ESPE Abstracts (2015) 84 P-1-93

aCentro de Investigaciones Endocrinológicas ‘Dr César Bergadá’ (CEDIE) CONICET – FEI – División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina; bEndocrinología, Hospital Universitario Austral, Buenos Aires, Argentina; cInmunología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina; dDivision of BM transplantation and Immunodeficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; eDivision of Endocrinology, Cincinnati Center for Growth Disorders, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; fInstituto de Agrobiotecnología de Rosario (INDEAR), CONICET, Rosario, Argentina

Background: Primary IGF1 deficiency can result from molecular defects in genes encoding for the GHR, IGF1, 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 IGF1 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 years, 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 HiSDefault 1500. P1: elevated GH (20 ng/ml), low IGF1 (20 ng/ml), normal IGFBP3 (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 IGF1 deficiency. In contrast to STAT5b deficiency, patients carrying activating STAT3 mutations appear to preserve partial GH responsiveness.

Funding: This work was supported by grants from the Agencia Nacional de Promoción Científica y Tecnológica (PICT-2010 Nro.1916), and SANDOZ International GmbH, Business Unit Biopharmaceuticals.

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