Hepatoerythropoietic Porphyria

Clinical characteristics: Hepatoerythropoietic porphyria (HEP) is characterized by blistering skin lesions, hypertrichosis, and scarring over the affected skin areas. Disease manifestations occur during infancy or childhood and with similar frequency in females and males. Mild anemia/hemolysis are not uncommon.

Diagnosis/testing: The diagnosis of HEP is established in a proband with elevated porphyrins in the urine (predominantly uroporphyrin and heptacarboxylporphyrin), significantly increased erythrocyte zinc protoporphyrin, and/or biallelic pathogenic (or likely pathogenic) variants in UROD identified by molecular genetic testing.

Management: Treatment of manifestations: No treatment regimens can restore uroporphyrinogen decarboxylase (UROD enzyme levels in individuals with HEP. The mainstays of therapy are avoidance of sunlight (including the long-wave ultraviolet light sunlight that passes through window glass) by use of protective clothing and topical application of opaque sunscreens. On sun-exposed areas of the skin, bullous lesions develop that require prompt management of resultant skin infections when appropriate. Phlebotomy and chloroquine, which are usually effective in treating the allelic disorder familial porphyria cutanea tarda, are generally ineffective in individuals with HEP.

Agents/circumstances to avoid: Exposure to sunlight in persons of all ages. Older individuals should avoid known susceptibility factors: alcohol, oral estrogen, iron overload, smoking, and drugs that induce the cytochrome P450s.

Evaluation of relatives at risk: If the family-specific UROD pathogenic variants are known, it is reasonable to clarify the genetic status of at-risk relatives so that those with biallelic UROD pathogenic variants can be counseled regarding sun protection and avoidance of known susceptibility factors.

Genetic counseling: HEP is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a UROD pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic UROD pathogenic variants and having HEP, a 50% chance of inheriting one pathogenic variant and having familial porphyria cutanea tarda, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the UROD pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.