Pediatric Drugs

, Volume 12, Issue 4, pp 257–268 | Cite as

Hereditary Angioedema in Childhood

An Approach to Management
  • Didier G. Ebo
  • Marjoke M. Verweij
  • Kathleen J. De Knop
  • Margo M. Hagendorens
  • Chris H. Bridts
  • Luc S. De Clerck
  • Wim J. Stevens
Review Article


Hereditary angioedema (HAE) is an inherited disorder characterized by recurrent, circumscribed, nonpitting, non-pruritic, and rather painful subepithelial swelling of sudden onset, which fades during the course of 48–72 hours, but can persist for up to 1 week. Lesions can be solitary or multiple, and primarily involve the extremities, larynx, face, esophagus, and bowel wall. Patients with HAE experience angioedema because of a defective control of the plasma kinin-forming cascade that is activated through contact with negatively charged endothelial macromolecules leading to binding and auto-activation of coagulation factor XII, activation of prekallikrein to kallikrein by factor XIIa, and cleavage of high-molecular-weight kininogen by kallikrein to release the highly potent vasodilator bradykinin. Three forms of HAE have currently been described. Type I and type II HAE are rare autosomal dominant diseases due to mutations in the C1-inhibitor gene (SERP1NG1). C1-inhibitor mutations that cause type I HAE occur throughout the gene and result in truncated or misfolded proteins with a deficiency in the levels of antigenic and functional C1-inhibitor. Mutations that cause type II HAE generally involve exon 8 at or adjacent to the active site, resulting in an antigenically intact but dysfunctional mutant protein. In contrast, type III HAE (also called estrogen-dependent HAE) is characterized by normal C1-inhibitor activity. The diagnosis of HAE is suggested by a positive family history, the absence of accompanying pruritus or urticaria, the presence of recurrent gastrointestinal attacks of colic, and episodes of laryngeal edema. Estrogens may exacerbate attacks, and in some patients attacks are precipitated by trauma, inflammation, or psychological stress. For type I and type II HAE, diminished C4 concentrations are highly suggestive for the diagnosis. Further laboratory diagnosis depends on demonstrating a deficiency of C1-inhibitor antigen (type I) in most kindreds, but some kindreds have an antigenically intact but dysfunctional protein (type II) and require a functional assay to establish the diagnosis. There are no particular laboratory findings in type III HAE.

Prophylactic administration of either 17α-alkylated androgens or synthetic antifibrinolytic agents has proven useful in reducing the frequency or severity of attacks. Plasma-derived C1-inhibitor concentrate, recombinant C1-inhibitor, ecallantide (DX88; a plasma kallikrein inhibitor) and icatibant (a bradykinin B2 receptor antagonist) have demonstrated significant efficacy in the treatment of acute attacks, whereas the C1-inhibitor concentrate has also provided a significant benefit as long-term prophylaxis. However, these drugs are not licensed in all countries and are not always readily available.


  1. 1.
    Quincke H. Concerning the acute localized oedema of the skin. Monatsh Prakt Derm 1882; 1: 129–31Google Scholar
  2. 2.
    Osler W. Hereditary angio-neurotic oedema. Am J Med Sci 1888; 95: 362–7CrossRefGoogle Scholar
  3. 3.
    Crowder JR, Crowder TR. Five generations of angioneurotic oedema. Arch Intern Med 1917; 20: 840–52CrossRefGoogle Scholar
  4. 4.
    Verpy E, Biasotto M, Brai M, et al. Exhaustive mutation scanning by fluorescence-assisted mismatch analysis discloses new genotype-phenotype correlations in angiodema. Am J Hum Genet 1996; 59: 308–19PubMedGoogle Scholar
  5. 5.
    Bissler JJ, Aulak KS, Donaldson VH, et al. Molecular defects in hereditary angioneurotic edema. Proc Assoc Am Physicians 1997; 109: 164–73PubMedGoogle Scholar
  6. 6.
    Kalmar L, Hegedus T, Farkas H, et al. HAE: a novel interactive, locus-specific mutation database for the C1 inhibitor gene. Hum Mutat 2005; 25: 1–5PubMedCrossRefGoogle Scholar
  7. 7.
    Laimer M, Klausegger A, Aberer W, et al. Haploinsufficiency due to deletion within the 3’-UTR of C1-INH-gene associated with hereditary angioedema. Genet Med 2006; 8: 249–54PubMedCrossRefGoogle Scholar
  8. 8.
    Pappalardo E, Caccia S, Suffritti C, et al. Mutation screening of C1 inhibitor gene in l08 unrelated families with hereditary angioedema: functional and structural correlates. Mol Immunol 2008; 45: 3536–44PubMedCrossRefGoogle Scholar
  9. 9.
    Gosswein T, Kocot A, Emmert G, et al. Mutational spectrum of the C1INH (SERPING1) gene in patients with hereditary angioedema. Cytogenet Genome Res 2008; 121: 181–8PubMedCrossRefGoogle Scholar
  10. 10.
    Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a broad review for clinicians. Arch Intern Med 2001; 161: 2417–29PubMedCrossRefGoogle Scholar
  11. 11.
    Donaldson VH, Evans RR. A biochemical abnormality in hereditary angioneurotic edema: absence of serum inhibitor of C1-esterase. Am J Med 1963; 35: 37–44PubMedCrossRefGoogle Scholar
  12. 12.
    Schreiber AD, Kaplan AP, Austen KF. Inhibition by C1INH of Hagemann factor fragment activation of coagulation, fibrinolysis, and kinin generation. J Clin Invest 1973; 52: 1402–9PubMedCrossRefGoogle Scholar
  13. 13.
    Davis III AE. C1 inhibitor and hereditary angioneurotic edema. Annu Rev Immunol 1988; 6: 595–628PubMedCrossRefGoogle Scholar
  14. 14.
    Nielsen EW, Johansen HT, Hogasen K, et al. Activation of the complement, coagulation, fibrinolytic and kallikrein-kinin systems during attacks of hereditary angioedema. Scand J Immunol 1996; 44: 185–92PubMedCrossRefGoogle Scholar
  15. 15.
    Cugno M, Cicardi M, Bottasso B, et al. Activation of the coagulation cascade in C1-inhibitor deficiencies. Blood 1997; 89: 3213–8PubMedGoogle Scholar
  16. 16.
    Davis III AE. Mechanism of angioedema in first complement component inhibitor deficiency. Immunol Allergy Clin North Am 2006; 26: 633–51PubMedCrossRefGoogle Scholar
  17. 17.
    Agostoni A, Ygoren-Pursun E, Binkley KE, et al. Hereditary and acquired angioedema: problems and progress. Proceedings of the Third C1 Esterase Inhibitor Deficiency Workshop and Beyond. J Allergy Clin Immunol 2004; 114: S51–131PubMedCrossRefGoogle Scholar
  18. 18.
    Cicardi M, Zingale LC. The deficiency of C1 inhibitor and its treatment. Immunobiology 2007; 212: 325–31PubMedCrossRefGoogle Scholar
  19. 19.
    Davis III AE. Hereditary angioedema: a current state-of-the-art review. III: mechanisms of hereditary angioedema. Ann Allergy Asthma Immunol 2008; 100: S7–12PubMedCrossRefGoogle Scholar
  20. 20.
    Joseph K, Tuscano TB, Kaplan AP. Studies of the mechanisms of bradykinin generation in hereditary angioedema plasma. Ann Allergy Asthma Immunol 2008; 101: 279–86PubMedCrossRefGoogle Scholar
  21. 21.
    Schachter M, Uchida Y, Longridge DJ, et al. New synthetic antagonists of bradykinin. Br J Pharmacol 1987; 92: 851–5PubMedCrossRefGoogle Scholar
  22. 22.
    Whalley ET, Nwator IA, Stewart JM, et al. Analysis of the receptors mediating vascular actions of bradykinin. Naunyn Schmiedebergs Arch Pharmacol 1987; 336: 430–3PubMedCrossRefGoogle Scholar
  23. 23.
    Han ED, MacFarlane RC, Mulligan AN, et al. Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor. J Clin Invest 2002; 109: 1057–63PubMedGoogle Scholar
  24. 24.
    Bas M, Adams V, Suvorava T, et al. Nonallergic angioedema: role of bradykinin. Allergy 2007; 62: 842–56PubMedCrossRefGoogle Scholar
  25. 25.
    Byrd JB, Adam A, Brown NJ. Angiotensin-converting enzyme inhibitor-associated angioedema. Immunol Allergy Clin North Am 2006; 26: 725–37PubMedCrossRefGoogle Scholar
  26. 26.
    Bork K, Barnstedt SE, Koch P, et al. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet 2000; 356: 213–7PubMedCrossRefGoogle Scholar
  27. 27.
    Binkley KE, Davis III A. Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema. J Allergy Clin Immunol 2000; 106: 546–50PubMedCrossRefGoogle Scholar
  28. 28.
    Dewald G, Bork K. Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun 2006; 343: 1286–9PubMedCrossRefGoogle Scholar
  29. 29.
    Cichon S, Martin L, Hennies HC, et al. Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. Am J Hum Genet 2006; 79: 1098–104PubMedCrossRefGoogle Scholar
  30. 30.
    Farsetti A, Misiti S, Citarella F, et al. Molecular basis of estrogen regulation of Hageman factor XII gene expression. Endocrinology 1995; 136: 5076–83PubMedCrossRefGoogle Scholar
  31. 31.
    Colman RW. Surface-mediated defense reactions: the plasma contact activation system. J Clin Invest 1984; 73: 1249–53PubMedCrossRefGoogle Scholar
  32. 32.
    Cicardi M, Bergamaschini L, Zingale LC, et al. Idiopathic nonhistaminergic angioedema. Am J Med 1999; 106: 650–4PubMedCrossRefGoogle Scholar
  33. 33.
    Gupta S, Yu F, Klaustermeyer WB. New-variant hereditary angioedema in three brothers with normal C1 esterase inhibitor level and function. Allergy 2004; 59: 557–8PubMedCrossRefGoogle Scholar
  34. 34.
    Bork K, Gul D, Dewald G. Hereditary angio-oedema with normal C1 inhibitor in a family with affected women and men. Br J Dermatol 2006; 154: 542–5PubMedCrossRefGoogle Scholar
  35. 35.
    Agostoni A, Cicardi M. Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients. Medicine (Baltimore) 1992; 71: 206–15Google Scholar
  36. 36.
    Frank MM. Hereditary angioedema: the clinical syndrome and its management in the United States. Immunol Allergy Clin North Am 2006; 26: 653–68PubMedCrossRefGoogle Scholar
  37. 37.
    Bork K, Staubach P, Eckardt AJ, et al. Symptoms, course, and complications of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency. Am J Gastroenterol 2006; 101: 619–27PubMedCrossRefGoogle Scholar
  38. 38.
    Donaldson VH, Rosen FS. Hereditary angioneurotic edema: a clinical survey. Pediatrics 1966; 37: 1017–27PubMedGoogle Scholar
  39. 39.
    Ohela K. Hereditary angioneurotic oedema in Finland: clinical, immunological and genealogical studies. Acta Med Scand 1977; 201: 415–27PubMedCrossRefGoogle Scholar
  40. 40.
    Zeana C. Hereditary angioedema due to deficit of C1 esterase inhibitor. Med Interne 1989; 27: 143–7PubMedGoogle Scholar
  41. 41.
    Frank MM. Hereditary angioedema. Curr Opin Pediatr 2005; 17: 686–9PubMedCrossRefGoogle Scholar
  42. 42.
    Boyle RJ, Nikpour M, Tang ML. Hereditary angio-oedema in children: a management guideline. Pediatr Allergy Immunol 2005; 16: 288–94PubMedCrossRefGoogle Scholar
  43. 43.
    Bork K, Meng G, Staubach P, et al. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med 2006; 119: 267–74PubMedCrossRefGoogle Scholar
  44. 44.
    Farkas H, Varga L, Szeplaki G, et al. Management of hereditary angioedema in pediatric patients. Pediatrics 2007; 120: 713–22CrossRefGoogle Scholar
  45. 45.
    Farkas H, Jakab L, Temesszentandrasi G, et al. Hereditary angioedema: a decade of human C1-inhibitor concentrate therapy. J Allergy Clin Immunol 2007; 120: 941–7PubMedCrossRefGoogle Scholar
  46. 46.
    Sanchez A, Ecochard A, Maestracci M, et al. Hereditary angioedema causing colocolic intussusception. Arch Pediatr 2008; 15: 271–4PubMedCrossRefGoogle Scholar
  47. 47.
    Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndrome and its management. Ann Intern Med 1976; 84: 580–93PubMedGoogle Scholar
  48. 48.
    Cicardi M, Bergamaschini L, Marasini B, et al. Hereditary angioedema: an appraisal of 104 cases. Am J Med Sci 1982; 284: 2–9PubMedCrossRefGoogle Scholar
  49. 49.
    Sim TC, Grant JA. Hereditary angioedema: its diagnostic and management perspectives. Am J Med 1990; 88: 656–64PubMedCrossRefGoogle Scholar
  50. 50.
    Winnewisser J, Rossi M, Spath P, et al. Type I hereditary angio-oedema: variability of clinical presentation and course within two large kindreds. J Intern Med 1997; 241: 39–46PubMedCrossRefGoogle Scholar
  51. 51.
    Sofia S, Casali A, Bolondi L. Sonographic findings in abdominal hereditary angioedema. J Clin Ultrasound 1999; 27: 537–40PubMedCrossRefGoogle Scholar
  52. 52.
    Shah TJ, Knowles WO, McGeady SJ. Hereditary angioedema with recurrent abdominal pain and ascites. J Allergy Clin Immunol 1995; 96: 259–61PubMedCrossRefGoogle Scholar
  53. 53.
    De Backer AI, De Schepper AM, Vandevenne JE, et al. CT of angioedema of the small bowel. Am J Roentgenol 2001; 176: 649–52Google Scholar
  54. 54.
    Sunder TR, Balsam MJ, Vengrow MI. Neurological manifestations of angioedema: report of two cases and review of the literature. JAMA 1982; 247: 2005–7PubMedCrossRefGoogle Scholar
  55. 55.
    Neri S, Ierna D, Sfogliano L. Unusual manifestations of hereditary angioedema. Eur J Emerg Med 2000; 7: 111–2PubMedCrossRefGoogle Scholar
  56. 56.
    Van Dellen RC, Myers RP. Bladder involvement in hereditary angioedema. Mayo Clin Proc 1980; 55: 277–8PubMedGoogle Scholar
  57. 57.
    De Knop KJ, Hagendorens MM, Stevens WJ, et al. Angioedema beyond histamine: an educational case series. Acta Clin Belg 2009; 64: 520–8PubMedGoogle Scholar
  58. 58.
    Brickman CM, Tsokos GC, Balow JE, et al. Immunoregulatory disorders associated with hereditary angioedema: I. Clinical manifestations of autoimmune disease. J Allergy Clin Immunol 1986; 77: 749–57PubMedCrossRefGoogle Scholar
  59. 59.
    Carugati A, Pappalardo E, Zingale LC, et al. C1-inhibitor deficiency and angioedema. Mol Immunol 2001; 38: 161–73PubMedCrossRefGoogle Scholar
  60. 60.
    Zingale LC, Beltrami L, Zanichelli A, et al. Angioedema without urticaria: a large clinical survey. CMAJ 2006; 175: 1065–70PubMedCrossRefGoogle Scholar
  61. 61.
    Roche O, Blanch A, Caballero T, et al. Hereditary angioedema due to C1 inhibitor deficiency: patient registry and approach to the prevalence in Spain. Ann Allergy Asthma Immunol 2005; 94: 498–503PubMedCrossRefGoogle Scholar
  62. 62.
    Pappalardo E, Cicardi M, Duponchel C, et al. Frequent de novo mutations and exon deletions in the C1 inhibitor gene of patients with angioedema. J Allergy Clin Immunol 2000; 106: 1147–54PubMedCrossRefGoogle Scholar
  63. 63.
    Bailey E, Shaker M. An update on childhood urticaria and angioedema. Curr Opin Pediatr 2008; 20: 425–30PubMedCrossRefGoogle Scholar
  64. 64.
    Novembre E, Cianferoni A, Mori F, et al. Urticaria and urticaria related skin condition/disease in children. Eur Ann Allergy Clin Immunol 2008; 40: 5–13PubMedGoogle Scholar
  65. 65.
    Krishnamurthy A, Naguwa SM, Gershwin ME. Pediatric angioedema. Clin Rev Allergy Immunol 2008; 34: 250–9PubMedCrossRefGoogle Scholar
  66. 66.
    Quastel M, Harrison R, Cicardi M, et al. Behavior in vivo of normal and dysfunctional C1 inhibitor in normal subjects and patients with hereditary angioneurotic edema. J Clin Invest 1983; 71: 1041–6PubMedCrossRefGoogle Scholar
  67. 67.
    Gompels MM, Lock RJ, Morgan JE, et al. A multicentre evaluation of the diagnostic efficiency of serological investigations for C1 inhibitor deficiency. J Clin Pathol 2002; 55: 145–7PubMedCrossRefGoogle Scholar
  68. 68.
    Karim Y, Griffiths H, Deacock S. Normal complement C4 values do not exclude hereditary angioedema. J Clin Pathol 2004; 57: 213–4PubMedCrossRefGoogle Scholar
  69. 69.
    Tarzi MD, Hickey A, Forster T, et al. An evaluation of tests used for the diagnosis and monitoring of C1 inhibitor deficiency: normal serum C4 does not exclude hereditary angio-oedema. Clin Exp Immunol 2007; 149: 513–6PubMedCrossRefGoogle Scholar
  70. 70.
    Davis CA, Vallota EH, Forristal J. Serum complement levels in infancy: age related changes. Pediatr Res 1979; 13: 1043–6PubMedCrossRefGoogle Scholar
  71. 71.
    Lockitch G, Halstead AC, Quigley G, et al. Age- and sex-specific pediatric reference intervals: study design and methods illustrated by measurement of serum proteins with the Behring LN Nephelometer. Clin Chem 1988; 34: 1618–21PubMedGoogle Scholar
  72. 72.
    Roach B, Kim Y, Jerome E, et al. Influence of age and sex on serum complement components in children. Am J Dis Child 1981; 135: 918–20PubMedGoogle Scholar
  73. 73.
    Nielsen EW, Johansen HT, Holt J, et al. C1 inhibitor and diagnosis of hereditary angioedema in newborns. Pediatr Res 1994; 35: 184–7PubMedCrossRefGoogle Scholar
  74. 74.
    Bowen T, Cicardi M, Bork K, et al. Hereditary angiodema: a current state-of-the-art review: VII. Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema. Ann Allergy Asthma Immunol 2008; 100: S30–40PubMedCrossRefGoogle Scholar
  75. 75.
    Jackson J, Sim RB, Whelan A, et al. An IgG autoantibody which inactivates C1-inhibitor. Nature 1986; 323: 722–4PubMedCrossRefGoogle Scholar
  76. 76.
    Alsenz J, Bork K, Loos M. Autoantibody-mediated acquired deficiency of C1 inhibitor. N Engl J Med 1987; 316: 1360–6PubMedCrossRefGoogle Scholar
  77. 77.
    Cicardi M, Beretta A, Colombo M, et al. Relevance of lymphoproliferative disorders and of anti-C1 inhibitor autoantibodies in acquired angio-oedema. Clin Exp Immunol 1996; 106: 475–80PubMedCrossRefGoogle Scholar
  78. 78.
    Cicardi M, Zingale LC, Pappalardo E, et al. Autoantibodies and lymphoproliferative diseases in acquired C1-inhibitor deficiencies. Medicine (Baltimore) 2003; 82: 274–81Google Scholar
  79. 79.
    Donaldson VH, Wagner CJ, Davis III AE. An autoantibody to C1-inhibitor recognizes the reactive center of the inhibitor. J Lab Clin Med 1996; 127: 229–32PubMedCrossRefGoogle Scholar
  80. 80.
    Varga L, Szeplaki G, Visy B, et al. C1-inhibitor (C1-INH) autoantibodies in hereditary angioedema: strong correlation with the severity of disease in C1-INH concentrate naive patients. Mol Immunol 2007; 44: 1454–60PubMedCrossRefGoogle Scholar
  81. 81.
    Zuraw BL. Hereditary angioedema. N Engl J Med 2008; 359: 1027–36PubMedCrossRefGoogle Scholar
  82. 82.
    Farkas H, Harmat G, Kaposi PN, et al. Ultrasonography in the diagnosis and monitoring of ascites in acute abdominal attacks of hereditary angioneurotic oedema. Eur J Gastroenterol Hepatol 2001; 13: 1225–30PubMedCrossRefGoogle Scholar
  83. 83.
    Gadek JE, Hosea SW, Gelfand JA, et al. Replacement therapy in hereditary angioedema: successful treatment of acute episodes of angioedema with partly purified C1 inhibitor. N Engl J Med 1980; 302: 542–6PubMedCrossRefGoogle Scholar
  84. 84.
    Phillips M. C1-inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med 1980; 303: 526–7PubMedCrossRefGoogle Scholar
  85. 85.
    Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl J Med 1996; 334: l630–4CrossRefGoogle Scholar
  86. 86.
    Kunschak M, Engl W, Maritsch F, et al. A randomized, controlled trial to study the efficacy and safety of C1 inhibitor concentrate in treating hereditary angioedema. Transfusion 1998; 38: 540–9PubMedCrossRefGoogle Scholar
  87. 87.
    Visentin DE, Yang WH, Karsh J. C1-esterase inhibitor transfusions in patients with hereditary angioedema. Ann Allergy Asthma Immunol 1998; 80: 457–61PubMedCrossRefGoogle Scholar
  88. 88.
    Bork K, Barnstedt SE. Treatment of l93 episodes of laryngeal edema with C1 inhibitor concentrate in patients with hereditary angioedema. Arch Intern Med 2001; 161: 714–8PubMedCrossRefGoogle Scholar
  89. 89.
    de Serres J, Groner A, Lindner J. Safety and efficacy of pasteurized C1 inhibitor concentrate (Berinert P) in hereditary angioedema: a review. Transfus Apher Sci 2003; 29: 247–54PubMedCrossRefGoogle Scholar
  90. 90.
    Bork K, Meng G, Staubach P, et al. Treatment with C1 inhibitor concentrate in abdominal pain attacks of patients with hereditary angioedema. Transfusion 2005; 45: 1774–84PubMedCrossRefGoogle Scholar
  91. 91.
    Levi M, Choi G, Picavet C, et al. Self-administration of C1-inhibitor concentrate in patients with hereditary or acquired angioedema caused by C1-inhibitor deficiency. J Allergy Clin Immunol 2006; 117: 904–8PubMedCrossRefGoogle Scholar
  92. 92.
    Longhurst HJ, Carr S, Khair K. C1-inhibitor concentrate home therapy for hereditary angioedema: a viable, effective treatment option. Clin Exp Immunol 2007; 147: 11–7PubMedGoogle Scholar
  93. 93.
    Bork K, Barnstedt SE. Laryngeal edema and death from asphyxiation after tooth extraction in four patients with hereditary angioedema. J Am Dent Assoc 2003; 134: 1088–94PubMedGoogle Scholar
  94. 94.
    Pickering RJ, Good RA, Kelly JR, et al. Replacement therapy in hereditary angioedema: successful treatment of two patients with fresh frozen plasma. Lancet 1969; 1: 326–30PubMedCrossRefGoogle Scholar
  95. 95.
    Hill BJ, Thomas SH, McCabe C. Fresh frozen plasma for acute exacerbations of hereditary angioedema [letter]. Am J Emerg Med 2004; 22: 633PubMedCrossRefGoogle Scholar
  96. 96.
    Prematta M, Gibbs JG, Pratt EL, et al. Fresh frozen plasma for the treatment of hereditary angioedema. Ann Allergy Asthma Immunol 2007; 98: 383–8PubMedCrossRefGoogle Scholar
  97. 97.
    Pekdemir M, Ersel M, Aksay E, et al. Effective treatment of hereditary angioedema with fresh frozen plasma in an emergency department. J Emerg Med 2007; 33: 137–9PubMedCrossRefGoogle Scholar
  98. 98.
    Dingle JT, Gordon J. Research monographs in cell and tissue physiology: proteinase inhibitors. Cambridge: Elsevier, 1988Google Scholar
  99. 99.
    Williams A, Baird LG. DX-88 and HAE: a developmental perspective. Transfus Apher Sci 2003; 29: 255–8PubMedCrossRefGoogle Scholar
  100. 100.
    Levy JH, O’Donnell PS. The therapeutic potential of a kallikrein inhibitor for treating hereditary angioedema. Expert Opin Investig Drugs 2006; 15: 1077–90PubMedCrossRefGoogle Scholar
  101. 101.
    Frank MM. Hereditary angioedema. J Allergy Clin Immunol 2008; 121 Suppl.: S398–401PubMedCrossRefGoogle Scholar
  102. 102.
    van Doorn MB, Burggraaf J, van DT, et al. A phase I study of recombinant human C1 inhibitor in asymptomatic patients with hereditary angioedema. J Allergy Clin Immunol 2005; 116: 876–83PubMedCrossRefGoogle Scholar
  103. 103.
    Koles K, van Berkel PH, Pieper FR, et al. N- and O-glycans of recombinant human C1 inhibitor expressed in the milk of transgenic rabbits. Glycobiology 2004; 14: 51–64PubMedCrossRefGoogle Scholar
  104. 104.
    Longhurst H. Rhucin, a recombinant C1 inhibitor for the treatment of hereditary angioedema and cerebral ischemia. Curr Opin Investig Drugs 2008; 9: 310–23PubMedGoogle Scholar
  105. 105.
    Atkinson JC, Frank MM. Oral manifestations and dental management of patients with hereditary angioedema. J Oral Pathol Med 1991; 20: 139–42PubMedCrossRefGoogle Scholar
  106. 106.
    Maeda S, Miyawaki T, Nomura S, et al. Management of oral surgery in patients with hereditary or acquired angioedemas: review and case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003; 96: 540–3PubMedCrossRefGoogle Scholar
  107. 107.
    Jaffe CJ, Atkinson JP, Gelfand JA, et al. Hereditary angioedema: the use of fresh frozen plasma for prophylaxis in patients undergoing oral surgery. J Allergy Clin Immunol 1975; 55: 386–93PubMedCrossRefGoogle Scholar
  108. 108.
    Spaulding WB. Methyltestosterone therapy for hereditary episodic edema (hereditary angioneurotic edema). Ann Intern Med 1960; 53: 739–45Google Scholar
  109. 109.
    Sheffer AL, Fearon DT, Austen KF. Clinical and biochemical effects of impeded androgen (oxymetholone) therapy of hereditary angioedema. J Allergy Clin Immunol 1979; 64: 275–80PubMedCrossRefGoogle Scholar
  110. 110.
    Gelfand JA, Sherins RJ, Alling DW, et al. Treatment of hereditary angioedema with danazol: reversal of clinical and biochemical abnormalities. N Engl J Med 1976; 295: 1444–8PubMedCrossRefGoogle Scholar
  111. 111.
    Agostoni A, Cicardi M, Bergamaschini L, et al. C1-inhibitor concentrate for treatment of hereditary angioedema [letter]. N Engl J Med 1980; 303: 527PubMedCrossRefGoogle Scholar
  112. 112.
    Sheffer AL, Fearon DT, Austen KF. Clinical and biochemical effects of stanozolol therapy for hereditary angioedema. J Allergy Clin Immunol 1981; 68: 181–7PubMedCrossRefGoogle Scholar
  113. 113.
    Cicardi M, Bergamaschini L, Tucci A, et al. Morphologic evaluation of the liver in hereditary angioedema patients on long-term treatment with androgen derivatives. J Allergy Clin Immunol 1983; 72: 294–8PubMedCrossRefGoogle Scholar
  114. 114.
    Sheffer AL, Fearon DT, Austen KF. Hereditary angioedema: a decade of management with stanozolol. J Allergy Clin Immunol 1987; 80: 855–60PubMedCrossRefGoogle Scholar
  115. 115.
    Cicardi M, Castelli R, Zingale LC, et al. Side effects of long-term prophylaxis with attenuated androgens in hereditary angioedema: comparison of treated and untreated patients. J Allergy Clin Immunol 1997; 99: 194–6PubMedCrossRefGoogle Scholar
  116. 116.
    Szeplaki G, Varga L, Valentin S, et al. Adverse effects of danazol prophylaxis on the lipid profiles of patients with hereditary angioedema. J Allergy Clin Immunol 2005; 115: 864–9PubMedCrossRefGoogle Scholar
  117. 117.
    Sloane DE, Lee CW, Sheffer AL. Hereditary angioedema: safety of long-term stanozolol therapy. J Allergy Clin Immunol 2007; 120: 654–8PubMedCrossRefGoogle Scholar
  118. 118.
    Pappalardo E, Zingale LC, Cicardi M. Increased expression of C1-inhibitor mRNA in patients with hereditary angioedema treated with danazol. Immunol Lett 2003; 86: 271–6PubMedCrossRefGoogle Scholar
  119. 119.
    Bork K, Pitton M, Harten P, et al. Hepatocellular adenomas in patients taking danazol for hereditary angio-oedema. Lancet 1999; 353: 1066–7PubMedCrossRefGoogle Scholar
  120. 120.
    Bork K, Schneiders V. Danazol-induced hepatocellular adenoma in patients with hereditary angio-oedema. J Hepatol 2002; 36: 707–9PubMedCrossRefGoogle Scholar
  121. 121.
    Shahidi NT. A review of the chemistry, biological action, and clinical applications of anabolic-androgenic steroids. Clin Ther 2001; 23: 1355–90PubMedCrossRefGoogle Scholar
  122. 122.
    Church JA. Oxandrolone treatment of childhood hereditary angioedema. Ann Allergy Asthma Immunol 2004; 92: 377–8PubMedCrossRefGoogle Scholar
  123. 123.
    Frank MM, Sergent JS, Kane MA, et al. Epsilon aminocaproic acid therapy of hereditary angioneurotic edema: a double-blind study. N Engl J Med 1972; 286: 808–12PubMedCrossRefGoogle Scholar
  124. 124.
    Sheffer AL, Austen KF, Rosen FS. Tranexamic acid therapy in hereditary angioneurotic edema. N Engl J Med 1972; 287: 452–4PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  • Didier G. Ebo
    • 1
  • Marjoke M. Verweij
    • 2
  • Kathleen J. De Knop
    • 1
  • Margo M. Hagendorens
    • 2
  • Chris H. Bridts
    • 1
  • Luc S. De Clerck
    • 1
  • Wim J. Stevens
    • 1
  1. 1.Department of Immunology, Allergology and RheumatologyUniversity Hospital Antwerp, Antwerp UniversityAntwerpBelgium
  2. 2.Department of PaediatricsUniversity Hospital Antwerp, Antwerp UniversityAntwerpBelgium

Personalised recommendations