Congenital Erythropoietic Porphyria

Clinical characteristics.

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 bone loss and/or expansion of the bone marrow. The phenotypic spectrum, however, is broad and ranges from nonimmune hydrops fetalis in utero to late-onset disease with only mild cutaneous manifestations in adulthood.

Diagnosis/testing.

The diagnosis of CEP in a proband with suggestive clinical and biochemical findings is most commonly established by identification of biallelic pathogenic variants in UROS, and – on rare occasion – by identification of a hemizygous pathogenic variant in the X-linked gene GATA1.

Management.

Treatment of manifestations: There is no FDA-approved treatment for CEP or specific treatment for the photosensitivity. Currently, 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.

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 affected individuals.

Agents/circumstances to avoid: All affected individuals: avoid sunlight and UV light. In those with hepatic dysfunction: avoid drugs that may induce cholestasis.

Evaluation of relatives at risk: 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.

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

Genetic counseling.

CEP caused by biallelic UROS pathogenic variants is inherited in an autosomal recessive (AR) manner. CEP caused by a hemizygous 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.
• 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.
• Both AR and XL CEP. Once the pathogenic variant(s) in the family have been identified, carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

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

Clinical findings

• Nonimmune 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 the face and extremities

Laboratory findings include 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).

Table 1.

Biochemical Characteristics of Congenital Erythropoietic Porphyria

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity) or, rarely, X-linked inheritance (e.g., no male-to-male transmission). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of CEP is established by biochemical testing, which shows marked elevation of the uroporphyrin and coproporphyrin I isomers (see Table 1), and should be confirmed by molecular genetic testing for biallelic UROS pathogenic variants. On rare occasion, a hemizygous pathogenic variant in the X-linked gene GATA1 can be identified [Phillips et al 2007] (see Table 2).

Note:

• In the absence of biochemical or enzymatic testing results, identification of biallelic UROS variants of uncertain significance (or identification of one known UROS pathogenic variant and one UROS variant of uncertain significance) does not establish or rule out a diagnosis autosomal recessive CEP.
• If the diagnosis cannot be established by molecular genetic testing, the findings of reduced URO-synthase activity in erythrocytes and markedly elevated urinary or erythrocyte uroporphyrin and coproporphyrin I isomers (Table 1) confirm the diagnosis and indicate that the variants of uncertain significance may be pathogenic.
• Identification of a hemizygous GATA1 variant of uncertain significance does not establish or rule out a diagnosis of X-linked CEP.

Molecular genetic testing approaches can include gene-targeted testing (single gene or multigene panel) or comprehensive genomic testing (exome sequencing, genome sequencing).

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of CEP has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 2.

Molecular Genetic Testing Used in Congenital Erythropoietic Porphyria

Clinical Description

Most individuals with congenital erythropoietic porphyria (CEP) experience severe cutaneous photosensitivity 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 erythrocyte transfusions in some. The phenotypic spectrum ranges from severe (nonimmune hydrops fetalis) to milder disease (adult-onset with isolated cutaneous manifestations) [Warner et al 1992]. (See Genotype-Phenotype Correlations for variants that correlate with disease severity.)

Skin. Cutaneous photosensitivity is present at birth or in 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), manifestations such as tingling, burning, itching, or swelling usually do not occur in persons with CEP after light exposure.

Hemolytic anemia. 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 [Bishop et al 2006].

Those with severe hemolytic anemia often require chronic erythrocyte transfusions, which decrease 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 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.

Genotype-Phenotype Correlations

The genotype-phenotype correlations that have been established in CEP are largely determined by the amount of residual enzyme activity encoded by the specific pathogenic variants (Table 5).

UROS. The most common UROS pathogenic variant, c.217T>C (p.Cys73Arg), is observed in about one third of individuals with CEP.

• Homozygosity for the c.217T>C (p.Cys73Arg) variant results in less than 1% of normal URO-synthase activity and a severe phenotype that may manifest as nonimmune hydrops fetalis [Frank et al 1998, Desnick & Astrin 2002].
• Compound heterozygosity for the c.217T>C (p.Cys73Arg) variant and a pathogenic variant that expresses a very low level of residual activity results in a severe or moderately severe phenotype.

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 [Desnick & Astrin 2002].

Determination of genotype-phenotype correlations for erythroid-specific promoter pathogenic variants showed the following:

• Compound heterozygotes with the c.-203T>C variant (2.9% of normal activity in vitro) in combination with the c.217T>C (p.Cys73Arg)table4 variant led to nonimmune hydrops fetalis [Solis et al 2001].
• The c.-223C>A variant (8.3% of normal activity in vitro) when in compound heterozygosity with another variant with low residual enzyme activity (c.673G>A [p.Gly225Ser]), 1.2% of normal activity in vitro) led to a moderately severe phenotype in one individual [Solis et al 2001].
• The two other known erythrocyte-specific promoter pathogenic variants, c.-209G>A and c.-219C>A, with high residual activities (53.9% and 43.4% of normal in vitro, respectively) in individuals in whom the second variant was c.217T>C (p.Cys73Arg), led to mild cutaneous disease [Desnick & Astrin 2002].

GATA1. The c.646C>T (p.Arg216Trp) pathogenic variant is predicted to dramatically alter the binding of GATA1 to URO-synthase, resulting in significantly reduced (~20% of normal) URO-synthase activity [Phillips et al 2007].

Nomenclature

Obsolete terms for CEP are erythropoietic porphyria, congenital porphyria, congenital hematoporphyria, and erythropoietic uroporphyria.

Prevalence

CEP is an ultra-rare disorder. To date, about 220 affected individuals have been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with congenital erythropoietic porphyria (CEP), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Hematologic indices including reticulocytes and bilirubin (to assess hemolysis) and iron profile (to assess iron storage)
• Serum calcium and vitamin D concentrations; bone densitometry
• Hepatic function tests, especially in transfusion-dependent individuals given the risk for liver disease due to iron storage
• Dermatologic evaluation to assess photosensitivity, photomutilation, and secondary skin changes (thickening, hyper- or hypopigmentation, hypertrichosis)
• Ophthalmologic evaluation for corneal ulcers and scarring and other ocular manifestations
• Dental assessment for erythrodontia (reddish-brown color from porphyrin deposition)
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of CEP in order to facilitate medical and personal decision making

Treatment of Manifestations

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:

• Sun protection using protective clothing including long sleeves, gloves, and wide-brimmed hats
• Protective window films for cars and windows at home as well as at school/work to prevent exposure to UV light
• Replacement of LED and fluorescent lights with reddish incandescent bulbs or installation of filtering screens
• Reflectant sunscreens containing zinc oxide or titanium dioxide. Note, however, that these may be cosmetically unacceptable and, in any case, do not replace strict avoidance of sun/light exposure.

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.

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.

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.

Ocular manifestations

• Avoidance of damage to the eyelids and cornea by wearing wraparound sunglasses
• Topical antibiotics for corneal ulcers, scleritis, and blepharitis
• Artificial tears and lubricants to help prevent dry eyes in those with ectropion
• Corrective surgery of eyelids to help protect the cornea from injury in those with ectropion [Katugampola et al 2012a]

Bone manifestations. Bisphosphonates can be considered in individuals with osteoporosis [Katugampola et al 2012a].

Hemolytic anemia

• Consider frozen matched-erythrocyte transfusions when hemolysis is significant, or bone marrow transplantation
• Chronic transfusions (every 2-4 weeks) with a target hematocrit greater than 35% can suppress erythropoiesis and decrease porphyrin production, which reduces porphyrin levels and photosensitivity [Piomelli et al 1986].
• Note: In those who receive frequent transfusions, the body iron burden can be reduced with parenteral or oral chelators [Poh-Fitzpatrick et al 1988].
• Experimental induction of iron deficiency either using treatment with iron chelators or via phlebotomies improved photosensitivity and hemolysis in a few affected individuals [Egan at al 2015, Blouin et al 2020, Blouin et al 2021, Mirmiran et al 2021].

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].

Successful bone marrow transplantation (BMT) is an effective 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]. Urine and erythrocyte porphyrins can be measured periodically after bone marrow transplantation to monitor engraftment.

The age of children with CEP receiving BMT ranges from younger than one year to 13 years [Katugampola et al 2012b]. Some of the first individuals with CEP to successfully undergo BMT in childhood are now in their 20s [Thomas et al 1996, Zix-Kieffer et al 1996]. Although there is limited information available regarding their long-term outcome post BMT, experts have learned that individuals successfully transplanted have essentially no photosensitivity to artificial light sources or sunlight.

Surveillance

Monitor the following:

• Hematologic indices including iron profile, reticulocyte count, and bilirubin to assess hemolysis every six months
  Note: Individuals receiving transfusion therapy need closer monitoring.
• Iron profile on a regular basis to assess for iron overload for those who are transfusion dependent
• Hepatic function every six to twelve months
• Vitamin D 25-OH levels in all individuals whether or not they are receiving vitamin D supplements

Agents/Circumstances to Avoid

The following are appropriate:

• Avoidance of sunlight and UV light
• In individuals with hepatic dysfunction, avoidance of drugs that may induce cholestasis (e.g., estrogens)
• In individuals undergoing surgeries, use of protective filters for artificial lights in the operating room to prevent phototoxic damage [Wahlin et al 2008]

Evaluation of Relatives at Risk

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:

• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Biochemical testing for urinary or erythrocyte uroporphyrin I and coproporphyrin I isomer elevation if the pathogenic variants in the family are not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Successful pregnancies in women with CEP resulting in healthy and unaffected children have been described [Hallai et al 2007, Katugampola et al 2012b].

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].

Therapies Under Investigation

Although there are no clinical trials at the present time, therapeutic approaches under investigation include phlebotomy or iron chelation strategies to reduce the hemolysis and decrease the accumulated porphyrins and, thus, photosensitivity [Egan at al 2015, Blouin et al 2020, Blouin et al 2021, Mirmiran et al 2021].

A murine CEP model is being used to investigate pharmacologic chaperone therapy (i.e., administration of small-molecule drugs to enhance the residual activity of mutated enzymes that have low activities or are unstable). Specifically, use of the antimicrobial agent ciclopirox as a chaperone-stabilized UROIII-synthase and reversed CEP-related findings such as abnormal URO I levels in the blood, splenomegaly, and liver porphyrins [Urquiza et al 2018]. Studies involving use of this medication in humans have not yet been performed.

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.

Mode of Inheritance

Congenital erythropoietic porphyria (CEP) caused by biallelic UROS pathogenic variants is inherited in an autosomal recessive manner.

CEP caused by a hemizygous GATA1 pathogenic variant is inherited in an X-linked manner. To date only three such individuals have been identified [Phillips et al 2007, Di Pierro et al 2015].

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one UROS pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a UROS pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband.
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a UROS pathogenic variant, each sib of an affected individual has at conception 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 and are not at risk of developing the disorder.

Offspring of a proband. Unless an individual with congenital erythropoietic porphyria has children with an affected individual or a carrier, the offspring of a proband will be obligate heterozygotes (carriers) for a pathogenic variant in UROS.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a UROS pathogenic variant.

X-Linked Inheritance – Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder nor will he be hemizygous for the GATA1 pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the GATA1 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier, the affected male may have a de novo GATA1 pathogenic variant (in which case the mother is not a carrier), or the mother may have somatic/germline mosaicism.
  The frequency of de novo GATA1 pathogenic variants is unknown.
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.

Sibs of a male proband. The risk to sibs of a male proband depends on the genetic status of the mother:

• If the mother of the proband has 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 with predominantly hematologic and/or cutaneous abnormalities due to skewed X-chromosome inactivation [Phillips et al 2007, Di Pierro et al 2015].
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the GATA1 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but slightly greater than that of the general population because of the theoretic possibility of maternal germline mosaicism.

Offspring of a male proband. Affected males transmit the GATA1 pathogenic variant to all of their daughters and none of their sons.

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunts' offspring, depending on their sex, may be at risk of being carriers or of being affected.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the UROS pathogenic variants or the GATA1 pathogenic variant have been identified in an affected family member, prenatal and preimplantation genetic testing 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.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

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 (100-1,000x 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 visible light in the Soret band (400-410 nm) and to a lesser extent long-wave ultraviolet light 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.

Mechanism of disease causation

• UROS pathogenic variants result in either absent or reduced UROS enzymatic activity.
• GATA1 pathogenic variants alter the binding of GATA1 to URO-synthase, resulting in significantly reduced (~20% of normal) URO-synthase activity [Phillips et al 2007].

Table 4.

Congenital Erythropoietic Porphyria: Gene-Specific Laboratory Considerations

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].

Table 5.

Congenital Erythropoietic Porphyria: Notable Pathogenic Variants by Gene

Acknowledgments

The GeneReview "Congenital Erythropoietic Porphyria" was supported in part by the Porphyrias Consortium of the NIH-supported Rare Diseases Clinical Research Network (NIH grant: 5 U54 DK083909).

Revision History

• 15 April 2021 (bp) Comprehensive update posted live
• 7 April 2016 (bp) Comprehensive update posted live
• 12 September 2013 (me) Review posted live
• 5 March 2013 (ae) Original submission

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