Protoporphyria Clinical Presentation
- Author: Maureen B Poh-Fitzpatrick, MD; Chief Editor: William D James, MD more...
Uncomfortable sensations in skin exposed to sunlight typically begin during infancy or childhood, most often involving dorsal hands, the face and ears, and, occasionally, legs and dorsal feet, after short periods of exposure. If exposure is promptly discontinued, visible skin lesions may not ensue. Longer exposure, or multiple exposures on sequential days, can elicit swelling with or without redness in the exposed skin that evolves into sheets of petechiae. This exquisitely painful reaction resolves over several days to leave skin that may appear normal. Eventually, chronic changes may develop that are highly suggestive, but, when subtle, can be overlooked.
Individuals with protoporphyria who report skin pain but have minimal objective findings may be considered malingerers until an acute reaction is observed. Gallstones may remain silent or evoke reports of indigestion and/or right upper quadrant abdominal pain consistent with symptomatic cholelithiasis. Individuals with protoporphyria associated with hepatotoxicity may report loss of appetite, nausea, vomiting, weakness and fatigue, anorexia, malaise, weight changes, increasing abdominal girth, pain in the epigastrium or right upper quadrant and back, jaundice, and increasing photosensitivity.
The acute phototoxic reaction typically includes edema, erythema, and petechiae. Blisters, crusted erosions, and scarring may occur but are less florid and less frequent than in other porphyrias. Chronic changes include shallow, elongated depressions in facial skin, especially over the nose; perioral furrowing; and prematurely aged, thickened, or coarsely textured skin of the dorsal hands, often most prominent over the knuckles. In more severe cases, sclerodermalike waxy induration or a cobblestone texture of facial and hand skin may develop. Mechanical fragility, when present, is less severe than in other porphyrias; hypertrichosis is infrequent.
Some individuals with autosomal recessive (2 deleterious FECH mutations) protoporphyria exhibit palmar keratoderma that often worsens in summer and remits in winter.[34, 35] Associated features include severe photosensitivity despite relatively mild erythrocyte protoporphyrin accumulations, but high plasma protoporphyrin levels and fecal protoporphyrin content. Neuropathy has been observed in some of these individuals, but not severe liver dysfunction, suggesting that protoporphyrin hepatotoxicity may be mitigated in this subset of recessive protoporphyria patients by efficient hepatobiliary protoporphyrin excretion mechanisms yet to be elucidated.
With progressive liver dysfunction, hepatosplenomegaly and jaundice may develop, as may signs of increasing cutaneous photosensitivity. End-stage liver disease is signaled by intense jaundice, ascites, vomiting, fever, encephalopathy, axonal polyneuropathy that may progress to paresis and respiratory failure, hemorrhage from esophageal varices, and extreme photosensitivity.
Loss of activity by as much as 50% as the result of 1 FECH mutant gene is generally insufficient to cause overt disease when its complementary allele has normal function. FECH genotypes composed of either 2 mutant alleles (approximately 4% of cases) or 1 mutation and a variant allele with a specific intronic single nucleotide polymorphism (IVS3-48C) (approximately 94% of cases) have been found in most symptomatic individuals.[12, 13, 37] This polymorphism enhances aberrant splicing and rapid degradation of FECH mRNA, with resultant low expression. The allele frequency of this polymorphism varies widely in diverse populations studied, as follows:
Southeast Asian - 31% 
White French - 11.3% 
North African - 2.7% 
Black West African - < 1% 
United States - 3.5% 
South Africans of European descent - 9% 
United Kingdom - 6.5% 
Chinese (different regions) - 28-41.4% 
Swedish - 8% 
The pairing of a mutated allele encoding a severely impaired enzyme protein with this low-expressing polymorphic allele typically yields enzyme activity diminished to less than 30% of normal, low enough to cause protoporphyrin accumulation. Individuals with no FECH mutation but who are heterozygous for this polymorphism typically do not have sufficiently diminished FECH activity to cause clinical abnormalities. Individuals with no FECH mutation, but who are homozygous for this polymorphism, may exhibit slightly abnormal erythrocyte protoporphyrin levels and mild photosensitivity.
Adult-onset protoporphyric photosensitivity and increased protoporphyrin levels have been associated with an acquired somatic mutation or deletion of a FECH gene due to myelodysplastic or myeloproliferative disorders.[14, 15, 16]
Eight families were described in 2008 with a protoporphyric disorder indistinguishable clinically from the predominant form of the disease, but without FECH mutations, that is now called X-linked dominant protoporphyria or X-linked protoporphyria (XLDPP, XLP or XLEPP [OMIM 300752]). Two different C-terminal deletions in the gene encoding the erythroid-specific isoform of aminolevulinic acid synthase were identified among these families.
The locus for this gene was identified on the X-chromosome, and the inheritance pattern in the families was consistent with X-linked dominant transmission. Both mutations caused a marked increase in activity of ALAS2 that eventuated in large accumulations of erythrocyte metal-free protoporphyrin and zinc-protoporphyrin. Seventeen percent of affected individuals in that study exhibited overt liver disease (40% of affected males), a significantly greater number than the 2-5% of individuals with ferrochelatase-deficient protoporphyria who develop this complication.
Additional cases of X-linked dominant protoporphyria and novel associated gain-of-function ALAS2 mutations have subsequently been recognized.[9, 11, 24, 18, 28, 29] A higher prevalence (approximately 10%) of X-linked protoporphyria was found among 155 unrelated North American individuals with the protoporphyria phenotype; this is 2-5 times greater than what has been observed among Western Europeans previously studied.
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