A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings

Abstract

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.

Impaired natural killer cell functions in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations

“…In particular, there is evidence in STAT5b-deficient and, to lower extent, STAT5a-deficient animals that the number of NK cells is reduced 37 and that children carrying STAT5b mutations display severe immunologic dysfunctions characterized by moderate lymphopenia and NK cytolytic activity defect. 38,39 Although STAT5 expression was normal in NK cells from patients with STAT1 GOF mutations, the extent of STAT5 phosphorylation in response to IL-2 or IL-15 was significantly reduced, suggesting that abnormal functioning of the STAT1 pathway might affect the cellular response of NK cells to these cytokines. In fact, we have observed in NK cells from a patient with a STAT1 GOF mutation that lower levels of STAT5 phosphorylation in response to IL-15 are associated with impaired upregulation of STAT5 binding to IL2RA, a gene strictly dependent on STAT5.…”

Novel inactivating mutations in the GH secretagogue receptor gene in patients with constitutional delay of growth and puberty

“…Therefore, we hypothesize that in the presence of GHSR mutations, there is a decrease in ghrelin-mediated appetite, resulting in relatively low BMI, which contributes to the delayed onset of puberty. Furthermore, delayed puberty is observed in clinical conditions associated with low IGF1 (41,42), suggesting that IGF1 also exerts stimulatory, synergistic, or permissive effects on the onset of puberty (43). Thus, low IGF1 levels due to a decrease in GH secretion caused by GHSR1a haploinsufficiency may also negatively modulate the timing of puberty onset.…”

Deficiência da STAT5B: uma nova síndrome de insensibilidade ao hormônio de crescimento associada a acometimento imunológico

“…Dos dez pacientes descritos até o momento, dois são irmãos nascidos na cidade de Criciúma -Santa Catarina (13). Os pais dos meninos, heterozigotos para a mutação identificada nos filhos (c.424_427del), negam consanguinidade e, mesmo após revisão da genealogia de ambas as famílias por três gerações, não foram observados laços entre as famílias materna e paterna.…”

“…O diagnóstico (confirmado por biópsia pulmonar em alguns pacientes e presuntivo em outros) foi de pneumonite intersticial linfocítica, uma patologia de etiologia desconhecida, rara em crianças e frequentemente associada a doenças autoimunes. Essa doença causa fibrose pulmonar progressiva, sendo que duas pacientes faleceram por insuficiência respiratória e um foi submetido a transplante pulmonar, até o momento com boa evolução (13). Outras manifestações relatadas foram varicela grave/hemorrágica em seis pacientes e eczema grave em outros sete.…”

“…Em pessoas com IGH causada por mutações no GHR, essa terapia já foi avaliada e um dos estudos, envolvendo 76 indivíduos tratados, mostrou um incremento mediano na velocidade de crescimento do primeiro ano de tratamento de 5,3 cm/ano (16). No entanto, nos dois irmãos brasileiros foi tentada a terapia com rhI-GF-1 e não se notou melhora do padrão de crescimento, possivelmente pelo estado de doença crônica (13).…”