Erythropoietic Protoporphyria, Autosomal Recessive

Abstract

Erythropoietic protoporphyria (EPP) is characterized by cutaneous photosensitivity (usually beginning in infancy or childhood) that results in tingling, burning, pain, and itching within 30 minutes after exposure to sun or ultraviolet light and may be accompanied by swelling and redness. Symptoms (which may seem out of proportion to the visible skin lesions) may persist for hours or days after the initial phototoxic reaction. Photosensitivity remains for life. Multiple episodes of acute photosensitivity may lead to chronic changes of sun-exposed skin (lichenification, leathery pseudovesicles, grooving around the lips) and loss of lunulae of the nails. Approximately 20%-30% of individuals with EPP have some degree of liver dysfunction, which is typically mild with slight elevations of the liver enzymes. Up to 5% may develop more advanced liver disease which may be accompanied by motor neuropathy similar to that seen in the acute porphyrias. The diagnosis of EPP is established by detection of markedly increased free erythrocyte protoporphyrin and/or by the identification of biallelic pathogenic variants in FECH on molecular genetic testing. Treatment of manifestations: Afamelanotide (Scenesse®), a synthetic α-melanocyte stimulating hormone analog was approved for treatment of EPP by the European Medicines Agency in 2014 and is awaiting approval in the US by the FDA. This medication increases pain-free sun exposure and has improved quality of life in those with EPP. The phototoxic pain is not responsive to narcotic analgesics. Current management centers on prevention of the painful attacks by avoidance of sun/light (including the long-wave ultraviolet light sunlight that passes through window glass) through use of protective clothing (e.g., long sleeves, gloves, wide-brimmed hats, protective tinted glass for cars and windows). Although topical sunscreens are typically not useful, some tanning products containing creams that cause increased pigmentation may be helpful. Severe liver complications are difficult to treat: cholestyramine and other porphyrin absorbents (to interrupt the enterohepatic circulation of protoporphyrin and promote its fecal excretion) and plasmapheresis and intravenous hemin are sometimes beneficial. Liver transplantation may be required. Prevention of primary manifestations. Sun avoidance. Prevention of secondary complications: Vitamin D supplementation to prevent vitamin D insufficiency due to sun avoidance. Immunization for hepatitis A and B. Surveillance: Monitoring of: hepatic function every six to 12 months and hepatic imaging if cholelithiasis is suspected; erythrocyte protoporphyrin levels (free and zinc-chelated), hematologic indices, and iron profile annually; vitamin D 25-OH levels. Agents/circumstances to avoid: Avoid: sunlight and UV light; for those with hepatic dysfunction, drugs that may induce cholestasis (e.g., estrogens). For those with cholestatic liver failure, use of protective filters for artificial lights in the operating room to avoid phototoxic damage. Evaluation of relatives at risk: If both FECH pathogenic variants have been identified in an affected family member, at-risk relatives can be tested as newborns or infants so that those with biallelic pathogenic variants can benefit from early intervention (sun protection) and future monitoring for signs of liver dysfunction. EPP is inherited in an autosomal recessive manner. In about 96% of cases an affected individual inherits a loss-of-function FECH allele from one parent and a low-expression FECH allele from the other parent. In about 4% of cases, an affected individual has two loss-of-function FECH alleles. 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) and individuals who inherit two low-expression alleles are asymptomatic. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.