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; Sociedad Latinoamericana de Endocrinologia Pediatrica; 2015

Background: Primary IGF-I deficiency with immune dysfunction has been associated to STAT5B inactivating mutations. More recently, activating mutations in the STAT3 gene have been described in children with severe growth failure associated with a spectrum of early-onset autoimmune disease.Objective and hypothesis: Whole Exome Sequencing (WES) approach was used to identify the affected gene, presumably a member of the GH-signaling cascade, in two unrelated patients (P1 and P2) presenting GH insensitivity associated to immune dysfunction and autoimmune disease. Methods: In P1, no STAT5B mutation was identified by Sanger sequencing. WES was performed in both patients, and parents and sister of P1, using Illumina HiSeq 1500. WES findings were confirmed by 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 respiratory infections. At 3 years, she presented height -6.0 SD, lymphocytic interstitial pneumonia with non-necrotizing granulomas. She had normal IgG and IgM with elevated IgA and non-detectable IgE 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 elevated prolactin (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 of IPEX-like syndrome with dermatitis, chronic diarrhea, colitis, and thyroiditis (no FOXP3 mutation). He also presented low IGF-I (57 ng/ml) and normal IGFBP-3 (2.3 µg/ml). WES analysis identified two different heterozygous STAT3 variants: a private de novo c.1847_1849delAAG (p.Glu616del) in P1, and a missense c.1276T>C (p.Cys426Arg) in P2. The patients´ phenotypes suggest that the identified STAT3 variants could be activating mutations. In vitro functional characterization is required to confirm this assumption. 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.