Short Stature in a Boy with Multiple Early-Onset Autoimmune Conditions due to a <b><i>STAT3</i></b> Activating Mutation: Could Intracellular Growth Hormone Signalling Be Compromised?

Abstract

Background: Germline STAT3 gain-of-function (GOF) mutations cause multiple endocrine and haematologic autoimmune disorders, lymphoproliferation, and growth impairment. As the JAK-STAT pathway is known to transduce the growth hormone (GH) signalling, and STAT3 interacts with STAT5 in growth regulation, we hypothesised that short stature in STAT3 GOF mutations results mostly from GH insensitivity via involving activation of STAT5. Case Report: A boy with a novel STAT3 c.2144C>T (p.Pro715Leu) mutation presented with short stature (–2.60 SD at 5.5 years). He developed diabetes mellitus at 11 months, generalised lympho­proliferation, autoimmune thyroid disease, and immune bicytopenia in the subsequent years. At 5.5 years, his insulin-like growth factor-1 (IGF-I) was 37 µg/L (–2.22 SD) but stimulated GH was 27.7 µg/L. Both a standard IGF-I generation test (GH 0.033 mg/kg/day sc; 4 days) and a high-dose prolonged IGF-I generation test (GH 0.067 mg/kg/day sc; 14 days) failed to significantly increase IGF-I levels (37–46 and 72–87 µg/L, respectively). The boy underwent haematopoietic stem cell transplantation at 6 years due to severe neutropenia and massive lymphoproliferation, but unfortunately deceased 42 days after transplantation from reactivated generalised adenoviral infection. Conclusions: Our findings confirm the effect of STAT3 GOF mutation on the downstream activation of STAT5 resulting in partial GH insensitivity.

Partial growth hormone insensitivity and dysregulatory immune disease associated with de novo germline activating STAT3 mutations

“…However, short stature is a key clinical finding in these patients. To our knowledge, 15 out of 22 reported patients with available growth data (Flanagan et al, 2014; Haapaniemi et al, 2015; Milner et al, 2015; Sediva et al, 2017; Velayos et al, 2017; Weinreich et al, 2017) (~68%, including our patients) had growth impairment (Supplementary Table 4 and Supplementary Fig. 2) and our in vitro studies suggest a disruptive role of STAT3 GOF variants in the GH signaling pathway.…”

“…Unfortunately, SCT was also unsuccessful in two out of three other patients, who succumbed shortly after the procedure (Haapaniemi et al, 2015; Milner et al, 2015; Sediva et al, 2017). This suggests that other therapeutic approaches, such as specific small-molecule STAT3 inhibitors, are perhaps more appropriate therapies for these patients.…”

Case Report: Signal Transducer and Activator of Transcription 3 Gain-of-Function and Spectrin Deficiency: A Life-Threatening Case of Severe Hemolytic Anemia

“…Patients with STAT3 GOF mutations can have very heterogeneous clinical and immunological disease features ( 12 ). Most patients present within the first year of life with lymphoproliferation, autoimmune organ disease (especially endocrine disease), autoimmune cytopenias and growth impairment ( 8 ). The STAT3 P715L mutation we identified has been associated with enhanced transcriptional activation, according to luciferase reporter assays previously conducted ( 12 , 13 ).…”

“…In spite of the hyperactivated profile associated with the mutation, our case can be considered an atypical presentation of STAT3 GOF, as suggested by delayed onset, mild lymphoproliferation, hypogammaglobulinemia and cytopenia evident as isolated hemolytic anemia. Notably, even though splenomegaly, lymphoproliferation and cytopenia were described in most patients with this condition, hypogammaglobulinemia was not a predominant feature ( 8 ). Additionally, our patient displayed highly positive direct Coombs test, but no other autoimmune markers were found.…”

“…In light of the patient’s clinical presentation, laboratory findings, and poor response to first- and second-line treatments of AIHA, the patient was suspected of having a Primary Immune Regulatory Disorder. Given this suspicion, whole exome sequencing (WES) for immune dysregulation-associated genes analyses were performed, revealing a de novo heterozygous germline STAT3 mutation (c.2144C>T, p.P715L), previously reported as a GOF mutation ( 8 ). Cytokine analysis showed increased IL-17A and IL-10 serum levels ( Table 1 ).…”