NOVEL STAT5b GENE MUTATION IN A PATIENT PRESENTING GH INSENSITIVITY AND IMMUNODEFICIENCY

MARTÍNEZ A; SCAGLIA P; RIVAS ME; BEZRODNIK L; GAILLARD M; HEINRICH J; BALLERINI G; JASPER H; DOMENÉ H

Helsinski, Finland

Congreso; 46th Annual Meeting of the European Society for Paediatric Endocrinology (ESPE); 2007

European Society for Pediatric Endocrinology

Mouse KO model and naturally occurring mutations of STAT5b gene have demonstrated its requirement for the GH-mediated activation of the IGFI gene and normal postnatal growth. In previously described patients with STAT5b deficiency, GH insensitivity (GHI) was associated with variable degree of immunodeficiency, resulting in a broad spectrum of skin and respiratory infections. We report a female patient who presented severe cutaneous eczema associated with extreme growth retardation, gbirdh facies, micrognathia, frontal bossing, and synofrigia. She was adopted at four days of age. Birth weight 2.250 g, birth length 44 cm. In the first year of life she presented otitis media, pneumonia, and severe dermatitis associated with failure to thrive. Neurological development was normal. At 4.5 years she presented autoimmune thyroiditis, starting L-T4 treatment. Immunological evaluation revealed T lymphopenia (low CD3/CD4 and very low CD8 cell numbers), poor proliferative response after antigen stimulation, and normal B cells counts. She had a normal GH response to provocative tests (GHmax 27.1 ng/ml) and low levels of IGF-I. GHI was confirmed by a negative IGFI/ IGFBP-3 generation test. At 12.5 years of age she entered puberty, attaining a height of 121.5 cm (-5.95 SDS) at the age of 14.8 years (Tanner stage B IV, PH II). At this time IGF-I and IGFBP-3 remained extremely low: 11 ng/ml and 0.98 ƒÊg/ml, respectively. PRL level was 83 ng/ml. By sequencing the STAT5b exons encoding for both the SH2 and the DNA binding domains, a homozygous T¨C transition was found, resulting in a missense mutation at codon 646 (p.F646S), a highly conserved residue among STAT proteins. This mutation lies into the SH2 domain critical for STAT5b recruitment to the activated GHR complex, dimerization, and translocation to the nucleus. This patient confirms the crucial role of STAT5b in IGF-I production and normal postnatal growth, emphasizing the heterogeneity of clinical presentation and laboratory manifestations of the immunodeficiency, with a more consistent severe impact on linear growth.