Xeroderma Pigmentosum (XP)

Xeroderma Pigmentosum (XP) is a rare, hereditary disease where patients experience skin hypersensitivity to ultraviolet (UV) light. It is characterized by dry skin, increased freckling as well as patches of hypo pigmentation and signs of premature aging. Affected individuals are particularly susceptible to developing actinic keratoses and squamous and basal cell carcinomas due to a defect in or lack of nucleotide excision repair (NER). Eye and neurological problems are likely to occur over time but neurological defects only develop those with the greatest impairment of DNA repair.


Squamous cell carcinoma skin cancer. Patients with XP have an extreme risk of contracting skin cancer.

Squamous cell carcinoma skin cancer. Patients with XP have an extreme risk of contracting skin cancer.

Squamous cell carcinoma skin cancer. Patients with XP have an extreme risk of contracting skin cancer.

There are currently 8 known complementation groups (XPA through to XPG and XPV), all with corresponding defects in their gene products. These groups differ in frequencies, with XPC being fairly common and XPE being relatively rare and severity of the disease, with XPG being severe and XPF being mild.

XP occurs worldwide, with the prevalence of 1 in 250,000 in the general population. It appears to affect men and women equally across all races. However Japan has a higher frequency of the disease with 1 in 40,000 having XP with XPA being the most common variant. The prevalence in the U.S is also 1 in 250,000.

Being a genetic disease, familial history and consanguinity increases the chance of inherited. An estimated 80% of XP sufferers will develop eye abnormalities and 30% will develop neurological disorders.

Mutation prevalence

Whilst mutations occurring in any one of the XP genes can lead to the disease, splice mutations have been found to be more common in the XPA and XPC complementation groups. An estimated 1% of the Japanese population has a splice mutation in exon 3 of the XPA gene and on the other end of the scale; only 2 individuals have been reported to carry mutations in the XPE gene. XPC is the most common form of XP amongst Americans.


XP is an autosomal recessive disease, which means the individual with the disease has inherited two copies of the mutated gene (one from each parent) that causes XP. If only one XP gene is inherited then that person carries of the disease gene but is not affected by it. Having two XP genes causes skin cells to be hypersensitive to UV light, resulting in a range of symptoms.

Essentially, the symptoms are caused by faulty DNA repair mechanisms in the skin. A defect in nucleotide excision repair (NER) results in an inefficient DNA repair mechanism in XP. Sun exposure damages DNA. As the cells are unable to repair it, the DNA remains damaged, which leads to cell death or the development of cancerous cells.

XP can be separated into 8 different groups based on what and where the mutation is. Each can vary in symptoms and have different susceptibilities to developing certain symptoms. Neurological abnormalities have only been seen in XP patients with mutations in the complementation groups XPA, XPB, XPD and XPG.

DNA damage and NER in-depth

The majority of DNA damage is induced by UVB light but recently UVA rays have also been linked to the same mutations. The most common forms of DNA damage occurs via the cross linking of adjacent pyrimidines resulting in the formation of cyclobutane pyrimidine dimers (CPDs) and 6-pyrimidine-4-pyrimidone photoproducts. Mutations caused are almost always located at the interface of pyrimidine-pyrimidine interactions, characterized by C to T, C to C or T to T sequence.

The electromagnetic spectrum highlighting UV radiation which causes skin damage.

The electromagnetic spectrum highlighting UV radiation which causes skin damage.

NER repairs mutations caused by UV light. NER can be divided into two subtypes; global genome repair (GGR) that can function throughout the entire genome and transcription-coupled repair (TCR) that is restricted to the transcribed strand of active genes. 7 out of 8 groups of XP genes are involved with NER and if one or more of those genes are mutated, the repair process is disrupted. XPV is a variant of XP and does not affect NER. Instead, there is a defect in DNA polymerase ? which alters post replication repair. NER functions by removing and replacing damaged DNA with newly synthesized DNA. It begins with a detection phase, performed in GGR by a complex involving the product of the XPC gene and another factor. In addition, the XPA gene product has been reported to have an affinity for damaged DNA. Therefore, it is likely that XPA has a role in the damage detection phase. When DNA damage is detected, Transcription factor II H (TFIIH) helicases unwind the DNA. The XPG gene product forms an open complex called the ‘pre-incision complex’. XPB and XPD gene products are part of a 9-subunit protein complex (TFIIH) that is also needed for the open complex formation. After the assembly of the pre-incision complex, single strand incisions are made in the damaged strand by complexes involving the XPG and XPF genes which encode endonucleases. Subsequently the damaged DNA is removed and the resulting gap is filled in with new DNA by the DNA polymerases and DNA ligase.

The NER genes that encode XPB and XPD are a part of the TFIIH basal transcription factor and are essential to life.

Three stages of XP

Figure 1. Xeroderma Pigmentosum. (Warning: graphic medical content)

Figure 1. Xeroderma Pigmentosum. (Warning: graphic medical content)

At birth, the skin appears normal. Onset of the disease usually begins at around 6 months and generally progresses through 3 stages.

Stage 1 is usually demonstrated by about 6 months with the following signs:

  • Areas exposed to the sun show diffuse erythema and freckling;
  • Irregular dark spots may begin to appear;
  • Xerosis and scaling may follow.

Continuous sun exposure will lead to stage 2.

Stage 2 is presented as poikiloderma, which is a result of an accumulation of actinic changes. Often, it appears at the median age of 2 and is characterized by the following:

  • Solar lentigines;
  • Skin atrophy and thinning;
  • Telangiectasias;
  • Patches of hypopigmentation and hyperpigmentation.

Stage 3 is the development of actinic keratoses and skin cancer. This stage may occur as early as 4-5 years or as late as adolescence.


Figure 2. Xeroderma Pigmentosum. (Warning: graphic medical content)

Figure 2. Xeroderma Pigmentosum. (Warning: graphic medical content)


XP normally presents early after birth, with it extreme sun sensitivity being detected at the age of 1-2 years. Freckling from sun exposure typically occurs in young children with XP which rarely occurs in normal children. The accumulation of DNA damage results in many other symptoms including:

  • Diffuse redness
  • Sunburn from minimal sun exposure
  • Dry, scaly skin
  • Thin skin
  • Patches of discolored skin
  • Talangiectasias


Individuals with XP have a 1,000 fold risk of developing skin cancer then the normal population. It will typically manifest before the age of 20 and is common in XP. Skin cancers are more prevalent in sun exposed patches of skin such as the face, neck and forearms. There is also a 10 – 20 fold increase in the likelihood of developing cancer or tumors affecting internal organs.

Eye abnormalities

Any structure of the eye can develop abnormalities from UV exposure. Many individuals experience:

 XP Electromagnetic spectrum of UVA & UVB

XP Electromagnetic spectrum of UVA & UVB

  • Photophobia – pain/discomfort from light
  • Conjunctivitis
  • Loss of vision
  • Irritation
  • Loss of eyelashes
  • Blepharitis – inflammation of the eyelids
  • Keratits – inflammation of the cornea

Patients also have an increased risk of developing cancerous or non cancerous growths in the eye

Neurological Disorders

Neurological disorders mainly occur due to neuronal degeneration and are only seen in particular subsets of XP with symptoms varying in severity. The most common abnormality is a loss of high-frequency hearing. Other neurological defects include poor co-ordination, decreased reflex responses (hyporeflexia), progressive mental retardation, seizures and spasticity.

Differential Diagnoses

The NER pathway involves many genes including the XP genes. Because of this, other rare disorders that have defects in NER such as Trichothiodystrophy (TTD) and Cockayne syndrome (CS) can be mistaken for XP and vice versa. The clinical features of these patients have some similarities and but also have marked differences. While XP patients have 1000-fold increase in risk of developing to skin cancer, TTD and CS patients don’t. Several of the genes involved in NER also affect somatic growth and developments, meaning some patients have growth retardation and immature sexual development. Progressive loss of hearing is also a feature of XP and CS. Neurological abnormalities in XP are primarily due to neuronal degeneration. In contrast, CS and TTD patients have reduced myelination of the neurons in the brain which are unrelated to sun exposure but could be due to faulty DNA repair mechanisms.


Being a genetic disorder there is no curative treatment. Preventative therapy must begin immediately upon diagnosis, which is usually in childhood. This means minimal exposure to the sun where possible and using a combination of UV protection such as complete coverage from the sun with clothing and hats, UV-protective glasses and constant application of sunscreen (SPF30+ or above is recommended).

Skin treatment

Manifestations of the condition are treatable but there is no guarantee that the symptoms will not recur. Larger areas of sun damaged skin may be removed by dermabrasion to remove the superficial layers of skin. This allows for regeneration of the population of skin cells that were not affected by UV rays.

Avoidance of the sun is crucial in preventing the symptoms seen in the skin. However, XP progresses to skin cancer then standard anti-cancer therapies would be used such as topical 5-fluorouracil, freezing with liquid nitrogen or surgical excision of the cancerous cells. If other malignancies develop they would be treated in the same manner as cancer patients without XP. Physicians may also prescribe medications such as high-dose oral Isotretinoin to prevent new cancers from forming, but there are toxic side effects to this treatment.

It is also recommended that frequent skin examinations are performed in order for early detection of any new lesions and monitor any growths for changes in shape, color and size.

Ocular treatment

Corneal transplantation has been successful in restoring vision to those with corneal opacities and severe keratitis, however immunosuppressive therapy is necessary in order to prevent rejection and can increase the chance of infections. Abnormal growths in the eye and tissue surrounding the eye would be treated surgically.

Neurological treatment

Neurological treatment is restricted due to lack of known treatments as well as fact that many drugs cannot get into to brain or they would cause too many unwanted side effects. Drug use for these symptoms is limited to anticonvulsants such as Phenytoin to prevent seizures.

Experimental treatments

Recently novel enzyme and gene therapies have been developed based on the etiology of XP. T4N5, a bacteriophage T4 endonuclease 5 has been utilized for topical therapy in a liposomal lotion. It is able to diffuse into the nucleus without a nuclear localization sequence and enables NER to recognize and cleave CPDs using light energy. This lotion holds significant promise for those with XP, receiving a Fast Track designation from the FDA.

Gene therapy using recombinant retroviruses carrying additional DNA repair genes to correct damaged cells and restore the capacity of NER are still being developed with aims of validating the procedure.


Due to its genetic basis, XP cannot be prevented. Carriers of the disease are asymptomatic and need not worry. Preventative therapy can slow down the progression of the disease and must begin immediately upon diagnosis, which is usually in childhood by the age of 2. This means minimal exposure to the sun where possible and using a combination of UV protection such as complete coverage from the sun with clothing and hats, UV-protective glasses and constant application of sunscreen (SPF30+ or above is recommended).

As individuals with XP have cells that are hypersensitive to environmental mutagens, cigarette smoke and alcohol should be avoided. It has also been reported that some individuals with XPV are sensitive to caffeine and it increases the amount of defective DNA repair.


Many patients with XP die at an early age from skin cancers and less than 40% will live past the age of 20. However, if a person is diagnosed early, does not have severe neurological symptoms and takes all the precautionary measures to avoid exposure to UV light, they may survive beyond that age.


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  • Zahid, S, Brownell, I (2008) ‘Repairing DNA damage in Xeroderma Pigmentosum: T4N5 lotion and gene therapy’. Journal of Drugs in Dermatology, Vol 7, pp.405-408.
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Urticaria Pigmentosa (UP)

Urticaria pigmentosa (UP) is a rare disease that affects the skin and occasionally other parts of the body. UP is a type of mastocytosis (also known as mastocytoma), which affects a sub-type of immune cells known as mast cells. UP is characterised by skin lesions and itching. Mast cells are formed in the bone marrow from pluripotent stem cells, under the influence of stem cell factor (SCF). SCF aids mast cell proliferation and survival. Mast cells are the primary effector cells in immunoglobulin E (IgE) mediated inflammatory reactions. They have been implicated both in innate and acquired immune responses. Mastocytosis is characterised by a pathological accumulation of mast cells and associated symptoms.

Hives may form if the skin lesions are rubbed or stroked. In addition to the skin, the bone marrow, liver, spleen, lymph nodes, or the gastrointestinal tract may be affected in rare cases of UP.


The exact number of affected individuals with urticaria pigmentosa is unknown, but the disease is rare. It has been estimated that mastocytosis, of which UP is the most common sub-type, is present in 1 in 1000 to 1 in 8000 individuals who attend a dermatology clinic. The disease is more common in children than in adults. About 75% of cases occur during infancy or early childhood. Incidence peaks again in mid-adulthood (30 to 49 years).

Childhood UP usually resolves or becomes less severe before adulthood. Conversely, adults with UP may develop a more aggressive form of the disease with a prolonged clinical course and systemic involvement. Men are slightly more frequently affected by UP than women. Also, UP is more common in Caucasians compared with other races.


Urticaria pigmentosa is caused by an excess of inflammatory mast cells, which are made in the bone marrow and help fight infections. Mast cells, when activated, release a compound called histamine, which causes swelling, itchiness and redness in the affected area. It is not known what causes the excess of mast cells that characterises UP, but environmental triggers have been identified that activate mast cells and cause symptoms associated with UP. These include:

  • Stress;
  • Physical stimuli, such as heat or cold, exercise and sunlight;
  • Venoms, such as bee stings;
  • Certain foods, such as lobster, crayfish, cheese, hot beverages and spicy foods;
  • Alcohol; and
  • Certain drugs, such as narcotics and quinine.

Cellular involvement in urticaria pigmentosa

The mechanisms involved in the pathogenesis of UP is not known. Increased mast cell growth factors in skin lesions of UP are thought to stimulate mast cell proliferation, melanocyte proliferation and the production of melanin pigment. The hyperpigmentation associated with UP can be attributed to melanocyte proliferation and melanin production. It has been hypothesized that BCL-2, a protein that prevents apoptosis, is upregulated in patients with UP and other forms of mastocytosis, leading to a reduction in mast cell apoptosis. Mutations in the proto-oncogene, KIT, which encodes a cytokine receptor that binds to stem cell factor and allows mast cell proliferation and survival, have been identified in patients with UP. The precise role of these mutations in the disease process is not clear. Interleukin-6 is elevated in patients with UP and is correlated with the severity of the condition. The systemic involvement of UP is thought to be mediated by mast cell-derived modulators, such as histamine and prostaglandins. Mast cell infiltration can also explain the development of extra-cutaneous symptoms.


Urticaria pigmentosa can affect any part of the skin, but usually involves the trunk. Urticaria pigmentosa usually appears as lesions (macules), yellow-tan to red-brown in colour, with the trunk almost selectively affected. Limbs and face may be affected, but rarely so. The size of the lesions can range from 1 mm to several centimeters. Once UP becomes widespread, the lesions become symmetrical.

On the skin, UP may appear as

  • Freckle like brown patches;
  • Nodules (lumps), papules or plaques
  • Itchy rashes;
  • Hives or welts may arise if the lesions are rubbed or scratched. This phenomenon is known as the Darier sign and the presence of Darier sign may aid in the diagnosis of mastocytosis;
  • Blister formation; and/or
  • Flushing of the face

Rarely, if other parts of the body are involved, UP can cause:

  • Diarrhea;
  • Fast heart rate;
  • Fainting due to low blood pressure; or
  • Rarely, some adults may develop telangiectasia eruptive macularis perstans (TEMP). TEMP is associated with red macules that overlie dilated capillaries (i.e. telangiectasia).

Systemic involvement

In adults UP can cause systemic involvement, severe allergic reaction and, rarely, death. About 85% of individuals with all forms of systemic mastocytosis have UP as a characteristic feature. About 15 – 30% of adults with skin lesions have extra-cutaneous symptoms. Headache and itching are common symptoms. Involvement of the vasculature can lead to palpitations, lightheadedness (due to hypotension) and syncope. If the gastrointestinal system is affected, nausea, vomiting, abdominal pain, diarrhoea, gastritis and peptic ulcers can occur. Hepatomegaly and splenomegaly with mast cell infiltration is often present. Lymphadenopathy is present in some cases. Involvement of the bone marrow can lead to fractures, anaemia and osteoporosis.

It should be noted that the systemic symptoms mentioned above are very rare in individuals diagnosed with UP, but may occur with other forms of mastocytosis, such as aggressive systemic mastocytosis.

Darier sign

When the lesions are rubbed or scratched, welt or hives formation can occur on the skin. This is known as the Darier sign and is useful in the diagnosis of UP and other mastocytotic disorders.


Diagnosis of UP is based on the appearance of the skin, the presence of the Darier sign, elevated levels of urine histamine and skin biopsy that confirms the presence of increased numbers of mast cells.


Identifying and avoiding the environmental triggers may be sufficient in preventing the symptoms of mild forms of urticaria pigmentosa. If treatment is required, as in the more severe cases, the following options are available:

  • Antihistamines, with H1 angtagonists used to relieve skin symptoms, itching and flushing and H2 antagonists used to treat hyperacidity that may occur in patients with UP. For anaphylaxis, both H1 and H2 antagonists need to be used. In the rare, but severe, possibility of anaphylaxis, a medical alert bracelet must be worn and an injectable adrenaline (epinephrine) solution should be carried at all times. A similar course of action is needed if circulatory collapse and shock occurs.
  • Mast cell stabilizers, such as Disodium cromoglicate, inhibit mast cell degranulation following exposure to specific antigens. These agents improve diarrhoea, abdominal pain, headaches and bone pain associated with UP. Several weeks of treatment may be needed before improvement in symptoms is noticed.
  • Low-dose aspirin may help, although in some cases, exacerbations can occur. Treatment with low-dose aspirin is usually restricted to patients with vascular collapse who are unresponsive to H1 and H2 antagonists, as aspirin has the potential to cause degranulation of mast cells and worsen the symptoms.
  • Photochemotherapy, or PUVA, utilizes long wave UVA radiation (340 – 400 nm) for the treatment of UP. Irradiated skin shows a reduction in mast cells. Two to three treatments are required each week for several months. PUVA reduces the severity of pruritis and improves the appearance of skin lesions. Recurrence is likely to occur within 12 months and further PUVA therapy may be necessary.Topical steroids;
  • High potency topical steroids may offer transient relief from symptoms, especially with pruritis. The lesions, however, invariably tend to recur. For severe UP with systemic involvement, systemic steroids may be necessary.


The precise causes of urticaria pigmentosa are unknown and, therefore, the disease cannot be prevented or cured. It is, however, possible to identify factors that may trigger UP and to circumvent them. Certain foods, physical exertion and stress are potential triggers in exacerbating UP and these should be avoided. Lesions should not be rubbed or scratched, as this may cause hives. In rare cases, where anaphylactic reactions can occur, patients need to be educated about symptoms and treatments, including the use of injectable adrenaline (also known as epinephrine), or EpiPen, where necessary. If extra-cutaneous (beyond the skin) involvement is present, it is important to regularly review the progress of the condition.


The prognosis of urticaria pigmentosa depends on the age of onset. UP generally begins during infancy or early childhood. The prognosis of childhood-onset UP is good, with resolution of the disease, or marked improvement in symptoms before adulthood. If UP begins in late-childhood or during adulthood, the prognosis is poor, as the disease tends to be persistent with systemic involvement. Haematological malignancies are a severe, but remote, possibility.


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  • Ritambhra, H M & Tahlan, A (2001). ‘Urticaria Pigmentosa’. Indian Journal of Dermatology, Venereology and Leprology, Vol 67(1), pp. 33-34.
  • Simon, J C, Pfieger, D & Schopf, E (2000). ‘Recent advances in phototherapy’. European Journal of Dermatology, Vol 10(8), pp. 642-645.
  • Slavkovic-Jovanovic, M, Jovanovic, D, Petrovic, A & Mihailovic, D (2008). ‘Utricaria Pigmentosa: a case report’. ACTA Dermatovenereologica APA, Vol 17(2), pp. 79-82.
Solar urticaria (SU)
Solar Urticaria reaction on skin

Solar Urticaria reaction on skin

Solar urticaria (SU) is a rare, sunlight or UV induced hypersensitivity (allergic) reaction that causes wheals (raised red skin welts) very soon after or during sun or light exposure. In solar urticaria, the reaction is triggered by exposure to UV or visible light. It may be severely disabling and can even be life threatening.


Solar urticaria is rare but occurs worldwide. 3.1 per 100,000 people are affected and females are more likely to be affected than males.


Following limited exposure to sunlight, sufferers may develop an itchy or burning redness on exposed skin. Initial presentation has also been reported after first solarium use.

Symptoms usually develop within five minutes of sun/UV exposure and often develop from an unpleasant sensation to itching, redness and swelling, followed by localized or widespread development of wheals (an urticarial flare). Gradual resolution then follows over 1-2 hours.

Rarely, a more prolonged exposure may be required for symptoms to develop, or the onset of symptoms may be delayed for several hours. With extensive whealing some patients also experience headache, nausea, bronchospasm (asthma-type respiratory symptoms) and syncope (dizziness) which may become life threatening (although this is rare). Conversely, in some people with mild disease, or in those who quickly recognize their onset and avoid further exposure, whealing may not be reported.

Sun-exposed areas are most commonly affected, although occasionally reactions are seen in dermal areas that are not exposed to the sun. Rarely sun-exposed sites are spared suggesting that tolerance may occur.


Solar urticaria may be primary or secondary.

Primary solar urticaria is an immediate hypersensitivity response (IgE mediated allergic reaction) towards an allergen (a compound produced in the body when UV light is absorbed by a cellular pre-cursor) induced in the body following sunlight exposure. The responsible allergen is not know but is termed a photoallergen. The allergic reaction that follows prolonged sunlight exposure leads to a widespread inflammatory response.

Mast cell degranulation and histamine release are important factors in SU but many other inflammatory cells, particularly neutrophils and eosinophils are involved in amplifying the whealing response.

Many wavelengths light may trigger the production of different photoallergens but SU is most commonly caused by UVA or visible light. There appears to be no genetic basis for this condition.

Very rarely, secondary solar urticaria occurs in association with other photosensitivity disorders, such as cutaneous porphyria or lupus, or with certain medications known to cause photosensitivity.


Complete potential action spectrum for Solar Urticaria

Complete potential action spectrum for Solar Urticaria

Phototesting confirms the diagnosis and reveals the wavelengths responsible for inducing an urticarial response. Phototesting may be performed with a monochromator (single wavelengths of light selected at a time), broad spectrum source or natural sunlight to estimate the minimal urticarial dose (MUD) of light required to induce symptoms. Screening tests to exclude lupus (ANA,eNA) and cutaneous porphyria (porphyrin studies) must be done to exclude these conditions. Medications must also be considered as a possible cause.

Differential diagnosis

  • Cutaneous lupus
  • Polymorphic light eruption (PLE)
  • Photo-exacerbated dermatoses i.e. eczema
  • Other physical urticarias


Treatment of solar urticaria is usually directed towards relief of symptoms and avoidance of their onset through behavioural change. High doses of H1-antihistamines taken an hour before sun exposure are very effective in one third of patients and give another third partial relief.

Avoidance of sunlight, photoprotective clothing and broad-spectrum sunscreens are necessary to prevent symptoms; however this may not always be useful in cases where visible light is responsible for the solar urticaria.

Desensitisation with phototherapy may be useful for some patients however therapy generally needs to be continued to maintain its benefit and so consequently carries a risk of long-term risks such as skin cancers. In severely affected individuals, this treatment also carries the risk of disease onset and anaphylaxis (severe, often life threatening allergic reaction) and so should be undertaken with extreme caution.

In extreme cases these patients need to be hospitalized to undergo plasmaphoresis (a procedure similar to dialysis where the plasma in their blood is removed and the blood cells are returned to the patient). Immunosuppressant medications such as Cyclosporin and intravenous immunoglobulins may also need to be considered in the most severe cases.


For the majority of patients symptoms will persist indefinitely. For a small proportion of patients solar urticaria will deteriorate however some do experience improvement with an estimated 26% chance of resolution at 10 years.


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Porphyria Cutanea Tarda (PCT)

Porphyria cutanea tarda (PCT) is the most frequently seen disease of a group of disorders (the Porphyrias) that can be acquired or inherited. It is caused by low levels of an enzyme (uroporphyrinogen decarboxylase or UROD) involved in the production of haem (heme).

Haem is a component of hemoglobin in red blood cells and is vital as it needs it to carry oxygen around the body. These result in a build-up of chemicals called porphyrins. In PCT, porphyrins accumulate in the skin, causing the skin to be very sensitive to light (photosensitive).

In PCT, porphyrins accumulate in the skin, causing the skin to be very sensitive to light (photosensitive), causing blistering of the skin in areas that receive higher levels of exposure to sunlight.


Haem Synthesis Pathway

Haem Synthesis Pathway

Porphyria cutanea tarda is the most common of all the Porphyrias and occurs throughout the world, yet PCT is considered to be an uncommon condition, affecting about 1 in 25,000 of the population. All races are equally affected.

Before the widespread use of oestrogens in hormone replacement therapies and oral contraceptives, the disease developed predominantly in males but the incidence among sexes is approximately equal now. It should also be noted that males that are on oestrogen therapy have also developed PCT. Age of onset is usually around the ages of 30 – 40; to see the disorder before puberty it quite unusual.

An estimated 80% of porphyria cutanea tarda sufferers have sporadic PCT (Type I – acquired, not inherited) and the remaining 20% have familial PCT (Type II – inherited). Onset of the disease is usually in late adulthood between the ages of 30 – 40 years. It is unusual for the disease to manifest before puberty.


Porphyria cutanea tarda is caused by either an inherited or acquired deficiency of Uroporphyrin Decarboxylase (UROD), the enzyme involved in fifth step of haem synthesis. A decreased level of UROD causes accumulation of haem building-blocks (porphyrins) that have failed to be incorporated into haem. The porphyrins build up in the skin where they absorb both visible and ultraviolet light, causing the main symptoms of PCT. Porphyrin accumulation does not occur in normal people.

Not all family members that inherit the gene mutations associated with PCT will present with the disorder, therefore it is proposed that PCT requires other factors that increase the production of porphyrins to be present as well.

Most classifications of PCT separate it into two types, in which both are associated with low UROD activity.

  • Type I – Sporadic or acquired PCT. It encompasses around 80% of cases. The enzyme deficiency is restricted to the liver with an approximated 50% of UROD levels. Acquired PCT occurs most commonly in patients who also have haemochromatosis or chronic hepatitis C infection. This form most often occurs after use of alcohol, oestrogens, oral contraceptives, other drugs and certain environmental pollutants but sometimes no cause can be found. Most people who consume alcohol and take estrogens do not develop a porphyria; therefore, it is likely that genetic factors are of higher importance even though there is no family history of PCT.
  • Type II – Familial or hereditary. This type of PCT is an autosomal dominant disorder but inheritance of the mutated gene/s does not necessarily mean expression of skin disease nor can it predict the severity of the condition.The UROD gene has been mapped to chromosome 1p34. Mutations have been identified in the UROD gene, including DNA base substitutions and deletions. These mutations result in reduced activity of the enzyme. Some mutations result in PCT and others result in the recessively inherited HEP. HEP is the homozygous forms of familial PCT. Levels of UROD are also decreased to approximately to 50% in all tissues although porphyrins only accumulate in the liver. Many UROD mutations have been identified in patients with familial PCT and most carriers of mutant UROD alleles do not express a clinical phenotype unless additional factors are present.

Numerous precipitating factors are known to contribute to the development of both types of PCT. Each of these is discussed briefly in the following sections.


Ethanol has long been recognized to precipitate PCT. It has been shown to induce the hepatic enzyme ALA-synthase in patients along with diminished UROD activity after acute ingestion or in those who are chorinic alcoholics. Alcohol and cyclic hydrocarbons may also induce the ALA-synthetase gene, increasing Urogen, the precursor of UROD inhibitors thereby also decrease the activity of available UROD. Chronic alcoholism can also lead to the suppression of erythropoesis and increased absorption of dietary iron.


The important role of iron the in the pathogenesis of PCT is confirmed by elevated levels of ferritin and serum iron in individuals with PCT. Hepatic iron overload is almost present in all cases of PCT with total iron stores being approximately twice of normal levels. PCT is particularly common in those with alcoholism and iron overload together.

There are many complex hypotheses proposed about iron and its role in PCT pathogenesis:

  • It may directly inhibit UROD.
  • An ionic state of iron acts as a catalyst for the formation if reactive oxygen species that can cause lipid peroxidation and damage the lipid rich membranes of microsomes and mitochondria in the liver.
  • Increased mutations in the HFE gene (encodes a human leukocyte antigen class I-like protein) have been found in British patients with type I PCT. This hemochromatosis mutation appears to be responsible for iron overload in many populations.
  • Induction of the enzyme ALA-synthase by iron could also participate in the accumulation of porphyrins.

Reduction of iron levels has been shown to lead to the improvement or remission of many cutaneous lesions.

Viral infections

Research has found an association between human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Their roles in the pathogenesis of PCT is unclear but it has been suggested that chronic viral hepatitis may cause increased deposition of iron in the liver, which has been observed in biopsy specimens from patients with chronic hepatitis C.


The role of oestrogens in PCT is also unclear but an association between the use of oral contraceptives containing oestrogen and hormone supplements for both males, as an adjunct therapy for prostatic cancer and females, as post-menopausal hormone replacement therapy, has been found.

From the known of the affects from the above factors, it is possible that all or any of these could contribute to the excessive porphyrinogenesis characteristic of PCT.


The main clinical manifestation is blistering of the skin of sun-exposed areas, such as the back of the hands, forearms, face, ears, and neck. The skin becomes increasingly sensitive and fragile and any minor trauma leads to lesions and ulcerations that can become crusty and result in scarring when they resolve. Numerous small milia (cysts commonly known as ‘milk spots’) can also develop and patients find that they become very sensitive to light. This photosensitivity is due to the overproduction of porphyrins in the liver, due to the enzyme deficiency. They then leak out into the blood and build up in the skin, absorbing both UV and visible light. Other skin changes that can be seen include hyper or hypopigmentation, particularly on the face in spotty of diffuse patterns. Sclerodermoid plaques can also develop on sun exposed areas. These come in the form of scattered, white to yellow waxy plaques.

Hypertrichosis is frequently observed on the cheeks, temples, eyebrows and, less frequently, arms, legs and trunk. The hair can vary from a fine or course texture, vary in length and differ in colour. The hair may continue to grow, darken or thicken and is more apparent in females. Males often complain about changes in growth pattern of their beards and difficulty in shaving.


There is no curative treatment for porphyria cutanea tarda but avoidance of trigger factors that may have caused exacerbation of the disease can result in improvement. The main focus of treatment is to remove or decrease any triggers for PCT, reduce iron levels and to remove the excess porphyrin that has accumulated in the body. Avoidance of sunlight, alcohol and oestrogens and paying attention to skin care is particularly helpful in PCT. The most widely recommended treatment is repeated phlebotomies (removal of blood, see below) to deplete excess iron levels in the liver, thereby effectively reducing iron stores in the body. Antimalarials, chloroquine or hydroxychloroquin, are another approach to treatment when phlebotomies are contraindicated in patients with other medical conditions, as these work to increase porphyrin excretion through the urine.

If there is an inadequate response to either treatment alone, a combination of both therapies is used. Any viral infections found to be present should be treated accordingly.


Phlebotomies are the treatment of choice for PCT. It is effective because it depletes the excessive stores of iron in the liver and reducing iron levels in the body. Phlemboomies are considered safe and are associated with minimum morbidity. The amount of blood removed varies but is repeated every 2nd or every 3rd week; shorter intervals unnecessarily risk causing anemia. When serum iron or ferritin levels fall slightly below normal, phlebotomy is stopped. Usually, only 5 to 6 sessions are needed. Urine and plasma porphyrins fall gradually with treatment and continue to fall even after therapy is stopped. The skin eventually returns to normal but this can take several months to several years. After remission, further phlebotomy is needed only if there is a recurrence.


Phlebotomies are contraindicated in some patients because of the presence of anemia and cardiovascular disorders. Instead, low dose antimalarials such as chloroquine and hydroxychloroquine as used. They work by removing excess porphyrins from the liver by increasing the excretion rate. The mechanism might relate to forming water solubledrug-porphyrin complexes that are easily excreted. Remission can be seen within 6-12 months. Originally, higher doses were used to treat the condition but are no longer recommended because of liver toxicity.


If a trigger factor has been identified to have set off the disease then effort should be taken to reduce or eliminate exposure to that factor. Patients should avoid sun exposure where possible. Typical sunscreens that block UV light are ineffective, but UVA-absorbing sunscreens may be more beneficial. Wearing a hat and protective clothing is also highly recommended and considered the best form of protection from the sun.

Alcohol ingestion should be avoided permanently, but oestrogen supplementation can usually be resumed safely after the disease undergoes remission.

These treatments are not suitable for PCT patients who have advance renal disease. This is because there is usually underlying anemia and since renal activity is already low, drug-porphyrin complexes are not filtered out by the kidneys. The use of human recombinant erythropoietin mobilizes and reduces excess iron. It resolves the anemia enough to permit successful low volume phlebotomy.


Porphyria cutanea tarda is an important medical condition because it can be disfiguring if skin lesions are not treated. Remission can be achieved through avoidance of trigger factors or treatment and any reoccurrences respond well to the same treatments.


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  • Bulaj et al. (2000). ‘Hemochromatosis genes and other factors contributing to the pathogenesis of porphyria cutanea tarda’ Blood, Vol. 95, pp.1565-1571.
  • Haberman, H F, Rosenberg, F & Menon, I A (1975). ‘Porphyria cutanea tarda: comparison of cases precipitated by alcohol and estrogens’ Canadian Medical Association, Vol.113, pp.653-655.
  • Phillips et al. (2001). ‘A mouse model of familial porphyria cutanea tarda’ Proceedings of the National Academyof Sciences. Vol. 98, pp.259-264.
  • Poh-Fitzpatrick, M (2007). ‘Porphyria Cutanea Tarda’ [Online] Available online [Accessed on 11/12/2008] .
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  • Woolff, K, Goldsmith, L A, Katz, S I, Gilchrest, B A, Paller, A S & Leffer, D J (2003) Fitzpatrick’s Dermatology in General Medicine, 7e. Ch. 79. The McGraw Hill Companies.
Hydroa Vacciniforme (HV)

Hydroa vacciniforme (HV) is a rare, chronic photosensitivity disorder which chiefly occurs in children. The disease is characterised by the eruption of inflamed bumps and fluid-filled blisters (vesicles) on the skin following exposure to sunlight. Commonly presenting on the face, ears and hands, these vesicles heal over time as pox-like or “vacciniform” scars. Ultraviolet A (UVA) radiation (320-400nm) is the main wavelength of light which has been demonstrated to induce symptoms.

Figure 1. Blisters/lesions in a HV patient

Figure 1. Blisters/lesions in a HV patient

HV was first described in 1862 in France by Antoine Pierre Ernest Bazin and Emile Baudot. The vast majority of cases begin in childhood and resolve spontaneously in adolescence or early adulthood. The disease is not fatal, however, due to its prevalence in pediatric patients, the level of discomfort suffered and the long-term scarring which results, HV is considered to have a high impact upon patient quality of life.


HV is a rare disease and prevalence data is limited, but in Scotland rates are reported as approximately one in 300,000. Occurring predominantly in children aged 3-15, one study indicates a median onset age of 7.9 years for HV. A few cases have also been reported in infants and elderly people up to 60 years of age. There is a higher incidence of HV in females and the disease also presents at a younger age in female patients than in males. It has been found, however, that there is a longer course of the disease in males.


The exact cause of HV is unknown, though the distribution of the lesions on sun exposed areas of skin tend to suggest a causal relationship with sunlight. Reproduction of HV papules following repeated exposure to artificial sources of UV light indicates that UVA is the wavelength responsible for the symptoms. While the precise pathologic mechanism is unknown, HV is believed to be caused by an auto-immune disorder. Hence, it is classified along with polymorphic light eruption, actinic prurigo, chronic actinic dermatitis and solar urticaria as an IMP or “immunologically mediated photodermatosis”. These are a group of immune-influenced diseases which elicit symptoms in the skin upon exposure to light, mainly that in the UVA spectrum.

Figure 2. Child with HV scars

Figure 2. Child with HV scars

There have been two familial cases of HV in siblings which have led to the notion of there being a genetic component to the disease, though further study is required to substantiate this theory. In addition, a single case has been reported following treatment with the immunosuppressant drug “cyclosporine”. Due to the inconsistent responses to a broad range of treatments and disparity in the ages of onset/remission, some also speculate that HV may be a disease arising from different origins that present as a similar clinical syndrome.


The first symptoms of HV generally appear on the cheeks and nose in the spring or summer months, though can occur on any sun-exposed skin. Initially patients will experience a mild burning or tingling sensation, this has also been described as stinging and itching. Erythema (redness of skin caused by inflammation) leads to the development of multiple small blisters, bumps or lesions within 30 minutes to 2 hours following sun exposure. These lesions are originally taut and swollen with accumulated fluid then slowly form necrotic, pox-like crusts and scabs (sometimes blackish in colour). They heal over several days, eventually becoming light or unpigmented scars which tend to be depressed or indented; these may last for a number of years. The vesicles, or blisters, recur upon subsequent exposure to solar radiation.

Figure 3. Child with HV blisters

Figure 3. Child with HV blisters

Some HV patients experience ocular problems – light sensitivity (photophobia), mild inflammation of the eyes (keratoconjunctivitis) and clouding/inflammation of the cornea (the front part of the eye), known as keratitis. Uncommon symptoms, described by only a couple of patients, include: bone and cartilage reabsorption, earlobe mutilation, separation of nails from their nail-beds and systemic (whole-body) effects.

A high rate of Epstein-Barr Virus (EBV) infection in HV patients has been reported in medical literature. The pathological association between the disease and the virus is unclear, though one theory is that the disease is mediated by the T-cells of the immune system which can become infected with EBV. One study revealed that individuals with severe HV had more chronic, active infections, whereas those with more subtle forms of the disease tended to have mild or latent infections.

Severe forms of HV-like eruptions have been linked with an aggressive type of T-cell lymphoma (EBV-associated) mainly found in children from Asia and Latin America. While some researchers claim that HV can evolve into T-cell lymphoma, most insist that this is a disease distinct from the classical HV.

Diagnosis and Treatment

HV diagnosis is difficult since the characteristic lesions are similar to those produced by other skin disorders such as porphyria and polymorphous light eruption. Repetitive UVA phototesting involves deliberately exposing a section of skin to an artificial source of UVA radiation to determine the cutaneous reaction generated. This is the best available method of diagnosis, though it is by no means definitive.

A range of preventative treatments have been employed with efficacy varying between patients. To date, no consistent therapy has been discovered. The mainstay of treatment remains photoprotection of skin; with UVA blocking sunscreens, tight-weave, sun-protective clothing (including wide brimmed hats) and avoidance of sunlight. When lesions occur they are usually treated with wet dressings and topical antibiotics.

The following treatments have been trialed with varying success:
Narrowband and broadband UVB phototherapy – The aim of UVB phototherapy is to harden the skin of HV patients against the lesion-inducing effects of UVA radiation without provoking symptoms. UVB radiation consists of wavelengths between 280 and 315 nanometres (nm), Traditional sources of UVB radiation give off wavelengths of light across the spectrum (broadband). It has been found that the shorter wavelengths are particular harmful and more carcinogenic than longer wavelengths. Moreover, it is the longer wavelengths which generally provide greater therapeutic effects for a range of skin disorders (commonly psoriasis). Thus, narrowband therapy was developed to utilize only those wavelengths which provided beneficial effects. Special tubes have been created which emit the wavelengths necessary to produce the therapeutic effect (305-315); for instance, the phosphor tube light (TL-01) emission is 311 to 312 nm. Narrowband is preferable to broadband therapy as it has remedial value while minimising potential damage. UVB phototherapy has been shown to reduce the severity of HV in several cases, but some consider it too dangerous due to the known deleterious effects of UV radiation. Furthermore, the treatments, which are administered several times over weeks or months, often involve the patient standing or lying in a booth with tube lights for a period of time; some children may find this experience intimidating.

Fish oil/Omega 3 oral supplements – A diet rich in omega-3 fatty acids (commonly obtained from fish oil) has traditionally been shown to reduce erythema in response to UV radiation in a range of patients, particularly those with polymorphic light eruption. It was therefore hoped to reduce the sensitivity of skin of patients with HV. One study of 3 boys resulted in significant improvement in one patient, moderate improvement in the second and no noticeable reduction in the third’s lesions at all. This is typical of the unpredictable and variable nature of HV treatments to date.

Pharmaceutical therapies – A few individuals treated with oral antimalarials such as chloroquine noted fewer, less severe lesions and increased resistance to UVA radiation, but overall these have been found widely insufficient. Some patients have been shown to benefit from carotenoids such as beta-carotene (an antioxidant) and canthaxanthin, with a few even claiming total resolution of symptoms. Immunosuppressant drugs, including cyclosporine A and azathioprine, can be given alone or intermittently with steroids, this option has also had some success.


Most cases of HV will remit by late adolescence or early adulthood, but a few have been reported to continue into adulthood. Lifelong HV symptoms have been encountered but are extremely rare. There has been the occasional report of late onset HV in the patients 20’s, with one as late as 58 years of age. As previously mentioned, boys tend to suffer longer than girls and the average duration of the disease from follow-up studies has been established as nine years.

Online associations

Hydroa Vacciniforme online support group, for those with a family member suffering from the condition.


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  • Bickers, D.R et al., 1978, ‘Hydroa Vacciniforme’, Archives of Dermatology, 114(8):1193-1196.
  • Blackwell, V, McGregor, J.M & Hawk, J.L, 1998, ‘Hydroa vacciniforme presenting in an adult successfully treated with cyclosporin A’, Clinical Experimental Dermatology, 23(2):73-76.
  • Bruderer, P et al., 1995, ‘Hydroa vacciniforme treated by a combination of beta-carotene and canthaxanthin’, Dermatology, 190(4):343-345.
  • De Pietro, U et al., 1999, ‘Hydroa vacciniforme persistent in a 60-year-old man’, European Journal of Dermatology, 9(4):311-312.
  • Ferguson, J, 1995, ‘Narrow-Band UVB (TL-01) Phototherapy: An Advance in the Treatment of Psoriasis’, Journal Watch Dermatology, 1 October, Feature.
  • Gambichler, T, Al-Muhammadi, R & Boms, S, 2009, ‘Immunologically mediated photodermatoses: diagnosis and treatment’, American Journal of Clinical Dermatology, 10(3):169-180.
  • Garip, F et al., 2007, ‘Hydroa Vacciniforme’, Journal of the Turkish Academy of Dermatology, 1(2):71202c.
  • Gupta, G, Man, I & Kemmett, D, 2000, ‘Hydroa vacciniforme: A clinical and follow-up study of 17 cases’, Journal of the American Academy of Dermatology, 42(2 pt.1):208-213.
  • Halasz, C.L et al., 1983, ‘Hydroa vacciniforme: induction of lesions with ultraviolet A’, Journal of the American Academy of Dermatology, 8(2):171-176.
  • Iwatsuki, K et al., 2006, ‘Pathogenic Link Between Hydroa Vacciniforme and Epstein-Barr Virus-Associated Hematologic Disorders’, Archives of Dermatology, 142:587-595.
  • Kim, W.S et al., 1998, ‘A case of hydroa vacciniforme with unusual ear mutilation’, Clinical Experimental Dermatology, 23(2):70-72.
  • Leroy, D et al., 1997, ‘Factors influencing the photo-reproduction of hydroa vacciniforme lesions’, Photodermatology, photoimmunology & photomedicine’, 13(3):98-102.
  • Lugović, M.L, 2008, ‘Allergic hypersensitivity skin reactions following sun exposure’, Collegium Antropologicum, 32(suppl. 2):153-157.
  • Ngan, V, 2006, Hydroa Vacciniforme, DermNet NZ, accessed 9th June 2010, <>.
  • Rhodes, L.E & White, S.L, 1998, ‘Dietary fish oil as a photoprotective agent in hydroa vacciniforme’, British Journal of Dermatology, 138(1):173-178.
  • Sebastian, Q.L, 2008, Hydroa Vacciniforme, eMedicine Specialties, accessed 9th June 2010, <>.
  • Verneuil, L et al. 2010, ‘Epstein-Barr virus involvement in the pathogenesis of hydroa vacciniforme: an assessment of seven adult patients with long-term follow-up’, British Journal of Dermatology, accepted for publication, retrieved June 9th 2010, Wiley InterScience.
  • Wong, S.N, Tan, S.H & Khoo, S.W, 2001, ‘Late-onset hydroa vacciniforme: two case reports’, British Journal of Dermatology, 144(4):874-877.
Erythropoietic Protoporphyria (EPP)

Erythropoietic protoporphyria (EPP) is a rare inherited metabolic disorder of the haem (heme) pathway causing severe phototoxicity (toxic reactions to light) in skin due to the build up of a phototoxic chemical in the skin.

EPP belongs to a heterogenous group of disorders (porphyrias) that result from a dysfunction of specific enzymes involved in the haem biosynthesis. Haem serves many essential functions in the body one of which is oxygen transport via haemoglobin.


Erythropoietic Protoporphyria (EPP) reaction

Erythropoietic Protoporphyria (EPP) reaction

Erythropoietic protoporphyria is rare, and few studies have been done on its prevalence. Geographic location generally doesn’t seem to bias the incidence of EPP, although one study has suggested that the incidence in Slovenia is 1:58,000. Other studies include incidence that range from 1:75,000 to 1:200,000. Case reports suggest that EPP is prevalent globally.

It is estimated that between 5,000-10,000 individuals worldwide have EPP.


Typically, erythropoietic protoporphyria symptoms begin in childhood and are characterized by episodes of phototoxicity. The main symptoms are pain, which is often described as heat, prickling, itch or extreme sensitivity of skin exposed to light. The pain is often very severe, and swelling and blistering of the skin may result. Skin lesions resolve slowly often leaving waxy or pitted scars. Repeated exposure leads to scarring and waxy thickening of the skin on the backs of the knuckles and nose.

Erythropoietic Protoporphyria (EPP) reaction

Erythropoietic Protoporphyria (EPP) reaction

As little as a few minutes of sunlight (which may overcast or window transmitted) may be sufficient to evoke symptoms. Symptoms are due to visible light (at wavelength above 400 nanometers, part of the electromagnetic spectrum). In most affected individuals, skin involvement persists throughout life, although some people become less symptomatic with time. Symptoms can be seasonal, starting early in the spring, continuing through summer and diminishing in winter. Some patients report that wind may exacerbate their symptoms.

Erythropoietic protoporphyria patients will sometimes have a mild microcytic anaemia, presumably due to the inability or reduced ability to form haem. This should not be confused with iron deficiency anaemia and patients should not take iron replacement for this as it may actually exacerbate the porphyria. Gall stones, usually pigment stones, are more common at an earlier age in EPP.

Liver failure occurs in 5% of erythropoietic protoporphyria patients; this is thought to be related to the increased work of the liver to clear the excessive intermediate by-products from the defective haem pathway. If liver failure occurs it can be fatal.

This lack of permanent symptoms in erythropoietic protoporphyria leads to frequent misdiagnosis by doctors, much to the frustration of parents and their child.


Protoporphyrin IX molecule

Protoporphyrin IX molecule

Erythropoietic protoporphyria is inherited and can be autosomal dominant or recessive. This disorder causes a chemical known as protoporphyrin IX to accumulate in the skin. When the skin is exposed to the sun, these molecules undergo a chemical reaction that results in swelling, severe and intolerable pain and scarring, a condition known as phototoxicity.

The pain is sometimes described as like having hot needles stuck into the skin. The lifelong pain experienced by these patients typically resigns them to become socially isolated, due to the lack of an efficacious treatment and their need to continuously avoid sunlight.

Ferrochelatase deficiency

The specific defective enzyme in erythropoietic protoporphyria is ferrochelatase, the last of eight enzymes in the porphyrin-haem pathway. Consequently there is an inability to chelate iron with protoporphyrin IX to form haem. Intermediates from the pathway accumulate before this final step and cause toxic effects which are involved in the dermal symptoms of EPP.

The gene for the ferrochelatase enzyme, which shares the same name, is located on chromosome 18q21.3. Molecular studies on the gene indicate that more than 60 different mutations exist, most of which are insertions or deletions.


Diagnosis of erythropoietic protoporphyria is based on the detection of increased levels of free protoporphrin IX in red blood cells. Monitoring of liver function tests and red cell porphyrins are sometimes performed to pick up any early signs of liver failure.


Action spectrum of PPIX

Action spectrum of PPIX

Sun avoidance by remaining indoors or wearing sun protective clothing including cotton gloves and a wide brimmed hat is the first line in erythropoietic protoporphyria management. The remaining treatment is focused upon symptomatic relief, although no effective symptomatic treatments have been reported. Patients have reported immersing affected skin in water (both hot and cold) to try and relieve the phototoxicity.

Most commercially available sunscreens are of no value as a treatment, but a large particle size titanium dioxide sunscreen may be of some benefit if used with other forms of sun protection.

Drugs such as β-carotene, cysteine (an amino acid which has been shown to decrease photosensitivity) and cimitedine have been used with various disappointing results and because the disease is inherited, genetic counselling is recommended.

Hematin infusion may temporarily decrease the production of haem and may also result in a decrease of plasma and faecal porphyrins. Also, there is sporadic evidence that autologous blood cell transfusion with washed red blood cells may successfully induce clinical and biochemical remission for erythropoietic protoporphyria patients. Finally, narrow band UVB phototherapy as a treatment option may provide some protection, presumably through epidermal thickening and tanning.

Since sun avoidance is recommended, patients lead lives where they are in the sun for very limited time. This can prevent normal social activities and the intense pain that is experienced interferes with normal daily activities and can prevent adequate sleep.

Liver transplantation in EPP

Liver failure occurs in 2-5% of patients with erythropoietic protoporphyria; this is thought to be related to the increased workload of the liver to clear excessive intermediate by-products from the defective haem pathway. If liver failure occurs it can be fatal.

31 European liver transplants in EPP patients have been reported in medical literature from 1983 and 2008. A 2005 US study followed up 20 patients who had undergone the procedure.

When conducting transplants and other surgery in EPP patients, it has been recommended that yellow filters be fixed to surgical lights to remove light wavelengths below 470nm and prevent phototoxic reactions resulting from exposure.

Psychological and social impact

EPP has been widely recognised as having a serious impact on the quality of patients’ lives due to sun avoidance leading to social exclusion. Depression, anxiety due to fear of reactions and suicidal thoughts have been reported by EPP patients in the literature. A 2010 UK study has also shown that individuals with photosensitive disorders, including EPP, have a greater unemployment rate.

Misdiagnosis and ‘invisible’ reaction symptoms can compound these issues as patients also report accusations of hypochondria when experiencing reactions or avoiding situations which may cause the onset of symptoms.


Symptoms of erythropoietic protoporphyria are usually with patients for life; however a few people have described symptoms reducing over time.


  • Lecha, M et al., (2009). ‘Erythropoietic protoporphyria’, Orphanet Journal of Rare Diseases. 14(9) available online at
  • Marko PB et al., (2007). ‘Erythropoietic protoporphyria patients in Slovenia’, Acta Dermatoven. 16(3):99-104.
  • McGuire BM, et al, (2005). Liver transplantation for erythropoietic protoporphyria liver disease. Liver Transpl. 11(12):1590-6.
  • Murphy GM, (2003). ‘Diagnosis and Management of the Erythropoitetic Porphyrias’, Dermatologic Therapy. 16:57-64.
  • Rufener EA (1987). ‘Erythropoietic protoporphyria: a study of its psychosocial aspects’, British Journal of Dermatology. 116:703-708.
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  • Thunell S, Harper P & Brun A, (2000). ‘Porphyrins, Porphyrin Metabolism and Porphyrias, IV, Pathophysiology of Erythropoietic Protoporphyria – Dianosis, Care and Monitoring of the Patient’, Scandinavian Journal of Clinical and Laboratory Investigation. 60:581-604.
  • Todd DJ. ‘Clinical Implications of the Molecular Biology of Erythropoietic Protoporphyria’, Journal of European Academy of Dermatology Venereology. 11:207-213.
  • Wahlin S, et al, (2008). “Protection from phototoxic injury during surgery and endoscopy in erythropoietic protoporphyria.” Liver Transpl. 14(9):1340-6.
  • Wahlin S, et al, (2011). “Liver transplantation for erythropoietic protoporphyria in Europe.” Liver Transpl. epublished May 20.
Actinic Prurigo (AP)

Actinic Prurigo (AP) is a rare chronic, idiopathic skin condition, which is characterised by abnormal cutaneous responses to ultraviolet radiation (i.e. photosensitivity). AP is thought to be mediated by an abnormal immune response in the background of genetic predisposition. AP is a rare condition and is usually seen in certain populations of the Americas. Skin lesions can appear hours to days after sun exposure and rarely, non-exposed skin can be affected. AP is also known as Hutchinson prurigo. Although AP is not associated with mortality, it can cause significant morbidity in afflicted individuals.


Typically, AP first appears in the sunnier months and patients often report exacerbations in symptoms during summer and spring. Rarely, however, the symptoms are worse during winter and autumn, and immunological tolerance during summer is thought to be responsible for this phenomenon. AP tends to occur equally in both the sexes in children and adolescents. In adults, however, females are twice as frequently affected as males. A positive family history of AP or PLE is present in one-fifth of individuals with APThe prevalence of AP in the general population is not known, but is thought to be less than 5% in the above-mentioned populations. In Europe and the Asia-Pacific, where a pathogenetically similar but clinically distinct disease known as polymorphic light eruption (PLE) is more common, rare cases of AP have been reported.AP usually begins in childhood. In some individuals, it may resolve before adulthood. In others, however, it is chronic and tends to recur persistently. Rarely, the disease may arise in adults and the clinical course in these cases is usually chronic.Actinic prurigo can affect the skin of all races, although it is more commonly observed in Latin-American Mestizo and Native American populations. Sporadic cases have been reported in the United Kingdom, the United States, Europe, Australia and Japan.


Sun-exposure, i.e. exposure to ultraviolet A and B radiation, is the predominant cause of actinic prurigo, yet the reason for the abnormal response to sun exposure is not fully understood. AP is believed to be delayed-type hypersensitivity reaction to antigens exposed or changed following exposure of the skin to ultraviolet radiation. The exact nature of these antigens is not known. It is also believed that genetic predilection may play a role in the pathogenesis of AP, with up to 90% of patients with AP showing various human leukocyte antigen (HLA) variants. In particular, HLA type DRB1*0401 and HLA type DRB1*0407 have been associated with AP.

Cellular involvement in actinic prurigo

Langerhans cells (LC) are believed to play a role in the pathogenesis of AP. LC are antigen presenting cells that are involved in the induction of cell-mediated immune responses to antigens located in the skin. LCs in patients with AP show a reduced susceptibility to ultraviolet radiation. UV-resistant LCs in patients with AP activate immune responses via putative antigens. Because of the presence of UV-resistant LCs, the putative antigens may be delivered to lymphocytes in large amounts or in a chronic fashion, leading to inflammation seen in AP. Thus, a combination of altered expression of adhesion molecules and UV-resistant LCs may be involved in the pathogenesis of AP. Further studies are required to elucidate the identity of these putative antigens and to gain a better understanding of the disease process.Expression of cell adhesion and activation molecules has been shown to be increased in AP. This suggests that lymphocytes in skin lesions of AP are, therefore, activated and may play a role in the damage observed in this condition. An increased adhesiveness of lymphocytes, as a result of increased expression of adhesion molecules, enables them to migrate through the endothelium and extracellular matrix. Similarly, the activation molecules can act on their respective receptors to induce lymphocyte proliferation and activation. Ultraviolet radiation is thought to activate adhesion molecules, such as ICAM-1, via activated lymphocyte infiltrates in keratinocytes, leading to inflammation that is observed in AP.Skin lesions in AP have been shown to be infiltrated by CD4+ T cells. An abnormal immune sensitization occurs against epidermal antigens in AP. AP can be considered as an autoimmune disease, because lymphocyte activation occurs in response to patient’s own ultraviolet-irradiated keratinocytes.


The symptoms of actinic prurigo include:

  • Extremely itchy (pruritic) skin rash;
  • Red and inflamed bumps (papules);
  • Thickened patches (plaques); and/or
  • Lumps (nodules)

The symptoms of AP are often described as similar to those seen in atopic dermatitis (eczema).

In addition to the symptoms listed above, skin ulcerations, crusting and scaling can occur.

Although areas exposed to the sun, such as the cheeks, nose and hands, are more commonly affected, non-exposed areas can rarely occur in severe AP. Pseudo-alopecia of the eyebrows can occur if the face is constantly scratched. In severe cases, permanent mild scarring and hypopigmented lesions may develop.

In about 65% of the patients affected with AP, the lips are affected. Inflammation of the lip (cheilitis) and pruritis are commonly observed. Other features such as oedema, crusting, ulceration and scales may be present. Interestingly, in 10% of the patients with AP, the lips are the only sites that are affected.

In about 45% of AP patients conjunctivae of the eyes are affected. Hyperaemia, brown pigmentation, photophobia, epiphora (excess production of tears), and formation of pseudopterygium (where the conjunctiva adheres to the cornea) are potential symptoms associated with the involvement of conjunctivae.


Observational diagnosis of actinic prurigo

Nevertheless, blood tests may be performed to rule out systemic diseases with involvement of the skin. The presence of HLA type DRB1*0401, or DRB1*0407 in genetic testing is suggestive of AP. Histological studies may be helpful. As a skin disease that does not involve internal organs, no blood tests are available to diagnose AP.Histologically, mild acanthosis, exocytosis, and spongiosis of the epidermis are observed. Lymphocyte infiltration and lymphoid follicles may be present. Eosinophils are often present. With the conjunctival histology, the epithelium appears thinned and atrophied. The basal cells are vacuolised with lymphocytic infiltration in the sub-mucosal follicles. Eosinophils are conjunctival pigmentation are common findings. The presence of lymphoid follicles in the mucosal and conjunctival laminae is the most characteristic pathological finding in AP.AP is diagnosed based on clinical assessment and the pathological study of the mucosae of the lips, conjunctivae, or the skin.

Phototesting and actinic prurigo

Other laboratory tests are used to rule out other systemic diseases with a photosensitivity component, rather than to diagnose AP. The presence of anti-nuclear antibodies and extractable nuclear antibodies should be undertaken to rule out lupus. The highly contagious Scabies should always be ruled out prior to diagnosing AP. When the skin on the nose is not affected, the condition is more likely to be photosensitive atopic dermatitis than AP. Polymorphic light eruption and prurigo nodularis are other morphologically similar diseases that should be excluded during the diagnosis of AP.Phototesting may help with the diagnosis, but is non-specific and does not rule out other photosensitive disorders. The minimal erythema dose, the minimum dose of narrow-band ultraviolet (UVB) radiation that is required to produce redness 24 hours after exposure, is reduced in patients with AP. It should be noted that a negative cutaneous phototesting does not exclude the diagnosis of AP.


Actinic prurigo is seldom cured and so preventative measures are important in managing actinic prurigo. The disease may resolve before adulthood in some individuals. In others, however, it is persistent and seasonal outbreaks during summer and spring may occur. Rarely, AP may arise in adulthood and persist throughout life. Treatment is aimed at prevention and controlling symptoms. Avoiding UV exposure and appropriate sun protection measures may be beneficial.

Prophylactic phototherapy may be helpful in some cases. Other treatment options include:

  • Emollients to relieve itching.
  • Topical steroids as anti-inflammatories. Oral steroids may be necessary in more severe disease. Hypersensitivity and infections are possible side-effects of steroid use.
  • Anti-malarial drugs, such as chloroquine, may be effective in some cases. These drugs have anti-inflammatory and photoprotective effects. Also, topical calcineurin inhibitors, such as tacrolimus, may be used to treat relatively mild AP
  • Oral thalidomide, an immune suppressant, is usually effective in treating more resistant AP in all age groups. Adverse effects include drowsiness, headache and weight gain. Nerve conduction studies should be performed regularly to assess for peripheral neuropathy, another side-effect of thalidomine treatment. Thalidomide is teratogenic and pregnancy must be avoided.
  • Oral immunosuppressants, such as azathioprine or cyclosporine.
  • Prophylactic phototherapy with UVB or PVB in spring, when the symptoms usually worsen, may be effective in some patients.


Actinic prurigo is an idiopathic disease – i.e. the precise cause(s) of AP are unknown. As sun exposure is the primary trigger of the disease, prudent steps must be taken to reduce or avoid exposure to the sun. The use of sunglasses, wearing appropriate clothing, and the appropriate use of sunscreen may be beneficial. In case of excoriations, sunscreen should be used cautiously. Patients should be taught about the appropriate application of sunscreens. Patients should also be made aware that even minor exposure to ultraviolet radiation may result in outbreaks or exacerbations of symptoms. Annual prophylactic phototherapy may be of benefit in some patients.

Actinic prurigo usually arises in childhood, and persists into adulthood. In some individuals, AP can improve or resolve before adulthood. Rarely, it may arise in adulthood, and persist chronically. Although not a fatal disease, AP can lead to significant morbidity, with exacerbations during the sunnier months. Secondary infections and impetigo are potential complications. Irritant contact dermatitis can manifest with inappropriate use of sunscreens.


  • (2008) Actinic Prurigo. [Online]. Available online [Accessed 10/12/2008].
  • (2008) Actinic Prurigo. [Online]. Available online [Accessed 10/12/2008].
  • Hawk, J L & Ferguson, J (2008). ‘Chapter 90. Abnormal Responses to Ultraviolet Radiation: Idiopathic, Probably Immunologic, and Photo-Exacerbated’. In Wolff, K, Goldsmith, L A, Katz, S I, Gilchrest, B, Paller, A S & Leffell, D J: Fitzpatrick’s Dermatology in General Medicine, 7th Edition. Available online [Accessed 10/12/2008].
  • McGregor, J M, Grabczynska, S, Vaughan, R, Hawk, J L, Lewis, C L (2000). ‘Genetic Modeling of Abnormal Photosensitivity in Families with Polymorphic Light Eruption and Actinic Prurigo’. The Journal of Investigative Dermatology, Vol 115, pp. 471-476.
  • Ortiz-Castillo, J V, Boto-de Los-Bueis, A, de Lucas-Laguna, R, Pastor-Nieto, B, Pelaez-Restrepo, N, & Fonseca-Sandomingo, A (2006). ‘Topical cyclosporine in the treatment of ocular actinic prurigo’. Archivos de la Sociedad Espanola de Oftalmologia, Vol 81, pp. 661-664.
  • Torres-Alvarez, B, Baradana, L, Fuentes, C, Delgado, C, Santos-Martinez, L, Portales-Perez, D, Moncada, B & Gonzalez-Amaro, R (1998). ‘An immunohistochemical study of UV-induced skin lesions in actinic prurigo: Resistance of Langerhans cells to UV light’. European Journal of Dermatology, Vol 8(1), pp. 24-28.
Congenital Erythropoietic Porphyria (CEP)

Congenital erythropoietic porphyria, or CEP, is an extremely rare, inherited metabolic disorder. It is caused by genetic defects which lead to deficiency of the enzyme uroporphyrinogen III cosynthase (UROS). The disease is characterised by extreme photosensitivity (abnormal cutaneous reaction to sunlight) which can leave severe scarring, blister formation and the loss of digits or other features. Damaged skin can become infected, leading to further necrosis and deformities. The face, hands and arms are the most significantly affected as they are frequently exposed; sometimes presenting as severe disfiguration.


The incidence of CEP is not known, but it is exceedingly rare; as of 2006, there were approximately 150 cases reported worldwide. Onset is usually during the early years of life as the genetic defects are present from birth. A milder form with onset in adulthood has been described in a small number of patients; six individuals as of 1990.


Congenital erythropoietic porphryia belongs to a family of diseases known as porphyrias. These are characterised by the overproduction and accumulation of chemicals, known as porphyrins, in various tissues within the body. The porphyrias come about due to faults or deficiencies in the pathway which leads to the production of haem (a major component of the haemoglobin in red blood cells).

CEP is caused by a genetic defect, or mutation, in the UROS gene. This gene encodes an enzyme, uroporphyrinogen III cosynthase, which is essential to the step-wise progression of haem synthesis (see Figure 1). The effect of the mutation is that the enzyme is only marginally active. This means that not only is haem synthesis severely impeded, but also that the pathway takes an alternative route, leading to the build of porphyrins. In the case of CEP, the particular porphyrins in excess are uroporphyrin I and coproporphyrin I.
Haem Biosynthetic pathway

 Figure 1. The Haem Biosynthetic Pathway, illustrating the defect in CEP

Figure 1. The Haem Biosynthetic Pathway, illustrating the defect in CEP

While the enzyme’s activity is dramatically reduced in CEP patients, it is not entirely absent as this would likely result in the complete absence of red blood cells and therefore death. The porphyrins are partially excreted in the urine and faeces, though a large portion enters into circulation and is deposited in bodily tissues; primarily the bone marrow, skin, blood and teeth. Porphyrin accumulation has toxic effects on the cells in these organs. This accounts for many of the symptoms experienced by CEP patients, including their heightened photosensitivity.

CEP’s rarity is partially due to its pattern of inheritance as a recessive trait. This means that an individual needs to have two copies of the defective gene – one from their mother and one from their father – in order for the condition to be present. An individual with just one defective gene will be a carrier of the disease but will not exhibit any symptoms, since the properly functioning gene is able to produce intermediate levels of the enzyme. There is typically no family history of CEP and both parents are healthy.

A number of mutations in the UROS gene have been discovered in CEP patients, all cause dysfunction of the UROS enzyme. Of the 35 described, the C73R mutation is the most common, present in about a third of all cases. This particular mutation is associated with a severe form of the disease.


Symptoms of CEP are diverse and can range from mild to severe. Along with cutaneous damage due to enhanced photosensitivity, CEP patients commonly suffer anaemia due to the breakdown of red blood cells (hemolysis). The following symptoms may be present to differing extents in individual patients:


  • Blistering and rashes on light-exposed skin
  • Scarring
  • Increased skin fragility
  • Skin destruction and erosion
  • Abnormal hair growth (hypertrichosis/hirsutism)
  • Loss of eyebrows and eyelashes
  • Mutilation of cartilage structures, such as the ears and nose
  • Loss of digits and facial features
  • Bacterial infection of damaged skin, possibly leading to further necrosis and deformation

Blood and other tissues

  • Anaemia due to the breakdown of red blood cells
  • Excessive red blood cell production (erythrocyte hyperplasia)
  • Bone loss, fragility or hardening
  • Enlarged spleen (splenomegaly)
  • Brown, pink or red discolouration in urine, due to the presence of porphyrins
  • Teeth stained red (erythrodontia), also due to accumulation of porphyrins
  • Ocular (eye) lesions


  • Brownish colour to the amniotic fluid
  • Accumulation of fluid in the fetus whilst still in utero (hydrops fetalis)

In addition to the physical symptoms, CEP patients often suffer poor mental health. This is due to both the level of pain and discomfort experienced and the psychological impacts of their appearance. These individuals can be stigmatised and often avoid interaction with other people. Many struggle both socially and professionally, thus CEP has an extreme impact upon patient quality of life.


CEP is the only porphyria that can be diagnosed prenatally. It is indicated by raised levels of uroporphyrin I in the amniotic fluid as early as 16 weeks in utero. More commonly, diagnosis is in infancy or childhood through a combination of the following methods:

  • History of patient symptoms
  • Quantitative screening using spectrophotometry or fluorimetry is considered the most accurate method of diagnosis. When uroporphyrin I and coporphyrin I are present in blood a plasma spectrofluorimetry is seen at 615-620 nm.
  • Measurement of elevated levels of uroporphyrin I and coproporphyrin I in blood, urine or faecal analyses
  • Examination of the eyes or urine using a Wood’s lamp


Total avoidance of sunlight and other sources of visible/UV light (i.e. solariums) is vital to preventing skin damage in CEP. Sun-protective clothing and sunscreen containing the light-blocking compounds zinc oxide or titanium dioxide may offer some protection. Plastic window films and window tinting around the home and in the car can reduce damaging wavelengths of light penetrating the skin. In addition, incandescent light bulbs emit less phototoxic wavelengths of light than fluorescent lights. Physicians recommend CEP patients try to avoid physical injury which may worsen fragile or damaged skin.

CEP treatments can be radical and patient response is varied:
Bone marrow transplantation (BMT) – the only therapy to date that presents a potential cure for CEP. It has proved extremely successful in a handful of patients, however the long-term results of BMT are not yet known. This form of therapy also comes with significant risks, including infectious complications and a high mortality rate. In a few children, BMT has resulted in complete remission of CEP. Improvements included normal haemoglobin, considerably reduced uroporphyrin I in the urine and no skin lesions in spite of unrestricted sun exposure; this is evidence of the best case scenario. Stem cell cord blood transplantation has also been reported effective in a few CEP patients.

Blood transfusions – these decrease the production of red blood cells and hence porphyrins in CEP patients. Transfusions have successfully reduced disease symptoms in several patients, however there are complications associated with chronic transfusions (i.e. iron overload).

Splenectomy – a splenectomy is the surgical removal of the spleen. It can increase the lifespan of red blood cells, reducing anaemia.

Oral sorbent medications – these include activated charcoal and cholestyramine which act by binding the excess porphyrins and preventing their absorption. In several patients these have reduced porphyrins in the blood and urine, in one case leading to complete remission. In contrast, there are also several reports of no effect and one of exacerbated condition; thus, caution should be exercised. Further, this treatment may be accompanied by the mild complication of poor nutrient absorption.

Oral beta-carotene – may act as a mild photoprotectant to reduce the symptoms of photosensitivity, though treatment usually requires unreasonably large doses. It has been trialed in CEP with minimal efficacy.

Oxygen quenchers – these are oral medications, such as ascorbic acid and alpha-tocopherol, which mop up excess reactive oxygen species to lessen porphyrin-induced photodamage; also only marginally effective.


The prognosis for a CEP patient depends on both the clinical severity of the condition and their response to available treatment. Severity is mainly dependent on the amount of residual activity the UROS enzyme has. Into the future, potential therapies may exist in the form of stem cell transplantation and gene therapy to correct the mutation and produce a functional UROS enzyme.

During puberty, a child’s haemoglobin levels increase to that of an adult. Along with an increase in haem comes a rise in porphyrin levels in CEP patients, therefore increase in symptoms or relapse may occur during adolescence. Where treatment is ineffective, the life expectancy of CEP patients is shortened.


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  • Canadian Association for Porphyria, n.d, Congenital Erythropoietic Porphyria, accessed 23rd August 2010, (no longer online).
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  • Hift, R.J, Meissner, P.N & Kirsch, R.E, 1993, ‘The effect of oral activated charcoal on the course of congenital erythropoietic porphyria’, The British Journal of Dermatology, 129(1):14-17.
  • National Organization for Rare Disorders, 2008, Porphyria, Congenital Erythropoietic, accessed 22nd December 2015,<>.
  • Singh, D.K & Rai, R, 2008, ‘Congenital Erythropoietic Porphyria’, Indian Pediatrics, 45:865.
  • Wiederholt, T, 2006, ‘Identification of mutations in the uroporphyrinogen III cosynthase gene in German patients with congenital erythropoietic porphyria’, Physiological Research, 55(suppl. 2):S85-S92.