Successful Hematopoietic Stem Cell Transplantation for Autosomal Recessive STAT1 Complete Deficiency

Abstract

To the Editor: Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that mediates signal transduction via several factors, including interferon (IFN)-α/β and IFN-γ. Germline mutations in STAT1 cause the following four types of primary immunodeficiency disorders (PIDs): (1) autosomal recessive (AR) STAT1 complete deficiency, (2) AR STAT1 partial deficiency, (3) autosomal dominant (AD) STAT1 partial deficiency, and (4) STAT1 gain of function [1]. AR STAT1 complete deficiency is a rare form of PID, with only nine cases in seven families reported to date [2–6]. It is characterized by a fatal course following severe viral and mycobacterial infections based on impaired IFN-α/β and IFN-γ responses, respectively. We previously reported a case of AR STAT1 complete deficiency due to compound heterozygous intronic mutations [4]. Herein, we describe a case of successful treatment and recovery via hematopoietic stem cell transplantation (HSCT). Long-term survival has been achieved in two of four previously reported cases in which HSCT was attempted for the treatment of AR STAT1 complete deficiency [5–8]. Therefore, ours is the third case in which long-term survival was achieved following HSCT. Given its poor prognosis, this illness requires early diagnosis and HSCT. However, in our case, the patient underwent transplantation at an age more advanced than that reported previously because the diagnosis could not be established until intronic mutations were identified [4]. The detailed clinical manifestation before HSCT is described in a previous report [4]. Briefly, our patient developed Bacille Calmette-Guerin lymphadenitis, with osteomyelitis due to mycobacteria and severe viral infections since early infancy. In addition, the patient had a history of pyrexia developing approximately once per month from the age of 5 years. During or after pyrexia, cellulitis-like skin redness and pustules sometimes occurred, mainly in the extremities. However, the pathogen had never been identified by biopsy, culture investigation, or other tests, suggesting the presence of hyperinflammatory responses against unidentified infectious pathogen [8]. The patient was diagnosed AR STAT1 complete deficiency due to compound heterozygous mutations at the age of 5 years and was referred to our hospital for transplantation [4]. A whole-body CT scan and bone scintigraphy revealed mandibular osteomyelitis and associated cellulitis but no deep-seated abscess. Blood tests showed sustained increases in C-reactive protein, procalcitonin, and β-D-glucan levels. The causative bacteria of osteomyelitis were not identified; however, the involvement of atypical mycobacteria was suspected because the patient had a history of mediastinal lymphadenitis and osteomyelitis of the tibia due to Mycobacterium malmoense. Treatment with rifampicin, ethambutol, clarithromycin, fluconazole, amikacin, sulfamethoxazole-trimethoprim, and acyclovir failed to control the infections. No other obvious organ disorders were noted. Allogeneic bone marrow transplantation was performed with the consent of the parents. Antituberculous drugs were discontinued before starting conditioning for HSCT, but no obvious exacerbation of mandibular osteomyelitis was observed in the course of HSCT. * Shuhei Karakawa [email protected]