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X-Linked Protoporphyria.


Balwani M1, Bloomer J2, Desnick R1; Porphyrias Consortium of the NIH-Sponsored Rare Diseases Clinical Research Network.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.
2013 Feb 14.

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Mount Sinai School of Medicine, New York, New York
University of Alabama at Birmingham, Birmingham, Alabama



X-linked protoporphyria (XLP) is characterized in affected males by cutaneous photosensitivity (usually beginning in infancy or childhood) that results in tingling, burning, pain, and itching within minutes of sun/light exposure and may be accompanied by swelling and redness. Vesicular lesions are uncommon. Pain, which may seem out of proportion to the visible skin lesions, may persist for hours or days after the initial phototoxic reaction. Photosensitivity usually 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. An unknown proportion of individuals with XLP develop liver disease. Except for those with advanced liver disease, life expectancy is not reduced. The phenotype in heterozygous females ranges from asymptomatic to as severe as affected males.


Detection of markedly increased free erythrocyte protoporphyrin and zinc-chelated erythrocyte protoporphyrin is the most sensitive biochemical diagnostic test for XLP. Identification of pathogenic gain-of-function variants in ALAS2, the gene encoding erythroid specific 5-aminolevulinate synthase 2, confirms the diagnosis.


Treatment of manifestations: There is no FDA-approved treatment for this disease or specific treatment for the acute photosensitivity. The pain is not responsive to narcotic analgesics. Currently the only effective treatment is prevention of the painful attacks by avoidance of sun/light (including the long-wave ultraviolet light 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 which cause increased pigmentation may be helpful. Oral Lumitene™ (β-carotene) may improve tolerance to sunlight by causing mild skin discoloration due to carotenemia. 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 can be a life-saving measure in individuals with severe protoporphyric liver disease; combined bone marrow and liver transplantation is indicated in those with liver failure to prevent future damage to the allografts. Prevention of secondary complications: Vitamin D supplementation to prevent vitamin D insufficiency due to sun avoidance. Surveillance: Monitoring of: hepatic function every 6-12 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: 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 the ALAS2 pathogenic variant has been identified in an affected family member, at-risk relatives can be tested as newborns or infants so that those with the pathogenic variant can benefit from early intervention (sun protection) and future monitoring for signs of liver dysfunction. Therapies under investigation: Clinical trials are underway for afamelanotide, an α-melanocyte stimulating hormone analogue, which increases skin pigmentation by increasing melanin production.


XLP is inherited in an X-linked manner. Affected males transmit the pathogenic variant to all of their daughters and none of their sons. Women with an ALAS2 pathogenic variant have a 50% chance of transmitting the variant to each child. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant has been identified in an affected family member.

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