Urticaria Pigmentosa

The most common symptoms of UP include skin efflorences such as papules and macula that are generally of light brown color and thus look similar to freckles. Contrary to the latter, these skin changes are accompanied by considerable pruritus. In most cases, UP lesions are restricted to the skin. Only very rarely do they affect other organs of the body, e.g. bones.

Confirmation of the Darier's sign strongly indicates mastocytosis and therefore UP. It may be provoked by exposing mastocyte-containing papules and macula to touch or heat and consists in the appearance of slightly elevated, smooth wheals that generally differ in color from the surrounding skin. These wheals are associated with strong pruritus. Occasionally, they may appear to be filled with fluid.

Since mast cells liberate considerable amounts of mediators such as histamine and heparine, systemic symptoms may also be observed. Patients may thus present with headaches, flushing, hypotension and syncopes, tachycardia, anorexia, dizziness, nausea and vomiting, neuropsychiatric symptoms, abdominal pain and diarrhea [8].

Patients do present with typical skin symptoms. Swelling, reddening and itching wheals provoked by touching the light brown skin lesions constitute the Darier's sign and are characteristic of mastocytosis.

Even though generally not necessary, further skin tests may be applied to rule out differential diagnostics. Analysis of a skin biopsy may allow to confirm the diagnosis of UP [9].

Additional biopsies may be taken to clarify systemic complications and possible involvement of other organs. Here, X-rays may reveal a diminished bone density. Excretion of histamine or its metabolites (1,4-methylimidazole acetic acid) via the urinary tract may be proved by urine tests and also hint at systemic involvement. Of note, the absence of pathological findings in liver function tests does not rule out liver involvement.

Mild forms of UP may be treated by identifying and avoiding environmental triggers of urticaria. More severe cases require pharmacological treatment mainly consisting in stabilizing mast cells and antagonizing the effects of mast cell-derived mediators. The following drugs may be administered:

• Antihistamines. H1-receptor antagonists are applied to treat skin symptoms such as pruritus and flushing and provide the mainstay for pharmacological therapy. H2-receptor antagonists may be prescribed in some cases and may help to relieve systemic symptoms. Antihistamines are not sufficient to treat life-threatening complications such as anaphylaxis, circulatory collapse and shock. These reactions are only rarely observed but require immediate attention. The patient should be aware of this possibility and carry an injectable adrenaline solution.
• Mast cell stabilizers. These drugs avoid mast cell degranulation triggered upon contact with certain antigens. Several weeks of treatment may be necessary to achieve an improvement of headaches, abdominal pain, diarrhea and bone pain.
• Acetylsalicylic acid. Aspirin may be given in low doses to patients unresponsive to H1- and H2-receptor antagonists. This treatment option should be limited to such cases, since acetylsalicylic acid possible enhances mast cell degranulation and may even aggravate symptoms.
• Photochemotherapy with long wave ultraviolet A radiation (wave length 340-400 nm, PUVA) may be of use in cases of UP [10]. For skin irradiation to cause a significant reduction of mast cells, two or three weekly treatments are required over the course of several months. Skin lesions and pruritus are diminished for up to a year. Repeated photochemotherapy may then be necessary.
• Steroids are mainly applied topically and constitute a symptomatic therapy aimed at providing relief from pruritus. UP lesions may not be cured with such drugs. If systemic symptoms are detected, steroids may need to be administered systemically.
• Immune therapies based on interferon and imatinib may support therapy of severe UP with systemic complications [11]. Data regarding long-term efficacy is not yet available.

Patients should be advised to minimize consumption of drugs such as aspirin, codeine and other opiates. Alcohol may trigger urticaria and should also be avoided.

There's a strong correlation between age of onset and prognosis. If UP is diagnosed in children younger than 2 years, the prognosis is very good. Here, UP is generally self-limiting and resolves until puberty, although skin lesions usually last for some years and deviations in skin color may persist in some patients.

However, UP is more likely to worsen if detected in adult patients. This is particularly true if internal organs such as the skeletal system, the cardiovascular system, the gastrointestinal tract or the central nervous systems are compromised. If such complications are detected, regular monitoring of disease progress is indicated.

Although some cases of UP develop sporadically without any identifiable cause, an autosomal dominant genetic disorder is thought responsible for others [3]. The defective gene may be inherited from any parent or result from a newly acquired mutation. The probability that a child inherits said gene from mother or father is equal and boys and girls do inherit it likewise. Additionally, patients with confirmed genetic defects do not necessarily fully develop UP due to reduced genetic penetrance.

Comprehensive epidemiologic data is not available and the disease is generally considered rare [4]. Estimations reached from 1 in 1,000 to 1 in 8,000 cases of mastocytosis among patients consulting dermatologists. Since UP is the most common form of mastocytosis, it presumably accounts for the majority of these cases.

Children are affected more frequently than adults, and about 75% of UP cases are reported in infants. A second, less pronounced peak of manifestation occurs during mid-adulthood, particularly affecting people aged 30 to 50 years.

Regarding prognosis, there are considerable differences between UP cases in children and adults. While childhood UP is generally self-limiting, cases occurring during adulthood may considerably worsen and bring systemic consequences.

UP does affect men slightly more often than women and can be observed most frequently in Caucasians.

UP is the most common form of mastocytosis and is characterized by cutaneous accumulations of mast cells. Furthermore, melanocytes proliferate in these lesions and melanin synthesis is augmented. While aggregated mast cells are responsible for the pruritus associated with UP, melanocyte-mediated hyperpigmentation explains why skin changes appear in a light brown color.

Mastocytosis and melanocyte proliferation are thought to be triggered by locally elevated soluble mast cell growth factor. An impaired mast cell apoptosis has also been proposed to contribute to mastocytosis. This hypothesis is supported by the fact that antiapoptotic protein Bcl-2 is upregulated in patients suffering from UP [5]. On the other hand, the proto-oncogene c-kit apparently undergoes activating mutations and local concentrations of interleukin 6 have been found to be augmented [6]. Although interleukin 6 levels were reported to correlate with disease severity, a direct link to pathophysiology of UP has not yet been identified [7].

Systemic consequences are caused by direct mast cell infiltration or by mast cell-derived mediators acting on different tissues. Such mediators may include histamine, heparine, prostaglandins, neutral proteases and hydrolases. Frequently observed symptoms are headaches, flushing, tachykardia, abdominal pain and diarrhea.

Since no direct causes of UP other than genetic disorders are known, preventive measures cannot be recommended [3].

However, if UP is diagnosed, efforts should be undertaken to identify possible triggers of urticaria. Avoidance of such triggers may be sufficient to treat mild cases of UP. Stress, physical exercise and specific foods are common triggers of UP.

Since mast cell degranulation is stimulated when exposing skin lesions to touch or heat, the corresponding behavior should be avoided.

Patients potentially prone to anaphylaxis need a detailed explanation of possible symptoms and treatment. They should also be educated in using injectable adrenaline solutions.

Urticaria pigmentosa (UP) is the most common form of mastocytosis. It is still considered a rare disease and is most frequently diagnosed in infants. UP is accompanied by skin lesions mainly affecting the trunk, but face, neck, arms and legs may also be compromised [1].

Skin efflorescences usually comprise macula and papules of light brown or reddish color. Since these lesions harbor great numbers of mast cells that liberate mediators such as histamine, heparin, prostaglandines, proteases and hydrolases upon manipulation, rubbing of these spots turns them into itching wheals, in some cases even into blisters [2]. This reaction, also known as Darier's sign, is of utmost importance when diagnosing UP.

UP generally affects children that are only a few months old, but the disease may also be detected in adults. Children do usually develop rather mild cases and symptoms primarily affect the skin. Here, the disease is often self-limiting and skin lesions diminish during the following years until the patient reaches puberty. In contrast, more severe cases are observed in adults. Beyond skin lesions, systemic symptoms may occur. These involve headaches, hypotension, tachykardia, nausea, abdominal pain and diarrhea. They can mainly be explained by the effects of mast cell-derived mediators on different tissues, but direct mast cell infiltration is also possible.

UP is a disease affecting the skin. It is characterized by light brown skin lesions that, in turn, are caused by an excessive accumulation of mast cells. Mast cells are part of the immune system and an excessive accumulation of these cells is called mastocytosis.

Upon touch, mast cells in skin lesions liberate specific mediators responsible for the appearance of intensively itching wheals. Such mediators may be histamine, heparine and other active substances. These pro-inflammatory mediators fulfill important functions in skin and body, but can trigger pathological conditions if liberated in excess.

Causes

Although some genetic disorders have been related to UP, as of yet no direct cause could be identified. Said genetic defects usually affect cell proliferation and cell death and may thus lead to augmented numbers of mast cells.

Patients diagnosed with UP should try to identify certain environmental factors aggravating their disease. Avoidance of such triggers can contribute significantly to reduce symptoms:

• Stress
• Physical exertion
• Physical stimuli (friction, heat)
• Alcohol
• Drugs such as aspirin, codeine and opiates

Symptoms

UP typically leads to light brown, sometimes yellowish or reddish skin lesions of the trunk. Skin, arms and legs are rarely affected. These lesions are termed macula and papules and are of different size, they may measure only a few millimeters but can extend to several centimeters. They are generally symmetrical.

Itching is characteristic for UP. If skin lesions are touched, scratched or otherwise manipulated, wheals or hives may develop. Even blisters may be observed. The physician calls this Darier's sign and it points at mastocytosis.

Face flushing may be present in UP, but also headaches, an accelerated heart rate, abdominal pain and diarrhea. These symptoms are, however, less frequent than the aforementioned skin lesions.

Diagnosis

Diagnosis is generally based on clinical examination. A very important finding is the development of elevated, smooth, itching wheals upon manipulation of skin lesions. If doubts remain, a skin biopsy may be taken to confirm diagnosis.

In some cases of UP, internal organs may be compromised. If the physician suspects such complications, additional diagnostic measures such as X-ray examination and urine tests are indicated.

Treatment

There is no causal therapy for UP. If young children are affected, the disease usually resolves until puberty. Meanwhile symptomatic treatment is carried out. This also applies if UP is diagnosed in adults.

Patients should try to identify environmental factors aggravating their disease. Such factors may include stress, exercise and certain foods and should be avoided. On the other hand, the physician may prescribe antihistamines, mast cell stabilizers or steroids to control itching, skin flushing and possible inflammation. The exact therapy will depend on the severity of the case and individual factors.

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5. Hartmann K, Artuc M, Baldus SE, et al. Expression of Bcl-2 and Bcl-xL in cutaneous and bone marrow lesions of mastocytosis. Am J Pathol. 2003 Sep; 163(3):819-26.
6. Bodemer C, Hermine O, Palmerini F, et al. Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations. J Invest Dermatol. 2010 Mar; 130(3):804-15.
7. Brockow K, Akin C, Huber M, Metcalfe DD. IL-6 levels predict disease variant and extent of organ involvement in patients with mastocytosis. Clin Immunol. 2005 May; 115(2):216-23.
8. Kirsch R, Geboes K, Shepherd NA, et al. Systemic mastocytosis involving the gastrointestinal tract: clinicopathologic and molecular study of five cases. Mod Pathol. 2008 Dec; 21(12):1508-16.
9. Vano-Galvan S, Álvarez-Twose I, De las Heras E, et al. Dermoscopic features of skin lesions in patients with mastocytosis. Arch Dermatol. 2011; 147(8):932-940.
10. Kinsler VA, Hawk JL, Atherton DJ. Diffuse cutaneous mastocytosis treated with psoralen photochemotherapy: case report and review of the literature. Br J Dermatol. 2005 Jan; 152(1):179-80.
11. Hoffmann KM, Moser A, Lohse P, et al. Successful treatment of progressive cutaneous mastocytosis with imatinib in a 2-year-old boy carrying a somatic KIT mutation. Blood. 2008 Sep 1; 112(5):1655-7.