A 5-month-old female infant was admitted to the First Affiliated Hospital of Shantou University Medical College due to recurring fever and productive cough for 2 weeks unresponsive to cephalosporin and penicillin in a local hospital. She was born full-term with a weight of 2.7 kg (3 < P < 10). BCG vaccine, routinely administered at birth in China, was given at 2 months of age because of meconium aspiration pneumonia after birth. She had been hospitalized locally for 7 days for generalized small papules and pustules at 4 months and recovered gradually after supportive treatment. No tuberculosis contact was noted. Her non-consanguineous parents and only older brother were all healthy. There was no family history of similar or genetic diseases. Her total white blood cell count, neutrophil count percentage, and C-reactive protein were apparently elevated along with a low to normal lymphocyte count; chest radiograph showed bilateral infiltrations (thymus shadow not mentioned) before her current admission.
On physical examination, her weight was 5.2 kg (<P1). Several enlarged axillary lymph nodes were palpable bilaterally. Her oral mucosa was intact. Coarse breath sounds and rhonchi were audible bilaterally. Throat swab was positive for parainfluenza virus (PIV) and respiratory syncytial virus (RSV) by PCR assays, while routine cerebrospinal fluid analysis/culture and blood HIV testing were all negative. Chest CT revealed bilateral parenchymal and interstitial infiltrations, multiple enlarged lymph nodes in the mediastinum and right axilla, and hypoplasia of the thymus.
The patient was treated sequentially with intravenous ceftriaxone, piperacillin/tazobactam, and vancomycin, but her symptoms were not relieved.
From her blood samples, the sequences of M. tuberculosis and P. jirovecii were mapped through next-generation sequencing. Acid-fast bacilli were found in the concentrated smears of the sputum aspirate and gastric aspirate; M. tuberculosis and P. jirovecii were not isolated after culturing. The subtypes of M. tuberculosis failed to be identified prior to antituberculosis therapy. To clarify the source of tuberculosis infection, her older brother, parents, and grandparents underwent chest X-ray examinations and purified protein derivative (PPD) skin tests, which were all negative. In addition, low numbers of T cells and natural killer (NK) cells and increased B lymphocytes from lymphocyte subset analyses confirmed T-B+NK- immunodeficiency ( Table 1 ). Subsequent gene sequencing identified two heterozygous missense mutations in the Janus homology 7 (JH7) domain of the JAK3 gene of the patient, each inherited from her parents ( Figure 1 ). The paternal mutation C.301A>G at nucleotide 301 encoded by exon 3 changed amino acid 101 from arginine to glycine (i.e., p.Arg101Gly), and the maternal mutation C.331G>A at nucleotide 331 encoded by exon 4 altered amino acid 111 from glycine to arginine (i.e., p.Gly111Arg). These two mutations were predicted to be pathogenic by Sorting intolerant from tolerant (SIFT) (both <0.05, deleterious), PolyPhen2_HVAR (paternal: 0.997, maternal: 0.992; both probably damaging), PolyPhen2_HDIV (both >0.957, probably damaging), and Rare exome variant ensemble learner (REVEL) (paternal: 0.809, maternal: 0.655; both pathogenic).
Consequently, her treatment strategy was switched to rifampicin, isoniazid, and ethambutol for tuberculosis, intravenous immunoglobulin to enhance immune functions, and further trimethoprim/sulfamethoxazole for PJP, after which improvements in symptoms (cough and fever) and lab results (e.g., decreased serum lactate dehydrogenase) were noted. After being hospitalized for 28 days, the patient improved but was discharged upon request of her parents who were satisfied with the timely diagnosis and treatment. During our follow-up, the patient continued antituberculosis treatment routinely at the assigned local tuberculosis prevention clinic and died without hematopoietic stem cell transplantation (HSCT) or autopsy at 13 months of age mainly because of severe infections in addition to hepatic injury (autopsy is culturally unacceptable and therefore uncommon in China). Her other laboratory results are shown in  Table 1 . Written informed consent for laboratory examinations and submission/publications of this work was obtained from her parents. This study was approved by the Ethics Committee of the First Affiliated Hospital of Shantou University Medical College.