Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Congenital erythropoietic porphyria

Karl E Anderson, MD, FACP
Section Editors
Donald H Mahoney, Jr, MD
Moise L Levy, MD
Deputy Editor
Jennifer S Tirnauer, MD


The porphyrias are metabolic disorders caused by altered activities of enzymes within the heme biosynthetic pathway. Congenital erythropoietic porphyria (CEP; OMIM #263700, also called Günther disease) is a rare, autosomal recessive porphyria. It results from an inherited deficiency of the heme biosynthetic enzyme uroporphyrinogen III synthase (UROS; EC, hydroxymethylbilane hydrolase [cyclizing]) [1,2].

In patients with CEP, reduced UROS activity in developing red blood cell precursors causes accumulation of pathogenic heme intermediates (porphyrin isomers uroporphyrin I and coproporphyrin I) during hemoglobin synthesis; porphyrins are also elevated in mature red blood cells, plasma, feces, teeth, and bones. These accumulated porphyrins cause hemolytic anemia and severe cutaneous photosensitivity. In addition, the teeth, bones, and urine of affected individuals contain excess porphyrins and are often red or brown and fluoresce on exposure to light, especially with a wavelength of 400 to 420 nm.

The pathophysiology, diagnosis, and management of CEP will be reviewed here [3]. A general overview of the porphyrias and detailed discussions of the other cutaneous porphyrias are presented separately. (See "Porphyrias: An overview" and "Erythropoietic protoporphyria and X-linked protoporphyria" and "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Clinical manifestations and diagnosis".)


Enzymatic defect — In the heme biosynthetic pathway, uroporphyrinogen III synthase (UROS, previously termed uroporphyrinogen III cosynthase), catalyzes the conversion of the linear tetrapyrrole hydroxymethylbilane (HMB) to the cyclic tetrapyrrole uroporphyrinogen III (figure 1). This occurs with inversion of one of the four pyrroles, which becomes ring D of the product uroporphyrinogen III (see step 4 in the figure) (figure 1 and figure 2) [4]. Patients with congenital erythropoietic porphyria (CEP) lack normal UROS activity, and as a result the HMB intermediate accumulates excessively in bone marrow red blood cell (RBC) precursors that are actively synthesizing hemoglobin. HMB does not accumulate in the liver or other tissues that synthesize heme.

Excess HMB is converted non-enzymatically (by spontaneous ring closure without inversion of pyrrole ring D) to the non-physiologic porphyrin isomer uroporphyrinogen I (figure 2), some of which is then enzymatically converted to coproporphyrinogen I by uroporphyrinogen decarboxylase, as in step 5 of the figure (figure 1). Coproporphyrinogen I cannot be metabolized further, because coproporphyrinogen oxidase is stereospecific for the coproporphyrinogen III isomer. The excess porphyrinogens that accumulate in CEP are oxidized nonenzymatically to the corresponding porphyrins, primarily uroporphyrin I and coproporphyrin I, which are markedly elevated in circulating erythrocytes, plasma, urine and feces. These porphyrins are also deposited in teeth and bones.


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Jul 2017. | This topic last updated: Jul 11, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Romeo G, Levin EY. Uroporphyrinogen 3 cosynthetase in human congenital erythropoietic porphyria. Proc Natl Acad Sci U S A 1969; 63:856.
  2. Deybach JC, de Verneuil H, Phung N, et al. Congenital erythropoietic porphyria (Günther's disease): enzymatic studies on two cases of late onset. J Lab Clin Med 1981; 97:551.
  3. Desnick RJ, Astrin KH. Congenital erythropoietic porphyria: advances in pathogenesis and treatment. Br J Haematol 2002; 117:779.
  4. BOGORAD L. The enzymatic synthesis of porphyrins from porphobilinogen. II. Uroporphyrin III. J Biol Chem 1958; 233:510.
  5. Xu W, Astrin KH, Desnick RJ. Molecular basis of congenital erythropoietic porphyria: mutations in the human uroporphyrinogen III synthase gene. Hum Mutat 1996; 7:187.
  6. Fontanellas A, Bensidhoum M, Enriquez de Salamanca R, et al. A systematic analysis of the mutations of the uroporphyrinogen III synthase gene in congenital erythropoietic porphyria. Eur J Hum Genet 1996; 4:274.
  7. Desnick RJ, Glass IA, Xu W, et al. Molecular genetics of congenital erythropoietic porphyria. Semin Liver Dis 1998; 18:77.
  8. Moruno Tirado A, Herrera Saval A, Martinez Montero E, et al. Congenital erythropoietic porphyria, description of a new mutation in two brothers. Eur J Pediatr 1997; 156:817.
  9. Takamura N, Hombrados I, Tanigawa K, et al. Novel point mutation in the uroporphyrinogen III synthase gene causes congenital erythropoietic porphyria of a Japanese family. Am J Med Genet 1997; 70:299.
  10. Tezcan I, Xu W, Gurgey A, et al. Congenital erythropoietic porphyria successfully treated by allogeneic bone marrow transplantation. Blood 1998; 92:4053.
  11. Deybach JC, de Verneuil H, Boulechfar S, et al. Point mutations in the uroporphyrinogen III synthase gene in congenital erythropoietic porphyria (Günther's disease). Blood 1990; 75:1763.
  12. Boulechfar S, Da Silva V, Deybach JC, et al. Heterogeneity of mutations in the uroporphyrinogen III synthase gene in congenital erythropoietic porphyria. Hum Genet 1992; 88:320.
  13. de Verneuil H, Deybach JC, Grandchamp B, et al. Coexistence of two point mutations in the uroporphyrinogen III synthase gene in one case of CEP. Blood 1989; 74:105A.
  14. Bensidhoum M, Ged C, Hombrados I, et al. Identification of two new mutations in congenital erythropoietic porphyria. Eur J Hum Genet 1995; 3:102.
  15. Tanigawa K, Bensidhoum M, Takamura N, et al. A novel point mutation in congenital erythropoietic porphyria in two members of Japanese family. Hum Genet 1996; 97:557.
  16. Ged C, Mendez M, Robert E, et al. A knock-in mouse model of congenital erythropoietic porphyria. Genomics 2006; 87:84.
  17. Bishop DF, Johansson A, Phelps R, et al. Uroporphyrinogen III synthase knock-in mice have the human congenital erythropoietic porphyria phenotype, including the characteristic light-induced cutaneous lesions. Am J Hum Genet 2006; 78:645.
  18. Phillips JD, Steensma DP, Pulsipher MA, et al. Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria. Blood 2007; 109:2618.
  19. Warner CA, Yoo HW, Roberts AG, Desnick RJ. Congenital erythropoietic porphyria: identification and expression of exonic mutations in the uroporphyrinogen III synthase gene. J Clin Invest 1992; 89:693.
  20. Xu W, Warner CA, Desnick RJ. Congenital erythropoietic porphyria: identification and expression of 10 mutations in the uroporphyrinogen III synthase gene. J Clin Invest 1995; 95:905.
  21. Shady AA, Colby BR, Cunha LF, et al. Congenital erythropoietic porphyria: identification and expression of eight novel mutations in the uroporphyrinogen III synthase gene. Br J Haematol 2002; 117:980.
  22. Fortian A, González E, Castaño D, et al. Intracellular rescue of the uroporphyrinogen III synthase activity in enzymes carrying the hotspot mutation C73R. J Biol Chem 2011; 286:13127.
  23. Blouin JM, Bernardo-Seisdedos G, Sasso E, et al. Missense UROS mutations causing congenital erythropoietic porphyria reduce UROS homeostasis that can be rescued by proteasome inhibition. Hum Mol Genet 2017; 26:1565.
  24. Warner CA, Poh-Fitzpatrick MB, Zaider EF, et al. Congenital erythropoietic porphyria. A mild variant with low uroporphyrin I levels due to a missense mutation (A66V) encoding residual uroporphyrinogen III synthase activity. Arch Dermatol 1992; 128:1243.
  25. Ged C, Mégarbané H, Chouery E, et al. Congenital erythropoietic porphyria: report of a novel mutation with absence of clinical manifestations in a homozygous mutant sibling. J Invest Dermatol 2004; 123:589.
  26. Katugampola RP, Badminton MN, Finlay AY, et al. Congenital erythropoietic porphyria: a single-observer clinical study of 29 cases. Br J Dermatol 2012; 167:901.
  27. To-Figueras J, Ducamp S, Clayton J, et al. ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria. Blood 2011; 118:1443.
  28. Fritsch C, Bolsen K, Ruzicka T, Goerz G. Congenital erythropoietic porphyria. J Am Acad Dermatol 1997; 36:594.
  29. Hsu MM, Yang CC. Uraemic pruritus responsive to broadband ultraviolet (UV) B therapy does not readily respond to narrowband UVB therapy. Br J Dermatol 2003; 149:888.
  30. Piomelli S, Poh-Fitzpatrick MB, Seaman C, et al. Complete suppression of the symptoms of congenital erythropoietic porphyria by long-term treatment with high-level transfusions. N Engl J Med 1986; 314:1029.
  31. Eriksen L, Seip M. Congenital erythropoietic porphyria: a family study. Clin Genet 1973; 4:166.
  32. Kondo M, Yano Y, Shirataka M, et al. Porphyrias in Japan: compilation of all cases reported through 2002. Int J Hematol 2004; 79:448.
  33. Stenberg B, With TK. The first Swedish case of congenital erythropoietic porphyria, with a revised view of the porphyrin excretion pattern in this disease. Acta Derm Venereol Suppl (Stockh) 1982; 100:87.
  34. Tanigawa K, Takamura N, Yamashita S. [Congenital erythropoietic porphyria]. Nihon Rinsho 1995; 53:1422.
  35. Kontos AP, Ozog D, Bichakjian C, Lim HW. Congenital erythropoietic porphyria associated with myelodysplasia presenting in a 72-year-old man: report of a case and review of the literature. Br J Dermatol 2003; 148:160.
  36. Murphy A, Gibson G, Elder GH, et al. Adult-onset congenital erythropoietic porphyria (Günther's disease) presenting with thrombocytopenia. J R Soc Med 1995; 88:357P.
  37. Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Blood 2012; 120:4496.
  38. Pandhi D, Suman M, Khurana N, Reddy BS. Congenital erythropoietic porphyria complicated by squamous cell carcinoma. Pediatr Dermatol 2003; 20:498.
  39. Jacobo A, Almeida HL Jr, Jorge VM. Congenital erythropoietic porphyria in two siblings. Dermatol Online J 2005; 11:15.
  40. SCHMID R, SCHWARTZ S, SUNDBERG RD. Erythropoietic (congenital) porphyria: A rare abnormality of the normoblasts. Blood 1955; 10:416.
  41. Cernik C, Haller N, Mostow EN. Adult-onset erythropoietic porphyria in the setting of MDS. Arch Dermatol 2009; 145:948.
  42. Aguilera P, Badenas C, Whatley SD, To-Figueras J. Late-onset cutaneous porphyria in a patient heterozygous for a uroporphyrinogen III synthase gene mutation. Br J Dermatol 2016; 175:1346.
  43. Oguz F, Sidal M, Bayram C, et al. Ocular involvement in two symptomatic congenital erythropoietic porphyria. Eur J Pediatr 1993; 152:671.
  44. Tanigawa K, Takamura N, Nakata K, et al. Ocular complication in congenital erythropoietic porphyria. Ophthalmologica 1996; 210:183.
  45. Ueda S, Rao GN, LoCascio JA, et al. Corneal and conjunctival changes in congenital erythropoietic porphyria. Cornea 1989; 8:286.
  46. Veenashree MP, Sangwan VS, Vemuganti GK, Parthasaradhi A. Acute scleritis as a manifestation of congenital erythropoietic porphyria. Cornea 2002; 21:530.
  47. Laorr A, Greenspan A. Severe osteopenia in congenital erythropoietic porphyria. Can Assoc Radiol J 1994; 45:307.
  48. Kappas A, Sassa S, Galbraith RA, Nordmann Y. The porphyrias. In: Metabolic and Molecular Bases of Inherited Disease, 7th ed, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds), McGraw-Hill, New York 1995. Vol 2, p.2103.
  49. Fayle SA, Pollard MA. Congenital erythropoietic porphyria--oral manifestations and dental treatment in childhood: a case report. Quintessence Int 1994; 25:551.
  50. Bhavasar R, Santoshkumar G, Prakash BR. Erythrodontia in congenital erythropoietic porphyria. J Oral Maxillofac Pathol 2011; 15:69.
  51. Kaiser IH. Brown amiotic fluid in congenital erythropoietic porphyria. Obstet Gynecol 1980; 56:383.
  52. Deybach JC, Grandchamp B, Grelier M, et al. Prenatal exclusion of congenital erythropoietic porphyria (Günther's disease) in a fetus at risk. Hum Genet 1980; 53:217.
  53. Ged C, Moreau-Gaudry F, Taine L, et al. Prenatal diagnosis in congenital erythropoietic porphyria by metabolic measurement and DNA mutation analysis. Prenat Diagn 1996; 16:83.
  54. Verstraeten L, Van Regemorter N, Pardou A, et al. Biochemical diagnosis of a fatal case of Günther's disease in a newborn with hydrops foetalis. Eur J Clin Chem Clin Biochem 1993; 31:121.
  55. Kramer S, Viljoen E, Meyer AM, Metz J. The anaemia of erythropoietic prophyria with the description of the disease in an elderly patient. Br J Haematol 1965; 11:666.
  56. Rank JM, Straka JG, Weimer MK, et al. Hematin therapy in late onset congenital erythropoietic porphyria. Br J Haematol 1990; 75:617.
  57. Katugampola RP, Anstey AV, Finlay AY, et al. A management algorithm for congenital erythropoietic porphyria derived from a study of 29 cases. Br J Dermatol 2012; 167:888.
  58. Kaye ET, Levin JA, Blank IH, et al. Efficiency of opaque photoprotective agents in the visible light range. Arch Dermatol 1991; 127:351.
  59. Mathews-Roth MM, Pathak MA, Fitzpatrick TB, et al. Beta carotene therapy for erythropoietic protoporphyria and other photosensitivity diseases. Arch Dermatol 1977; 113:1229.
  60. Kumar M, Bose S, Darlong V, Punj J. Congenital erythropoietic porphyria: anesthetic implications. J Anesth 2009; 23:569.
  61. Jensen NF, Fiddler DS, Striepe V. Anesthetic considerations in porphyrias. Anesth Analg 1995; 80:591.
  62. Guarini L, Piomelli S, Poh-Fitzpatrick MB. Hydroxyurea in congenital erythropoietic porphyria. N Engl J Med 1994; 330:1091.
  63. Watson CJ, Bossenmaier I, Cardinal R, Petryka ZJ. Repression by hematin of porphyrin biosynthesis in erythrocyte precursors in congenital erythropoietic porphyria. Proc Natl Acad Sci U S A 1974; 71:278.
  64. VARADI S. [Haematological aspects in a case of erythropoietic porphyria]. Br J Haematol 1958; 4:270.
  65. Kaufman BM, Vickers HR, Rayne J, Ryan TJ. Congenital erythropoietic porphyria. Report of a case. Br J Dermatol 1967; 79:210.
  66. Moore MR, Thompson GG, Goldberg A, et al. The biosynthesis of haem in congenital (erythropoietic) porphyria. Int J Biochem 1978; 9:933.
  67. Pain RW, Welch FW, Woodroffe AJ, et al. Erythropoietic uroporphyria of Gunther first presenting at 58 years with positive family studies. Br Med J 1975; 3:621.
  68. Weston MJ, Nicholson DC, Lim CK, et al. Congenital erythropoietic uroporphyria (Günther's disease) presenting in a middle aged man. Int J Biochem 1978; 9:921.
  69. Tishler PV, Winston SH. Rapid improvement in the chemical pathology of congenital erythropoietic porphyria with treatment with superactivated charcoal. Methods Find Exp Clin Pharmacol 1990; 12:645.
  70. Minder EI, Schneider-Yin X, Möll F. Lack of effect of oral charcoal in congenital erythropoietic porphyria. N Engl J Med 1994; 330:1092.
  71. Hift RJ, Meissner PN, Kirsch RE. The effect of oral activated charcoal on the course of congenital erythropoietic porphyria. Br J Dermatol 1993; 129:14.
  72. Egan DN, Yang Z, Phillips J, Abkowitz JL. Inducing iron deficiency improves erythropoiesis and photosensitivity in congenital erythropoietic porphyria. Blood 2015; 126:257.
  73. Kauffman L, Evans DI, Stevens RF, Weinkove C. Bone-marrow transplantation for congenital erythropoietic porphyria. Lancet 1991; 337:1510.
  74. Fritsch C, Lang K, Bolsen K, et al. Congenital erythropoietic porphyria. Skin Pharmacol Appl Skin Physiol 1998; 11:347.
  75. Dupuis-Girod S, Akkari V, Ged C, et al. Successful match-unrelated donor bone marrow transplantation for congenital erythropoietic porphyria (Günther disease). Eur J Pediatr 2005; 164:104.
  76. Bedel A, Taillepierre M, Guyonnet-Duperat V, et al. Metabolic correction of congenital erythropoietic porphyria with iPSCs free of reprogramming factors. Am J Hum Genet 2012; 91:109.
  77. de Verneuil H, Robert-Richard E, Ged C, et al. [Successful gene therapy of mice with congenital erythropoietic porphyria]. Med Sci (Paris) 2008; 24:615.
  78. Hallai N, Anstey A, Mendelsohn S, et al. Pregnancy in a patient with congenital erythropoietic porphyria. N Engl J Med 2007; 357:622.