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Since its description in the late 19th century, around 220 cases of congenital erythropoietic porphyria (CEP) have been reported in the literature.

The disease most often manifests from birth as extremely severe, mutilating cutaneous photosensitivity, sometimes revealed by phototherapy used for the treatment of neonatal jaundice. The main symptoms include rapidly-erosive bullous skin lesions on photoexposed surfaces (hands, face, feet), which can progress to mutilating lesions and disabling retractive scars. Hypertrichosis is common. Urine is often pink to dark red and stains the diaper of affected infants. In severe forms, patients present more or less intense hemolysis. Significant splenomegaly may appear, linked to hemolytic anemia. Bone involvement is constant, with rarefaction of the architecture and risk of multiple fractures.

CEP is caused by a deficiency in uroporphyrinogen synthase (UROS, the fourth enzyme in the heme biosynthesis pathway), which leads to a massive accumulation of isomeric type I porphyrins (uro and coproporphyrins) in the bone marrow. The enzyme deficiency is due to mutations of the UROS gene (NM_000375.3), coding for UROS. A certain degree of genotype-phenotype correlation has been demonstrated by the identification of so-called "severe" or "moderate" mutations. In 50 % of cases, the "severe" C73R mutation is present.

The diagnosis is easily made based on the evidence of massive accumulation of isomeric type I porphyrins in urine and blood. Detection of UROS deficiency in red blood cells and identification of causative mutations in the UROS gene confirm the diagnosis.

The differential diagnosis includes hepatoerythropoietic porphyria, porphyria cutanea tarda, acute hepatic porphyrias with cutaneous expression, and epidermolysis bullosa.

In families at risk, antenatal diagnosis is possible by amniotic fluid analysis, UROS enzyme activity assay, and/or molecular genetic analysis of amniotic fluid cells.

The pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a heterozygous pathogenic variant) informing them that there is a 25% risk of having an affected child at each pregnancy.

Intense preventive photoprotection is necessary to avoid the skin lesions and their aggravation. It incorporates the preventive measures proposed for erythropoietic protoporphyria. The risk of lesion infection is constant, but generally controlled by antibiotic therapy. Hemolytic anemia, splenic sequestration, and thrombocytopenia characterize the severity of the disease, often requiring repeated blood transfusions and associated iron overload, which is often difficult to manage. Splenectomy is often necessary. Induction of iron deficiency in moderate forms of CEP by careful phlebotomy has proved effective in some cases, and could be a lifelong supportive treatment option with varying degrees of acceptance by patients and their families. Allogeneic bone marrow transplantation remains the curative treatment of choice for CEP, with spectacular results including disappearance of hemolytic anemia and healing of skin lesions.

In severe forms, the prognosis is dominated by hemolytic anemia and, above all, thrombocytopenia, which can greatly reduce patients' life expectancy. Multiple fractures often lead to motor disability. For the treatment of CEP, an ex vivo gene therapy project using bone marrow cells is currently under development.

Last update: March 2024 - Expert reviewer(s): Dr Neila TALBI | MetabERN*

* European Reference Network