X-linked chronic granulomatous disease misdiagnosed as non-Langerhans cell histiocytosis: A case report.

Abstract

To the Editor, Chronic granulomatous disease (CGD) is a rare primary immune deficiency caused by a defect in the phagocyte nicotinamide adenine dinucleotide phosphate oxidase enzyme complex and is X-linked recessive or autosomal recessive (AR) inherited.1 X-linked CGD is found most commonly in outbred populations, while AR-CGD is more common in areas with high consanguinity. In children, the hallmark clinical manifestation of CGD is a severe life-threatening bacterial or fungal infection, especially caused by catalase-positive organisms or Aspergillus species and also from complications due to the Bacillus Calmette-Guérin (BCG) vaccination in developing countries.2 However, granulomas consisting of lymphocytes and histiocytes may develop instead of overt pyogenic infections when stalemates occur between the pathogen and the CGD patient's leucocytes.3 Although typical clinical manifestations combined with small gene panel analysis or next-generation sequencing can provide relatively rapid and accurate diagnoses of CGD in children, there has been a lag between onset and diagnosis of CGD, especially in developing countries.2 Histiocytic disorders are a group of highly heterogeneous diseases in terms of clinical manifestation and histocytomorphology.4 Biopsy is mandatory for the diagnosis or differential diagnosis of each subgroup in histiocytic disorders, but sometimes, histology is not specific for the disease. Here, we report an interesting case of an X-linked CGD patient misdiagnosed with non-Langerhans cell histiocytosis who underwent inappropriate chemotherapy for 1 month. We make the points that clinicians should pay extreme attention to a patient's medical history to gain clues for diagnosing CGD and CGD patients can present with isolated bone granuloma showing CD68 and CD163 expression, which is easily misdiagnosed as histiocytic disorders. A 6-year-old boy visited our outpatient department for a painful mass on his left distal radius lasting 1 month without any symptoms of infection. Before he came to our hospital, he had a surgical biopsy of the radius at another hospital. We observed the plaster fixation of his left forearm without any other remarkable findings on physical examination. From his previous discharge record, we knew that the mass was hard and caused severe pain. It measured approximately 4 × 4 cm without red swelling or fever of the skin. Enhanced magnetic resonance imaging of the left wrist joint showed that the bone of the left distal radius was destroyed with increased T2 signal and the mass was obviously enhanced. Radius biopsy revealed a granuloma with a large number of monocytes, neutrophils, and lymphocytes and a few plasma cells and eosinophils infiltrated. Immunohistochemical staining showed that CD68 and CD163 were positive, while CD1a, Langerin and S-100 were negative. The BRAF-V600E mutation and tuberculosis DNA fragments were not detected in the sample. In our hospital, X-ray of his left radius showed punched-out like bone destruction (Figure 1A). Chest computed tomography (CT) found scattered nodules and diffuse interstitial changes with local honeycomb cystic lesions (Figure 1B). He had no cough, polypnea, cyanosis or other respiratory symptoms. Complete blood count, C-reactive protein, erythrocyte sedimentation rate, liver function and kidney function were all normal. His parents had no similar symptoms, and his elder brother (14 years old) and sister (19 years old) were both healthy. In the absence of CD1a or Langerin expression in the lesion, we diagnosed him with non-Langerhans cell histiocytosis and it was still not clear which histiocytosis group our patient belonged to. After being treated with a chemotherapy regimen of vinblastine and prednisone for 1 month, the pain in his left radius was relieved, but his surgical incision was still poorly healed. The patient also had a persistent fever and his left ankle became swollen with pain and purulent exudation. The patient was admitted to the inpatient department of our hospital. His abdomen was distended with obvious hepatosplenomegaly. Serratia marcescens and Salmonella enteritidis were found in cultures of the purulent exudation and blood, respectively. Retrospectively, we knew the patient had previously suffered twice from tuberculosis, a cervical lymph node abscess, a perianal abscess and multiple fungal infections by inquiring past medical history, which cured by anti-infection and surgical treatment. Molecular analysis revealed the patient harboured a pathogenic mutation of c.483 + 1 (IVS5) G > T in the cytochrome B-245 beta chain (CYBB) gene (PVS1 + PS1 + PM2 + PP3), inherited from his mother (Figure 1C), which has been proven pathogenic in the ClinVar database. His elder sister had the same mutation in CYBB (Figure 1C), and the gene analysis of his elder brother was not finished because he was not a suitable donor. His mother and sister had recurrent oral ulcers. Taken together, X-linked CGD due to a pathogenic CYBB mutation was unequivocally proven. After effective control of the infections with ceftriaxone and vancomycin for 29 days, the patient's condition improved and so far, he is still waiting for a suitable donor for an allogeneic hematopoietic stem cell transplantation without infection again. Infections and inflammatory complications are the main clinical manifestations of CGD patients. Aspergillus, Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia, Nocardia and Salmonella spp. are the most frequent pathogens cultured from CGD patients.5 Recently, a retrospective study of 48 Chinese CGD patients found that 4% of patients with bone infection and complications due to BCG vaccination were particularly prevalent.2 In this case, the patient first came to our hospital because of a painful mass in his left distal radius at 6 years of age instead of a pyogenic infection in a common site. We did not know he had previously suffered several times from pneumonia (including tuberculosis and multiple fungal infections), a lymph node abscess and a perianal abscess because we had a limited understanding of his medical history due to a short time in the outpatient department. These were the main reasons of failure to consider CGD at first. Finally, the patient also was infected with Serratia marcescens and Salmonella enteritidis which is consistent with the above common pathogens cultured from CGD patients. However, when stalemates occur between the pathogen and CGD patient's leucocytes, chronic inflammatory cell reactions and granulomas may develop instead of overt pyogenic infections.3 CGD granulomas are typically non-caseating, but there is little data regarding biopsies from granulomas. It has been found the CGD granulomas can appear in the brain, lungs, liver, spleen and gastrointestinal tract of patients, but are rarely found in the skeletal system.6 The findings from our patient show that CGD granuloma can occur in isolated bone, presenting as a painful mass without red swelling or fever of the local tissue. Our patient had no symptoms of infection, and inflammation-related indexes were normal. Imaging examination revealed obvious bone destruction and an enhanced mass. Moreover, the CGD granulomas expressed CD68 and CD163. Based on the above characteristics, it is easy to be misdiagnosed with histiocytosis. In addition to recurrent and severe infections, inflammatory complications are commonly seen in CGD patients, affecting almost 90% of patients.7 The most commonly affected organs were the gastrointestinal tract, lungs, urogenital tract and eyes. Our patient had no symptoms of inflammatory complications due to his young age; therefore, it is necessary to follow him up. Female carriers of X-linked CGD may experience discoid lupus erythematosus, photosensitivity rashes, inflammatory bowel disease and other autoimmune phenomena.8 In this case, the patient's mother and older sister are X-linked CGD carriers and they experienced recurrent oral ulcers. CGD diagnosis should be considered in all patients who present with recurrent severe catalase-positive organisms or Aspergillus species infection, or early-onset inflammatory bowel disease. The diagnosis of CGD can be made by measuring the cellular level of phagocytic leucocytes. However, identifying a pathogenic genetic mutation is an essential next step to offer genetic advice, perform a prenatal diagnosis, and for choosing a suitable bone marrow donor. The survival of patients with CGD is strongly associated with residual superoxide production instead of the specific gene affected.9 Antimicrobial prophylaxis, the advent of azole antifungals, and interferon prophylaxis have considerably improved the survival of CGD patients.10 To date, hematopoietic stem cell transplantation is still the only curative treatment. In recent years, gene therapy has been examined in clinical trials, but results have not been encouraging. In conclusion, it is important to correctly recognize clinical features of CGD, to establish the diagnosis confirmed by genetic evidence for suitable blood donor and to adequately control any infections in preparation for transplantation for the clinicians. We learned from our patient that a sufficient understanding of the patient's medical history is very important for making an accurate diagnosis of CGD. Moreover, CGD patients can present with isolated bone granuloma containing CD68 and CD163 expression. The authors declare that they have no relevant conflicts of interest.