Clinical Guidance

About 96% of affected individuals are compound heterozygotes for a loss-of-function variant that markedly decreases ferrochelatase (FECH) activity and a second low-expression pathogenic variant which also decreases the FECH activity by about 50%. Persons with low residual activity may have a more severe clinical presentation. Palmar keratoderma was reported in persons with two loss-of-function FECH variants . Some reports have indicated that null variants in FECH may be associated with liver complications , Individuals with EPP with pathogenic missense variants have significantly lower median erythrocyte protoporphyrin levels than those with deletions or nonsense or consensus splice site variants.

Source: GeneReviews — "Erythropoietic Protoporphyria, Autosomal Recessive"

Penetrance

EPP appears to be 100% penetrant when there are biallelic FECH loss-of-function variants or compound heterozygosity for a FECH loss-of-function variant and a variant that causes low expression of the other FECH allele.

Source: GeneReviews — "Erythropoietic Protoporphyria, Autosomal Recessive"

Diagnostic Criteria

Suggestive Findings

Erythropoietic protoporphyria (EPP) should be suspected in individuals with the following clinical features and suggestive laboratory findings.

Clinical features

• Cutaneous photosensitivity, usually beginning in childhood

• Burning, tingling, and itching (the most common findings); may occur within minutes of sun/light exposure, followed later by erythema and swelling

• Burning, itching, and intense pain; may occur without obvious skin damage

• Absent or sparse blisters and bullae (Note: The absence of skin damage [e.g., scarring], vesicles, and bullae often make it difficult to establish the diagnosis.)

• Hepatic dysfunction; may occur in 20%-30% of individuals (~2%-5% have severe liver disease that may be life threatening, necessitating liver transplantation.)

Source: GeneReviews — "Erythropoietic Protoporphyria, Autosomal Recessive"

Differential Diagnosis

Other causes of the erythropoietic protoporphyria (EPP) phenotype include the following.

Acquired causes

• Polymorphous light eruption

• Solar urticaria

• Drug-induced photosensitivity

Source: GeneReviews — "Erythropoietic Protoporphyria, Autosomal Recessive"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with erythropoietic protoporphyria (EPP), the following evaluations are recommended:

• Assessment of erythrocyte protoporphyrin levels (free and zinc-chelated), hematologic indices, and iron profile if not performed as part of diagnostic testing

• Assessment of hepatic function as well as imaging studies such as abdominal sonogram if cholelithiasis is suspected

• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Acute photosensitivity. Afamelanotide (Scenesse®), a synthetic -melanocyte-stimulating hormone analog was approved for treatment of EPP by the European Medicines Agency in 2014. The drug is administered through a subcutaneously inserted bioresorbable implant which results in increased pigmentation due to an increase in eumelanin. Phase III clinical trials in the US and Europe showed an increase in pain-free sun exposure and improved quality of life in individuals with EPP. In the United States, the drug is pending FDA approval. 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:

Source: GeneReviews — "Erythropoietic Protoporphyria, Autosomal Recessive"

Clinical Guidance

The following are appropriate:

• Avoidance of sunlight and UV light

• In patients with hepatic dysfunction, avoidance of drugs that may induce cholestasis (e.g., estrogens)

• In patients with cholestatic liver failure, use of protective filters for artificial lights in the operating room to prevent phototoxic damage during procedures such as endoscopy and surgery

Source: GeneReviews — "Erythropoietic Protoporphyria, Autosomal Recessive"

Therapies Under Investigation

Phase III clinical trials from the US and Europe with a subcutaneous insertion of a biodegradable, slow-released -melanocyte-stimulating hormone analog, afamelanotide (Scenesse®), which increases pigmentation by increasing melanin, showed increased pain-free sun exposure and improved quality of life in those with EPP [, , , ]. A long-term observational study of 115 individuals receiving Scenesse® for up to eight years showed improved quality of life and high compliance with the drug .

• Scenesse® is currently approved for use in patients with EPP in the European Union.

• In the United States, the drug is pending FDA review.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "Erythropoietic Protoporphyria, Autosomal Recessive"

Surveillance Guidelines

Annual assessment of erythrocyte protoporphyrin levels (free and zinc-chelated), hematologic indices, and iron profile is appropriate. Hepatic function should be monitored every six to 12 months. Hepatic imaging studies including abdominal sonogram are indicated if cholelithiasis is suspected. Vitamin D 25-OH levels should be monitored in all patients whether or not they are receiving supplements.

Source: GeneReviews — "Erythropoietic Protoporphyria, Autosomal Recessive"