title: Short Stature in a Boy with Multiple Early-Onset Autoimmune Conditions due to a STAT3 Activating Mutation: Could Intracellular Growth Hormone Signalling Be Compromised? .
abstract: BACKGROUND
  Germline STAT3 gain-of-function (GOF) mutations cause multiple endocrine and haematologic autoimmune disorders, lymphoproliferation, and growth impairment. As the JAK-STAT pathway is known to transduce the growth hormone (GH) signalling, and STAT3 interacts with STAT5 in growth regulation, we hypothesised that short stature in STAT3 GOF mutations results mostly from GH insensitivity via involving activation of STAT5.
  
  
  METHODS
  A boy with a novel STAT3 c.2144C>T (p.Pro715Leu) mutation presented with short stature (-2.60 SD at 5.5 years). He developed diabetes mellitus at 11 months, generalised lympho-proliferation, autoimmune thyroid disease, and immune bicytopenia in the subsequent years. At 5.5 years, his insulin-like growth factor-1 (IGF-I) was 37 µg/L (-2.22 SD) but stimulated GH was 27.7 µg/L. Both a standard IGF-I generation test (GH 0.033 mg/kg/day sc; 4 days) and a high-dose prolonged IGF-I generation test (GH 0.067 mg/kg/day sc; 14 days) failed to significantly increase IGF-I levels (37-46 and 72-87 µg/L, respectively). The boy underwent haematopoietic stem cell transplantation at 6 years due to severe neutropenia and massive lymphoproliferation, but unfortunately deceased 42 days after transplantation from reactivated generalised adenoviral infection.
  
  
  CONCLUSIONS
  Our findings confirm the effect of STAT3 GOF mutation on the downstream activation of STAT5 resulting in partial GH insensitivity.  .
authors.affiliation: Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Sediva
authors.affiliation: Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Dusatkova
authors.affiliation: Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Veronika
authors.initials: V
authors.lastname: Kanderova
authors.affiliation: Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Obermannova
authors.affiliation: Department of Immunology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Kayserova
authors.affiliation: Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Sramkova
authors.affiliation: Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Dana
authors.initials: D
authors.lastname: Zemkova
authors.affiliation: Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Elblova
authors.affiliation: Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Svaton
authors.affiliation: Department of Immunology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Radana
authors.initials: R
authors.lastname: Zachova
authors.affiliation: Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Stanislava
authors.initials: S
authors.lastname: Kolouskova
authors.affiliation: Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Fronkova
authors.affiliation: Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Sumnik
authors.affiliation: Department of Immunology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Sediva
authors.affiliation: Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Lebl
authors.affiliation: Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic.
authors.forename: Stepanka
authors.initials: S
authors.lastname: Pruhova
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D017809:Fatal Outcome; D006130:Growth Disorders / Q000235:genetics* / Q000378:metabolism; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D014427:Twins
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019382:Human Growth Hormone
keywords: Activating mutation; Growth hormone; Growth hormone sensitivity; Growth hormone signal transduction; STAT3; STAT5 ; Short stature