eMedicine Specialties > Dermatology > Metabolic Diseases

Variegate Porphyria

Author: Maureen B Poh-Fitzpatrick, MD, Professor Emerita of Dermatology and Special Lecturer, Columbia University; Professor of Medicine (Dermatology), University of Tennessee
Contributor Information and Disclosures

Updated: Feb 18, 2009

Introduction

Background

Variegate porphyria (VP) is an inherited disorder of porphyrin-heme metabolism arising from mutations of the gene encoding the enzyme protoporphyrinogen oxidase.1,2,3,4 Manifestations of variegate porphyria in any given individual may include cutaneous photosensitivity, systemic symptoms arising from neurologic dysfunction, or both.3,5,6,7,8

Pathophysiology

Inherited as an autosomal dominant trait, variegate porphyria is biochemically characterized by accumulations of the photosensitizing porphyrins protoporphyrin and coproporphyrin.5 In addition, abnormally high levels of the porphyrin precursors porphobilinogen and aminolevulinic acid are found during episodic attacks of systemic symptoms.5,9 These episodes are caused by dysfunctions of central, autonomic, and peripheral nervous systems that appear to be effects of deranged heme synthesis on neurons.10

Frequency

United States

No porphyria registry exists in the United States; therefore, accurate figures are not available. Unknown numbers of cases may still be unrecognized or misdiagnosed as another porphyria.

International

Incidence is estimated at 1 case in 300 persons in South Africa, where a protoporphyrinogen oxidase gene mutation traceable to Dutch immigrants who married there in 1680 has been widely disseminated.11,12 In other parts of the world, variegate porphyria is considered uncommon to rare.

Mortality/Morbidity

Cutaneous photosensitivity may cause difficulty performing manual labor and may limit many daily activities. Neurovisceral disorders vary from relatively mild symptoms that can remit spontaneously to profound crises that can be fatal or incapacitating for months to years.3,5,6,7,13

Race

No well-established racial predilection is known, although the disease is common among South Africans of Dutch ancestry, many of whom inherit a founder gene propagated in that population.

Sex

Variegate porphyria occurs in both men and women.

Age

Variegate porphyria usually presents after puberty. Very rare childhood cases have been ascribed to the presence of 2 mutant protoporphyrinogen oxidase genes in the same individual.14,15

Clinical

History

  • A family history of variegate porphyria may or may not be present. Studies of the clinical penetrance of the variegate porphyria trait found that approximately 60% of all individuals harboring a single protoporphyrinogen oxidase mutation remained silent carriers.16,17  Among the 40% who did manifest symptoms, photosensitivity alone was the presenting complaint far more often than neurological disturbances alone, while only a small minority (4-8%) experienced both types of symptoms.
  • A porphyric attack is typically described as abdominal discomfort that may have progressed over several hours to severe pain extending into the back and thighs. Nausea with vomiting, constipation, hypertension, tachycardia, anxiety, and agitation may be reported. Pain and weakness developing in the arms and legs indicates an accelerating attack that may progress to flaccid quadriparesis. Central nerve paralysis, respiratory distress, confusion and bizarre behavior, seizures, and coma may have developed before the patient is initially seen by medical personnel. Attack episodes of variegate porphyria can often be linked to history of a new medication. Factors historically associated with the onset of attacks in other acute porphyrias (eg, hormonal fluctuations due to menses, pregnancy or therapeutic hormones, infections, other stressors) appear to be less often responsible for attacks in variegate porphyria.13

Physical

  • Photocutaneous lesions are the most common presenting signs of variegate porphyria. Mechanical fragility, blistering, milia, furrowing, and scarring occur in sun-exposed skin. Hypertrichosis, dyspigmentation, sclerodermoid changes, and a weather-beaten or leathery texture may be present. Children with homozygous variegate porphyria experience photosensitivity of mutilating severity.14,18
  • Systemic signs occur less frequently and recur far less often in variegate porphyria than in acute intermittent porphyria (AIP).13
  • Pain in variegate porphyria may become excruciating; uncontrolled vomiting can lead to dehydration. Deteriorating neurological function produces multiple sequelae. Initial limb weakness may progress to areflexic quadriparesis. Respiratory distress may become profound. Heart rate and blood pressure can rise to critical levels. During such crises, dark-orange or reddish urine is excreted and bowel function is disturbed. Tonic-clonic seizures and coma may ensue.
  • Confusion, disorientation, agitation, mania, depression, and schizophrenialike behavior have all been reported. Psychiatric symptoms were noted in 80% of 18 Finnish patients during attacks, with 25% described as delirious and psychotic.6 In the larger South African experience, however, neuropsychiatric disturbances are infrequent in variegate porphyria, especially in the absence of other signs and symptoms of an attack.3 Metabolic encephalopathy does occur in variegate porphyria crises and may contribute to some of these phenomena, as well as to seizures and coma.
  • Hypervolemia and hyponatremia noted in more severe attacks may involve renal salt wasting, inappropriate antidiuretic hormone secretion, or infusion of inappropriate replacement fluids. Hypomagnesemia may also be present.
  • Because variegate porphyria may variably manifest with only neurovisceral symptoms, with only cutaneous photosensitivity, or with both, other diagnoses to be considered include porphyrias that share either type or both types of symptoms and nonporphyric bullous disorders that occur in sun-exposed skin.

Causes

Variegate porphyria arises from autosomal dominant inheritance of a gene mutation encoding a defective protoporphyrinogen oxidase enzyme protein. Individuals with one such mutation have enzyme activity diminished to approximately 50% of normal. The disease in most individuals with such a mutation remains clinically silent, but these persons are at risk of becoming symptomatic if exposed to environmental factors (most often drugs) that can induce overt phenotypical expression. Inheritance of 2 mutant protoporphyrin oxidase genes causes a more profound reduction in residual enzyme activity to 25% or less, with more severe disease manifestations presenting in childhood.15,19

More on Variegate Porphyria

Overview: Variegate Porphyria
Differential Diagnoses & Workup: Variegate Porphyria
Treatment & Medication: Variegate Porphyria
Follow-up: Variegate Porphyria
References
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References

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  2. Meissner PN, Day RS, Moore MR, Disler PB, Harley E. Protoporphyrinogen oxidase and porphobilinogen deaminase in variegate porphyria. Eur J Clin Invest. Jun 1986;16(3):257-61. [Medline].

  3. Kirsch RE, Meissner PN, Hift RJ. Variegate porphyria. Semin Liver Dis. 1998;18(1):33-41. [Medline].

  4. Whatley SD, Puy H, Morgan RR, et al. Variegate porphyria in Western Europe: identification of PPOX gene mutations in 104 families, extent of allelic heterogeneity, and absence of correlation between phenotype and type of mutation. Am J Hum Genet. Oct 1999;65(4):984-94. [Medline].

  5. Eales L, Day RS, Blekkenhorst GH. The clinical and biochemical features of variegate porphyria: an analysis of 300 cases studied at Groote Schuur Hospital, Cape Town. Int J Biochem. 1980;12(5-6):837-53. [Medline].

  6. Mustajoki P. Variegate porphyria. Twelve years' experience in Finland. Q J Med. Spring 1980;49(194):191-203. [Medline].

  7. Bonkowsky HL, Schady W. Neurologic manifestations of acute porphyria. Semin Liver Dis. May 1982;2(2):108-24. [Medline].

  8. Bonkovsky HL, Barnard GF. The Porphyrias. Curr Treat Options Gastroenterol. Dec 2000;3(6):487-500. [Medline].

  9. Meissner P, Adams P, Kirsch R. Allosteric inhibition of human lymphoblast and purified porphobilinogen deaminase by protoporphyrinogen and coproporphyrinogen. A possible mechanism for the acute attack of variegate porphyria. J Clin Invest. Apr 1993;91(4):1436-44. [Medline].

  10. Meyer UA, Schuurmans MM, Lindberg RL. Acute porphyrias: pathogenesis of neurological manifestations. Semin Liver Dis. 1998;18(1):43-52. [Medline].

  11. Dean G. The porphyrias. A story of inheritance and environment. London: Pitman Medical; 1971:2nd ed.

  12. Meissner PN, Dailey TA, Hift RJ, Ziman M, Corrigall AV, Roberts AG. A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria. Nat Genet. May 1996;13(1):95-7. [Medline].

  13. Hift RJ, Meissner PN. An analysis of 112 acute porphyric attacks in Cape Town, South Africa: Evidence that acute intermittent porphyria and variegate porphyria differ in susceptibility and severity. Medicine (Baltimore). Jan 2005;84(1):48-60. [Medline].

  14. Mustajoki P, Tenhunen R, Niemi KM, Nordmann Y, Kaariainen H, Norio R. Homozygous variegate porphyria. A severe skin disease of infancy. Clin Genet. Nov 1987;32(5):300-5. [Medline].

  15. Corrigall AV, Hift RJ, Davids LM, et al. Homozygous variegate porphyria in South Africa: genotypic analysis in two cases. Mol Genet Metab. Apr 2000;69(4):323-30. [Medline].

  16. von und zu Fraunberg M, Timonen K, Mustajoki P, Kauppinen R. Clinical and biochemical characteristics and genotype-phenotype correlation in Finnish variegate porphyria patients. Eur J Hum Genet. Oct 2002;10(10):649-57. [Medline].

  17. Hift RJ, Meissner D, Meissner PN. A systematic study of the clinical and biochemical expression of variegate porphyria in a large South African family. Br J Dermatol. Aug 2004;151(2):465-71. [Medline].

  18. Korda V, Deybach JC, Martasek P, et al. Homozygous variegate porphyria. Lancet. Apr 14 1984;1(8381):851. [Medline].

  19. Hift RJ, Meissner PN, Todd G, et al. Homozygous variegate porphyria: an evolving clinical syndrome. Postgrad Med J. Oct 1993;69(816):781-6. [Medline].

  20. Sassa S. Modern diagnosis and management of the porphyrias. Br J Haematol. Nov 2006;135(3):281-92. [Medline].

  21. Hift RJ, Davidson BP, van der Hooft C, Meissner DM, Meissner PN. Plasma fluorescence scanning and fecal porphyrin analysis for the diagnosis of variegate porphyria: precise determination of sensitivity and specificity with detection of protoporphyrinogen oxidase mutations as a reference standard. Clin Chem. May 2004;50(5):915-23. [Medline].

  22. Poh-Fitzpatrick MB. A plasma porphyrin fluorescence marker for variegate porphyria. Arch Dermatol. May 1980;116(5):543-7. [Medline].

  23. Logan GM, Weimer MK, Ellefson M, Pierach CA, Bloomer JR. Bile porphyrin analysis in the evaluation of variegate porphyria. N Engl J Med. May 16 1991;324(20):1408-11. [Medline].

  24. Zaider E, Bickers DR. Clinical laboratory methods for diagnosis of the porphyrias. Clin Dermatol. Mar-Apr 1998;16(2):277-93. [Medline].

  25. Epstein JH, Tuffanelli DL, Epstein WL. Cutaneous changes in the porphyrias. A microscopic study. Arch Dermatol. May 1973;107(5):689-98. [Medline].

  26. Timonen K, Niemi KM, Mustajoki P, Tenhunen R. Skin changes in variegate porphyria. Clinical, histopathological, and ultrastructural study. Arch Dermatol Res. 1990;282(2):108-14. [Medline].

  27. Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. Mar 15 2005;142(6):439-50. [Medline].

  28. Kalman DR, Bonkovsky HL. Management of acute attacks in the porphyrias. Clin Dermatol. Mar-Apr 1998;16(2):299-306. [Medline].

  29. Tschudy DP, Welland FH, Collins A, Hunter G Jr. The effect of carbohydrate feeding on the induction of delta-aminolevulinic acid synthatase. Metabolism. May 1964;13:396-406. [Medline].

  30. Bonkovsky HL, Healey JF, Lourie AN, Gerron GG. Intravenous heme-albumin in acute intermittent porphyria: evidence for repletion of hepatic hemoproteins and regulatory heme pools. Am J Gastroenterol. Aug 1991;86(8):1050-6. [Medline].

  31. Anderson KE, Spitz IM, Sassa S, Bardin CW, Kappas A. Prevention of cyclical attacks of acute intermittent porphyria with a long-acting agonist of luteinizing hormone-releasing hormone. N Engl J Med. Sep 6 1984;311(10):643-5. [Medline].

  32. Stojeba N, Meyer C, Jeanpierre C, et al. Recovery from a variegate porphyria by a liver transplantation. Liver Transpl. Jul 2004;10(7):935-8. [Medline].

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Further Reading

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Keywords

VP, porphyria variegata, South African porphyria, protocoproporphyria, mixed porphyria, porphyria cutanea tarda hereditaria, royal malady, porphyrin-heme metabolism, protoporphyrinogen oxidase, protoporphyrinogen oxidase gene

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Contributor Information and Disclosures

Author

Maureen B Poh-Fitzpatrick, MD, Professor Emerita of Dermatology and Special Lecturer, Columbia University; Professor of Medicine (Dermatology), University of Tennessee
Maureen B Poh-Fitzpatrick, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and New York Academy of Medicine
Disclosure: Lundbeck, Inc. Honoraria Review panel membership

Medical Editor

David Woodley, MD, Co-Chair, Professor, Department of Medicine, Division of Dermatology, University of Southern California
David Woodley, MD is a member of the following medical societies: American Academy of Dermatology, American Association for the Advancement of Science, American College of Emergency Physicians, American College of Physicians, American Federation for Medical Research, American Society for Clinical Investigation, New York Academy of Medicine, Society for Investigative Dermatology, and Southern Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Julia R Nunley, MD, Professor, Program Director, Dermatology Residency, Department of Dermatology, Virginia Commonwealth University Medical Center
Julia R Nunley, MD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, American Society of Nephrology, International Society of Nephrology, Medical Dermatology Society, Medical Society of Virginia, National Kidney Foundation, Phi Beta Kappa, and Women's Dermatologic Society
Disclosure: Johnson and Johnson stock holder dividends; Amgen stock holder dividends; Forest Lab, Inc stock holder dividends; Galaxo Smith Klein stock holder dividends; Covidien stock holder dividends; Novartis Grant/research funds Consulting; Biolex  sub-investigator

CME Editor

Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania
Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology
Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds None; Genentech Consulting fee Consulting; Centocor Consulting fee Consulting; Centocor Grant/research funds None; Covance Consulting fee Consulting; Shire  Consulting

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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