Kyung Sue Shin

Prevalence of primary immunodeficiency in Korea

This study represents the first epidemiological study based on the national registry of primary immunodeficiencies (PID) in Korea. Patient data were collected from 23 major hospitals. A total of 152 patients with PID (under 19 yr of age), who were observed from 2001 to 2005, have been entered in this registry. The period prevalence of PID in Korea in 2005 is 11.25 per million children. The following frequencies were found: antibody deficiencies, 53.3% (n = 81), phagocytic disorders, 28.9% (n = 44); combined immunodeficiencies, 13.2% (n = 20); and T cell deficiencies, 4.6% (n = 7). Congenital agammaglobulinemia (n = 21) and selective IgA deficiency (n = 21) were the most frequently reported antibody deficiency. Other reported deficiencies were common variable immunodeficiencies (n = 16), X-linked agammaglobulinemia (n = 15), IgG subclass deficiency (n = 4). Phagocytic disorder was mostly chronic granulomatous disease. A small number of patients with Wiskott-Aldrich syndrome, hyper-IgE syndrome, and severe combined immunodeficiency were also registered. Overall, the most common first manifestation was pneumonia. This study provides data that permit a more accurate estimation PID patients in Korea.

Sonographic Growth Charts for Kidney Length in Normal Korean Children: A Prospective Observational Study

Kidney length is the most useful parameter for clinical measurement of kidney size, and is useful to distinguish acute kidney injury from chronic kidney disease. In this prospective observational study of 437 normal children aged between 0 and < 13 years, kidney length was measured using sonography. There were good correlations between kidney length and somatic values, including age, weight, height, and body surface area. The rapid growth of height during the first 2 years of life was intimately associated with a similar increase in kidney length, suggesting that height should be considered an important factor correlating with kidney length. Based on our findings, the following regression equation for the reference values of bilateral kidney length for Korean children was obtained: kidney length of the right kidney (cm) = 0.051 × height (cm) + 2.102; kidney length of the left kidney (cm) = 0.051 × height (cm) + 2.280. This equation may aid in the diagnosis of various kidney disorders.

Chronic Granulomatous Disease on Jeju Island, Korea

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 p22 phox ). 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.

Long-term outcome of patients with p22 phox - deficient chronic granulomatous disease on Jeju Island, Korea

Purpose This study investigated the long-term clinical outcomes of patients with p22phox-deficient chronic granulomatous disease (CGD) on Jeju Island and retrospectively evaluated the effects of interferon-gamma (IFN-γ) prophylaxis. Methods The medical records of 15 patients with CGD were retrospectively reviewed. The efficacy of IFN-γ prophylaxis was evaluated by comparing the frequency of severe infections before and after starting continuous prophylaxis with IFN-γ. Results At the time of the analysis, 14 patients were alive, with a median age of 14.3 years. The diagnosis of CGD was made at a median age of 2.4 years, and the median age at onset of severe infection was 0.3 years. Thirteen of the 15 patients had their first severe infection within the first year of life. The overall incidence of severe infection was 1.36 infections per patient-year; pneumonia, suppurative lymphadenitis, and skin and subcutaneous abscesses were the most common infections. Aspergillus species were the most frequently isolated microorganisms, present in 15.8% of isolates. IFN-γ did not significantly change the rate of severe infection. The survival rate for patients after 2 years of age was 93%; there was a prolonged survival plateau beyond the age of 2. Conclusion Compared with cases of X-linked CGD reported in other studies, patients with CGD on Jeju Island did not show obviously different clinical manifestations, but they had a significantly higher survival rate. Further studies with a substantially longer period of observation, and with more patients under intensive surveillance are necessary to elucidate the prophylactic efficiency of IFN-γ.

New method for detection of p22-phox-deficient chronic granulomatous disease heterozygote carriers in Jeju

Chronic granulomatous disease (CGD) is a genetically heterogeneous disease caused by defects in the genes encoding any one of the NADPH oxidase components. The estimated prevalence of CGD is between 1 in 200,000 and 1 in 250,000 individuals, with variable rates in different countries. According to a compilation by the Korean College of Pediatric Clinical Immunology, the prevalence of CGD in Korea is 0.9 in 1,000,000 individuals. Surprisingly, the prevalence of CGD in Jeju Island is 20.7 in 1,000,000 individuals. We reported an identical homozygous single-base substitution of C to T in exon 1 (c.7C > T) of the CYBA gene from 12 CGD patients in Jeju Island. We hypothesized that the high prevalence of CGD in Jeju Island is associated with an identical mutation inherited from a common ancestor or proband. The aim of this study was to develop an assay to detect heterozygote carriers of the genotype specific to Jeju Island. We developed three specific primers, and nested polymerase chain reaction was employed using whole blood samples as a source of genomic DNA. Using the new detection method, 704 individuals were tested, 9 of which were detected as carriers, and the expected number of carriers is 1.3 in 100 individuals.

Genetic analysis of CYBB gene in 26 korean families with X-linked chronic granulomatous disease

Chronic granulomatous disease (CGD) is a rare hereditary disorder that is characterized by a greatly increased susceptibility to life-threatening bacterial and fungal infections. CGD is caused by mutations in any one of the genes encoding subunits of phagocyte NADPH oxidase. X-linked CGD, more than half of all CGD cases, is caused by mutations in CYBB gene encoding gp91-phox subunit. We identified the mutations in the CYBB gene of 29 Korean patients with X-linked CGD from 26 unrelated families. Twenty-three mutations were identified: five splice site mutations (c.45 + 1G > C, c.141 + 5G > A, c.897 + 2T > C c.1461 + 1G > T, c.1586 + 2T > A), four frameshift mutations (c.27dupG, [c.737A > C; c.742delA], c.742dupA, c.1636 del C), seven non-sense mutations (c217C > T, c.469C > T, c.676C > T, c.868C > T, c.1222G > T, c.1272G > A, c.1281T > A), five missense mutations (c.164 C > A, c.422T > C, c.665 A > G, c.1012C > T, c.1461G > T) and two gross deletions. Eight out of 23 mutations identified in this study are novel mutations: two splice mutations(c.897 + 2T > C, c.1586 + 2T > A), two frame shift mutations ([c.737A > C; c.742delA], c.1636 del C), two nonsense mutations (c.1222G > T, c.1281T > A), one missense mutation (c.1461G > T), one gross deletion (c.1667_1629 del.). Our results confirmed that mutations of CYBB gene in the X-CGD are very heterogeneous and not show the peculiarity of the ethnic group.

Erratum to: Development of a lentiviral vector and an efficient infection method for gene therapy for p22phoxdefective chronic granulomatous disease

Chronic granulomatous disease (CGD) is caused by impaired antimicrobial activity in phagocytes due to the absence or malfunction of the respiratory burst NADPH oxidase. In a previous study, we found that 12 patients from 10 unrelated families on Jeju Island had an identical homozygous single-base C-to-T substitution in exon 1 (c.7C > T) of CYBA, which encodes p22phox. Autosomal recessive p22phox-defective CGD carrierderived white blood cells were efficiently transduced by the elongation factor 1-alpha lentivirus constructs, as up to 90% of cells were green fluorescent protein (eGFP)-positive at 3 days post-transduction. pLL3.7-driven eGFP expression was stable for at least 4 weeks after transduction and persisted after CGD carrierderived cells were immortalized by human telomerase reverse transcriptase (hTERT) and B lymphoma Mo-MLV insertion region 1 (Bmi-1). Upon macrophage-like differentiation of the transduced HL-60 cells by dimethyl sulfoxide, up to 28% of the cells had higher mean levels of superoxide production than undifferentiated cells, and lentivirus efficiently transduced cells and induced the expression of genes for extended periods.