Congenital Erythropoietic Porphyria

Abstract
Clinical CharacteristicsCongenital erythropoietic porphyria (CEP) typically presents with severe cutaneous photosensitivity, leading to blistering and increased skin fragility in areas exposed to light. Symptoms generally manifest at birth or early infancy, often first noticeable as pink-to-dark red discoloration of the urine. Hemolytic anemia is a common feature, ranging from mild to severe, with some individuals requiring chronic blood transfusions. Porphyrin deposition can result in complications such as corneal ulcers and scarring, reddish-brown discoloration of teeth (erythrodontia), and bone abnormalities, including bone loss and bone marrow expansion. The condition exhibits a wide phenotypic spectrum, from severe nonimmune hydrops fetalis in utero to mild, late-onset cutaneous symptoms in adulthood.CEP is diagnosed in individuals with characteristic clinical and biochemical features by identifying biallelic pathogenic variants in the UROS gene. In rare cases, a hemizygous pathogenic variant in the X-linked GATA1 gene may confirm the diagnosis.Currently, there is no FDA-approved treatment for CEP or its photosensitivity. Management focuses on preventing blistering through rigorous sun and light avoidance, including protection from long-wave ultraviolet light from windows or artificial sources. Recommended measures include: Wound care is essential to prevent infections in open blisters. Surgical intervention may be necessary for complications. Blood transfusions are required when hemolysis is severe. Bone marrow transplantation (BMT) is the only curative treatment for CEP and is considered for children with severe cutaneous and hematologic symptoms.

Monitor hematologic indices for hemolysis every six months; more frequent monitoring is required for those receiving transfusions or at risk of iron overload.Assess hepatic function and vitamin D 25-OH levels every six to twelve months. All individuals should avoid exposure to sunlight and ultraviolet light.Individuals with hepatic dysfunction should avoid medications that may induce cholestasis.Evaluation of At-Risk RelativesNewborn or infant siblings of affected individuals should be evaluated early to enable prompt interventions such as avoiding phototherapy, implementing strict sun protection, and monitoring for hemolytic anemia.For affected mothers, protective filters for artificial lights should be used in delivery or operating rooms to prevent phototoxic damage during childbirth.CEP caused by biallelic UROS variants follows an autosomal recessive (AR) inheritance pattern, while CEP due to a hemizygous GATA1 variant follows an X-linked (XL) inheritance pattern.Each sibling 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.Heterozygous carriers are asymptomatic.X-Linked CEP (XL)If the mother of an affected male is heterozygous for a GATA1 pathogenic variant, there is a 50% chance of transmitting it in each pregnancy.Males inheriting the variant will be affected.Females inheriting the variant may be heterozygotes and are typically asymptomatic or exhibit milder symptoms.Carrier Testing and Prenatal OptionsOnce Bavdegalutamide the pathogenic variant(s) in a family are identified, carrier testing for at-risk relatives and prenatal or preimplantation genetic testing are possible.