Congenital Erythropoietic Porphyria

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 bone loss and/or expansion of the bone marrow. The phenotypic spectrum, however, is broad and ranges from nonimmune hydrops fetalis in utero to late-onset disease with only mild cutaneous manifestations in adulthood.

Diagnosis/testing: The diagnosis of CEP in a proband with suggestive clinical and biochemical findings is most commonly established by identification of biallelic pathogenic variants in UROS, and – on rare occasion – by 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. Currently, 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.

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 affected individuals.

Agents/circumstances to avoid: All affected individuals: avoid sunlight and UV light. In those with hepatic dysfunction: avoid drugs that may induce cholestasis.

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.

Pregnancy management: Protective filters for artificial lights should be used in the delivery/operating room to prevent phototoxic damage to a mother with CEP during delivery.

Genetic counseling: CEP caused by biallelic UROS pathogenic variants is inherited in an autosomal recessive (AR) manner. CEP caused by a hemizygous GATA1 pathogenic variant is inherited in an X-linked (XL) manner.

1. 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.

2. 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.

3. Both AR and XL CEP. Once the pathogenic variant(s) in the family have been identified, carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.