We report a 9 year-old Chinese girl, born full term with no family history of recurrent infections or immunodeficiency. She had received hepatitis B and BCG vaccinations at birth without complications. She had multiple infections in infancy including Klebsiella pneumoniae urinary tract infection at 1 month and another two episodes of Klebsiella pneumoniae bacteremia at 2 and 10 months of age, all treated with intravenous ceftriaxone with good recovery and documented clearance. However at 10 months, after presenting with fever and a macular rash hepatosplenomegaly, she was diagnosed with extensive abdominal lymphadenopathy on CT scan. The abdominal lymph node biopsy showed granulomatous formation and sensitive Mycobacterium tuberculosis complex was cultured. The intestinal tuberculosis was treated with rifampicin, isoniazid and pyrazinamide for 12 months with resolution of abdominal lymphadenopathy. At this time, the skin biopsy was clear of mycobacterial species. Immunophenotyping and immunoglobulins levels were normal at the time (Supplementary table 1). The patient's blood was tested for IFN-gamma and IL-12 production after stimulation with BCG, BCG+IL-12 and BCG+IFN-gamma, respectively and showed a diminished production of both IFN-gamma and IL-12 after BCG+IL-12 and BCG+IFN-gamma, respectively as compared to the travel control (Supplementary table 2).
Six months after stopping anti-tuberculosis therapy, the patient had tuberculosis infection of the skin manifesting as a painful erythematous plaque with scabbed nodules over the face (lupus vulgaris) (Figure 1), elbows, shins and calves, and the skin biopsy demonstrated acid-fast bacilli, though no specific organism was cultured. Lupus vulgaris in children is very rare, and is almost exclusively due to infections by Mycobacterium tuberculosis or Mycobacterium bovis. She was commenced on isoniazid, rifampicin, pyrazinamide and clarithromycin for 15 months to cover for atypical mycobacterial organisms as well. Subcutaneous recombinant IFN-gamma (rIFN-gamma) was trialled at 20 mcg/m2 twice per week with good response. When anti-tuberculosis medications were changed to dual therapy after 12 months, there was recurrence of intestinal tuberculosis based on CT findings and granulomatous formation on lymph node biopsy (no organism cultured). Ethambutol and moxifloxacin were added to her treatment regimen with good response. These four anti-tuberculosis medications were continued for 3 years together with subcutaneous rIFN-gamma injection. Despite weaning to a very low, likely suboptimal dose of rIFN-gamma, she was free from both mycobacterial and interestingly, pyogenic infections for more than 3 years. It was at this point when a mutation in IkappaBalpha (S36Y) was diagnosed by whole exome sequencing (WES), and stem cell transplantation was offered, but declined by parents in view of stability.