Genetic Analysis of 10 Unrelated Korean Families with p22-phoxdeficient Chronic Granulomatous Disease: An Unusually Identical Mutation of the CYBA Gene on Jeju Island, Korea

김영미,남재국,조문재,신경수,박지은,김진영,임희경 대한의학회 2009 Journal of Korean medical science Vol.24 No.6

Chronic granulomatous disease (CGD) is a rare hereditary disorder characterized by recurrent life-threatening bacterial and fungal infections. The underlying defect in CGD is an inability of phagocytes to produce reactive oxygen species as a result of defects in NADPH oxidase. Considering that CGD generally affects about 3-4 in 1,000,000 individuals, it is surprising that the prevalence of CGD on Jeju Island is 20.7 in 1,000,000 individuals. We performed genetic analysis on 12 patients from 10 unrelated families and found that all patients had an identical homozygous single- base substitution of C to T in exon 1 (c.7C>T) of the CYBA gene, which was expected to result in a nonsense mutation (p.Q3X). Because Jeju Island has long been a geologically isolated region, the high prevalence of CGD on Jeju Island is presumably associated with an identical mutation inherited from a common ancestor or proband.

비결핵항산균 폐질환으로 오인되었던 사르코이드증

최현호 ( Hyun Ho Choi ),홍유아 ( Yu Ah Hong ),최재기 ( Jae Ki Choi ),김주상 ( Ju Sang Kim ),김승준 ( Seung Joon Kim ),김석찬 ( Seok Chan Kim ),이숙영 ( Sook Young Lee ),김영균 ( Young Kyoon Kim ),박성학 ( Sung Hak Park ),김태정 ( 대한결핵 및 호흡기학회 2009 Tuberculosis and Respiratory Diseases Vol.66 No.4

There are several respiratory diseases that show chronic granulomatous inflammation for the histologic finding. Among them, sarcoidosis and tuberculosis are not easy to differentiate when the clinical and radiological features present similar patterns. The increasing incidence of nontuberculous mycobacteria pulmonary disease is making it more difficult for clinicians to arrive at a proper diagnosis. A 69 year old male patient visited our hospital with chronic cough as his chief compliant. His radiologic findings were multiple enlarged mediastinal lymphadenpathies with innumerable micronodules and multiple patch infiltrations. The spleen biopsy finding showed chronic granulomatous inflammation, and Mycobacterium avium was identified on the bronchoscopic culture. Because of these findings, we treated him with drugs for nontuberculous mycobacteria disease other than sarcoidosis. However, during the treatment, his symptoms and radiological features became aggravated. Thus, we reviewed the radiologic and pathologic findings and decided to treat him with steroid, which relieved his symptoms and improved the radiologic findings. We report here on a case of sarcoidosis that was initially misdiagnosed as nontuberculous mycobacteria pulmonary disease.

Genetic Analysis of 10 Unrelated Korean Families with p22-phox-deficient Chronic Granulomatous Disease: An Unusually Identical Mutation of the <i>CYBA</i> Gene on Jeju Island, Korea

Kim, Young Mee,Park, Ji Eun,Kim, Jin Young,Lim, Hee Kyung,Nam, Jae Kook,Cho, Moonjae,Shin, Kyung-Sue The Korean Academy of Medical Sciences 2009 JOURNAL OF KOREAN MEDICAL SCIENCE Vol.24 No.6

<P>Chronic granulomatous disease (CGD) is a rare hereditary disorder characterized by recurrent life-threatening bacterial and fungal infections. The underlying defect in CGD is an inability of phagocytes to produce reactive oxygen species as a result of defects in NADPH oxidase. Considering that CGD generally affects about 3-4 in 1,000,000 individuals, it is surprising that the prevalence of CGD on Jeju Island is 20.7 in 1,000,000 individuals. We performed genetic analysis on 12 patients from 10 unrelated families and found that all patients had an identical homozygous single-base substitution of C to T in exon 1 (c.7C>T) of the <I>CYBA</I> gene, which was expected to result in a nonsense mutation (p.Q3X). Because Jeju Island has long been a geologically isolated region, the high prevalence of CGD on Jeju Island is presumably associated with an identical mutation inherited from a common ancestor or proband.</P>

Bone Marrow Involvement in Relapsed Sarcoidosis: A Case Report

이정민 대한진단검사의학회 2021 Laboratory Medicine Online Vol.11 No.3

Sarcoidosis can involve multiple organs and is characterized by non-caseating granuloma on biopsy, which is not pathognomonic of this disease. Therefore, diagnosis requires exclusion of other causes of granuloma, including malignant neoplasm, infections, autoimmune diseases, drug exposure, environmental causes, lymphoma, and tuberculosis. Herein, we present a rare case of a patient with a primary manifestation of sarcoidosis, with typical bilateral hilar adenopathy, and recurrence in the bone marrow. A 50-year-old female patient, who had been diagnosed with sarcoidosis at age 38, was admitted for petechia on both legs and pancytopenia. The patient was concluded to be “highly probable” for sarcoidosis, with at least 90% likelihood, according to the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) organ assessment instrument. Moreover, the patient had a bone marrow biopsy positive for granulomatous inflammation. Hence, all findings supported the diagnosis of sarcoidosis. Because sarcoidosis is difficult to definitively diagnose, it will be useful to better understand the application, interpretation, and limitations of the WASOG instrument for bone marrow involvement assessment.

만성육아종질환 환자에서 합병된 식도 폐쇄 사례 -만성육아종질환의 육아종성 식도 폐쇄

김지수,황진솔,최영훈,김우선,김중곤,Kim, Ji Soo,Hwang, Jinsol,Choi, Young Hun,Kim, Woo Sun,Kim, Joong Gon 대한소아감염학회 2014 Pediatric Infection and Vaccine Vol.21 No.1

CGD 환자에서는 면역 체계의 결함으로 인한 반복적인 감염과 육아종 형성이 특징적이다. CGD 환자에서 육아종의 형성에 의한 식도 폐쇄는 매우 드문 합병증 중 하나로 CGD 환자의 육아종 형성에 의한 식도 폐쇄의 치료에 대해서는 불현성 감염이 동반될 가능성이 있어 스테로이드 치료와 항생제 치료에 대한 논란이 있어왔다. 저자들은 항생제 치료에 반응하지 않는 육아종 형성에 의한 식도 폐쇄 증상을 보인 8세 만성육아종질환 환자를 보고하는 바이다. 환자는 스테로이드 치료 이후에 임상적 증상과 영상 검사 상의 급격한 호전을 보였으나 스테로이드 치료를 중단한 지 한 달 뒤 환자의 식도 폐쇄 증상은 재발하였고, 이는 스테로이드를 재 투약 후 호전되었다. 스테로이드 중단 이후 한 차례 다시 재발하였으나, 항생제 치료 후 호전되었고 이후 추가적 재발 없이 경과 관찰 중이다. Chronic granulomatous disease (CGD) is an inherited immunodeficient disease characterized by recurrent infections and granuloma formation. Granulomatous obstruction of esophagus is one of the rare complications of CGD. The use of steroids and antimicrobials for esophageal obstruction by granuloma in CGD patients has been controversial due to the possibility of concomitant inapparent infection. We report a case of esophageal obstruction in an 8-year-old CGD patient showing the poor response to antibiotics therapy. However, dramatic improvement of symptoms and radiologic findings of esophageal obstruction were achieved after steroid therapy. One month after discontinuation of steroid, esophageal obstruction recurred and the patient was re-treated with steroid. After that time, he experienced one more recurrence of esophageal obstruction. This symptom subsided after antibiotics therapy without steroid and he has been followed up to the present without further relapse.

2`7`-dichlorofluoroscein diacetate 를 사용하여 유세포분석법으로 진단된 반성유전 만성육아종성 질환 2 례

이정주(Jung Joo Lee),심정연(Jung Yeon Shim),홍수종(Soo Jong Hong),박찬정(Chan Jeoung Park),지현숙(Hyun Sook Chi) 대한소아알레르기호흡기학회 1997 소아알레르기 및 호흡기학회지 Vol.7 No.1

Chronic granulomatous disease is a group of rare X-linked or autosomal recessive genetic disorders due to the NADPH oxidase defect, which causes the defect in neutrophil respiratory burst function, the recurrent bacterial and fungal infection, and the granulomatous lesion. This disease can be diagnosed by measuring the decreased neutrophil respiratory burst activity in patient who shows X-linked recessive or autosomal recessive inheritance and the recurrent infection. To measure the neutrophil respiratory burst activity, NBT(nitroblue tetrazolium dye) test has been used. Recently, it has become possible to diagnose the chronic granulomatous disease patient as well as the carrier simply and rapidly with the flow cytometry which measures hydrogen peroxide within the neutrophil, using 2 7 dichlorofluorescein diacetate(DCF-DA). We diagnosed two boys with history of recurrent infections and their carrier mothers as X-linked chronic granulomatous disease by flow cytometry using DCF-DA, and could follow up neutrophil respiratory burst activity after the administration of interferon gamma(INF-γ) to these patients.

Rapid Determination of Chimerism Status Using Dihydrorhodamine Assay in a Patient with X-linked Chronic Granulomatous Disease Following Hematopoietic Stem Cell Transplantation

김현영,김희진,기창석,김대원,유건희,강은숙 대한진단검사의학회 2013 Annals of Laboratory Medicine Vol.33 No.4

Chronic granulomatous disease (CGD) is a rare genetic disease, which is caused by defects in the NADPH oxidase complex (gp91phox, p22phox, p40phox, p47phox, and p67phox) of phagocytes. This defect results in impaired production of superoxide anions and other reactive oxygen species (ROS), which are necessary for killing bacterial and fungal microorganisms and leads to recurrent, life-threatening bacterial and fungal infections and granulomatous inflammation. The dihydrorhodamine (DHR) flow cytometry assay is a useful diagnostic tool for CGD that can detect absent or reduced NADPH oxidase activity in stimulated phagocytes. We report a patient with X-linked CGD carrying a novel mutation of the CYBB gene whose chimerism status following hematopoietic stem cell transplantation (HSCT) has been rapidly determined using the DHR assay. The level of DHR activity correlates well with short tandem repeat PCR analysis. Considering the advantages of this simple,rapid, and cost-effective procedure, serial measurement of DHR assay would facilitate the rapid determination of a patient’s engraftment status, as a supplementary monitoring tool of chimerism status following HSCT.

Chronic Granulomatous Disease on Jeju Island, Korea

Moonjae Cho,Kyung-Sue Shin 대한의학유전학회 2013 대한의학유전학회지 Vol.10 No.1

Chronic granulomatous disease (CGD) is a rare inherited disorder of a defective NADPH oxidase enzyme, resulting in very low or no production of superoxide and subsequent reactive oxygen species. Consequently, patients with CGD are highly susceptible to severe bacterial and fungal infections. CGD is a genetically heterogeneous disease caused by defects in any one of the genes encoding the NADPH oxidase components. CGD generally affects about 3-4 per 1,000,000 individuals; thus, it is surprising that the prevalence of CGD on Jeju Island is 34.3 per 1,000,000 individuals. At present, 20 patients with CGD from 14 unrelated families on Jeju Island have been identified; nine males and 11 females. All patients with CGD tested on Jeju Island had an identical and homozygous mutation (c.7C>T in CYBA, p.Q3X in p22phox). Therefore, all patients were autosomal recessive form of CGD. This strongly suggests that the unique and identical mutation in CYBA may be inherited from a common proband. Using mutation-specific primers to detect the mutated allele in CYBA, the frequency of subjects carrying a mutated allele was 1.3% of enrolled subjects from Seogwipo City. Further studies are necessary to elucidate how frequently this mutant allele occurs in the population on Jeju Island. Additionally, it is important to construct a national registry system to understand the pathophysiology of CGD and develop a strategy for long-term therapy.

Chronic Granulomatous Disease on Jeju Island, Korea

조문제,신경수 대한의학유전학회 2013 대한의학유전학회지 Vol.10 No.1

Chronic granulomatous disease (CGD) is a rare inherited disorder of a defective NADPH oxidase enzyme, resulting in very low or no production of superoxide and subsequent reactive oxygen species. Consequently, patients with CGD are highly susceptible to severe bacterial and fungal infections. CGD is a genetically heterogeneous disease caused by defects in any one of the genes encoding the NADPH oxidase components. CGD generally affects about 3-4 per 1,000,000 individuals;thus, it is surprising that the prevalence of CGD on Jeju Island is 34.3 per 1,000,000 individuals. At present, 20 patients with CGD from 14 unrelated families on Jeju Island have been identified; nine males and 11 females. All patients with CGD tested on Jeju Island had an identical and homozygous mutation (c.7C>T in CYBA, p.Q3X in p22phox). Therefore, all patients were autosomal recessive form of CGD. This strongly suggests that the unique and identical mutation in CYBA may be inherited from a common proband. Using mutation-specific primers to detect the mutated allele in CYBA, the frequency of subjects carrying a mutated allele was 1.3% of enrolled subjects from Seogwipo City. Further studies are necessary to elucidate how frequently this mutant allele occurs in the population on Jeju Island. Additionally, it is important to construct a national registry system to understand the pathophysiology of CGD and develop a strategy for long-term therapy.

만성육아종질환 환자 단핵구에서 TNF-α 자극에 의한 IL-8과 IL-10의 발현 양상

신경수,Shin, Kyung-Sue 대한소아청소년과학회 2008 Clinical and Experimental Pediatrics (CEP) Vol.51 No.10

목적: 만성 육아종 질환은 백혈구 내에서 반응성 산소 대사물을 생성하는 효소인 NADPH oxidase의 유전적인 결함으로 인하여 반복적이고 치명적인 세균 감염과 진균 감염이 발생되는 유전성 면역 결핍 질환이다. 만성적인 염증 상태의 원인과 염증성 육아종 형성의 기전은 잘 알려져 있지 않으나 만성육아종질환의 염증 조절 부전과 관련이 있을 것으로 생각된다. 본 연구는 만성육아종질환 환자의 단핵구에서 $TNF-{\alpha}$의 자극으로 발현되는 IL-8과 IL-10을 측정하여 염증성 시토카인과 항염증성 시토카인의 발현 양상과 만성육아종질환 환자의 만성적인 염증 상태와의 관련성을 알아보고자 하였다. 방법: 만성 육아종 질환 환자 8명과 건강 대조군 10명의 말초 혈액에서 magnet cell isolation kit를 이용하여 단핵구를 분리하고, $TNF-{\alpha}$ (10 ng/mL)로 6시간 동안 자극한 후 실시간 정량적 중합효소 연쇄반응과 ELISA법으로 IL-8과 IL-10의 발현 정도를 측정하였고, 건강 대조군의 단핵구에 항산화제를 전처리한 후 $TNF-{\alpha}$로 자극하여 IL-8과 IL-10의 발현 정도를 측정하였다. 결 과: 만성육아종질환 환자에서 $TNF-{\alpha}$ 자극에 의한 IL-8의 발현 양상은 건강 대조군과 달리 최고 발현치가 60분 정도 늦게 관찰되었고, IL-8의 발현도 자극 시간이 경과하여도 지속되었다. 그리고 건강 대조군의 단핵구에 항산화제를 처리하여 만성육아종질환과 유사한 조건하에서 IL-8을 측정하였을 때 항산화제를 처리한 군에서 처리하지 않은 대조군에 비하여 IL-8의 발현이 증가하였고, catalase와 apocynin을 처리한 군에서 DPI를 처리한 군보다 IL-8의 발현이 증가하였다. $TNF-{\alpha}$ 자극에 의한 IL-10의 발현도 IL-8의 발현 양상과 유사하게 지연 반응과 과발현이 관찰되었다. 그러나 건강 대조군의 단핵구에 항산화제를 처리하였을 때의 IL-10 발현은 처리하지 않은 군과 큰 차이를 보이지 않았다. 결 론: 만성육아종질환 환자의 단핵구에서 $TNF-{\alpha}$ 자극에 의하여 염증성 시토카인인 IL-8과 항염증성 시토카인인 IL-10의 지연 반응과 과발현이 동시에 관찰되었으며, 건강 대조군의 단핵구에 항산화제를 처리하였을 때 IL-8의 발현 증가가 관찰되었다. 이는 만성육아종질환의 만성 염증 상태가 시토카인의 생성 조절의 부전과 연관이 있고, NADPH oxidase의 결함에 의한 반응성 산소대사물의 생성 부전과도 연관되어 있음을 알 수 있다. Purpose : Patients with chronic granulomatous disease (CGD) have genetic mutations in a component of the NADPH oxidase enzyme that is necessary for the generation of the superoxide anion. The profound defect in innate immunity is reflected by the patients susceptibility to catalase-positive bacteria and fungi. In addition, CGD patients display signs of persistent inflammation, which is not associated only with deficient superoxide anion production. The aim of this study was to elucidate the cytokine responses in CGD patients after $TNF-{\alpha}$ stimulation. Methods : Heparinized blood samples were collected from 8 CGD patients and 10 healthy volunteers. Monocytes ($1{\times}10^6cell/well$) isolated by the magnet cell isolation system were incubated with a constant amount of $TNF-{\alpha}$ (10 ng/mL) at $37^{\circ}C$ for 6 h. Incubated cells were harvested at 60-min intervals for IL-8 and IL-10 mRNA analysis, and the supernatant was collected at the same intervals to determine IL-8 and IL-10 expression. Monocytes from healthy volunteers were also incubated with antioxidants followed by $TNF-{\alpha}$ stimulation for IL-8 and IL-10 expression. Results : In CGD patients, a high expression of IL-8 together with a significantly higher IL-10 expression than in the healthy controls was seen after $TNF-{\alpha}$ stimulation. Moreover, normal monocytes treated with antioxidants exhibited increased IL-8 responses. Conclusion : The absence of phagocyte-derived reactive oxidants in CGD might be associated with a dysregulated production of pro- and antiinflammatory cytokines. Additional research related to reactive oxidants is needed to clarify the role of cytokines in CGD patients.