Background: GH insensitivity (GHI) syndrome caused by STAT5B mutations was recently reported, and it is characterized by extreme short stature and immune dysfunction. Treatment with recombinant human IGF1 (rhIGF1) is approved for patients with GHI, but the growth response to this therapy in patients with STAT5B mutations has not been reported. Objectives: To report the clinical features, molecular findings, and the short-term growth response to rhIGF1 therapy in patients with STAT5B mutation. Subjects and methods: Hormonal and immunological evaluations were performed in two male siblings with GHI associated with atopic eczema, interstitial lung disease, and thrombocytopenic purpura. STAT5B genes were directly sequenced. The younger sibling was treated with rhIGF1 at a dose of 110 mg/kg BID. Results: Both siblings had laboratory findings compatible with GHI associated with hyperprolactinemia. Lymphopenia and reduced number of natural killer cells without immunoglobulin abnormalities were observed. STAT5B sequence revealed a homozygous frameshift mutation (p.L142fsX161) in both siblings. The younger sibling (9.9 years of age) was treated with rhIGF1 at appropriate dosage, and he did not present any significant change in his growth velocity (from 2.3 to 3.0 cm/year after 1.5 years of therapy). The presence of a chronic illness could possibly be responsible for the poor result of rhIGF1 treatment. Further studies in patients with STAT5B defects are necessary to define the response to rhIGF1 treatment in this disorder. Conclusion: GHI associated with immune dysfunction, especially interstitial lung disease, and hyperprolactinemia is strongly suggestive of a mutation in STAT5B in both sexes.

Context and objective Growth hormone insensitivity with immune dysfunction caused by signal transducer and activator of transcription 5B (STAT5B) mutations is an autosomal recessive condition. Heterozygous mutations in other genes involved in growth regulation were previously associated with a mild height reduction. Our objective was to assess for the first time the phenotype of heterozygous STAT5B mutations. Methods We genotyped and performed clinical and laboratorial evaluations in 52 relatives of 2 previously described Brazilian brothers with homozygous STAT5B c.424_427del mutation (21 heterozygous). Additionally, we obtained height data and genotype from 1,104 adult control individuals from the same region in Brazil and identified 5 additional families harboring the same mutation (18 individuals, 11 heterozygous). Furthermore, we gathered the available height data from first-degree relatives of patients with homozygous STAT5B mutations (17 individuals from 7 families). Data from heterozygous individuals and non-carriers were compared. Results Individuals carrying heterozygous STAT5B c.424_427del mutation were 0.6 SDS shorter than their non-carrier relatives (p= 0.009). Heterozygous subjects also had significantly lower SDS for serum concentrations of IGF-1 (p=0.028) and IGFBP-3 (p=0.02) than their non-carrier relatives. The 17 heterozygous first-degree relatives of patients carrying homozygous STAT5B mutations had an average height SDS of −1.4 ± 0.8 when compared with population-matched controls (p < 0.001). Conclusions STAT5B mutations in heterozygous state have a significant negative impact on height (approximately 3.9 cm). This effect is milder than the effect seen in the homozygous state, with height usually within the normal range. Our results support the hypothesis that heterozygosity of rare pathogenic variants contributes to normal height heritability.