Urticaria pigmentosa

What Is Causing This Skin Eruption?

Alexander K. C. Leung, MD—Series Editor, and Benjamin Barankin, MD

A 7-month-old girl presented with an eruption on her trunk. The lesions were noted in the immediate neonatal period and they increased in size and number with time. The infant was born to a 23-year-old gravida 2, para 1 mother at term following an uncomplicated pregnancy and unremarkable vaginal delivery. She was asymptomatic and was otherwise in good health. The family history was noncontributory.

 Physical examination results revealed multiple, pink-brown, oval to round macules and papules on the chest, abdomen, and back (Figures 1 and 2). The macules and papules measured 2 to 5 mm in diameter and had well-demarcated borders. Gentle rubbing of the lesion resulted in a wheal with a surrounding erythematous flare. The rest of the physical examination results were unremarkable. In particular, there was no hepatosplenomegaly or any palpable lymphadenopathy.

What’s your diagnosis?

skin eruption

 

skin eruption

ANSWER: Urticaria pigmentosa 

Urticaria pigmentosa, also known as maculopapular cutaneous mastocytosis, is a cutaneous form of mastocytosis, characterized by aggregates of mast cells in the dermis leading to the development of pigmented maculopapules that urticate with friction.1 The condition was first described in 1869 by Nettleship and Tay who reported a case of chronic urticaria leaving brown stains.2 The term urticaria pigmentosa was coined by Sangster in 1878 who described a similar case with “anomalous mottled rash, accompanied by pruritus, factitious urticaria, and pigmentation.”3 Unna in 1887 pointed out the relationship between urticaria pigmentosa and mast cells.4

Mastocytosis is characterized by a pathologic accumulation of mast cells in tissues, such as the skin, bone marrow, gastrointestinal tract, liver, spleen, and lymph nodes.5 Mast cell accumulation can be limited to the skin (cutaneous mastocytosis) or involve extracutaneous tissues, often combined with skin involvement (systemic mastocytosis). Cutaneous mastocytosis can be subclassified into urticaria pigmentosa, diffuse cutaneous mastocytosis, and solitary mastocytoma of the skin.6

Epidemiology 

Urticaria pigmentosa accounts for 70% to 90% of pediatric mastocytosis.7,8 Its incidence has been estimated to be 1 in 150,000.6 Approximately 80% of cases occur within the first year of life.5,9 Congenital cases have been described in 15% to 25% of patients,5,10 and the male to female ratio is approximately equal.5,8,11 The condition is more commonly reported in Caucasian patients.8,12 The majority of cases occur sporadically,5,8 but familial cases have also been reported.13 An autosomal dominant mode of inheritance with incomplete penetrance has been described.1

Pathogenesis

Activating mutations in the c-KIT proto-oncogene that encodes KIT (also called CD117), a transmembrane protein that binds to stem cell factor and promotes cell division, have been shown to result in abnormal proliferation of mast cells and melanocytes.5,11-13 A proliferation of melanocytes accounts for the hyperpigmented lesions seen in urticaria pigmentosa.12,14

Symptoms and signs such as pruritus, flushing, and wheals with rubbing or scratching are caused by spontaneous or induced activation of mast cells with resulting release of vasoactive mediators.9 These mast cell mediators include histamine, heparin, tryptase, leukotrienes, prostaglandins, platelet-activating factor, proteases, and cytokines.9 Common triggers include local friction or rubbing, physical exertion, emotional stress, elevated temperature, alcohol ingestion, drugs (nonsteroidal anti-inflammatory drugs, opiates, anticholinergic medications), and hymenoptera stings.8,12

Histopathology

Histologic findings include increased melanization of the basal layer with sheets of mast cells infiltrating the upper and lower dermis.15 Mast cells are best observed using special stains such as Giemsa, toluidine blue, Astra blue, and Leder (chloroacetate esterase).14,16 

Clinical Manifestations 

The most common presentation is pruritic, yellow-tan to reddish-brown macules/papules on the trunk and proximal extremities. The lesions are polymorphic and are larger than those seen in adult-onset ones.6 The margins can be sharp or indistinct. Plaques and nodules may also occur; these lesions usually flatten with time.9,11 The trunk and proximal extremities are most commonly affected.8,9,16 The palms and soles are typically spared.9 The lesions may spontaneously urticate and/or urticate when stroked or rubbed (Darier sign); this sign is considered pathognomonic.6 Pruritus is the most common symptom.7,9 Dermographism is often present. Flares usually manifest as lesional erythema, edema, and intense pruritus.8 Although flushing is more commonly seen in patients with systemic mastocytosis, flushing occurs in 17% to 36% of patients with urticaria pigmentosa.16 Some of the lesions may blister upon irritation.6 Organomegaly and lymphadenopathy are characteristically absent.

A small number of children present with numerous small monomorphic round lesions similar to those observed in adult-onset urticaria pigmentosa.6,16 In contrast to those children with large polymorphic lesions who have the onset of disease usually during infancy, children with small monomorphic round lesions usually have the onset of disease after the age of 2 years.11

Diagnosis 

The diagnosis is mainly clinical, based on the morphology of lesions and the presence of a positive Darier sign. Dermoscopy typically shows a light-brown blot and a pigment network that corresponds to the accumulation of melanin in basal keratinocytes.14 The diagnosis can be confirmed, if necessary, by a skin biopsy that confirms infiltrate of mast cells in the dermis and demonstration of KIT mutation in lesional skin.6 

Differential Diagnosis

Differential diagnosis includes chronic urticaria, postinflammatory hyperpigmentation, café-au-lait macules, Spitz nevi, arthropod bites, nodular scabies, drug-related eruptions, xanthomas, histiocytosis, herpes simplex, impetigo, and linear immunoglobulin A bullous dermatosis.

Prognosis

The prognosis is good. Most patients who have onset of skin lesions within the first 2 years of life have spontaneous resolution of the lesions before puberty.8,9 In some patients, the disease may persist into adulthood and may have systemic involvement in other organs, especially in those patients with numerous small monomorphic round lesions who have onset of the disease after 2 years of age.6 On the other hand, adult-onset urticaria pigmentosa has a much higher chance of progression to systemic disease.

Management 

Treatment is mainly symptomatic. Oral H1-receptor antagonist antihistamines such as hydroxyzine are the cornerstone of treatment for pruritus and flushing.16 In severe cases, oral H2-receptor antagonist antihistamines such as ranitidine can be added for additional benefit.8 Preventative measures include elimination/avoidance of provoking factors.  

Alexander K. C. Leung, MD, is a clinical professor of pediatrics at the University of Calgary and a pediatric consultant at the Alberta Children’s Hospital in Calgary, Alberta, Canada. 

Benjamin Barankin, MD, is a dermatologist and the medical director and founder of the Toronto Dermatology Centre in Toronto, Ontario, Canada.

References 

1. Fett NM, Teng J, Longley BJ. Familial urticaria pigmentosa: report of a family and review of the role of KIT mutations. Am J Dermatopathol. 2013;35(1):113-116.

2. Nettleship E, Tay W. Rare forms of urticaria. Br Med J. 1869;2:323-324.

3. Sangster A. An anomalous mottled rash, accompanied by pruritus, factitious urticaria and pigmentation, “urticaria pigmentosa”? Trans Clin Soc London. 1878;11:161-163.

4. Unna PG. Anatomie and pathogenese der urticaria simplex und pigmentosa. Monatschr Prakt Dermatol. 1887;6:EH1.

5. Brockow K. Urticaria pigmentosa. Immunol Allergy Clin North Am. 2004;24(2):287-316, vii.

6. Hartmann K, Escribano L, Grattan C, et al. Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology. J Allergy Clin Immunol. 2016;137(1):35-45.

7. Barnes M, Van L, DeLong LP. Severity of cutaneous findings predict the presence of systemic symptoms in pediatric maculopapular cutaneous mastocytosis. Pediatr Dermatol. 2014;31(3):271-275.

8.   Mir A, Chamlin SL. A 1-year-old boy with persistent, generalized eruption. Urticaria pigmentosa. Pediatr Ann. 2014;43(1):e13-e15.

9.   Castells M, Akin C. Mastocytosis (cutaneous and systemic): epidemiology, pathogenesis, and clinical manifestations. UpToDate. http://www.uptodate.com/contents/mastocytosis-cutaneous-and-systemic-epidemiology-pathogenesis-and-clinical-manifestations. Updated November 13, 2015. Accessed April 22, 2016.

10. Tuysüz G, Özdemir N, Apak H, Kutlubay Z, Demirkesen C, Celkan T. Childhood mastocytosis: results of a single center. Turk Pediatr Ars. 2015;50(2):108-113.

11. Wiechers T, Rabenhorst A, Schick T, et al. Large maculopapular cutaneous lesions are associated with favorable outcome in childhood-onset mastocytosis. J Allergy Clin Immunol. 2015;136(6):1581-1590.

12. Cowart D, Cowart K, Hougeir FG. A 39-year-old woman with spots covering her body. BMJ Case Rep. 2013. doi: 10.1136/bcr-2013-201434.

13. Azana JM, Torrelo A, Matito A. Update on mastocytosis (part 1): pathophysiology, clinical features, and diagnosis. Actas Dermosifiliogr. 2016;107(1):5-14.

14. Miller MD, Nery NS, Gripp AC, Maceira JP, Nascimento GM. Dermatoscopic findings of urticaria pigmentosa. An Bras Dermatol. 2013;88(6):986-988.

15. Vasani RJ, Medhekar SV. Urticaria pigmentosa. Indian Dermatol Online J. 2015;6(6):464-465.

16. Allison MA, Schmidt CP. Urticaria pigmentosa. Int J Dermatol. 1997;36:321-325.