Published online October 9, 2006
PEDIATRICS Vol. 118 No. 5 November 2006, pp. e1584-e1592 (doi:10.1542/peds.2005-2882)

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EXPERIENCE & REASON

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

Andrea Bernasconi, PhD^a, Roxana Marino, PhD^b, Alejandra Ribas, PhD^a, Jorge Rossi, PhD^a, Marta Ciaccio, MD^b, Matías Oleastro, MD^a, Alicia Ornani, MD^a, Rubén Paz, MD^a, Marco A. Rivarola, MD^b, Marta Zelazko, MD^a and Alicia Belgorosky, MD, PhD^b

^a Immunology Service
^b Endocrinology Service, Hospital de Pediatria Garrahan, Buenos Aires, Argentina

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 CT 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 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.

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Key Words: STAT5b • STAT5b mutation • immunodeficiency • growth hormone insensitivity

Abbreviations: IL, interleukin • GH, growth hormone • JAK, Janus kinase • STAT, signal transducer and activator of transcription • GHR, growth hormone receptor • IL-2R, interleukin 2 receptor • Treg, regulatory T cell • NK, natural killer • SDS, SD score • EBV, Epstein-Barr virus • Ig, immunoglobulin • IGF-I, insulin-like growth factor I • IGFBP-3, insulin-like growth factor–binding protein 3 • FC, flow cytometry • mAb, monoclonal antibody • PBMC, peripheral blood mononuclear cell • rIL-2R, recombinant interleukin 2 receptor • MCFI, mean channel of fluorescence intensity • TCR, T-cell receptor

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Accepted Jun 13, 2006.

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