De novo germline STAT3 mutations associated with severe IGF-I deficiency and multi-organ autoimmune disease in two unrelated patients.

SCAGLIA, PAULA; KESELMAN, ANA; GUTIERREZ, MARIANA; DOMENÉ SABINA; BLANCO, MIGUEL; SANGUINETTI, NORA; BEZRODNIK, LILIANA; DI GIOVANNI, DANIELA; CALDIROLA, MARIA SOLEDAD; MARTUCCI, LUCIA; KARABATAS, LILIANA; JONES, NANA HAWA; HWA, VIVIAN; REVALE, SANTIAGO; VAZQUEZ, MARTIN; JASPER, HECTOR; KUMAR, ASHISH; DOMENE, HORACIO

Puerto Varas

Congreso; XXV Reunión anual de la Sociedad Latinoamericana de Endocrinología; 2015

Sociedad Latinoamericana de Endocrinología

Background: Primary IGF-I deficiency with immune dysfunctionhas been associated to STAT5B inactivating mutations. Morerecently, activating mutations in the STAT3 gene have been describedin children with severe growth failure associated with aspectrum of early-onset autoimmune disease.Objective and Hypothesis: Whole Exome Sequencing (WES)approach was used to identify the affected gene, presumably amember of the GH-signaling cascade, in two unrelated patients(P1 and P2) presenting GH insensitivity associated to immunedysfunction and autoimmune disease.Methods: In P1, no STAT5B mutation was identified by Sangersequencing. WES was performed in both patients, and parents andsister of P1, using Illumina HiSeq 1500. WES findings were confirmedby Sanger sequencing in both patients.Results: P1, a 3.6 year old girl, born at term with normal weight(3155 g), presented congenital hypothyroidism, descamative eczema,chronic diarrhea, recurrent candidiasis and severe respiratoryinfections. At 3 years, she presented height ?6.0 SD, lymphocyticinterstitial pneumonia with non-necrotizing granulomas.She had normal IgG and IgM with elevated IgA and non-detectableIgE levels. Lymphocyte subset, FOXP3 and Treg CD127 were normal,but Th17 were low. She presented elevated GH (20 ng/ml),low IGF-I (20 ng/ml), normal IGFBP-3 (2.2 μg/ml) and elevatedprolactin (30.6 ng/ml) levels. After 17 months of rhGH treatment,IGF-I levels increased (240 ng/ml) with a partial recovery of height(?4.8 SD). P2, a 3 year old male (height ?5.36 SD), had a history ofIPEX-like syndrome with dermatitis, chronic diarrhea, colitis, andthyroiditis (no FOXP3 mutation). He also presented low IGF-I (57ng/ml) and normal IGFBP-3 (2.3 μg/ml). WES analysis identifiedtwo different heterozygous STAT3 variants: a private de novoc.1847_1849delAAG (p.Glu616del) in P1, and a missensec.1276T>C (p.Cys426Arg) in P2. The patients? phenotypes suggestthat the identified STAT3 variants could be activating mutations.In vitro functional characterization is required to confirm this assumption.Conclusion: Activating STAT3 mutations represent a novelmonogenic defect presenting multi-organ autoimmune disease associatedwith severe growth retardation as the result of markedIGF-I deficiency. In contrast to STAT5b deficiency, patients carryingactivating STAT3