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.
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].