Case Report
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Dec 6, 2020; 8(23): 6130-6135
Published online Dec 6, 2020. doi: 10.12998/wjcc.v8.i23.6130
Hemophagocytic lymphohistiocytosis caused by STAT1 gain-of-function mutation is not driven by interferon-γ: A case report
Nan Liu, Fen-Ying Zhao, Xiao-Jun Xu
Nan Liu, Fen-Ying Zhao, Xiao-Jun Xu, Department of Hematology-oncology, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
Author contributions: Xu XJ was the principal investigator and takes primary responsibility for the manuscript; Liu N and Zhao FY analyzed and interpreted the patient data and wrote the manuscript draft which was amended by Xu XJ; all authors read and approved the final version of the manuscript.
Informed consent statement: Written informed consent was obtained from the patient’s guardian for publication of this case report and accompanying images.
Conflict-of-interest statement: The authors declare that they have no competing interests.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xiao-Jun Xu, MD, Chief Doctor, Department of Hematology-oncology, Children’s Hospital, Zhejiang University School of Medicine, No. 57 Zhuganxiang Road, Yan-an Street, Hangzhou 310003, Zhejiang Province, China. xuxiaojun@zju.edu.cn
Received: June 28, 2020
Peer-review started: June 28, 2020
First decision: September 29, 2020
Revised: October 13, 2020
Accepted: October 27, 2020
Article in press: October 27, 2020
Published online: December 6, 2020
Processing time: 159 Days and 7.4 Hours
Abstract
BACKGROUND

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyper-inflammatory syndrome caused by many genetic defects. STAT1 is a DNA-binding factor that regulates gene transcription. HLH caused by STAT1 gain-of-function (GOF) mutations has rarely been reported and its clinical manifestations and mechanisms are not clearly defined.

CASE SUMMARY

A 2-year-old boy presented to our hospital with recurrent fever for > 20 d. The patient had a personal history of persistent oral candidiasis and inoculation site infection during the past 2 years. Hepatosplenomegaly was noted. Complete blood cell count showed severe anemia, thrombocytopenia and neutropenia. Other laboratory tests showed liver dysfunction, hypertriglyceridemia and decreased fibrinogen. Hemophagocytosis was found in the bone marrow. Chest computed tomography showed a cavitary lesion. Tests for fungal infection were positive. Serum T helper (Th) 1/Th2 cytokine determination demonstrated moderately elevated levels of interleukin (IL)-6 and IL-10 with normal interferon (IFN)-γ concentration. Mycobacterium bovis was identified in bronchoalveolar lavage fluid by polymerase chain reaction. Genetic testing identified a heterozygous mutation of c.1154C>T causing a T385M amino acid substitution in STAT1. Despite antibacterial and antifungal therapy, the febrile disease was not controlled. The signs of HLH were relieved after HLH-94 protocol administration, except fever. Fever was not resolved until he received anti-tuberculosis therapy. Hematopoietic stem cell transplantation was refused and the patient died six months later due to severe pneumonia.

CONCLUSION

Patients with STAT1 GOF mutation have broad clinical manifestations and may develop HLH. This form of HLH presents with normal IFN-γ level without cytokine storm.

Keywords: Hemophagocytic lymphohistiocytosis; Signal transducer and activator of transcription 1; Gain-of-function; Interferon gamma; Mycobacterial disease; Case report

Core Tip: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome caused by many genetic defects. Cytokine storm is frequent and interferon (IFN)-γ is considered to play a key role. We present a case of HLH caused by STAT1 gain-of-function (GOF) mutation. The cytokine profile showed moderately elevated interleukin (IL)-6 and IL-10 and normal IFN-γ. In STAT1 GOF mutation, although inhibition of IL-12R/IL-23R signaling leads to diminished T helper (Th) 1/Th17 and IL-12 response, which then prevent a cytokine storm, overactivity of phagocytic cells due to hyperphosphorylation of STAT1 can lead to HLH.