ESPE Abstracts (2014) 82 P-D-1-1-140

Severe Short Stature and GH Insensitivity Due to a De Novo Heterozygous STAT5B Missense Mutation

Jürgen Klammta, David Neumannb, Shayne F Andrewc, Marcela Drahosovab, Heike Stobbea, Kyle Buckhamc, Ron G Rosenfeldc, Roland Pfäfflea & Vivian Hwac

aHospital for Children and Adolescents, University of Leipzig, Leipzig, Germany; bDepartment of Pediatrics and Department of Clinical Immunology and Allergology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic; cDepartment of Pediatrics, CDRCP, Oregon Health and Science University, Portland, Oregon, USA

Background: GH insensitivity is caused by disturbances of GH receptor function or inability to transduce the hormone signal. Affected children are severely growth retarded and may also present immune complications when the transducer STAT5B is defective. Only autosomal-recessive STAT5B mutations have been described to date.

Clinical case: Two male 14.5 year monozygotic twins presented with heights of 131.5 cm (−5.3 SDS). Bone age of the index patient was retarded by 4.9 years. Endocrine evaluation revealed normal stimulated GH concentrations (16.2 ng/ml) but borderline IGF1 level (56 μg/l) indicative of GH resistance. rhIGF1 therapy was commenced (0.12 mg/kg twice daily). At 17.1 years his height was 149.0 cm (−4.33 SDS) and weight 42.0 kg (−3.49 SDS). Biochemical re-evaluation indicated reduced IGF1 (102.7 μg/l, −5.13 SDS) and ALS levels (418 pmol/l, normal: 986–1678); IGFBP3 (2.33 mg/l, −1.69 SDS), prolactin (290.6 mU/l, RR: 86–324), GHBP were normal. In addition to severe short stature, the proband also presented with eczema but was otherwise healthy. Immunological phenotyping was unremarkable, except IgE concentration (340.0 kU/l, normal <114). Evaluation of the twin brother yielded similar results. Molecular analysis revealed a novel heterozygous variant in the STAT5B gene (c.530A>C, exon 5; p.Gln177Pro) that was not found in the parents, suggesting a de novo germline mutation, nor was the variant listed in >6000 individuals (Exome Sequencing Project; No additional variant(s) was identified in the GH1, GHR, IGFALS, IGF1, or IGF1R genes. Functional evaluation of FLAG-STAT5Bp.Gln177Pro (HEK293 reconstitution system) indicated protein expression and GH-induced phosphorylation comparable to WT FLAG-STAT5B, but transcriptional functions were compromised as the FLAG-STAT5Bp. Gln177Pro could not translocate to the nucleus, and limited nuclear localization of the WT STAT5B.

Conclusion: We describe a novel heterozygous p.Gln177Pro STAT5B mutation with potential dominant-negative properties conferring clinical manifestations comparable to reported STAT5B deficient patients but with less severe co-morbidities.