ESPE Abstracts

Background: Homozygous mutations in STAT5B result in GH insensitivity and immune dysfunction. Heterozygous dominant negative mutations have not been described.

Aims and objectives: To characterize genomic STAT5B DNA in two families exhibiting short stature.

Methods: Sanger sequencing of STAT5B from genomic DNA. Mutant STAT5B constructs were expressed in HEK293 cells.

Results: Family 1: The index case grew at −2.9S.D. from the age of 2 years. Investigations revealed IGF1 <25 ng/ml, IGFBP3 1.29 ng/ml (NR0.8–3.9), prolactin 265–65 3 mU/l (NR59-271), GH-peak (glucagon test) 17.3 μg/l, and normal GH-peaks on overnight sampling. A standard and extended 3-step IGF1-generation test (2 weeks GH sc at 0.7, 1.4 and 2.4; mg/m² per day) showed a poor response. His brother had short stature (−2.9S.D.), mild speech delay, eczema, undetectable IGF1, a GH peak of 13.9 μg/l and poor response in the IGF1-generation test. Both brothers had elevated IgE concentrations. Family histories were positive for short stature, eczema and transient hyperprolactinaemia. A heterozygous missense variant c.1433C>T (p.Ala478Val) was identified within the conserved STAT5B DNA-binding domain, and segregated with the phenotype. Family 2: Male monozygotic twins presented at age 14 years with short stature (−5.3SDS), eczema and a history of mild respiratory infections. Investigations revealed a provoked GH peak of 16.2 μg/l, low IGF1 (56 μg/l) and elevated IgE concentrations. rhIGF1 therapy led to modest catch-up growth. A de novo heterozygous variant (c.530A>C; p.Gln177Pro) was identified. Neither of the STAT5B variants are listed in control databases. Functional evaluation of the FLAG-STAT5B mutants indicated normal protein expression and phosphorylation but severely compromised nuclear translocation and transcriptional function compared to WT. Both variants inhibited translocation and transcription activity of WT FLAG-STAT5B, suggesting a dominant-negative mode of action.

Conclusion: This is the first description of dominant-negative STAT5B mutations in subjects with short stature and mild GH insensitivity. Eczema may also be related to impaired STAT5B function.