Pediatric Nephrology

, Volume 22, Issue 6, pp 874–880 | Cite as

Complete factor H deficiency-associated atypical hemolytic uremic syndrome in a neonate

  • Hee Yeon Cho
  • Byong Sop Lee
  • Kyung Chul Moon
  • Il Soo Ha
  • Hae Il Cheong
  • Yong Choi
Original Article


Recent advances have shown that atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation. Almost 50% of cases are associated with mutations in the three complement regulatory genes, factor H (HF1), membrane co-factor protein (MCP) and factor I (IF). The corresponding gene products act in concert and affect the same enzyme, alternative pathway convertase C3bBb, which initiates the alternative pathway and amplification of the complement system. Factor H (FH) deficiency-associated aHUS usually occurs in infants to middle-aged adults and only rarely in neonates. Moreover, the vast majority of patients are heterozygous for the HF1 gene mutations. We report on a case of neonatal-onset aHUS associated with complete FH deficiency due to novel compound heterozygous mutations in the HF1 gene. A 22-day-old baby girl developed acute renal failure and a remarkably low serum complement C3 level, which was rapidly followed by the development of micro-angiopathic hemolytic anemia. Western blot analysis revealed nearly zero plasma FH levels, and an HF1 gene study showed compound heterozygous mutations, C1077W/Q1139X. Renal pathology findings were compatible with glomerular involvement in HUS. The baby recovered completely after the repetitive infusion of fresh frozen plasma. During follow-up (until she was 20 months old) after the initial plasma therapy, the disease recurred three times; twice after the tapering off of plasma therapy, and once during a weekly plasma infusion. All recurrence episodes were preceded by an upper respiratory tract infection, and were successfully managed by restarting or increasing the frequency of plasma therapy.


Factor H deficiency Atypical hemolytic uremic syndrome Plasma therapy Neonate 


  1. 1.
    Ruggenenti P, Noris M, Remuzzi G (2001) Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int 60:831–846PubMedCrossRefGoogle Scholar
  2. 2.
    Kavanagh D, Goodship THJ, Richards A (2006) Atypical haemolytic uraemic syndrome. Br Med Bull 77–78:5–22PubMedCrossRefGoogle Scholar
  3. 3.
    Noris M, Remuzzi G (2005) Non-Shiga toxin-associated hemolytic uremic syndrome. In: Zipfel PF (ed) Complement and kidney disease. Birkhäuser, pp 65–83Google Scholar
  4. 4.
    Warwicker P, Goodship THJ, Donne RL, Pirson Y, Nicholls A, Ward RM, Turnpenny P, Goodship JA (1998) Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int 53:836–844PubMedCrossRefGoogle Scholar
  5. 5.
    Caprioli J, Bettinaglio P, Zipfel PF, Amadei B, Daina E, Gamba S, Skerka C, Marziliano N, Remuzzi G, Noris M (2001) The molecular basis of familial hemolytic uremic syndrome: mutation analysis of factor H gene reveals a hot spot in short consensus repeat 20. J Am Soc Nephrol 12:297–307PubMedGoogle Scholar
  6. 6.
    Perez-Caballero D, Gonzalez-Rubio C, Gallardo ME, Vera M, Lopez-Trascasa M, Rodriguez de Cordoba S, Sanchez-Corral P (2001) Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome. Am J Hum Genet 68:478–484PubMedCrossRefGoogle Scholar
  7. 7.
    Richards A, Buddles MR, Donne RL, Kaplan BS, Kirk E, Venning MC, Tielemans CL, Goodship JA, Goodship TH (2001) Factor H mutations in hemolytic uremic syndrome cluster in exons 18–20, a domain important for host cell recognition. Am J Hum Genet 68:485–490PubMedCrossRefGoogle Scholar
  8. 8.
    Caprioli J, Castelletti F, Bucchioni S, Bettinaglio P, Bresin E, Pianetti G, Gamba S, Brioschi S, Daina E, Remuzzi G, Noris M, International Registry of Recurrent and Familial HUS/TTP (2003) 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 12:3385–3395PubMedCrossRefGoogle Scholar
  9. 9.
    Neumann HP, Salzmann M, Bohnert-Iwan B, Mannuelian T, Skerka C, Lenk D, Bender BU, Cybulla M, Riegler P, Konigsrainer A, Neyer U, Bock A, Widmer U, Male DA, Franke G, Zipfel PF (2003) Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German speaking countries. J Med Genet 40:676–681PubMedCrossRefGoogle Scholar
  10. 10.
    Dragon-Durey MA, Fremeaux-Bacchi V, Loirat C, Blouin J, Niaudet P, Deschenes G, Coppo P, Herman Fridman W, Weiss L (2004) Heterozygous and homozygous factor H deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases. J Am Soc Nephrol 15:787–795PubMedCrossRefGoogle Scholar
  11. 11.
    Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, Mele C, Bresin E, Cassis L, Gamba S, Porrati F, Bucchioni S, Monteferrante G, Fang CJ, Liszewski MK, Kavanagh D, Atkinson JP, Remuzzi G, International Registry of Recurrent and Familial HUS/TTP (2006) Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 108:1267–1279PubMedCrossRefGoogle Scholar
  12. 12.
    Richards A, Kemp EJ, Liszewski MK, Goodship JA, Lampe AK, Decorte R, Muslumanoglu MH, Kavukcu S, Filler G, Pirson Y, Wen LS, Atkinson JP, Goodship TH (2003) Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proc Natl Acad Sci USA 100:12966–12971PubMedCrossRefGoogle Scholar
  13. 13.
    Noris M, Brioschi S, Caprioli J, Todeschini M, Bresin E, Porrati F, Gamba S, Remuzzi G, International Registry of Recurrent and Familial HUS/TTP (2003) Familial haemolytic uraemic syndrome and an MCP mutation. Lancet 362:1542–1547PubMedCrossRefGoogle Scholar
  14. 14.
    Esparza-Gordillo J, Jorge EG, Garrido CA, Carreras L, Lopez-Trascasa M, Sanchez-Corral P, de Cordoba SR (2006) Insights into hemolytic uremic syndrome: segregation of three independent predisposition factors in a large, multiple affected pedigree. Mol Immunol 43:1769–1775PubMedCrossRefGoogle Scholar
  15. 15.
    Fremeaux-Bacchi V, Dragon-Durey MA, Blouin J, Vigneau C, Kuypers D, Boudailliez B, Loirat C, Rondeau E, Fridman WH (2004) Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet 41:e84–e88PubMedCrossRefGoogle Scholar
  16. 16.
    Kavanagh D, Kemp EJ, Mayland E, Winney RJ, Duffield JS, Warwick G, Richards A, Ward R, Goodship JA, Goodship TH (2005) Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome. J Am Soc Nephrol 16:2150–2155PubMedCrossRefGoogle Scholar
  17. 17.
    Zipfel PF, Skerka C (2006) Complement dysfunction in hemolytic uremic syndrome. Curr Opin Rheumatol 18:548–555PubMedCrossRefGoogle Scholar
  18. 18.
    Licht C, Heinen S, Józsi M, Löschmann I, Saunders RE, Perkins SJ, Waldherr R, Skerka C, Kirschfink M, Hoppe B, Zipfel PF (2006) Deletion of Lys224 in regulatory domain 4 of factor H reveals a novel pathomechanism for dense deposit disease (MPGN II). Kidney Int 70:42–50PubMedCrossRefGoogle Scholar
  19. 19.
    Licht C, Schlötzer-Schrehardt U, Kirschfink M, Zipfel PF, Hoppe B (2007) MPGN II—genetically determined by defective complement regulation? Pediatr Nephrol 22:2–9PubMedCrossRefGoogle Scholar
  20. 20.
    Imbasciati E, Gherardi G, Morozumi K, Gudat F, Epper R, Basler V, Mihatsch MJ (1991) Collagen type III glomerulopathy: a new idiopathic glomerular disease. Am J Nephrol 11:422–429PubMedCrossRefGoogle Scholar
  21. 21.
    Vogt BA, Wyatt RJ, Burke BA, Simonton SC, Kashtan CE (1995) Inherited factor H deficiency and collagen type III glomerulopathy. Pediatr Nephrol 9:11–15PubMedCrossRefGoogle Scholar
  22. 22.
    Bircan Z, Toprak D, Kilicaslan I, Solakoglu S, Uysal V, Ponard D, Turker G (2004) Factor H deficiency and fibrillary glomerulopathy. Nephrol Dial Transplant 19:727–730PubMedCrossRefGoogle Scholar
  23. 23.
    Ault B, Schmidt B, Fowler N, Kashtan C, Ahmed A, Vogt B, Colten HR (1997) Human factor H deficiency: mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism. J Biol Chem 272:25168–25175PubMedCrossRefGoogle Scholar
  24. 24.
    Skerka C, Józsi M (2006) Role of complement and factor H in haemolytic uraemic syndrome. In: Zipfel PF (ed) Complement and kidney diseases. Birkhäuser, pp 85–109Google Scholar
  25. 25.
    Remuzzi G, Ruggenenti P, Codazzi D (2002) Combined kidney and liver transplantation for familial haemolytic uraemic syndrome. Lancet 359:1671–1672PubMedCrossRefGoogle Scholar
  26. 26.
    Cheong HI, Lee BS, Kang HG, Hahn H, Suh K-S, Ha IS, Cho Y (2004) Attempted treatment of factor H deficiency by liver transplantation. Pediatr Nephrol 19:454–458PubMedCrossRefGoogle Scholar
  27. 27.
    Zipfel PF, Misselwitz J, Licht C, Skerka C (2006) The role of defective complement control in hemolytic uremic syndrome. Semin Thromb Hemost 32:146–154PubMedCrossRefGoogle Scholar
  28. 28.
    Licht C, Weyersberg A, Heinen S, Stapenhorst L, Devenge J, Beck B, Waldherr R, Kirschfink M, Zipfel PF, Hoppe B (2005) Successful plasma therapy for atypical hemolytic uremic syndrome caused by factor H deficiency owing to a novel mutation in the complement cofactor protein domain 15. Am J Kidney Dis 45:415–421PubMedCrossRefGoogle Scholar
  29. 29.
    Esparza-Gordillo J, Goicoechea de Jorge E, Buil A, Carreras Berges L, Lopez-Trascasa M, Sanchez-Corral P, Rodriguez de Cordoba S (2005) Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32. Hum Mol Genet 14:703–712PubMedCrossRefGoogle Scholar
  30. 30.
    Saland JM, Emre SH, Shneider BL, Benchimol C, Ames S, Bromberg JS, Remuzzi G, Strain L, Goodship THJ (2006) Favorable long-term outcome after liver–kidney transplant for recurrent hemolytic uremic syndrome associated with a factor H mutation. Am J Transplant 6:1948–1952PubMedCrossRefGoogle Scholar
  31. 31.
    Karim Y, Masood A (2002) Haemolytic uraemic syndrome following mumps, measles, and rubella vaccination. Nephrol Dial Transplant 17:941–942PubMedCrossRefGoogle Scholar
  32. 32.
    Davin J-C, Olie KH, Verlaak R, Horuz F, Florquin S, Weening JJ, Groothoff JW, Strain L, Goodship THJ (2006) Complement factor H-associated atypical hemolytic uremic syndrome in monozygotic twins: concordant presentation, discordant response to treatment. Am J Kidney Dis 47:227–230, 2006CrossRefGoogle Scholar
  33. 33.
    Artz MA, Steenbergen EJ, Hoitsma AJ, Monnens LA, Wetzels JF (2003) Renal transplantation in patients with hemolytic uremic syndrome: high rate of recurrence and increased incidence of acute rejections. Transplantation 76:821–826PubMedCrossRefGoogle Scholar
  34. 34.
    Miller RB, Burke BA, Schmidt WJ, Gillingham KJ, Matas AJ, Mauer M, Kashtan CE (1997) Recurrence of haemolytic–uraemic syndrome in renal transplants: a single-centre report. Nephrol Dial Transplant 12:1425–1430PubMedCrossRefGoogle Scholar
  35. 35.
    Loirat C, Niaudet P (2003) The risk of recurrence of hemolytic uremic syndrome after renal transplantation in children. Pediatr Nephrol 18:1095–1101PubMedCrossRefGoogle Scholar
  36. 36.
    Zimmerhackl LB, Scheiring J, Prüfer F, Taylor CM, Loirat C (2007) Renal transplantation in HUS patients with disorders of complement regulation. Pediatr Nephrol 22:10–16PubMedCrossRefGoogle Scholar
  37. 37.
    Kavanagh D, Goodship T (2006) Membrane cofactor protein, factor I mutations and transplantation. Semin Thromb Hemost 32:155–159PubMedCrossRefGoogle Scholar
  38. 38.
    Remuzzi G, Ruggenenti P, Colledan M, Gridelli B, Bertani A, Bettinaglio P, Bucchioni S, Sonzogni A, Bonanomi E, Sonzogni V, Platt JL, Perico N, Noris M (2005) Hemolytic uremic syndrome: a fatal outcome after kidney and liver transplantation performed to correct factor H gene mutation. Am J Transplant 5:1146–1150PubMedCrossRefGoogle Scholar

Copyright information

© IPNA 2007

Authors and Affiliations

  • Hee Yeon Cho
    • 1
  • Byong Sop Lee
    • 2
  • Kyung Chul Moon
    • 3
  • Il Soo Ha
    • 1
  • Hae Il Cheong
    • 1
  • Yong Choi
    • 1
  1. 1.Department of PediatricsSeoul National University Children’s HospitalSeoulSouth Korea
  2. 2.Department of Pediatrics, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulSouth Korea
  3. 3.Department of PathologySeoul National University HospitalSeoulSouth Korea

Personalised recommendations