Congenital Erythropoietic Porphyria

  • Jul 6, 2020
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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

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SUMMARY

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 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.

DIAGNOSIS/TESTING.

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.

MANAGEMENT.

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.

GENETIC COUNSELING.

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.

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DIAGNOSIS

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

SUGGESTIVE FINDINGS

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)

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

1.

The deficient activity of uroporphyrinogen III synthase EC 4.2.1.75, 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.

2.

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

3.

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].

ESTABLISHING THE DIAGNOSIS

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 here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes UROS and GATA1) fails to confirm a diagnosis in an individual with features of congenital erythropoietic porphyria. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).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 (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

1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

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.

4.

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.

5.

Stenson et al [2003]

6.

Missense/nonsense variants, splice site variants, small deletions and small duplications, and an insertion/deletion, all detectable by routine sequencing, have been reported (see Molecular Genetics).

7.

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.

8.

Two gross deletions, two gross duplications, and one complex rearrangement have been reported [Boulechfar et al 1992, Shady et al 2002, Katugampola et al 2012a]

9.

A GATA1 pathogenic variant (p.Arg216Trp) was identified in three unrelated individuals with CEP and hematological abnormalities [Phillips et al 2007, Di Pierro et al 2015].

10.

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.

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CLINICAL CHARACTERISTICS

CLINICAL DESCRIPTION

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.

PATHOPHYSIOLOGY

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.

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 mutated alleles.

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

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.

Determination of genotype-phenotype correlations for erythroid-specific promoter pathogenic variants (see Molecular Genetics) showed the following:

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].

PENETRANCE

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.

NOMENCLATURE

Obsolete terms for CEP are: erythropoietic porphyria, congenital porphyria, congenital hematoporphyria, and erythropoietic uroporphyria (Günther's disease).

PREVALENCE

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].

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GENETICALLY RELATED (ALLELIC) DISORDERS

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:

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DIFFERENTIAL DIAGNOSIS

Other disorders presenting with a congenital erythropoietic porphyria (CEP)-like phenotype are listed in Table 3.

TABLE 3.

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
Facial hypertrichosis
Discolored urine
Usually manifests in adulthood
Distinct biochemical porphyrin profilePorphyria cutanea tarda (PCT) type IIURODADHepato-erythropoietic porphyriaURODAR
Phenotype similar to PCT
Manifests in early childhood
Discolored urine
Photosensitivity
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
KRT14AD 4
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
LAMB3
LAMC2
COL17A1AR
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
Oral involvement
Corneal erosions
Esophageal erosions
Severe nutritional deficiency & secondary problems
"Mitten" hands & feet
>90% lifetime risk of aggressive squamous cell carcinoma

AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance

1.

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.

2.

Fritsch et al [1997], Kontos et al [2003], Sarkany et al [2011]

3.

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.

4.

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.

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MANAGEMENT

EVALUATIONS FOLLOWING INITIAL DIAGNOSIS

To establish the extent of disease and needs of an individual diagnosed with congenital erythropoietic porphyria (CEP), the following evaluations 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
  • Dermatologic evaluation
  • Ophthalmologic evaluation
  • Dental assessment
  • Consultation with a clinical geneticist and/or genetic counselor

Urine and erythrocyte porphyrins can be determined periodically after bone marrow transplant as a monitor of engraftment.

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 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.

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 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 blood transfusions when hemolysis is significant.
  • 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].
  • Iron deficiency induced by treatment with deferasirox improved photosensitivity and hemolysis in one patient [Egan at al 2015].

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.

PREVENTION OF PRIMARY MANIFESTATIONS

Strict avoidance of sunlight and protection from light are indicated.

PREVENTION OF SECONDARY COMPLICATIONS

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.

SURVEILLANCE

Monitor the following:

  • Hematologic indices including iron profile, reticulocyte count, and bilirubin to assess hemolysis every six monthsNote: 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 patients whether or not they are receiving vitamin D supplements

AGENTS/CIRCUMSTANCES TO AVOID

The following are appropriate:

  • Avoidance of sunlight and UV light
  • In patients with hepatic dysfunction, avoidance of drugs that may induce cholestasis (e.g., estrogens)
  • In patients 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

To date, gene therapy has been evaluated only in the murine CEP model [de Verneuil et al 2008, Fortian et al 2011, Di Pierro et al 2015].

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.

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GENETIC COUNSELING

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.

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. Note: To date only three such individuals have been identified [Phillips et al 2007, Di Pierro et al 2015].

RISK TO FAMILY MEMBERS – AUTOSOMAL RECESSIVE INHERITANCE

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one UROS pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • 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 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, his/her offspring 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.

CARRIER (HETEROZYGOTE) DETECTION

Carrier testing for at-risk relatives requires prior identification of the UROS pathogenic variants in the family.

RISK TO FAMILY MEMBERS – X-LINKED INHERITANCE

Parents of a proband

  • The father of an affected male will not have the disease nor will he be a carrier of the GATA1 pathogenic variant; therefore, he does not require further evaluation/testing.
  • Women who have an affected son and another affected male relative are obligate heterozygotes.
  • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a de novo GATA1 pathogenic variant, in which case the mother is not a carrier. The frequency of de novo GATA1 pathogenic variants is unknown.

Sibs of a 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 abnormalities due to skewed X-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 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a proband. Affected males transmit the GATA1 pathogenic variant to:

  • All of their daughters, who will be (heterozygotes) carriers and can be either asymptomatic or have a milder phenotype with predominantly hematologic abnormalities due to skewed X-inactivation [Phillips et al 2007, Di Pierro et al 2015];
  • 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 gender, may be at risk of being carriers or of being affected.

CARRIER (HETEROZYGOTE) DETECTION

Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the GATA1 pathogenic variant has been identified in the proband.

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, clarification of carrier status, and discussion of the availability of prenatal 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 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.

PRENATAL TESTING AND PREIMPLANTATION GENETIC DIAGNOSIS

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.

Resources

British & Irish Porphyria Network (BIPNET)United Kingdomwww.bipnet.org.uk

 

REFERENCES

LITERATURE CITED

  • Anderson KE, Sassa S, Bishop DF, Desnick RJ. Disorders of heme biosynthesis: X-linked sideroblastic anemias and the porphyrias. In: Scriver CR, Beaudet AL, Sly WS, eds. The Metabolic and Molecular Basis of Inherited Disease. 8 ed. New York, NY: McGraw-Hill; 2001:2991.
  • Dawe SA, Peters TJ, Du Vivier A, Creamer JD. Congenital erythropoietic porphyria: dilemmas in present day management. Clin Exp Dermatol. 2002;27:680–3. [PubMed]
  • Phillips JD, Steensma DP, Pulsipher MA, Spangrude GJ, Kushner JP. Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria. Blood. 2007;109:2618–21. [PMC free article] [PubMed]

 

ACKNOWLEDGMENTS

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:

  • Dr Karl Anderson, University of Texas Medical Branch, Galveston, TX
  • Dr Montgomery Bissell, University of California, San Francisco, CA
  • Dr Joseph Bloomer, University of Alabama, Birmingham, AL
  • Dr Herbert Bonkovsky, Wake Forest University Health Sciences, Winston-Salem, NC
  • Dr Robert J Desnick, Icahn School of Medicine at Mount Sinai, New York, NY
  • Dr John Phillips, University of Utah School of Medicine, Salt Lake City, UT

 


 

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