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NCBI Bookshelf. 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.
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 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. 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 OH every six to twelve months in all patients. 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. 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. View in own window. 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. 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 ] 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. See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance , likely pathogenic, or pathogenic. For issues to consider in interpretation of sequence analysis results, click here. 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 base pairs upstream of the ATG can be detected by sequencing if the DNA region is included in the analysis.
Two gross deletions, two gross duplications, and one complex rearrangement have been reported [ Boulechfar et al , Shady et al , Katugampola et al a ]. A GATA1 pathogenic variant p. ArgTrp was identified in three unrelated individuals with CEP and hematological abnormalities [ Phillips et al , Di Pierro et al ]. 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 ].
See Genotype-Phenotype Correlations for predictors of disease severity. 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 ]. Photosensitivity symptoms are provoked mainly by visible light 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 ]. Hemolysis presumably results from the accumulation of uroporphyrinogen I in the erythrocytes see Pathophysiology [ Bishop et al ].
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 ].
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 , Weston et al , Phillips et al ]. 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 , Venkatesh et al , Siddique et al ]. 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. It can also cause expansion of the bone marrow, which can lead to hyperplastic bone marrow observed on biopsy [ Poh-Fitzpatrick , Anderson et al ].
Vitamin D deficiency. Individuals with CEP who avoid sunlight are at risk for vitamin D deficiency. When expressed in vitro, the residual enzyme activity of individual pathogenic variants ranges from less than 1. 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 , Poh-Fitzpatrick et al ]. 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 ]. Urinary porphyrin excretion is markedly increased , times normal and consists mainly of uroporphyrin I and coproporphyrin I, with lesser increases in hepta-, hexa-, and pentacarboxyl porphyrin isomers [ Fritsch et al ].
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 ].
Presumably, exposure of the skin to sunlight or other sources of long-wave ultraviolet light in the Soret band 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 , Bickers , Dawe et al ]. 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.
The most common UROS pathogenic variant , c. Cys73Arg , is observed in about one third of individuals with CEP. In contrast, individuals with pathogenic variants expressing higher residual activities such as c. AlaVal 7. Ala66Val 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. A novel c. 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. Four of her sibs, who were homozygous for the same pathogenic variant , had moderate to severe cutaneous disease [ Ged et al ].
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. CEP is pan ethnic and occurs equally in men and women [ Katugampola et al b ].
This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly.
Congenital erythropoietic porphyria
NCBI Bookshelf. 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. 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 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.
Congenital erythropoietic porphyria (CEP)
Gunther disease , is a congenital form of erythropoietic porphyria. The word porphyria originated from the Greek word porphura. Porphura actually means "purple pigment", which, in suggestion, the color that the body fluid changes when a person has Gunther's disease. In milder cases patients have not presented any symptoms until they have reached adulthood. In Gunther's disease, porphyrins are accumulated in the teeth and bones and an increased amount are seen in the plasma, bone marrow, feces, red blood cells, and urine.