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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 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 muta- tions have been found in neoplastic 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 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 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 , 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 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 Pruritis, increased vascular permeability, gastric hypersecretion, Children with cutaneous mastocytosis bronchoconstriction typically present with a spectrum of Heparin Local anticoagulation , other proteases Degradation of local connective tissues, bone lesions findings from solitary or multiple masto- cytomas to urticaria pigmentosa (UP), or Lipid derived diffuse cutaneous mastocytosis (DCM). Sulphidopeptide 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 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

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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. 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. 3. Acute myeloid leukaemia 4. Non-Hodgkin’s lymphoma

Systemic aggressive mastocytosis Mast cell leukaemia 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. 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 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 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 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 for- mation of haemorrhagic blisters is com- mon. There is a distinct pattern of mast cell infiltration around blood vessels, in skin appendages, and throughout the dermis. Patients with DCM appear to be at increased risk for flushing, hypoten- sion, , and death.29 Diarrhoea and other gastrointestinal manifestations are common.32 Extracutaneous manifestations Patients with mastocytosis may have other associated findings based on the concentration of mast cells in other organ systems or systemic production of Figure 2 Bullous eruption in a child with mastocytosis. Note the generalised erythematous, mediators. Thus, mastocytosis may affect crusted lesions and plaques, with a sterile bulla. the gastrointestinal tract, cardiovascular,

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(V816D).35 36 A number of case reports may occur, from the side affects of have documented an association be- used to control itching Arch Dis Child: first published as 10.1136/adc.86.5.315 on 1 May 2002. Downloaded from tween UP and haematological malig- and from problems in socialisation asso- nancies. The most frequent association ciated with the visible skin lesions. There appears to be with acute myeloid leukae- is no clear psychopathology that exists in mia and acute lymphoblastic children with mastocytosis.51 leukaemia.37 Systemic mast cell disease as defined by the presence of the classic DIAGNOSIS bone marrow lesion associated with sys- Mastocytosis is diagnosed on the basis of temic mastocytosis was not observed in history and clinical presentation, with these cases. In one instance, the Phila- confirmation of cutaneous involvement delphia translocation 46, XY,t(9;22) by . Stains such as toluidine blue (q34;q11)38 was observed. or Giemsa, and the demonstration of In one survey of children with cutane- mast cell tryptase by immunohistochem- ous mastocytosis, small perivascular and istry have been used to identify mast paratrabecular aggregates of mast cells, 52 cells within cutaneous tissues. In some early myeloid cells, and eosinophils were unusual circumstances of observed in occasional individuals.39 As- mast cells by a local anaesthetic may sociated symptoms in such patients complicate the identification of mast included pruritus (88%), flushing (65%), vesicles/bullae (53%), cells. (41%), bone pain (18%), and headache Mast cell mediator concentrations (12%).40 The results were microscopically may be increased in the plasma of distinct from mast cell aggregates ob- patients with mastocytosis, but may also served in the bone marrow of those with be increased in patients undergoing 52 53 adult onset disease, although rare chil- . Plasma tryptase and his- Figure 3 Mastocytoma on the sole of a 3 54 year old child. It usually occurs as a solitary dren with mastocytosis may have more tamine concentrations along with urine 41–43 55 nodule, but rarely on the palms and soles. severe bone marrow involvement. A prostaglandin D2 and histamine me- bone scan reflects skeletal involvement tabolite concentrations56 are reflective of the increase in tissue mast cells and/or haematological, hepatic, and lymphoid and is sometimes used as an adjunct to other positive tests. their activation. tissues. Abnormal mast cell mediator Haematological abnormalities are Plasma histamine concentrations are release may also alter the function of the thus rare in children with mastocytosis known to be increased in the majority of central nervous system and cardiovas- and in patients who have mastocytosis the patients with paediatric onset cular system. Patients with a non- 44 45 57 otherwise limited to the skin. Mild mastocytosis. Another study showed physiological increase in mast cells normochromic normocytic anaemia is high concentrations of N-methyl- found in the bone marrow33 or in an the most common abnormality, although histamine in the urine of children with organ system other than the skin are there have been reports of prolonged mastocytosis, with the highest concen- said to have systemic disease.34

bleeding time caused by abnormal trations suggestive of more severe and http://adc.bmj.com/ Paediatric disease is less frequently thrombin clotting times. Infants with extensive disease, although there was associated with bone marrow pathology DCM may be at greater risk for this some overlap with a normal control typical of systemic mastocytosis. Abnor- 32 58 complication. Hepatosplenomegaly is group. A commercially available en- malities in the bone marrow have, associated with systemic disease in the zyme linked immunosorbent assay however, been shown in some children. paediatric population. (ELISA) can determine amounts of These patients may have a substitution Studies of various subpopulations of plasma tryptase using a monoclonal of valine for aspartate in codon 816 patients with mastocytosis have con- antibody with a sensitivity of about 0.2

cluded that between 35% and 80% of ng/ml. Median total plasma tryptase in on September 24, 2021 by guest. Protected copyright. adult patients with systemic mastocytosis healthy controls was 5.0 ng/ml.52 A total Table 4 Pharmacological 33 34 46 have gastrointestinal involvement. tryptase >20 ng/ml in association with a agents and physical stimuli that However, gastrointestinal involvement is total tryptase to β tryptase ratio of >20 much less common in children.47 Gastro- may exacerbate mast cell identifies patients more likely to have intestinal bleeding is a potential compli- mediator release in patients with systemic mastocytosis.53 cation with severe disease. It is believed to mastocytosis A bone marrow biopsy in those with be provoked by high concentrations of Immunological stimuli paediatric onset cutaneous disease is not circulating plasma histamine, which Venoms (IgE mediated bee venom) drives gastric hypersecretion.1 Abdominal recommended unless there is evidence of Complement derived anaphylatoxins systemic disease. Such evidence includes Biological peptides (substance P, cramping and diarrhoea have also been somatostatin) reported. unexplained peripheral blood abnor- Polymers (dextran) Patients with mastocytosis may react malities, hepatosplenomegaly, and 57 adversely to mast cell degranulating lymphadenopathy. Non-immunological stimuli 48 49 Physical stimuli (extreme temperature, agents, such as narcotic analgesics or 50 TREATMENT friction, sunlight) polymixin B. Patients with mastocyto- Drugs sis may also be more sensitive to venoms Therapy for mastocytosis is focused on Acetylsalicylic acid and related of stinging insects. There are a number of providing symptomatic relief. Patients non-steroidal analgesics* activators of mast cell secretion, which and parents should be counselled on Thiamine avoidance of key triggers of mast cell Ketorolac tromethamine work through immunological and non- Alcohol immunological mechanisms, which are degranulation such as extremes of tem- Narcotics (codeine, morphine)* summarised in table 4. Children with perature, certain medications, and Hy- Radiographic dyes (iodine containing) cutaneous mastocytosis do not appear to menoptera exposure. Fortunately, the have any unique behavioural patterns symptoms of paediatric onset cutaneous *Appears to be a problem in less than other than those which would be ex- disease are usually less severe than those 10% of patients. pected from the intense pruritus which observed in patients with adult onset

www.archdischild.com 318 LEADING ARTICLE mastocytosis. Pruritus, the most com- clearing at an average of 6.1 years follow both -type and mucosal-type mon symptom, is usually controllable to up.27 The skin lesions resolve in approxi- characteristics in gut, trachea, and kidneys of Arch Dis Child: first published as 10.1136/adc.86.5.315 on 1 May 2002. Downloaded from IL-9 transgenic mice. J Immunol some degree with antihistamines and mately half of the patients by adoles- 1998;160:3989–96. skin care in the majority of children. It cence. Notable improvement was ex- 8 Thompson-Snipes L, Dhar V, Bond MW, et does not usually reach the intensity that pected in the remainder.31 Children al. Interleukin 10: a novel stimulatory factor for mast cells and their progenitors. J Exp Med is associated with other pruritic diseases whose mastocytosis persists into adult- 1991;173:507–10. such as atopic dermatitis. hood may experience a similar progres- 9 Tagaya Y, Burton JD, Miyamoto Y, The treatment of choice is an antihis- sion (15–30%) to systemic Waldmann TA. Identification of a novel 31 receptor/signal transduction pathway for tamine to block the H1 effects of hista- involvement. IL-15/T in mast cells. Embo J mine and control pruritis, flushing, and The prognosis for infants with cutane- 1996;15:4928–39. urticaria. Hydroxyzine, and more re- ous mastocytosis in part appears to 10 Kirshenbaum AS, Kessler SW, Goff JP, Metcalfe DD. Demonstration of the origin of cently cetirizine or loratidine for less depend on whether they exhibit bullae human mast cells from CD34+ bone marrow sedating properties, can be adminis- early in the neonatal period or if bullae progenitor cells. J Immunol tered. In a double blind, placebo control- are delayed relative to the appearance of 1991;146:1410–15. 70 11 Rottem M, Okada T, Goff JP, Metcalfe DD. led, crossover trial, hydroxyzine was their skin lesions. Children who mani- Mast cells cultured from the peripheral blood superior in children in reducing symp- fest diffuse cutaneous mastocytosis prior of normal donors and patients with toms scores compared to ketitofen and to bullous eruptions appear to have a mastocytosis originate from a CD34+/Fc 40 epsilon RI-cell population. Blood had a similar side affect profile. The better chance at gradual improvement in 1994;84:2489–96. addition of an H2 antagonist may be use- their disease. Several reports of the 12 Nilsson G, Metcalfe DD. Contemporary ful to alleviate the symptoms associated occurrence of acute lymphocytic leukae- issues in mast cell biology. Asthma Proc 1996;17:59–63. with hypersecretion of gastric acid. Dox- mia in rapidly progressive and late onset 13 Longley BJ Jr, Metcalfe DD, Tharp M, et al. epin, with H1 and H2 properties, can be paediatric onset mastocytosis suggest Activating and dominant inactivating c-KIT administered to children over 12 years. the possibility of a predilection for the catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc Natl Acad Orally administered disodium cromogly- development of a haematological malig- SciUSA1999;96:1609–14. 71 cate, although poorly absorbed, has been nancy in these patients. 14 Huizinga JD, Thuneberg L, Kluppel M, et al. shown to relieve diarrhoea and abdomi- In summary, paediatric onset masto- W/ gene required for interstitial cells of nal cramping in some individuals.59 cytosis is an unusual disease with an Cajal and for intestinal pacemaker activity. Nature 1995;373:347–9. Disodium cromoglycate has also been often benign course. The disease in chil- 15 Furitsu T, Tsujimura T, Tono T, et al. reported to relieve musculoskeletal pain, dren is less likely to have a systemic Identification of mutations in the coding headache, central nervous system com- component. Review of the literature sequence of the proto-oncogene c-kit in a human mast cell cell line causing plaints, and skin symptoms in some suggests that those at potential risk for ligand-independent activation of c-kit product. patients.60–64 experiencing shock or sudden death J Clin Invest 1993;92:1736–44. Mastocytosis with bullous lesions in include children with extensive bullous 16 Kanakura Y, Furitsu T, Tsujimura T, et al. Activating mutations of the c-kit infancy sometimes presents with a cutaneous involvement, those with proto-oncogene in a human shock like syndrome.65 As shown in one symptoms of vasodilatation, flushing, cell line. Leukemia 1994;8(suppl 1):S18–22. case study where the patient died of and hypotension, and those with early 17 Lux ML, Rubin BP, Biase TL, et al.KIT 65 extracellular and kinase domain mutations in massive hypotension secondary to mast onset of disease. gastrointestinal stromal tumors. Am J Pathol 65 cell degranulation, it is prudent to http://adc.bmj.com/ Arch Dis Child 2002;86:315–319 2000;156:791–5. administer and other therapy 18 Taniguchi M, Nishida T, Hirota S, et al. as indicated including fluids, glucocorti- Effect of c-kit mutation on prognosis of ...... gastrointestinal stromal tumors. Cancer Res coids, and H and H antihistamines. 59 1 2 Authors’ affiliations 1999; :4297–300. Bullae present in children less than 2 19 Kanakura Y, Ikeda H, Kitayama H, et al. M C Carter, D D Metcalfe, NIAID/NIH, Expression, function and activation of the years of age can be managed in a similar Bethesda, MD, USA 1 proto-oncogene c-kit product in human fashion to scald injury with blistering. leukemia cells. Leuk Lymphoma Care should be focused on prevention of Correspondence to: Dr M C Carter, 1993;10:35–41. NIH/NIAID/LAD, Building 10, Room 11-C206, infection and general skin health. Intra- 20 Wang C, Curtis JE, Geissler EN, et al.The on September 24, 2021 by guest. Protected copyright. 10 Center Dr. MSC 1881, Bethesda, MD expression of the proto-oncogene C-kit in the venous glucocorticoids have been used 20892-1881, USA; [email protected] blast cells of acute myeloblastic leukemia. successfully to treat progressive severe Leukemia 1989;3:699–702. 31 21 Akin C, Metcalfe, DD. Mastocytosis. In: Leung bullae in infantile UP. REFERENCES α DYMGM, ed. Allergic skin desease: a -2b has been used to treat 1 Kettelhut BV, Metcalfe DD. 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