Dermatologic Manifestations of Hereditary Angioedema Clinical Presentation

  • Author: Warren R Heymann, MD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: Jan 6, 2012
 

History

Note the following for patient history:

  • A family history of hereditary angioedema (HAE) is typically obtained, although spontaneous mutations may occur.
  • Symptoms are referable to 3 prominent sites: subcutaneous tissues (face, hands, arms, legs, genitals, and buttocks); abdominal organs (stomach, intestines, bladder, and kidneys), which may manifest as vomiting, diarrhea, or paroxysmal colicky pain and mimic a surgical emergency; and the upper airway (larynx) and tongue, which may result in laryngeal edema and upper airway obstruction.
  • Attacks usually occur at a single site, but simultaneous involvement of subcutaneous tissue, viscera, and the larynx is not uncommon. Nonpitting cutaneous swelling is the most commonly reported symptom, and it mainly affects the extremities, the genitalia, and the face. Acute abdominal pain, nausea, and vomiting are the dominant symptoms in 25% of patients with HAE and are rarely seen in people with other forms of angioedema. The lifetime incidence of a laryngeal attack is estimated at 70%.
  • Mucosal edema of the bladder or urethra can result in urinary retention, stammering, pain, or anuria.
  • Episodes of severe headaches, visual disturbances (eg, blurred vision, diplopia), and ataxia have been reported.
  • Cases of painful muscle swelling and unilateral hip or shoulder involvement have also been cited.
  • Attacks may be preceded several hours in advance by sudden mood changes, anxiety, sensory changes, or exhaustion.
  • Patients often report episodes of swelling worsening over a period of 12-24 hours, usually with resolution within 72 hours. Symptoms can persist for up to 5 days, with migration of swelling to different sites. The edema is usually unresponsive to antihistamines. Attacks are usually periodic and are commonly followed by weeks of remission.
  • Pediatric episodes are usually less frequent and commonly manifest as abdominal involvement.
Next

Physical

Physical examination findings may include the following:

  • Physical signs of hereditary angioedema (HAE) include overt, noninflammatory swelling of the skin and mucous membranes. Typical involvement includes the face, hands, arms, legs, genitalia, and buttocks, although the edema can localize subcutaneously at any site. Type III HAE patients tend to have more facial attacks.[8] In some patients with severe edema, tension vesicles or bullae may develop.
  • In approximately 25% of patients, erythema may precede the occurrence of edema. An estimated 30-50% of patients with HAE reportedly have erythema marginatum preceding or accompanying the attacks. Urticaria is not usually associated with HAE.[9]
  • Abdominal examination may reveal signs consistent with acute abdomen or abdominal obstruction. Ascites is often present with an abdominal attack associated with angioedema.
  • Mucosal involvement with glossal, pharyngeal, or laryngeal edema may cause respiratory obstruction and signs of distress.
  • Additional rare physical findings that have been reported are pleuritic symptoms with pleural effusions, seizures and hemiparesis secondary to cerebral edema, and bladder edema.
Previous
Next

Causes

Causes are as follows:

  • Precipitating factors of hereditary angioedema (HAE) attacks may include trauma (especially dental trauma), anxiety, menstruation, infection, exercise, alcohol consumption, and stress. Medications (eg, estrogen, ACE inhibitors, angiotensin II type 1 receptor antagonists) have also been shown to induce attacks.[10]
  • During pregnancy, symptoms may increase or decrease for HAE types I and II. In HAE type III, studies have reported first episodes or recurrences associated with estrogen-containing oral contraceptives, estrogen replacement therapy, or pregnancy.
  • As many as 2% of patients with HAE may have systemic lupus erythematosus. Less commonly, other autoimmune disorders, such as glomerulonephritis, rheumatoid arthritis, thyroiditis, Sjögren syndrome, and pernicious anemia, may be associated with HAE.
  • Those HAE patients infected with Helicobacter pylori have been found to be more symptomatic than those who are not infected.
Previous
Proceed to Differential Diagnoses
 
 
Contributor Information and Disclosures
Author

Warren R Heymann, MD  Head, Division of Dermatology, Professor, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Warren R Heymann, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Coauthor(s)

Amanda T Moon, MD  Resident Physician, Department of Dermatology, University of Rochester, Strong Memorial Hospital

Amanda T Moon, MD, is a member of the following medical societies: American Academy of Dermatology, American Medical Association, American Medical Student Association/Foundation, and Society for Pediatric Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Robert A Schwartz, MD, MPH  Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Michael J Wells, MD  Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association

Disclosure: Nothing to disclose.

Paul Krusinski, MD  Director of Dermatology, Fletcher Allen Health Care; Professor, Department of Internal Medicine, University of Vermont College of Medicine

Paul Krusinski, MD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Catherine M Quirk, MD  Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania

Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD  Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Kathleen M. Rossy, MD, to the development and writing of this article.

References

  1. Cugno M, Zanichelli A, Foieni F, Caccia S, Cicardi M. C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends Mol Med. Feb 2009;15(2):69-78. [Medline].

  2. Bork K. Hereditary angioedema with normal C1 inhibitor activity including hereditary angioedema with coagulation factor XII gene mutations. Immunol Allergy Clin North Am. Nov 2006;26(4):709-24. [Medline].

  3. Davis AE 3rd. Mechanism of angioedema in first complement component inhibitor deficiency. Immunol Allergy Clin North Am. Nov 2006;26(4):633-51. [Medline].

  4. Gompels MM, Lock RJ, Abinun M, et al. C1 inhibitor deficiency: consensus document. Clin Exp Immunol. Mar 2005;139(3):379-94. [Medline].

  5. Bork K, Wulff K, Hardt J, Witzke G, Staubach P. Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy. J Allergy Clin Immunol. Jul 2009;124(1):129-34. [Medline].

  6. Craig T, Riedl M, Dykewicz MS, et al. When is prophylaxis for hereditary angioedema necessary?. Ann Allergy Asthma Immunol. May 2009;102(5):366-72. [Medline].

  7. Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med. Mar 2006;119(3):267-74. [Medline].

  8. Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. Sep 4 2008;359(10):1027-36. [Medline].

  9. Starr JC, Brasher GW, Rao A, Posey D. Erythema marginatum and hereditary angioedema. South Med J. Oct 2004;97(10):948-50. [Medline].

  10. Bork K, Fischer B, Dewald G. Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy. Am J Med. Mar 2003;114(4):294-8. [Medline].

  11. Weiler CR, van Dellen RG. Genetic test indications and interpretations in patients with hereditary angioedema. Mayo Clin Proc. Jul 2006;81(7):958-72. [Medline].

  12. Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl J Med. Jun 20 1996;334(25):1630-4. [Medline].

  13. Kreuz W, Martinez-Saguer I, Aygoren-Pursun E, Rusicke E, Heller C, Klingebiel T. C1-inhibitor concentrate for individual replacement therapy in patients with severe hereditary angioedema refractory to danazol prophylaxis. Transfusion. May 20 2009;[Medline].

  14. Sachse MM, Khachemoune A, Guldbakke KK, Kirschfink M. Hereditary angioedema. J Drugs Dermatol. Oct 2006;5(9):848-52. [Medline].

  15. Cicardi M, Castelli R, Zingale LC, Agostoni A. Side effects of long-term prophylaxis with attenuated androgens in hereditary angioedema: comparison of treated and untreated patients. J Allergy Clin Immunol. Feb 1997;99(2):194-6. [Medline].

  16. Morgan BP. Hereditary angioedema - therapies old and new (Editorial). N Engl J Med. Aug 2010;363:581-3.

  17. Leiden, The Netherlands. Biotech company Pharming Group NV ("Pharming" or "the Company") (NYSE Euronext: PHARM) today announces that, in agreement with the European Medicines Agency (EMEA), the dossier for the European Marketing Authorisation Application (MAA) of Rhucin(R) will be submitted in September 2009. CheckOrphan. Available at http://www.checkorphan.org/news/pharming_confirms_rhucin_european_maa_filing_timeline.. Accessed 8/5/2009.

  18. Cicardi M, Banerji A, Bracho F, Malbrán A, Rosenkranz B, Riedl M, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med. Aug 5 2010;363(6):532-41. [Medline]. [Full Text].

  19. Lumry WR, et al. Results from FAST-3: A phase III randomized, double-blind, placebo-controlled, multicenter study of subcutaneous icatibant in patients with acute hereditary angioedema (HAE) attacks. American Academy of Allergy, Asthma, & Immunology Meeting. March 22, 2011; Abstract L2.

  20. A Study of Icatibant in Patients With Acute Attacks of Hereditary Angioedema (FAST-3). clinicaltrials.gov. Available at http://clinicaltrials.gov/show/NCT00912093. Accessed March 22 2010.

  21. EASSI - Evaluation of the Safety of Self-Administration With Icatibant. clinicaltrials.gov. Available at http://clinicaltrials.gov/show/NCT00997204.. Accessed March 22 2010.

  22. Krause K, Metz M, Zuberbier T, Maurer M, Magerl M. Successful treatment of hereditary angioedema with bradykinin B2-receptor antagonist icatibant. J Dtsch Dermatol Ges. Sep 16 2009;[Medline].

  23. Bouillet L, Boccon-Gibod I, Ponard D, Drouet C, Cesbron JY, Dumestre-Perard C, et al. Bradykinin receptor 2 antagonist (icatibant) for hereditary angioedema type III attacks. Ann Allergy Asthma Immunol. Nov 2009;103(5):448. [Medline].

  24. Bracho FA. Hereditary angioedema. Curr Opin Hematol. Nov 2005;12(6):493-8. [Medline].

  25. Frank MM. Hereditary angioedema: the clinical syndrome and its management in the United States. Immunol Allergy Clin North Am. Nov 2006;26(4):653-68. [Medline].

  26. Zuraw BL. Current and future therapy for hereditary angioedema. Clin Immunol. Jan 2005;114(1):10-6. [Medline].

  27. Zuraw BL. Novel therapies for hereditary angioedema. Immunol Allergy Clin North Am. Nov 2006;26(4):691-708. [Medline].

  28. Zuraw B, Yasothan U, Kirkpatrick P. Ecallantide. Nat Rev Drug Discov. Mar 2010;9(3):189-90. [Medline].

  29. US Food and Drug Administration. Advisory Committee Briefing Document:Kalbitor (ecallantide)For Acute Attacks of Hereditary Angioedema. Available at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM170334.pdf. Accessed March 16 2010.

  30. Cicardi M, Levy RJ, McNeil DL, et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med. Aug 2010;363:523-31.

  31. Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. Aug 2010;363:513-22.

  32. [Guideline] American Academy of Allergy, Asthma & Immunology. Consultation and referral guidelines citing the evidence: how the allergist-immunologist can help. J Allergy Clin Immunol. Feb 2006;117(2 Suppl Consultation):S495-523. [Medline].

  33. Agostoni A, Cicardi M. Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients. Medicine (Baltimore). Jul 1992;71(4):206-15. [Medline].

  34. Ariga T, Hoshioka A, Kohno Y, Sakamaki T, Matsumoto S. A de novo deletion in the C1 inhibitor gene in a case of sporadic hereditary angioneurotic edema. Clin Immunol Immunopathol. Oct 1993;69(1):103-5. [Medline].

  35. Borum ML. Hereditary angioedema: an unusual case in an African-American woman. J Natl Med Assoc. Feb 1998;90(2):115-8. [Medline].

  36. Bowen T, Cicardi M, Farkas H, et al. Canadian 2003 International Consensus Algorithm For the Diagnosis, Therapy, and Management of Hereditary Angioedema. J Allergy Clin Immunol. Sep 2004;114(3):629-37. [Medline].

  37. Boyle RJ, Nikpour M, Tang ML. Hereditary angio-oedema in children: a management guideline. Pediatr Allergy Immunol. Jun 2005;16(4):288-94. [Medline].

  38. Cicardi M, Zingale L. How do we treat patients with hereditary angioedema. Transfus Apher Sci. Dec 2003;29(3):221-7. [Medline].

  39. Heymann WR. Acquired angioedema. J Am Acad Dermatol. Apr 1997;36(4):611-5. [Medline].

  40. Kaplan AP, Greaves MW. Angioedema. J Am Acad Dermatol. Sep 2005;53(3):373-88; quiz 389-92. [Medline].

  41. Zuraw BL. Urticaria, angioedema, and autoimmunity. Clin Lab Med. Sep 1997;17(3):559-69. [Medline].

 
Previous
Next
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.