/CD8 ratio, and very low numbers of natural killer (18/mm3) and gammadelta T (5/mm3) cells. T cells presented a chronically hyperactivated phenotype. In vitro T-cell proliferation and interleukin 2 signaling were impaired. CD4+ and CD25+ regulatory T cells were significantly diminished, and they probably contributed to the signs of homeostatic mechanism deregulation found in this patient. This new case, in accordance with 2 previously reported cases, definitely demonstrates the significant role of the STAT5b protein in mediating growth hormone actions. Furthermore, the main immunologic findings bring about an explanation for the clinical immunodeficiency features and reveal for the first time the relevant role of STAT5b as a key protein for T-cell functions in humans.

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

“…Indeed, the elevated prolactin levels are suppressed upon IGF-I administration, in line with the inhibitory action of IGF-I on hypothalamic GHRH neurons (65). In patients with a STAT5b mutation, prolactin levels are even more elevated (52,54,66). This can be explained by the obligatory role of STAT5b in mediating the negative feedback action of prolactin on tuberoinfundibular dopamine neurons; in the absence of STAT5b, the signal transduction in the hypothalamic dopamine neurons is impaired (67).…”

“…Five patients have signs of immune deficiency. Clinically, this results in lymphoid interstitial pneumonia due to Pneumocystis carinii (52), recurrent pulmonary infections (53,77), recurrent infections of skin and respiratory tract, severe chronic lung disease, and herpetic keratitis (66). One patient suffers from juvenile idiopathic arthritis (53).…”

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

“…The JAK2-STAT5B pathway is most important for GH signaling in terms of growth and is also essential in interleukin 2 (IL2)-mediated T-cell signaling, as proven by the severe short stature due to GH insensitivity in combination with immunodeficiency in all patients except one (12) with homozygous STAT5B defects (3,4,5,13,14). The second pathway is the RAS-MAPK signaling pathway.…”

Deficiência da STAT5B: uma nova síndrome de insensibilidade ao hormônio de crescimento associada a acometimento imunológico

“…Foram descritos também dois casos de tireoidite autoimune, um caso de artrite reumatoide juvenil de início precoce (diagnóstico aos dois anos de idade) e um caso de púr-pura trombocitopênica (Tabela 1). (14). Foi sugerido também que a hipergamaglobulinemia poderia ser resultado de uma desregulação das células B secundária a um controle inadequado destas pelas células T disfuncionais (14).…”

“…(14). Foi sugerido também que a hipergamaglobulinemia poderia ser resultado de uma desregulação das células B secundária a um controle inadequado destas pelas células T disfuncionais (14).…”