Familial Porphyria Cutanea Tarda

Clinical characteristics Familial porphyria cutanea tarda (F-PCT) is characterized by: skin findings including blistering over the dorsal aspects of the hands and other sun-exposed areas of skin, skin friability after minor trauma, facial hypertrichosis and hyperpigmentation, and severe thickening of affected skin areas (pseudoscleroderma); and an increased risk for hepatocellular carcinoma (HCC). Diagnosis/testing The diagnosis of F-PCT is established in a proband by identification of elevated porphyrins in the urine (predominantly uroporphyrin and heptacarboxylporphyrin) and confirmed by the identification of a heterozygous UROD pathogenic variant. Management Treatment of manifestations: Reduction of body iron stores and liver iron content preferably by phlebotomy;low-dose antimalarial agents (chloroquine or hydroxychloroquine); eliminate known susceptibility factors including excess hepatic iron, alcohol consumption, smoking, oral estrogens, and hepatotoxins. In persons with end-stage renal disease, erythropoietin therapy has been shown to correct anemia, mobilize iron, and support phlebotomy. Iron chelation therapy (e.g., deferasirox, deferiprone, or desferrioxamine) may be considered if phlebotomy is contraindicated. Prevention of primary manifestations: Identification and avoidance of susceptibility factors (where applicable); protection from sunlight in the symptomatic phase; vaccination against hepatitis A and B. Surveillance: Monitor urinary porphyrin levels annuall; resume phlebotomies when levels begin to rise. Monitor annually for diabetes mellitus with fasting glucose. Monitor for HCC annually with serum AFP concentration and hepatic ultrasonography; monitor every six months in those with advanced chronic hepatitis C and/or alcoholic cirrhosis. Agents/circumstances to avoid: Susceptibility factors (e.g., iron supplements, alcohol consumption, smoking, oral estrogen, and hepatotoxins); exposure to sunlight in symptomatic phase. Evaluation of relatives at risk: If the family-specific UROD pathogenic variant is known, clarify the genetic status of at-risk relatives so that those with a UROD pathogenic variant can avoid known susceptibility factors. Genetic counseling F-PCT is inherited in an autosomal dominant manner. At least one parent of most individuals with F-PCT has a UROD pathogenic variant; however, few individuals diagnosed with F-PCT have a clinically affected parent because penetrance is significantly reduced. Each child of an individual with F-PCT has a 50% chance of inheriting the pathogenic variant. Because of reduced penetrance, the likelihood of the offspring developing clinical manifestations of F-PCT is small. Prenatal diagnosis for a pregnancy at increased risk is possible if the pathogenic variant in an affected family member is known. Because of reduced penetrance, results of prenatal testing are not useful in accurately predicting whether or not an individual with one UROD pathogenic variant will develop F-PCT or if so, the age of onset or specific symptoms.