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.
Initial Posting: September 12, 2013; Last Update: April 7, 2016.
Estimated reading time: 24 minutes
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.
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.
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 220.127.116.11, 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 Used in Congenital Erythropoietic Porphyria (CEP)
Gene 1Proportion of CEP Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 2 Detected by Test MethodSequence analysis 3Gene-targeted deletion/duplication analysis 4UROS~98% 5~90% 6, 7~10% 8GATA1~1% 9See footnote 10None reported
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Six regulatory variants approximately 200 base pairs upstream of the ATG can be detected by sequencing if the DNA region is included in the analysis.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in an affected male; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
In most individuals with congenital erythropoietic porphyria (CEP) severe cutaneous photosensitivity begins in early infancy; the first manifestation is often pink to dark red discoloration of the urine. Hemolytic anemia is common and can be mild to severe, requiring chronic blood transfusions in some. The phenotypic spectrum ranges from severe (non-immune hydrops fetalis) to milder disease (adult-onset with isolated cutaneous manifestations [Warner et al 1992]). (See Genotype-Phenotype Correlations for predictors of disease severity.)
Skin. Cutaneous photosensitivity is present at birth or early infancy and is characterized by blistering and increased friability of the skin over light-exposed areas. Bullae and vesicles are filled with serous fluid and are prone to rupture. Secondary infections with scarring and bone resorption (photomutilation) may lead to deformity and disfigurement of fingers, toes, and facial features including the nose, ears, and eyelids. Skin thickening, focal hyper- or hypopigmentation, and hypertrichosis of face and extremities may occur [Poh-Fitzpatrick 1986].
Photosensitivity symptoms are provoked mainly by visible light (400-410 nm Soret wavelength) and to a lesser degree by wavelengths in the long-wave UV region. Affected individuals are also sensitive to sunlight that passes through window glass that does not filter long-wave UVA or visible light as well as to light from artificial light sources.
Unlike the cutaneous manifestations in erythropoietic protoporphyria (EPP), symptoms such as tingling, burning, itching, or swelling usually do not occur in persons with CEP after light exposure.
Hematologic involvement. Mild to severe hemolytic anemia with anisocytosis, poikilocytosis, polychromasia, basophilic stippling, and reticulocytosis is common in CEP. Findings also include: the absence of haptoglobin, increased unconjugated bilirubin, and increased fecal urobilinogen [Schmid et al 1955]. Hemolysis presumably results from the accumulation of uroporphyrinogen I in the erythrocytes (see Pathophysiology) [Bishop et al 2006].
Those with severe hemolytic anemia often require chronic erythrocyte transfusions, which decreases porphyrin production by suppressing erythropoiesis, but can lead to iron overload and other complications [Piomelli et al 1986].
Secondary splenomegaly may develop as a consequence of hemolytic anemia. In addition to worsening the anemia, it can also result in leukopenia and thrombocytopenia, which may be associated with significant bleeding [Pain et al 1975, Weston et al 1978, Phillips et al 2007].
Ophthalmologic involvement. Deposition of porphyrins may lead to corneal ulcers and scarring, which can ultimately lead to blindness. Other ocular manifestations can include scleral necrosis, necrotizing scleritis, seborrheic blepharitis, keratoconjunctivitis, sclerokeratitis, and ectropion [Oguz et al 1993, Venkatesh et al 2000, Siddique et al 2011].
Erythrodontia. Porphyrin deposition in the teeth produces a reddish-brown color, termed erythrodontia. The teeth may fluoresce on exposure to long-wave ultraviolet light.
Bone involvement. Deposition of porphyrins in bone causes mild bone loss (osteopenia on x-ray) due to demineralization [Piomelli et al 1986, Laorr & Greenspan 1994, Fritsch et al 1997, Kontos et al 2003]. It can also cause expansion of the bone marrow, which can lead to hyperplastic bone marrow observed on biopsy [Poh-Fitzpatrick 1986, Anderson et al 2001].
Vitamin D deficiency. Individuals with CEP who avoid sunlight are at risk for vitamin D deficiency.
CEP results from markedly decreased (but not absent) URO-synthase activity (<1 to ~10% of normal). When expressed in vitro, the residual enzyme activity of individual pathogenic variants ranges from less than 1.0% to approximately 35% [Desnick & Astrin 2002].
URO-synthase, the fourth enzyme in the heme biosynthesis pathway, normally converts hydroxymethylbilane (HMB) to uroporphyrinogen III. When URO-synthase activity is deficient, HMB accumulates primarily in the erythron and is non-enzymatically converted to uroporphyrinogen I. Decarboxylation of uroporphyrinogen I by URO-decarboxylase leads to formation of hepta-, hexa-, and pentacarboxyl porphyrinogen I isomers, with coproporphyrinogen I being the final product. Since coproporphyrinogen oxidase is specific for the III isomer, coproporphyrinogen I cannot be further metabolized to heme and is therefore non-physiologic. Isomer I porphyrinogens are pathogenic when they accumulate in large amounts and are auto-oxidized to their corresponding porphyrins [Piomelli et al 1986, Poh-Fitzpatrick et al 1988].
Porphyrinogen I isomers accumulate in bone marrow erythroid precursors; erythrocytes undergo auto-oxidation, which causes damage of the erythrocytes and hemolysis. Porphyrin I isomers are released into the circulation and deposited in skin, bone, and other tissues as well as excreted in urine and feces [Desnick et al 1998].
Urinary porphyrin excretion is markedly increased (100-1,000 times normal) and consists mainly of uroporphyrin I and coproporphyrin I, with lesser increases in hepta-, hexa-, and pentacarboxyl porphyrin isomers [Fritsch et al 1997]. While isomer I porphyrins are predominant, isomer III porphyrins are also increased.
Cutaneous photosensitivity with blistering and increased friability occurs because the porphyrins deposited in the skin are photocatalytic and cytotoxic compounds [Poh-Fitzpatrick 1985]. Presumably, exposure of the skin to sunlight or other sources of long-wave ultraviolet light in the Soret band (400-410 nm) leads to a phototoxic excitation of the accumulated uroporphyrin I and coproporphyrin I isomers. This results in formation of singlet oxygen and other oxygen radicals, which presumably produce tissue and vessel damage [Kaufman et al 1967, Bickers 1987, Dawe et al 2002].
The bone marrow contains much larger amounts of porphyrins (mostly uroporphyrin I and coproporphyrin I) than other tissues and hemolysis is almost always present in persons with CEP. Whether it is accompanied by anemia depends on whether erythroid hyperplasia is sufficient to compensate for the increased rate of erythrocyte destruction, which may vary over time. More severely affected individuals are transfusion dependent.
Splenomegaly usually develops secondary to hemolysis and can also lead to thrombocytopenia and leukopenia. In addition, porphyrin deposition also occurs in the spleen and to a lesser degree in the liver.
The genotype-phenotype correlations that have been established in CEP are largely determined by the amount of residual enzyme activity encoded by the specific mutated alleles.
In contrast, individuals with pathogenic variants expressing higher residual activities such as c.244G>T (p.Val82Phe) (35% of normal activity in vitro), c.311C>T (p.Ala104Val) (7.7% of normal activity in vitro), and c.197C>T (p.Ala66Val) (14.5% of normal activity in vitro) have milder phenotypes even if heteroallelic for c.217T>C (p.Cys73Arg) or another pathogenic variant with very low or almost absent residual enzyme activity.
Disease modifiers. The CEP phenotype may be modulated by sequence variants in ALAS2, mutation of which typically causes X-linked protoporphyria (XLP). A novel c.1757A>T (p.Tyr586Phe) variant in exon 11 of ALAS2 was identified in a girl with severe CEP who had biallelic UROS pathogenic variants [To-Figueras et al 2011].
Most biallelic UROS pathogenic variants are 100% penetrant. One report to the contrary concerns a Palestinian girl who was asymptomatic (without cutaneous or hematologic signs) despite having a profound deficiency in URO-synthase activity due to homozygosity for the pathogenic missense variant c.139T>C. Four of her sibs, who were homozygous for the same pathogenic variant, had moderate to severe cutaneous disease [Ged et al 2004]. The molecular basis for the apparent non-penetrance in one sib is unknown but possibly involves unknown modifier genes that prevent the phototoxic effects of porphyrin accumulation.
Obsolete terms for CEP are: erythropoietic porphyria, congenital porphyria, congenital hematoporphyria, and erythropoietic uroporphyria (Günther's disease).
CEP is a rare porphyria. To date, more than 200 cases have been reported.
CEP is pan ethnic and occurs equally in men and women [Katugampola et al 2012b].
UROS. No phenotypes other than those discussed in this GeneReview are known to be associated with pathogenic variants in UROS.
GATA1. Pathogenic variants in this gene are also observed in:
Disorders to Consider in the Differential Diagnosis of Congenital Erythropoietic Porphyria
ADBlistering, often mild & limited to hands, feet, knees, elbows; heals w/scarringDystrophic nails possibly the only manifestationDisease NameGene(s)MOIClinical FeaturesOverlappingDistinguishingPorphyria cutanea tarda (PCT) type I (OMIM 176090)See footnote 1
Cutaneous photosensitivity w/blistering & friability of skin in sun-exposed areas
Usually manifests in adulthood
Distinct biochemical porphyrin profilePorphyria cutanea tarda (PCT) type IIURODADHepato-erythropoietic porphyriaURODAR
Phenotype similar to PCT
Manifests in early childhood
Distinct biochemical porphyrin profile
Developmental delay (in some)Hereditary coproporphyriaCPOXAD20% of affected individuals experience photosensitivity w/skin blistering in sun-exposed areas
Acute (hepatic) porphyria
Acute attacks of abdominal or generalized pain; can be associated w/neurologic symptoms
Incompletely penetrant in absence of environmental inducers
Usually manifests after pubertyVariegate porphyriaPPOXADMyeloid malignancyElderly adults w/myelodysplastic syndrome may exhibit features of CEP 2, 3Epidermolysis bullosa simplex (EBS)KRT5
Fragility of skin resulting in nonscarring blisters caused by little/no trauma
Major & minor subtypes share common feature of blistering above dermal-epidermal junction at the ultrastructural levelJunctional epidermolysis bullosa (JEB)LAMA3
Fragility of skin & mucous membranes, manifest by blistering w/little or no trauma
Herlitz JEB (classic severe form): blisters present at birth or become apparent in neonatal period
Non-Herlitz JEB: may be mild w/blistering localized to hands, feet, knees, elbowsDystrophic epidermolysis bullosaCOL7A1AR
Blisters affecting whole body may be present in neonatal period
Severe nutritional deficiency & secondary problems
"Mitten" hands & feet
>90% lifetime risk of aggressive squamous cell carcinoma
80% of cases are sporadic or acquired (type I PCT). Type I (or sporadic) PCT is characterized by normal URO-decarboxylase activity systemically when affected individuals are asymptomatic. Inhibition of the enzyme activity resulting in PCT can be caused by excessive alcohol intake, hemochromatosis, viral hepatitis (mostly hepatitis C), HIV infection, certain medications, and environmental exposures such as aromatic polyhalogenated hepatotoxins. Treatment consists of eliminating or treating the underlying cause and, if symptoms persist, frequent phlebotomies or therapy with oral low-dose hydroxychloroquine.
Affected individuals had normal erythrocyte URO-synthase activities. Presumably, the CEP-like manifestations resulted from genetic or functional changes associated with the bone marrow disorder.
EBS caused by pathogenic variants in KRT5 or KRT14 is usually inherited in an autosomal dominant manner; in rare families, especially those with consanguinity, it can be inherited in an autosomal recessive manner.
To establish the extent of disease and needs of an individual diagnosed with congenital erythropoietic porphyria (CEP), the following evaluations are recommended:
Urine and erythrocyte porphyrins can be determined periodically after bone marrow transplant as a monitor of engraftment.
Cutaneous photosensitivity. There is no FDA-approved treatment for this disease or specific treatment for the photosensitivity.
Currently the only effective treatment is prevention of blistering by avoidance of light exposure, including the long-wave ultraviolet sunlight that passes through window glass or light emitted by fluorescent sources:
Skin trauma should be avoided.
Wound care is essential to prevent infection of opened blisters. Antiseptic and topical/oral antibiotic treatment may be indicated to avoid progression to osteomyelitis and bone resorption with subsequent mutilation.
Surgical intervention may be indicated for severe mutilation (repair of microstomia, correction of ectropion, reconstruction of the nose).
Laser hair removal can be used to treat facial hypertrichosis.
Note: (1) Beta-carotene has been tried in some individuals but without significant benefit. (2) Phototherapy with narrowband ultraviolet B radiation did not show any benefit.
Bone manifestations. Bisphosphonates can be considered in individuals with osteoporosis [Katugampola et al 2012a].
Note: Although oral charcoal and cholestyramine were thought to increase fecal loss of porphyrins, a clear clinical benefit has not been shown [Tishler & Winston 1990].
Bone marrow transplantation (BMT) is the only cure for CEP and should be considered in children with severe cutaneous and hematologic involvement. Autologous as well as allogeneic stem cell transplants have been performed successfully [Thomas et al 1996, Tezcan et al 1998, Harada et al 2001, Shaw et al 2001, Dupuis-Girod et al 2005, Taibjee et al 2007, Faraci et al 2008]. The age of children with CEP receiving BMT ranges from younger than one year to 13 years [Katugampola et al 2012b]. Of note, although some of the first individuals with CEP to successfully undergo BMT in childhood should be in their 20s now [Thomas et al 1996, Zix-Kieffer et al 1996], no follow-up information is available and the long-term outcome in individuals with CEP post-BMT is unknown.
Strict avoidance of sunlight and protection from light are indicated.
Vitamin D supplementation is advised as affected individuals are predisposed to vitamin D insufficiency due to sun avoidance.
Immunization for hepatitis A and B is recommended.
Monitor the following:
The following are appropriate:
It is appropriate to evaluate at-risk sibs as newborns or infants in order to identify as early as possible those who would benefit from early intervention (no phototherapy, strict sun protection) and future monitoring for signs of hemolytic anemia. Evaluations include:
Protective filters for artificial lights should be used in the delivery/operating room to prevent phototoxic damage to the mother during delivery [Wahlin et al 2008].
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.
Parents of a proband
Sibs of a proband
Offspring of a proband. Unless an individual with congenital erythropoietic porphyria has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in UROS.
Carrier testing for at-risk relatives requires prior identification of the UROS pathogenic variants in the family.
Parents of a proband
Sibs of a proband. The risk to sibs of a male proband depends on the genetic status of the mother:
See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.
Molecular genetic testing. Once the UROS or GATA1 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for CEP are possible.
Biochemical genetic testing. Prenatal diagnosis is also possible by demonstrating markedly deficient URO-synthase activity in cultured amniotic cells or chorionic villi cells, and/or markedly elevated uroporphyrin I and coproporphyrin I concentrations in amniotic fluid (see Table 1).
Note: It is assumed that an elevation of uroporphyrin I and coproporphyrin I concentrations in amniotic fluid is also present in GATA1-related CEP; however, at this time data are insufficient to confirm this hypothesis.
British & Irish Porphyria Network (BIPNET)United Kingdomwww.bipnet.org.uk
The CEP contribution to GeneReviews was supported in part by the Porphyrias Consortium of the NIH-supported Rare Diseases Clinical Research Network (NIH grant: 5 U54 DK083909), including: