Atypical hemolytic uremic syndrome: Korean pediatric series
Jiwon M. Lee
Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea
Search for more papers by this authorYoung Seo Park
Department of Pediatrics, Asan Medical Center, University of Ulsan, Seoul, Korea
Search for more papers by this authorJoo Hoon Lee
Department of Pediatrics, Asan Medical Center, University of Ulsan, Seoul, Korea
Search for more papers by this authorSe Jin Park
Department of Pediatrics, Ajou University School of Medicine, Suwon, Korea
Search for more papers by this authorJae Il Shin
Department of Pediatrics, Severance Children's Hospital, Yonsei University, Seoul, Korea
Search for more papers by this authorYong-Hoon Park
Department of Pediatrics, Yeungnam University College of Medicine, Daegu, Korea
Search for more papers by this authorKee Hwan Yoo
Department of Pediatrics, Korea University Guro Hospital, Seoul, Korea
Search for more papers by this authorMin Hyun Cho
Department of Pediatrics, Kyungpook National University Hospital, Daegu, Korea
Search for more papers by this authorSu-Young Kim
Department of Pediatrics, Pusan National University Children's Hospital, Yangsan, Korea
Search for more papers by this authorSeong Heon Kim
Department of Pediatrics, Pusan National University Children's Hospital, Yangsan, Korea
Search for more papers by this authorMee Kyung Namgoong
Department of Pediatrics, Wonju College of Medicine, Yonsei University, Wonju, Korea
Search for more papers by this authorSeung Joo Lee
Department of Pediatrics, Ehwa University Mokdong Hospital, Seoul, Korea
Search for more papers by this authorJun Ho Lee
Department of Pediatrics, Bundang CHA Hospital, Seongnam, Korea
Search for more papers by this authorHee Yeon Cho
Department of Pediatrics, Samsung Medical Center, Seoul, Korea
Search for more papers by this authorKyoung Hee Han
Department of Pediatrics, Jeju University Hospital, Jeju, Korea
Search for more papers by this authorHee Gyung Kang
Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea
Research Coordination Center for Rare Diseases, Seoul National University Hospital, Seoul, Korea
Search for more papers by this authorIl Soo Ha
Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea
Search for more papers by this authorJun-Seok Bae
Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea
Search for more papers by this authorNayoung K. D. Kim
Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
Search for more papers by this authorWoong-Yang Park
Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
Sungkyunkwan University School of Medicine, Seoul, Korea
Search for more papers by this authorCorresponding Author
Hae Il Cheong
Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea
Research Coordination Center for Rare Diseases, Seoul National University Hospital, Seoul, Korea
Kidney Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
Correspondence: Hae Il Cheong, MD PhD, Department of Pediatrics, Seoul National University Children's Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea. Email [email protected]Search for more papers by this authorJiwon M. Lee
Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea
Search for more papers by this authorYoung Seo Park
Department of Pediatrics, Asan Medical Center, University of Ulsan, Seoul, Korea
Search for more papers by this authorJoo Hoon Lee
Department of Pediatrics, Asan Medical Center, University of Ulsan, Seoul, Korea
Search for more papers by this authorSe Jin Park
Department of Pediatrics, Ajou University School of Medicine, Suwon, Korea
Search for more papers by this authorJae Il Shin
Department of Pediatrics, Severance Children's Hospital, Yonsei University, Seoul, Korea
Search for more papers by this authorYong-Hoon Park
Department of Pediatrics, Yeungnam University College of Medicine, Daegu, Korea
Search for more papers by this authorKee Hwan Yoo
Department of Pediatrics, Korea University Guro Hospital, Seoul, Korea
Search for more papers by this authorMin Hyun Cho
Department of Pediatrics, Kyungpook National University Hospital, Daegu, Korea
Search for more papers by this authorSu-Young Kim
Department of Pediatrics, Pusan National University Children's Hospital, Yangsan, Korea
Search for more papers by this authorSeong Heon Kim
Department of Pediatrics, Pusan National University Children's Hospital, Yangsan, Korea
Search for more papers by this authorMee Kyung Namgoong
Department of Pediatrics, Wonju College of Medicine, Yonsei University, Wonju, Korea
Search for more papers by this authorSeung Joo Lee
Department of Pediatrics, Ehwa University Mokdong Hospital, Seoul, Korea
Search for more papers by this authorJun Ho Lee
Department of Pediatrics, Bundang CHA Hospital, Seongnam, Korea
Search for more papers by this authorHee Yeon Cho
Department of Pediatrics, Samsung Medical Center, Seoul, Korea
Search for more papers by this authorKyoung Hee Han
Department of Pediatrics, Jeju University Hospital, Jeju, Korea
Search for more papers by this authorHee Gyung Kang
Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea
Research Coordination Center for Rare Diseases, Seoul National University Hospital, Seoul, Korea
Search for more papers by this authorIl Soo Ha
Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea
Search for more papers by this authorJun-Seok Bae
Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea
Search for more papers by this authorNayoung K. D. Kim
Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
Search for more papers by this authorWoong-Yang Park
Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
Sungkyunkwan University School of Medicine, Seoul, Korea
Search for more papers by this authorCorresponding Author
Hae Il Cheong
Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea
Research Coordination Center for Rare Diseases, Seoul National University Hospital, Seoul, Korea
Kidney Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
Correspondence: Hae Il Cheong, MD PhD, Department of Pediatrics, Seoul National University Children's Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Korea. Email [email protected]Search for more papers by this authorAbstract
Background
Atypical hemolytic uremic syndrome (aHUS) is a rare disease with a genetic predisposition. Few studies have evaluated the disease in the Asian population. We studied a Korean pediatric cohort to delineate the clinical characteristics and genotypes.
Methods
A multicenter cohort of 51 Korean children with aHUS was screened for mutations using targeted exome sequencing covering 46 complement related genes. Anti-complement-factor-H autoantibody (anti-CFH) titers were measured. Multiplex ligation-dependent probe amplification assay was performed to detect deletions in the complement factor-H related protein genes (CFHR) in the patients as well as in 100 healthy Korean controls. We grouped the patients according to etiology and compared the clinical features using Mann–Whitney U-test and chi-squared test.
Results
Fifteen patients (group A, 29.7%) had anti-CFH, and mutations were detected in 11 (group B, 21.6%), including one with combined mutations. The remaining 25 (group C, 49.0%) were negative for both. The prevalence of anti-CFH was higher than the worldwide level. Group A had a higher onset age than group B, although the difference was not significant. Group B had the worst renal outcome. Gene frequencies of homozygous CFHR1 deletion were 73.3%, 2.7% and 1% in group A, group B + C and the control, respectively.
Conclusions
The incidence of anti-CFH in the present Korean aHUS cohort was high. Clinical outcomes largely conformed to the previous reports. Although the sample size was limited, this cohort provides a reassessment of clinicogenetic features of aHUS in Korean children.
Supporting Information
| Filename | Description |
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| ped12549-sup-0001-si.doc140.5 KB |
Table S1 List of 46 genes included in the targeted exome sequencing. Table S2 Other genetic variations detected by targeted exome sequencing and in silico tools for prediction. Table S3 In silico tools for functional prediction of the genetic variations. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1 Mele C, Remuzzi G, Noris M. Hemolytic uremic syndrome. Semin. Immunopathol. 2014; 36: 399–420.
- 2 Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N. Engl. J. Med. 2009; 361: 1676–1687.
- 3 Karpman D, Tati R. Complement activation in thrombotic microangiopathy. Hamostaseologie 2013; 33: 96–104.
- 4 Kavanagh D, Goodship TH, Richards A. Atypical hemolytic uremic syndrome. Semin. Nephrol. 2013; 33: 508–530.
- 5 Ruggenenti P, Noris M, Remuzzi G. Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int. 2001; 60: 831–846.
- 6 Joseph C, Gattineni J. Complement disorders and hemolytic uremic syndrome. Curr. Opin. Pediatr. 2013; 25: 209–215.
- 7 Kavanagh D, Goodship TH. Atypical hemolytic uremic syndrome. Curr. Opin. Hematol. 2010; 17: 432–438.
- 8 Dragon-Durey MA, Loirat C, Cloarec S et al. Anti-factor H autoantibodies associated with atypical hemolytic uremic syndrome. J. Am. Soc. Nephrol. 2005; 16: 555–563.
- 9 Delvaeye M, Noris M, De Vriese A et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N. Engl. J. Med. 2009; 361: 345–357.
- 10 Lemaire M, Fremeaux-Bacchi V, Schaefer F et al. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat. Genet. 2013; 45: 531–536.
- 11 Bu F, Maga T, Meyer NC et al. Comprehensive genetic analysis of complement and coagulation genes in atypical hemolytic uremic syndrome. J. Am. Soc. Nephrol. 2014; 25: 55–64.
- 12 Bresin E, Rurali E, Caprioli J et al. Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype. J. Am. Soc. Nephrol. 2013; 24: 475–486.
- 13 Geerdink LM, Westra D, van Wijk JA et al. Atypical hemolytic uremic syndrome in children: Complement mutations and clinical characteristics. Pediatr. Nephrol. 2012; 27: 1283–1291.
- 14 Warwicker P, Goodship TH, Donne RL et al. Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int. 1998; 53: 836–844.
- 15 Caprioli J, Castelletti F, Bucchioni S et al. Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: The C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease. Hum. Mol. Genet. 2003; 12: 3385–3395.
- 16 Caprioli J, Noris M, Brioschi S et al. Genetics of HUS: The impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 2006; 108: 1267–1279.
- 17 Roumenina LT, Jablonski M, Hue C et al. Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome. Blood 2009; 114: 2837–2845.
- 18 Noris M, Brioschi S, Caprioli J et al. Familial haemolytic uraemic syndrome and an MCP mutation. Lancet 2003; 362: 1542–1547.
- 19 Fremeaux-Bacchi V, Miller EC, Liszewski MK et al. Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood 2008; 112: 4948–4952.
- 20 Sadler JE. Thrombomodulin structure and function. Thromb. Haemost. 1997; 78: 392–395.
- 21 Jozsi M, Licht C, Strobel S et al. Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. Blood 2008; 111: 1512–1514.
- 22 Zipfel PF, Edey M, Heinen S et al. Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome. PLoS Genet. 2007; 3: e41.
- 23 Moore I, Strain L, Pappworth I et al. Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome. Blood 2010; 115: 379–387.
- 24 Dragon-Durey MA, Blanc C, Marliot F et al. The high frequency of complement factor H related CFHR1 gene deletion is restricted to specific subgroups of patients with atypical haemolytic uraemic syndrome. J. Med. Genet. 2009; 46: 447–450.
- 25 Abarrategui-Garrido C, Martinez-Barricarte R, Lopez-Trascasa M, de Cordoba SR, Sanchez-Corral P. Characterization of complement factor H-related (CFHR) proteins in plasma reveals novel genetic variations of CFHR1 associated with atypical hemolytic uremic syndrome. Blood 2009; 114: 4261–4271.
- 26 Burchard EG, Ziv E, Coyle N et al. The importance of race and ethnic background in biomedical research and clinical practice. N. Engl. J. Med. 2003; 348: 1170–1175.
- 27 Terrell DR, Vesely SK, Kremer Hovinga JA, Lammle B, George JN. Different disparities of gender and race among the thrombotic thrombocytopenic purpura and hemolytic-uremic syndromes. Am. J. Hematol. 2010; 85: 844–847.
- 28 Lee BH, Kwak SH, Shin JI et al. Atypical hemolytic uremic syndrome associated with complement factor H autoantibodies and CFHR1/CFHR3 deficiency. Pediatric. Res. 2009; 66: 336–340.
- 29 Cheong HI et al. Attempted treatment of factor H deficiency by liver transplantation. Pediatr. Nephrol. 2004; 19: 454–458.
- 30 Cho HY, Lee BS, Moon KC, Ha IS, Cheong HI, Choi Y. Complete factor H deficiency-associated atypical hemolytic uremic syndrome in a neonate. Pediatr. Nephrol. 2007; 22: 874–880.
- 31 Jung S, Kang ES, Ki CS, Kim DW, Paik KH, Chang YS. Successful therapeutic plasma exchange in a 3.2-kg body weight neonate with atypical hemolytic uremic syndrome. J. Clin. Apher. 2011; 26: 162–165.
- 32 Sinha A, Gulati A, Saini S et al. Prompt plasma exchanges and immunosuppressive treatment improves the outcomes of anti-factor H autoantibody-associated hemolytic uremic syndrome in children. Kidney Int. 2014; 85: 1151–1160.
- 33 Hofer J, Janecke AR, Zimmerhackl LB et al. Complement factor H-related protein 1 deficiency and factor H antibodies in pediatric patients with atypical hemolytic uremic syndrome. Clin. J. Am. Soc. Nephrol. 2013; 8: 407–415.
- 34 Fremeaux-Bacchi V, Fakhouri F, Garnier A et al. Genetics and outcome of atypical hemolytic uremic syndrome: A nationwide French series comparing children and adults. Clin. J. Am. Soc. Nephrol. 2013; 8: 554–562.
- 35 Noris M, Caprioli J, Bresin E et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin. J. Am. Soc. Nephrol. 2010; 5: 1844–1859.
- 36 Dragon-Durey MA, Blanc C, Garnier A, Hofer J, Sethi SK, Zimmerhackl LB. Anti-factor H autoantibody-associated hemolytic uremic syndrome: Review of literature of the autoimmune form of HUS. Semin. Thromb. Hemost. 2010; 36: 633–640.
- 37 Dragon-Durey MA, Sethi SK, Bagga A et al. Clinical features of anti-factor H autoantibody-associated hemolytic uremic syndrome. J. Am. Soc. Nephrol. 2010; 21: 2180–2187.
- 38 Bienaime F, Dragon-Durey MA, Regnier CH et al. Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome. Kidney Int. 2010; 77: 339–349.
- 39 Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA et al. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J. Am. Soc. Nephrol. 2007; 18: 2392–2400.
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