Genetic Basis of Patients with Bacille Calmette-Guérin Osteomyelitis in Japan: Identification of Dominant Partial Interferon-γ Receptor 1 Deficiency as a Predominant Type

Yuka Sasaki () 2 3 Akihiko Nomura 2 3 Koichi Kusuhara 2 3 Hidetoshi Takada 2 3 Saifuddin Ahmed 2 3 Kaoru Obinata 1 2 Keisuke Hamada 0 2 Yuri Okimoto 2 4 Toshiro Hara 2 3 0 Department of Pediatrics, Miyazaki Prefectural Hospital , Miyazaki 1 Department of Pediatrics, Koshigaya City Hospital , Saitama 2 Received 19 July 2001; revised 4 November 2001; electronically published 14 February 2002. Informed consent was obtained from patients, family members, or parents. Experimentation guidelines of the authors' institutions were followed in the conduct of this research. Financial support: Ministry of Education , Culture, Sports, Science , and Technology of Japan (grant 12204009). School of Medical Sciences, Kyushu University , 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 , Japan 3 Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University , Fukuoka 4 Department of Hematology/Oncology, Chiba Children's Hospital , Chiba , Japan Interferon (IFN)- g- mediated immunity plays an important role in host defense against intracellular pathogens, especially mycobacteria. Six Japanese children with bacille Calmette-Guerin (BCG) osteomyelitis were evaluated (1 disseminated, 3 multiple, and 2 solitary types) for mutations of genes involved in interleukin-12- dependent, IFN-g- mediated immunity. Heterozygous small deletions with frameshift (818del4 and 811del4) that are consistent with the diagnosis of partial dominant IFN-g receptor 1 (IFN-gR1) deficiency were detected in 3 unrelated patients. Expression of IFN-gR1 on monocytes was significantly increased in all 3 patients. Screening of family members with recurrent and disseminated mycobacterial infections found the identical deletion in 1 of the fathers. Antimycobacterial treatment was effective in these patients and resulted in good clinical outcome. This study demonstrated that partial dominant IFN-gR1 deficiency was the most common in Japanese patients who showed predisposition to curable BCG osteomyelitis. - Bacille Calmette-Guerin (BCG) osteomyelitis is a rare lateonset complication of BCG vaccination. An international survey on the complications of BCG vaccination showed that the incidence of osteomyelitis was 0.89 2.41 and 0.02 0.06 per 1 million among vaccine recipients at ages ,1 year and >1 year, respectively [1]. Only a few cases without any immunodeficiency have been reported annually in Japan, even though before age 3 years .90% of Japanese children receive multipuncture percutaneous inoculation with BCG Tokyo 172 strain, the least virulent substrain. Recently, mutations in IFNGR1 [2 4], IFNGR2 [5, 6], IL12B [7], IL12RB1 [8 10], and the signal transducer and activator of transcription 1 gene (STAT-1) [11] have been identified in humans who manifest higher susceptibility to BCG, nontuberculous mycobacteria, Mycobacterium tuberculosis, other intracellular microbes (e.g., Salmonella), Listeria monocytogenes [12], and certain viruses [13] in the absence of a known immu Patients Six unrelated patients with curable BCG osteomyelitis were investigated (table 1). All had been vaccinated with BCG in the upper arm. Unaffected family members of the 3 patients with IFNGR1 mutations were also analyzed. Patient 1. The patient developed lymphadenitis 2 months after BCG vaccination. Nine months after inoculation, she had papules and abscesses over the limbs and trunk. Radiographic studies showed multiple destructive lesions over 17 bones. Cultures from bone biopsy specimens grew M. bovis. She was treated with isoniazid, rifampicin, and streptomycin and showed slow improvement. Eighteen months after her initial presentation, she had recurrent osteomyelitis in her right femur. She is now recovering with antimycobacterial therapy. Patient 2. The patient presented with prolonged intermittent fever, lymphadenitis, and liver dysfunction 2 months after BCG inoculation. Antibiotics were not effective, but administration of isoniazid for 9 months improved his condition. Four months after discontinuation of isoniazid, he developed osteomyelitis at the left humerus and left calcaneus and was again treated with isoniazid. At age 3 years, he developed osteomyelitis of the left clavicle that healed with isoniazid therapy. Specimens were not processed or were not available for mycobacterial culture in each episode. His father (patient 20) also showed increased susceptibility to mycobacteria. Patienta 2 (BIII-3) 4 months Age at onset 1 year 5 months 1 year 7 months 1 year 7 months 2 years 2 months 4 months 1 year 5 months 3 months 1 year 9 months 11 months 1 year 4 months ND 31 years Osteomyelitis Type Multiple, recurrent Lymph nodec NOTE. ND, not determined; WBC, white blood cell. a Pedigree designations from figure 1 are indicated in parentheses for patients with IFNGR1 mutations. b Due to Mycobacterium avium complex. c Due to Mycobacterium tuberculosis. Immunologic studies CD3 cells, % He had M. tuberculosis lymphadenitis of the neck at age 3 years and bilateral inguinal lymphadenitis, which were shown by biopsy at age 23 years to be granulomatous lesions. At age 31, patient 20 developed M. avium osteomyelitis in his ribs, which subsided with antimycobacterial chemotherapy. Patient 3. The patient became spontaneously positive to the tuberculin purified protein derivative (PPD) skin test at age 11 months. There was no family history of tuberculosis. A chest radiograph showed no abnormal lesion. The PPD skin test became negative after 6 months of prophylactic treatment with isoniazid, and he was subsequently inoculated with BCG. Nine months later, he presented with claudication and limitation in rotation and anteflexion of the neck. Radiographic studies showed multiple destructive lesions over eight bones. Cultures from bone biopsy specimens grew M. bovis. He was successfully treated with isoniazid, rifampicin, and streptomycin. Patient 4. The patient presented with fever, claudication, and knee swelling 1 year after BCG vaccination. He had osteomyelitis in the distal metaphysis of the right femur. Cultures from bone curettage specimens grew M. bovis. The lesion resolved with isoniazid, rifampicin, and ethambutol treatment. Patient 5. The patient presented with claudication and knee swelling 18 months after BCG vaccination. Radiographic studies revealed lytic lesions in the left femur and tibia. Open biopsy was performed, but no organisms were isolated. The lesion improved gradually with antibiotics. Nine months after initial presentation, he was evaluated again with the same lesion. Cultures from a bone curettage specimen grew M. bovis. The lesion resolved with isoniazid, rifampicin, and ethambutol therapy. Patient 6. The patient presented with a limp, wryneck, and submandibular swelling 5 months after BCG vaccination. Radiographic studies showed multiple osteolytic lesions over 4 bones. He was treated under the tentative diagnosis of Langerhans cell histiocytosis for 8 months without improvement. Sixteen mont (...truncated)