History
Porphyria cutanea tarda (PCT), hereditary coproporphyria (HCP), and variegate porphyria (VP) usually manifest after the second decade, and skin symptoms are chronic and appear several days after sun exposure. Increased fragility, blistering, and scarring are noted, especially over the back of the hands. Remission may occur in the winter months, if sunlight exposure is decreased.
Erythropoietic protoporphyria (EEP) typically presents in early childhood, and skin symptoms arise immediately after sun exposure with a very different picture in comparison with other photosensitizing porphyrias. Patients experience burning, pain, edema, and erythema without bullous lesions, scarring, or pigmentation changes.
The presence of neurologic symptoms and abdominal pain, in association with cutaneous symptoms, would favor VP or HCP as the likely underlying porphyria.
Because many patients with cutaneous porphyria avoid sunlight, they may suffer from vitamin D deficiency. [24]
PCT is associated with several precipitating factors.
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Alcoholism
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Iron overload (eg, in transfused patients with thalassemia)
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Hemochromatosis or HFE locus mutations
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Dialysis
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Estrogen
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Hepatitis C virus (HCV), [25] cytomegalovirus (CMV), and human immunodeficiency virus (HIV) infection - A study by Aguilera et al suggested that in most cases, PCT is associated with HIV only if the patient is co-infected with HCV [26]
An Israeli study by Snast et al found that the rate of cutaneous symptoms in patients with EPP, VP, and HCP were 100%, 58%, and 5%, respectively. Photosensitivity was the predominant cutaneous symptom in patients with EPP, being found in 90% of them. The rates of photosensitivity, blistering, and scarring in VP patients with cutaneous symptoms were 52%, 52%, and 74%, respectively. The sites most affected by cutaneous symptoms in VP and EPP were the dorsal hands/forearms. [27]
Physical
Skin changes are the hallmark of the cutaneous porphyrias. They can be acute (CEP), with erythema, edema, and erosions that eventually lead to facial scarring, or more chronic (PCT, VP, HCP), with skin fragility, blistering, and scarring, often over the backs of the hands. [7]
Congenital erythropoietic porphyria (CEP)
See the list below:
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Diaper - Pink-stained or dark-stained urine
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Hair - Hypertrichosis, alopecia
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Teeth - Red or brown discoloration
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Eyes - Keratoconjunctivitis, vision loss
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Growth - Shortness of stature
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Abdomen - Splenomegaly, upper right quadrant tenderness, positive Murphy sign
Cutaneous lesions include the following:
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Subepidermal bullous lesions that worsen with exposure to sunlight
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Hyperpigmented or hypopigmented healing subepidermal lesions
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Epidermal atrophy
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Pseudoscleroderma
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Mutilation of facial skin and cartilage
Musculoskeletal findings include the following:
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Resorption of distal phalanges
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Contractures
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Decreased range of motion
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Pathological fractures
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Vertebral compression and collapse
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Osteolytic and sclerotic lesion
PCT
Cutaneous lesions include the following (see the Dermatology Online Atlas for images of cutaneous lesions):
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Vesicle and bullae formation occurs in areas exposed to light, including the dorsum of hands and face. [28]
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Legs and feet commonly are involved in women.
Secondary skin changes from vesicular and bullous lesions include the following:
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Skin fragility with erosion from mild shearing trauma
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Hyperpigmentation or hypopigmentation (vitiligo) of areas exposed to light [29]
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Melanosis and violaceous-brown discoloration in areas exposed to light
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Milia [28]
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Pseudoscleroderma [29]
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Atrophy and scaring of healed skin
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Nonscarring alopecia [29]
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Dystrophic calcification
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Nonhealing ulcerations
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Acquired ichthyosis [29]
Light urticaria (rare) and hypertrichosis (periorbital) that slowly develops are noted.
EPP
See the list below:
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Exposure to light, especially in the spring and summer, causes cutaneous stinging and burning followed by erythema and edema
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Petechiae, purpura, vesicles, and crusting may develop
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Lesions similar to those of PCT may be seen in severe sun exposure but are much less common
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Osteoporosis and osteopenia can occur [24]
Causes
Table 2. Causes by Type of Porphyria (Open Table in a new window)
Porphyria |
Deficient Enzyme |
Location |
Inheritance |
Chromosome Band |
CEP |
Uroporphyrinogen III synthase |
Cytosol |
Autosomal recessive (AR) |
10q25.3-26.3 |
PCT |
Uroporphyrinogen decarboxylase |
Cytosol |
Autosomal dominant (AD) |
1p34 |
HEP |
Uroporphyrinogen decarboxylase |
Cytosol |
AR |
1p34 |
HCP |
Coproporphyrinogen oxidase |
Mitochondrial |
AD |
3q12 |
VP |
Protoporphyrinogen oxidase |
Mitochondrial |
AD |
1q22-23 |
EPP |
Ferrochelatase |
Mitochondrial |
AD, AR |
18q22 |
CEP is associated with uroporphyrinogen III cosynthase activity of about 40% normal activity.
PCT type I occurs spontaneously, whereas type II and type III are inherited. Since type III is rare, severe, has childhood onset, and is caused by an underlying homozygous gene defect, it is often considered separately (HEP). Type I, or sporadic PCT, affects 75% of all patients, with localized defects in liver enzyme activity. Type II, or familial PCT, accounts for approximately 20% of patients, probably due to the low penetrance rate of the UROD gene defect, and involves a defect in both the liver and erythrocyte enzymes. Sporadic and familial PCT are often clinically indistinguishable.
Expression of the disorder is precipitated by many factors, including the following:
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Alcoholism
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Beta-thalassemia major [30]
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Diabetes mellitus
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Dialysis
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Estrogen
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HCV, CMV, and HIV infection [31]
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Hematologic malignancy
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Hemochromatosis
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Hepatocellular carcinoma
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Renal failure
HEP is considered the homozygous form of inherited PCT (type III), and is associated with a 75% decrease in enzyme activity in all tissues.
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The heme production pathway. Heme production begins in the mitochondria, proceeds into the cytoplasm, and is then resumed in the mitochondria for the final steps. This figure outlines the enzymes and intermediates involved in the porphyrias. Enzymes names are presented in the boxes. Names of the intermediates are outside the boxes, between arrows. Multiple arrows leading to a box demonstrate that multiple intermediates are required as substrates for the enzyme to produce one product.
Tables
Type of Porphyria |
Age of Onset |
Incidence per 100,000 Population |
Male-to-Female Ratio |
CEP |
Infancy to early childhood; rare in adults |
300 cases total |
1:1 |
PCT |
Type I: Adulthood Type II (heterozygous mutations): Adulthood Type III (homozygous mutations): Childhood |
United States: 4 United Kingdom: 0.05 |
1:1 |
HCP |
Predominantly adulthood Youngest report was child aged 4 y |
Japan: 1.5 Czech: 1.5 Israel: 0.7 Denmark: 0.05 |
1:20 1:4 2:1 1:1 |
VP |
Heterozygous mutation: After puberty Homozygous mutation: Childhood (rare) |
South Africa: 34 |
1:1 |
EPP |
Infancy to childhood |
0.02 |
1:1 |
Porphyria |
Deficient Enzyme |
Location |
Inheritance |
Chromosome Band |
CEP |
Uroporphyrinogen III synthase |
Cytosol |
Autosomal recessive (AR) |
10q25.3-26.3 |
PCT |
Uroporphyrinogen decarboxylase |
Cytosol |
Autosomal dominant (AD) |
1p34 |
HEP |
Uroporphyrinogen decarboxylase |
Cytosol |
AR |
1p34 |
HCP |
Coproporphyrinogen oxidase |
Mitochondrial |
AD |
3q12 |
VP |
Protoporphyrinogen oxidase |
Mitochondrial |
AD |
1q22-23 |
EPP |
Ferrochelatase |
Mitochondrial |
AD, AR |
18q22 |
Porphyrin Type |
CEP |
PCT |
HCP |
VP |
EPP |
Uroporphyrin |
Significantly increased |
Increased |
Within reference range |
Within reference range |
Within reference range |
Coproporphyrin |
Significantly increased |
Increased |
Significantly increased |
Increased |
Within reference range |
Protoporphyrin |
Within reference range |
Within reference range |
Increased |
Significantly increased |
Significantly increased |
Porphyrin type |
CEP and PCT |
HCP and VP |
5-Aminolevulinate |
Within reference range |
Significantly increased |
PBG |
Within reference range |
Significantly increased |
Uroporphyrin |
Significantly increased |
Increased |
Coproporphyrin |
Increased |
Significantly increased |
