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The Clinical, Immunological and Genetic Features of 12 Chinese Patients with STAT3 Mutations

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The Clinical, Immunological and Genetic Features of 12 Chinese Patients with STAT3 Mutations Lin et al. Allergy Asthma Clin Immunol (2020) 16:65 Allergy, Asthma & Clinical Immunology https://doi.org/10.1186/s13223-020-00462-w RESEARCH Open Access The clinical, immunological and genetic features of 12 Chinese patients with STAT3 mutations Li Lin1, Ying Wang1, Bijun Sun1, Luyao Liu1, Wenjing Ying1, Wenjie Wang1, Qinhua Zhou1, Jia Hou1, Haili Yao1, Liyuan Hu2*, Jinqiao Sun1* and Xiaochuan Wang1* Abstract Background: Loss-of-function (LOF) mutations in signal transducer and activator of transcription 3 (STAT3) is one of the causes of STAT3 hyperimmunoglobulin E (IgE) syndrome (STAT3-HIES), while gain-of-function (GOF) mutations in STAT3 lead to immune dysregulation diseases. We retrospectively analyzed the age, common clinical symptoms, immunologic and molecular manifestations in 11 patients with LOF STAT3 mutations and 1 patient with a GOF STAT3 mutation. Methods: Twelve patients were enrolled in our study. Serum immunoglobulin measurements, lymphocyte subset detection and whole-exome sequencing were performed. Results: The median age at diagnosis of STAT3-HIES patients was 4.74 years. Eczema, recurrent respiratory infections, fevers, abscesses and Staphylococcus aureus infections were the classic manifestations. Elevated serum IgE levels are not always observed in conjunction with high eosinophil counts. A moderate viral DNA load was also measured in peripheral blood mononuclear cells. We noticed that c. 1144C>T was the most common mutation site, followed by c.1311C>A. Additionally, c.1311C>A and c. 1826G>C are two novel mutations. Eight patients achieved notable improvement after receiving intravenous immunoglobulin. Conclusion: We updated the current knowledge of this topic. We found an earlier median age at diagnosis, a higher survival rate, and a general lack of nonimmunological abnormalities; we also described the treatment details and novel mutations involve in STAT3-HIES and compared STAT3 LOF and GOF mutations. Keywords: STAT3, Hyperimmunoglobulin E syndrome, HIES, Primary immunodefciency disease, STAT3 defciency Background (HIES). Te most current disease abbreviation is STAT3- Loss-of-function (LOF) mutations in the signal HIES [1]. STAT3-HIES was frst described as Job transducer and activator of transcription 3 (STAT3) gene syndrome in 1966, and it is characterized by eczematous constitute one of the underlying causes of the autosomal dermatitis, recurrent skin and pulmonary abscesses and dominant (AD) hyperimmunoglobulin E (IgE) syndrome elevated serum IgE levels [2–4]. Non-immunological abnormalities are bone abnormalities, retention of the primary teeth, specifc facial features and lack of growth *Correspondence: [email protected]; [email protected]; [5]. Tere is no predominant sex or ethnicity among [email protected] STAT3-HIES patients [6]. Staphylococcus aureus and 1 Department of Clinical Immunology, Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, China candidiasis are the most common pathogens [7]. In 2 Department of Neonatology, Children’s Hospital of Fudan University, 399 addition, STAT3-defcient patients are more susceptible Wanyuan Road, Shanghai 201102, China to bacterial and fungal infections and exhibit poor © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Lin et al. Allergy Asthma Clin Immunol (2020) 16:65 Page 2 of 10 control of Epstein–Barr virus (EBV) and Varicella–zoster (FITC; fuorescein isothiocyanate), anti-CD27 (APC; virus (VZV) infections [8]. allophycocyanin), anti-CD45RA (PE-Cy7), anti-TCRαβ Te use of antibiotics and the prevention of (PE; phycoerythrin) and anti-TCRγδ (BV421). Te complications are recommended as the treatment following B cell subsets were detected: anti-CD19 (APC), strategy for STAT3-HIES patients; hematopoietic stem anti-human CD24 (PE), anti-CD27 (BV450), anti-CD38 cell transplantation (HSCT) was found to be inefective (PerCP-Cy5.5) and anti-IgD (BV510) (BD Biosciences). [9]. Gain-of-function (GOF) mutations in STAT3 are Whole‑exome sequencing (WES) associated with multiorgan autoimmune disorders and WES and analysis protocols were adopted for the genetic immunodefciency. Immunosuppressive therapy and analysis. Briefy, genomic DNA was extracted from the targeted biotherapy are recommended for those patients whole blood samples of the patients and their parents. [10]. Ten, genomic DNA fragments were enriched for the Approximately 500 cases of STAT3-HIES have been target region of the consensus coding sequence exons and reported worldwide, but only 50 cases were in Chinese subsequently sequenced on the HiSeq 2000 sequencer individuals. Tere have only been two relatively large (Illumina, San Diego, CA). Te raw data were mapped cohort studies and sporadic case reports in diferent to the human genome reference sequence (hg19). areas of China [11, 12]. Herein, we describe a cohort Nucleotide changes observed in more than 5% of the of 12 Chinese patients carrying STAT3 mutations. We aligned reads were called and reviewed with NextGENe investigated their clinical, immunologic and genetic software (SoftGenetics, State College, PA). characteristics. Our description helps expand the Mutations in STAT3 were confrmed by Sanger spectrum of known STAT3 mutation diseases in diferent sequencing. DNA was extracted from the patients and ethnic groups. their relatives. Peripheral blood mononuclear cells (PBMCs) were isolated using the RelaxGene Blood DNA Methods System (Tiangen Biotech, Beijing, China) according to Patients the manufacturer’s protocol. Primers were designed to We collected data from 12 patients at the Children’s span each exon, and PCR amplifcation of STAT3 was Hospital of Fudan University from July 2017 to June carried out at 94 °C for 3 min, followed by 35 cycles at 2019. Written informed consent was obtained from all 94 °C for 30 s, 60 °C for 30 s and 72 °C for 40 s. Te fnal participants’ guardians before inclusion in the study. extension was performed at 72 °C for 10 min. Te PCR Te study was approved by the Ethics Committee of the product was sequenced in both directions by ABI Prism Children’s Hospital of Fudan University. BigDye terminators. Serum immunoglobulin and lymphocyte subset detection Statistical analysis As previously reported [13], serum IgG, IgA and IgM Te data management and statistical analysis were were determined by an automated clinical chemistry performed with GraphPad Prism 8 software (GraphPad analyzer (Erba Diagnostics, Mannheim, Germany). IgG Software, La Jolla, Calif). (Cat. No. 67731), IgA (Cat. No. 67746) and IgM (Cat. No. 67732) reagents were purchased from Orion Diagnostica Oy (Espoo, Finland). IgE reagent was purchased from Results Jing Yuan Corp. (Shanghai, China), and IgE was assessed Overview with UniCAP (Pharmacia, Uppsala, Sweden). Table 1 shows the general information of the patients. Flow cytometry was performed according to our Te 12 patients, including seven males and fve females, previously published protocol [14]. Briefy, staining were all from nonconsanguineous families. Eleven for lymphocyte surface markers was performed after patients were diagnosed with STAT3 LOF mutations, red blood cell lysis. After washing with cold phosphate and one patient (P12) was diagnosed with a STAT3 bufer solution containing 2% FBS two times, 1 104– GOF mutation. Eleven STAT3-defcient patients were 4 × 5×10 live cells were analyzed with a FACSCalibur fow diagnosed at a median age of 4.74 years (0.5–12 years cytometer (Becton–Dickinson, Franklin Lakes, NJ, USA) old), while the median age at symptom onset was using Diva software (BD Biosciences). B cells, total T 1.89 years (neonate-11.5 years old), with 5 infantile-onset cells, CD4+ T cells, CD8+ T cells and CD56+/CD16+ patients (P1, P7, P8, P10 and P11). Te age at symptom natural killer (NK) cells were detected with the BD onset in STAT3 GOF mutation patient was 13 years. All Multitest IMK Kit. T cell subsets were defned by anti- the patients were full-term, with either cesarean section human CD3 (PerCP-Cy5.5), anti-CD8 (BV510), anti-CD4 (2/12) or spontaneous (10/12) deliveries. Lin Table 1 General information of STAT3 mutation patients Asthma (2020) 16:65 ClinImmunol Allergy et al. P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 Gender Male Male Female Female Male Female Male Male Male Female Male Female Age at symptom Neonate 11.5 1 1.5 0.3 0.3 Neonate Neonate 5 Neonate Neonate 13 onset (year) Age on clinical 10 12 4.5 2.25 1.3 1.25 10 0.5 6 3.5 0.83 14 diagnosis (year) Mutation of STAT3 cDNA 1863C>G 1311C>G 1144C>T 1145G>C 1826G>C 1144C>T
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