Paediatric Mastocytosis

LEADING ARTICLE 315 Immunology and is essential for the development of ................................................................................... melanocytes, haematopoietic stem cells, Arch Dis Child: first published as 10.1136/adc.86.5.315 on 1 May 2002. Downloaded from and the interstitial cell of Cajal.14 Other phenotypic expressions of KIT Paediatric mastocytosis abnormalities are illustrated in the fol- lowing situations: (1) autosomal domi- M C Carter, D D Metcalfe nant piebaldism in which a mutation ................................................................................... decreasing KIT function results in a per- manent localised absence of melano- An unusual disease in infants and children cytes and melanosomes; (2) c-KIT mutations have been found in neoplastic mast cell lines15 16; (3) c-KIT somatic activating 3–9 astocytosis in infants and chil- 3, 4, 5, 6, 9, 10, and 15) and the princi- mutations have been found in human dren is an unusual disease char- pal mast cell growth factor, stem cell fac- gastrointestinal stromal tumours17 18; and Macterised by an excess of mast tor (SCF), that mast cells differentiate (4) KIT protein expression is found in cells in body tissues. The phenotypic from a CD34+ pluripotent haematopoi- the neoplastic cells of approximately 63% expression of the disease is dependent etic stem cell.10 This pluripotential cell of those with acute myelogenous on the pattern of localisation of the mast expresses the receptor for SCF, KIT leukaemia.19 20 However, paediatric ex- cells to specific organs and the release of (CD117), but does not yet express the pression of these abnormalities is seen mast cell mediators. The skin is the most high affinity IgE receptor, FceRI.11 SCF is predominately in piebaldism and in pae- common organ involved in children and present in a soluble and membrane diatric onset mastocytosis with extracu- may be the only manifestation of the bound form and is produced by fibro- taneous disease. There has been no iden- disease. Mastocytosis can present from blasts, endothelial cells, and bone mar- tified c-KIT abnormality reported to date 1 birth to adulthood, with adult onset dis- row stromal cells. This growth factor in familial mastocytosis.13 ease generally being more severe. The orchestrates the complete cycle of the The sequelae of aberrant mast cell cutaneous form was recognised over 100 mast cell from proliferation to numbers and mediator release are linked years ago, but the term mastocytosis, differentiation.12 Mastocytosis in some to three categories of products: pre- based on the offending cell, was initiated instances appears to be the clinical formed mediators, lipid metabolites, and 2 in 1936 by Sezary and Chauvillon. expression of disregulation of the pro- chemokines/cytokines. Symptoms of duction and function of mast cells mastocytosis are to a great extent a direct AETIOLOGY AND PATHOGENESIS caused by distinct activating somatic result of spontaneous mediator release, Mast cells are most abundant in connec- mutations in c-KIT (table 1).13 KITisa or mediator release in response to tive tissues, with a predilection for type III transmembrane tyrosine kinase immunological and non-immunological peripheral nerves, and blood and lym- with an extracellular domain that binds stimuli. Table 2 lists mast cell derived phatic vessels. It is at these sites, under mast cell growth factor, also known as mediators and their contributions to dis- the influence of cytokines (interleukins SCF. Additionally, KIT is expressed by ease manifestations.21 CLINICAL PRESENTATIONS http://adc.bmj.com/ Table 1 KIT mutations in children with sporadic disease Approximately 65% of individuals with mastocytosis present with disease in Mutation Phenotype childhood; 55% of these patients have Asp-816→Val Uriticaria pigmentosa, with or without extensive disease manifestations of disease by the age of 2 Asp-816→Phe years.1 The remaining 35% of those that Asp-816→Tyr Urticaria pigmentosa, with or without systemic disease develop their disease after puberty are classified as adult onset.22 Although the Glu-839→Lys Urticaria pigmentosa occurrence of mastocytosis appears to be on September 24, 2021 by guest. Protected copyright. sporadic, there are reports of familial mastocytosis with dominance in several families.23 Mastocytosis is classified based on prognosis and clinical presenta- 24 Table 2 Selected mast cell mediators and their effects tion (table 3). Preformed secretory granule mediators Cutaneous mastocytosis Histamine Pruritis, increased vascular permeability, gastric hypersecretion, Children with cutaneous mastocytosis bronchoconstriction typically present with a spectrum of Heparin Local anticoagulation Tryptase, other proteases Degradation of local connective tissues, bone lesions findings from solitary or multiple mastocytomas to urticaria pigmentosa (UP), or Lipid derived diffuse cutaneous mastocytosis (DCM). Sulphidopeptide leukotrienes Increased vascular permeability, bronchoconstriction, Blistering may occur in younger indi- vasoconstriction, vasodilatation viduals, particularly with UP or DCM.25 Prostaglandin D2 Vasodilatation, bronchoconstriction Platelet activating factor Increased vascular permeability, vasodilatation, Some children may exhibit features typi- bronchoconstriction cal of more than one distinct category, each category of which is discussed Cytokines below. Children with more extensive TNF-α Activation of vascular endothelial cells, cachexia, fatigue TGF-β Fibrosis skin involvement are more likely to IL-3 Stimulation of haematopoiesis exhibit systemic symptoms. Telangiecta- IL-5 Eosinophilia sia muscularis eruptive persitans is a IL-16 Lymphocyte accumulation variant of UP, is associated with adult onset disease, and presents with diffuse IL, interleukin; TGF, tumour growth factor; TNF, tumour necrosis factor. telangiectasias.26 www.archdischild.com 316 LEADING ARTICLE Table 3 Mastocytosis Arch Dis Child: first published as 10.1136/adc.86.5.315 on 1 May 2002. Downloaded from classification Cutaneous mastocytosis 1. Urticaria pigmentosa 2. Diffuse cutaneous mastocytosis 3. Mastocytoma of the skin Systemic mastocytosis (without AHNMD or leukaemic mast cell disease) 1. Systemic indolent mastocytosis 2. Systemic smouldering mastocytosis Systemic mastocytosis with an AHNMD 1. Myeloproliferative syndrome 2. Myelodysplastic syndrome 3. Acute myeloid leukaemia 4. Non-Hodgkin’s lymphoma Systemic aggressive mastocytosis Mast cell leukaemia Mast cell sarcoma Extracutaneous mastocytoma Clasification adopted from WHO classification.24 Figure 1 Child with urticaria pigmentosa. Both large and small pigmented lesions are AHNMD, associated haematological visible. non-mast cell disorder. described as the sequential development adolescence.29 Skin lesions of UP histo- of a flush, a flare, and a wheal that may logically show an accumulation of mast UP is the most frequent form of cuta- last for several hours. The most common cells within the papillary dermis with neous mastocytosis. A subvariant con- associated symptom of UP is pruritis variable extension throughout the re- sists of non-pigmented, plaque forming which varies in degree of intensity and ticular dermis and into the subcutaneous lesions that occur most often in infants. chronicity. Flushing has been reported in fat. Of interest, the incidence of atopic The lesions of UP appear as red-brown association with bathing in hot or cold disease in patients with UP approxi- macules, papules, or plaques. These water, friction of the lesions, and mates that observed in the general lesions are of varying size with the high- exercise.27 Bullae and blistering may population.30 est concentration usually on the trunk appear in the first few years of life and Mastocytomas occur as brownish soli- (fig 1). Darier’s sign, present in the must be distinguished from other bul- tary or multiple nodules, which when majority of patients with cutaneous lous diseases of childhood, such as pem- traumatised may cause systemic symp- mastocytosis, is the development of an phigoid (fig 2). Blister formation tends toms, such as flushing and hypotension http://adc.bmj.com/ urticarial wheal when a lesion is stroked to be tense and may become haemor- (fig 3). It is unusual for a child who and where the oedema is usually con- rhagic. Blistered areas usually heal with- presents with a solitary mastocytoma to fined to the border of the lesion. In con- out scar formation, unless the lesions develop further skin lesions more than trast, dermographism is the develop- become secondarily infected.28 When the two months after the presentation of the ment of a wheal formation after stroking lesions of UP are not associated with initial lesion.31 Histologically, sheets of or scratching normal appearing skin. The systemic disease, there is a tendency for mast cells without cytologic atypia fill triple response of Lewis is classically such lesions to fade during the papillary and reticular dermis with variable extension into the subcutaneous on September 24, 2021 by guest. Protected copyright. tissues. DCM is seen initially almost exclu- sively in infants, although it may persist into adult life.25 The skin may be thick- ened with a peau d’orange appearance and/or a reddish-brown discoloration.1 Lesions characteristic of UP may also be present. Dermographism with the formation of haemorrhagic blisters is common. There is a distinct pattern of mast cell infiltration around blood vessels, in skin appendages, and throughout the dermis. Patients with DCM appear

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