CEDIE   05498
CENTRO DE INVESTIGACIONES ENDOCRINOLOGICAS "DR. CESAR BERGADA"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Severe IGFI deficiency and multiorgan autoimmune disease associated with novel germline STAT3 mutations
Autor/es:
PAULA SCAGLIA; ANA KESELMAN; MARIANA GUTIÉRREZ; SABINA DOMENÉ; MIGUEL BLANCO; NORA SANGUINETTI; LILIANA BEZRODNIK; DANIELA DI GIOVANNI; MARÍA SOLEDAD CALDIROLA; LUCIA MARTUCCI; LILIANA KARABATAS; ASHISH KUMAR ; NANA-HAWA JONES ; VIVIAN HWA; SANTIAGO REVALE ; MARTÍN VÁZQUEZ ; HÉCTOR JASPER; HORACIO DOMENÉ
Lugar:
Barcelona
Reunión:
Congreso; 54th Annual Meeting of the European Society for Paediatric Endocrinology (ESPE).; 2015
Institución organizadora:
European Society for Pediatric Endocrinology
Resumen:
Background: Primary IGF-I deficiency can result from molecular defects in genes encoding for the GHR, IGF-I, STAT5b and ALS. Heterozygous, activating mutations in the STAT3 gene have been recently described in children with severe growth failure associated with a spectrum of early-onset autoimmune disease.Case Presentation: We report the molecular diagnosis in two unrelated patients with severe growth failure and IGF-I deficiency: P1, a 3.6 year old girl, born at term with normal weight (3155 g). She presented congenital hypothyroidism, descamative eczema, chronic diarrhea, recurrent candidiasis and severe respiratory infections. At 3 years, she presented height -6.0 SD, lymphocytic interstitial pneumonia with no-necrotizing granulomas. She had normal IgG and IgM with elevated IgA and no-detectable IgE levels. Lymphocyte subset was normal, presenting normal FOXP3 and Treg CD127, but low Th17. P2, a male, 6 yr, height SD of -5.36, who had a history of IPEX-like syndrome with dermatitis, chronic diarrhea, colitis, and thyroiditis (FOXP3 mutation negative). Whole-exome sequencing (WES) was performed on both patients, and parents and sister of P1, using Illumina HiSeq 1500. P1: elevated GH (20 ng/ml), low IGF-I (20 ng/ml), normal IGFBP-3 (2.2 µg/ml) and elevated prolactin (30.6 ng/ml) levels were noted. After 17 months of rhGH treatment IGF-I increased (240 ng/ml) with a partial recovery of height (-4.8 SD). WES analysis identified private heterozygous de novo STAT3 variants as candidate variants: c.1847_1849delAAG (p.Glu616del) in P1, and a missense p.Cys426Arg, in P2. Both variants are predicted to be activating, since inactivating STAT3 mutations are associated with hyper-IgE syndrome without growth failure.Conclusion: Activating STAT3 mutations represent a novel monogenic defect presenting multi-organ autoimmune disease associated with severe growth retardation as the result of marked IGF-I deficiency. In contrast to STAT5b deficiency, patients carrying activating STAT3 mutations appear to preserve partial GH responsiveness