Congenital Erythropoietic Porphyria

  • Jul 6, 2020
  • Permission to share. If you are looking for references to read about CEP this would be it.

Congenital Erythropoietic Porphyria

Synonym: Günther Disease

Angelika Erwin, MD, PhD, Manisha Balwani, MD, MS, Robert J Desnick, MD, PhD, FACMG; Porphyrias Consortium of the NIH-Sponsored Rare Diseases Clinical Research Network.

Author Information

Initial Posting: September 12, 2013; Last Update: April 7, 2016.

Estimated reading time: 24 minutes

Go to:



Congenital erythropoietic porphyria (CEP) is characterized in most individuals by severe cutaneous photosensitivity with blistering and increased friability of the skin over light-exposed areas. Onset in most affected individuals occurs at birth or early infancy. The first manifestation is often pink to dark red discoloration of the urine. Hemolytic anemia is common and can range from mild to severe, with some affected individuals requiring chronic blood transfusions. Porphyrin deposition may lead to corneal ulcers and scarring, reddish-brown discoloration of the teeth (erythrodontia), and mild bone loss and/or expansion of the bone marrow. The phenotypic spectrum, however, is broad and ranges from non-immune hydrops fetalis in utero to late-onset disease with only mild cutaneous manifestations in adulthood.


The diagnosis of CEP is supported by the biochemical findings of markedly decreased uroporphyrinogen (URO)-synthase activity in erythrocytes and/or markedly increased levels of urinary uroporphyrin I and coproporphyrin I isomers. The diagnosis is confirmed most commonly by identification of biallelic UROS pathogenic variants or on rare occasion by the identification of a hemizygous pathogenic variant in the X-linked gene GATA1.


Treatment of manifestations: There is no FDA-approved treatment for CEP or specific treatment for the photosensitivity. The only effective management is prevention of blistering by avoidance of sun and light exposure, including the long-wave ultraviolet light that passes through window glass or is emitted from artificial light sources. Therefore, the use of protective clothing, wraparound sunglasses, protective window films, reddish incandescent bulbs, filtering screens for fluorescent lights, and opaque sunscreens containing zinc oxide or titanium oxide is recommended. Wound care is necessary to prevent infection of opened blisters; surgical intervention may be necessary; blood transfusions are necessary when hemolysis is significant. Bone marrow transplantation (BMT) is the only cure for CEP and should be considered in children with severe cutaneous and hematologic involvement.

Prevention of primary manifestations: Strict avoidance of sunlight and other long-wave UV light exposure.

Prevention of secondary complications: Vitamin D supplementation, immunization for hepatitis A and B.

Surveillance: Monitor hematologic indices to assess hemolysis every six months. In those receiving transfusions: monitor for hemolysis more frequently and for iron overload. Monitor hepatic function and vitamin D 25-OH every six to twelve months in all patients.

Agents/circumstances to avoid: Avoidance of sunlight and UV light (see Treatment of manifestations). In those with hepatic dysfunction: avoid drugs that may induce cholestasis.

Evaluation of relatives at risk: Presymptomatic diagnosis is warranted in relatives at risk for initiation of early intervention (no phototherapy, strict sun protection) and future monitoring for signs of hemolytic anemia.

Pregnancy management: Protective filters for artificial lights should be used in the delivery/operating room to prevent phototoxic damage to the mother during delivery.

Other: Neither beta-carotene nor phototherapy with narrow-band ultraviolet B radiation has been beneficial.


CEP caused by biallelic UROS pathogenic variants is inherited in an autosomal recessive (AR) manner. CEP caused by a GATA1 pathogenic variant is inherited in an X-linked (XL) manner.

  • AR CEP. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.
  • XL CEP. If the mother of an affected male is heterozygous for a GATA1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and can be either asymptomatic or have a milder phenotype.

Go to:


Formal diagnostic criteria have not been established for congenital erythropoietic porphyria (CEP).


Congenital erythropoietic porphyria (CEP) should be suspected in individuals with the following clinical and laboratory findings.

Clinical findings

  • Non-immune hydrops fetalis
  • Signs of congenital erythropoietic porphyria
    Pink to dark red discoloration of the urine (pink or dark red urine-stained diapers are often the first sign in infants)
    Hemolytic anemia
    Severe cutaneous photosensitivity with onset usually in infancy or early childhood
    Blisters and vesicles in light-exposed areas, which are prone to rupture and infection
    Scarring and deformities (photomutilation) of digits and facial features, caused by recurrent blistering, infections, and bone resorption
    In light-exposed areas: friable skin, skin thickening, hypo- and hyperpigmentation
    Reddish-brown discoloration of teeth (fluoresce on exposure to long-wave ultraviolet light), also called erythrodontia
    Corneal ulcers and scarring
    Hypertrichosis of face and extremities

Laboratory findings. Markedly increased levels of uroporphyrin I and coproporphyrin I isomers in erythrocytes, urine, or amniotic fluid as well as coproporphyrin I in stool (see Table 1)


Biochemical Characteristics of Congenital Erythropoietic Porphyria (CEP)

Enzyme DefectEnzyme Activity 1Uroporphyrin 1Coproporphyrin 1Uroporphyrinogen III synthase (URO-synthase) 2Undetectable to ~10% of normal mean activity in erythrocytesErythrocytes↑↑Urine↑↑Stool↑Amniotic fluid 3↑↑

↑ = markedly elevated


The deficient activity of uroporphyrinogen III synthase EC, encoded by UROS, results in non-enzymatic conversion of hydroxymethylbilane to uroporphyrinogen I, which is then metabolized to coproporphyrinogen I. Coproporphyrinogen I cannot be metabolized further. These metabolites are then oxidized to uroporphyrin I and coproporphyrin I, respectively, which are non-physiologic and pathogenic.


The assay for the enzyme uroporphyrinogen III synthase is available on a clinical basis and can be used to establish the diagnosis of CEP.


Amniotic fluid appears red to dark brown. Prenatal diagnosis is also possible by demonstrating markedly deficient URO-synthase activity in cultured amniotic cells or chorionic villi cells [Daïkha-Dahmane et al 2001].


The diagnosis of CEP is established by biochemical testing and should be confirmed by identification of biallelic pathogenic variants in UROS or, on rare occasion, by the identification of a hemizygous pathogenic variant in the X-linked gene GATA1 [Phillips et al 2007] (Table 2). If the diagnosis cannot be established by the results of molecular genetic testing, analysis of URO-synthase activity in erythrocytes can be pursued (Table 1).

Molecular genetic testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

  • Serial single-gene testing
    Typically sequence analysis of UROS is performed first, followed by UROS gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
    If no UROS pathogenic variants are detected, sequencing of GATA1 should be considered.
  • A multigene panel that includes UROS and GATA1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click

    Blog Archive

    Click here to access the Purple Light Blog Archive for 2010 to 2019.