Growth hormone (GH) insensitivity syndrome (GHIS) is a rare clinical condition in which production of insulin-like growth factor 1 is blunted and, consequently, postnatal growth impaired. Autosomal-recessive mutations in signal transducer and activator of transcription (STAT5B), the key signal transducer for GH, cause severe GHIS with additional characteristics of immune and, often fatal, pulmonary complications. Here we report dominant-negative, inactivating STAT5B germline mutations in patients with growth failure, eczema, and elevated IgE but without severe immune and pulmonary problems. These STAT5B missense mutants are robustly tyrosine phosphorylated upon stimulation, but are unable to nuclear localize, or fail to bind canonical STAT5B DNA response elements. Importantly, each variant retains the ability to dimerize with wild-type STAT5B, disrupting the normal transcriptional functions of wild-type STAT5B. We conclude that these STAT5B variants exert dominant-negative effects through distinct pathomechanisms, manifesting in milder clinical GHIS with general sparing of the immune system.

Center for the Study of Rare Hereditary Diseases Niguarda Ca' Granda Metropolitan Hospital Milan Italy

Centre for Endocrinology William Harvey Research Institute Queen Mary University of London 1st Floor North John Vane Building Charterhouse Square London EC1M 6BQ UK

Department of Clinical Immunology and Allergology Faculty of Medicine University Hospital Hradec Kralove Charles University Prague 500 05 Hradec Kralove Czech Republic

Department of Molecular Microbiology and Immunology Oregon Health and Science University 3181 SW Sam Jackson Park Rd Portland OR 97239 USA

Department of Pediatric Endocrinology Royal London Children's Hospital Barts Health NHS Trust Whitechapel Road London E1 1 BB UK

Department of Pediatrics Faculty of Medicine University Hospital Hradec Kralove Charles University Prague 500 05 Hradec Kralove Czech Republic

Department of Pediatrics Oregon Health and Science University Portland OR USA

Department of Women's and Child Health University Hospital Leipzig Liebigstrasse 20a 04103 Leipzig Germany

Division of Endocrinology 240 Albert Sabin Way Cincinnati Children's Hospital Medical Center University of Cincinnati College of Medicine Cincinnati OH 45229 USA

Institute of Clinical Biochemistry Faculty of Medicine Catholic University and IRCCS Policlinico Agostino Gemelli Largo Francesco Vito 1 1 00168 Rome Italy

Mercy Kids Pediatric Endocrinology and Diabetes Mercy Children's Hospital and Mercy Clinic 1965 S Fremont Suite 260 Springfield MO 65804 USA

Section of Genetics and Epigenetics in Health and Disease Genetics and Genomic Medicine Programme University College London Great Ormond Street Institute of Child Health 30 Guilford Street London WC1N 1EH UK

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Monogenic causes of familial short stature

Analysis of children with familial short stature: who should be indicated for genetic testing?