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 with elevated porphyrins in the urine (predominantly uroporphyrin and heptacarboxylporphyrin) and a heterozygous pathogenic variant in UROD identified by molecular genetic testing.

Management: Treatment of manifestations: No treatment regimens can restore UROD enzyme levels in individuals with F-PCT. The mainstays of therapy are reduction of body iron stores and liver iron content, and use of low-dose antimalarial agents (hydroxychloroquine). In addition, modifiable risk factors can be addressed by ceasing alcohol/tobacco use, modifying estrogen use, and treating hepatitis C infection (if present).

Surveillance: Monitor urinary porphyrin levels annually. For those who have been treated by phlebotomy, resume iron reduction by therapeutic phlebotomies if and when urinary uroporphyrins and heptacarboxylporphyrins increase to greater than 400 µg/g creatinine. Monitor for diabetes mellitus annually with fasting glucose, particularly in individuals with hypertension. Monitor for HCC annually with serum AFP concentration and hepatic ultrasonography; monitor every six months in those with cirrhosis.

Agents/circumstances to avoid: Susceptibility factors (e.g., iron supplements, alcohol consumption, smoking, estrogen use, and hepatotoxins); exposure to sunlight in the symptomatic phase.

Evaluation of relatives at risk: If the family-specific UROD pathogenic variant is known, it is reasonable to 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 with reduced penetrance. Most individuals diagnosed with F-PCT inherited a UROD pathogenic variant from a heterozygous, asymptomatic parent. Each child of an individual with F-PCT has a 50% chance of inheriting the UROD pathogenic variant; because the penetrance of F-PCT is low, the likelihood of offspring developing signs and symptoms of PCT is small. Once the UROD pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. However, because of the low penetrance of F-PCT, the results of prenatal testing are not useful in accurately predicting whether an individual with one UROD pathogenic variant will develop clinical manifestations of PCT.