Growth hormone insensitivity and immunodeficiency: mutation in the STAT5b gene

ADRIANA BOYANOVSKY; GRACIELA TESTA; LILIANA MUÑOZ; ROXANA MARINO; ANDREA BERNASCONI; ALEJANDRO LOZANO; ALICIA BELGOROSKY; MIRTA MIRAS

Nueva York

Encuentro; LWPES/ESPE 8th Joint Meeting Paediatric Endocrinology; 2009

LWPES/ESPE

ABSTRACT Growth hormone insensitivity (GHI) can be caused by defects in the GH receptor or in the post-receptor signaling pathway. STAT5 proteins are components of the GH and interleukin 2 family of cytokine signaling pathway. Six patients from five families with five different homozigotic mutations of the STAT5b gene have been reported to have similar phenotypes to those of patients with GHR defects, but with wild-type receptors. The reported patients, however, showed several immunological aspects with no clear genotype-phenotype linkage. We describe a new case of homozygous nonsense mutation in the gene for STAT5b with several clinical characteristics of GH insensitivity (height: -5.3 SDS) and history of inmunologycal dysfunction in a 12-year-old girl. She was born at 35 weeks with 1650 g to Argentine parents and was adopted soon after birth. The first manifestation of immunological dysfunction was a neonatal sepsis. Since her earliest months of life she presented poor weight gain, severe growth failure, and generalized eczema. Other features observed were chronic diarrea, keratitis, herpes zoster, hemorrhagic varicella, autoimmune thyroiditis, and dyshidrotic ectodermal dysplasia. She had early history of recurrent pul- monary infections developing biopsy-proven lymphoid interstitial pneumonia as chronically activated cells expression and that constitutively expressed cytotoxic T lymphocyte- associated protein4(CTLA4) indicating the concept of general functional T-cell defect in the IL-2 signaling pathway. Then the pulmonary fibrosis evolved to progressive respiratory failure and death. Serum-stimulated max GH level was 12.4 ng/ml. Serum level IGF1 0.8ng/ml (DSL IRMA-6.4SDS) was very low without response to IGF1 generation test. IGFBP3 and ALS levels were strikingly reduced. The sequencing of genomic DNA for the STAT5b gene demonstrated a single nucleotide change, a homozygous C-T transition, which resulted in a nonsense mutation at codon 152 (R152X). This mutation is the same as another one already described in an Argentine patient in the 5 exon, which encoded the coiled-col domain, very close to the NH2 terminal-domain, and determines one immunodetectable protein absence. The fact that we found the same mutation in two unrelated patients with this infrequent pathology suggests that we should consider a founding effect. In patients with these clinical characteristics and immunological alterations, possible mutations in STAT5b gene should be investigated.