|Year : 2015 | Volume
| Issue : 2 | Page : 57-63
Mastocytosis in children
Sahana M Srinivas1, Sandipan Dhar2, Deepak Parikh3
1 Department of Pediatric Dermatology, Indira Gandhi Institute of Child Health, Bengaluru, Karnataka, India
2 Department of Pediatric Dermatology, Institute of Child Health, Kolkata, West Bengal, India
3 Department of Pediatric Dermatology, B.J Wadia Hospital for Children, Parel, Mumbai, Maharashtra, India
|Date of Web Publication||9-Apr-2015|
Sahana M Srinivas
Department of Pediatric Dermatology, Indira Gandhi Institute of Child Health, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
Mastocytosis is a heterogeneous group of disorders with increase in mast cells in the skin and other extracutaneous organs. Mastocytosis is seen in children and adults. Cutaneous mastocytosis is more common in children than systemic forms. Among the cutaneous form urticaria pigmentosa is the most common type of mastocytosis seen in children. There is a tendency of regression with age. Childhood onset mastocytosis has a good prognosis. Counseling forms a major role in the management of pediatric-onset mastocytosis.
Keywords: Cutaneous, mastocytosis, pediatric age group
|How to cite this article:|
Srinivas SM, Dhar S, Parikh D. Mastocytosis in children. Indian J Paediatr Dermatol 2015;16:57-63
| Introduction|| |
Mastocytosis is a clonal disease of hematopoietic stem cell characterized by local or diffuse increased growth and accumulation of mast cells (MCs) in skin, bone marrow, liver, spleen, and lymph nodes.  The disorder occurs in two spectrums: Pediatric onset mastocytosis and adult onset mastocytosis. The clinical manifestations of mastocytosis are not directly due to MCs but due the functional effects of MC degranulation enzymes. The presentation of pediatric mastocytosis is varied and differs clinically from adult onset. Pediatric mastocytosis has a benign nature and usually resolves spontaneously by puberty. This article will review the characteristic features of pediatric-onset mastocytosis, approach and the guidelines for their management.
| History|| |
Mastocytosis was first described by Nettleship and Tay in 1869 and later due to the appearance like urticaria, the term urticaria pigmentosa (UP) was coined by Sangster in 1878. , Ellis in 1949 while doing an autopsy in a child with fatal UP documented the presence of MC infiltration in skin, liver, spleen, lymph nodes, and bone marrow. 
| Classification|| |
The classification of mastocytosis has evolved over the years. Children present with cutaneous or systemic mastocytosis (SM) or overlap of these 2 conditions. Degos described many variants of UP in 1955; later many changes were incorporated in the classification over the years. In 2001, WHO adopted the classification of mastocytosis and in 2005 working conference on the mastocytosis put forward the criteria to diagnose and revised the classification of mastocytosis [Table 1]. , Cutaneous mastocytosis (CM) is diagnosed on the clinical and histopathological basis with absence of criteria for SM. SM is based on major and minor criteria [Table 2].  Diagnosis is based on fulfillment of one major and one minor criteria or three minor criteria.
|Table 1: Classification of mastocytosis (modified from Horny et al. 2008) |
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| Epidemiology|| |
Epidemiological data in Indian population are exactly not known. The incidence of mastocytosis in western literature varies from 1 in every 1000 to 1 in 8000 new patients. An annual incidence of 5-10 new cases per million population has been estimated. , Mastocytosis occurs at any age. It can present during the neonatal period, in infancy or childhood. In approximately 15% of children, the disease is congenital and in 50% of cases the onset is between birth and 2 years.  10% of children develop mastocytosis between 2 and 15 years. There is no sex predominance and is seen in all races. Few studies have documented a male preponderance. Familial cases have been reported, and mastocytosis in identical twins and triplets have been described. 
| Etiopathogenesis|| |
MCs are connective tissue cells that play a role in immunologic and inflammatory reactions. They originate from pluripotent progenitor cells in the bone marrow that express CD34, CD17 (kit), and CD13.  These MCs migrate in the blood and invade the tissues where they proliferate and differentiate into mature MCs. MCs play a role host defense by releasing mediators of inflammation leading to type 1 hypersensitivity reactions. The growth and development of MCs is influenced by stem cell factor (SCF, also called MC growth factor or kit ligand) which binds to the human kit protein, the receptor for SCF on the surface of human MCs.  Apart from MC and their progenitors, kit is also expressed on hematopoietic and nonhematopoietic cells.
The etiopathogenesis is multifactoriol. There is increased expression of soluble SCF in lesions of CM. There are a lot of studies documenting mutations in the c-kit gene in adult onset mastocytosis and patients associated with hematological malignancy. The most common mutation is found on the Asp to Val at codon 816 (c-kitD816V).  However, children with typical mastocytosis lack codon 816 mutation. In a recent study on Japanese patients, found that 12 out of 14 children with mastocytosis had D816 substitutions.  Patients with Asp 816Phe mutation appear to acquire the disease earlier than those presenting with Asp 816 Val mutations.
Dysregulation of MC apoptosis is another pathogenesis occurring in mastocytosis, and this is seen in SM. There is upregulation of antiapoptotic protein Bcl-2 and antiapoptotic protein Bcl-X in bone marrow of patients with indolent mastocytosis.  Chromosomal abnormalities may be increased in patients with mastocytosis associated with hematological disorder.  Bone marrow analysis has shown that MCs express CD2 and CD25. CD25 is a reliable immunohistochemical marker to differentiate neoplastic from normal MCs.
The clinical symptoms of mastocytosis are due to the release of MC mediators. MCs produce mediators histamine, heparin, tryptase, proteases, chymase, carboxypeptidase A, chondroitin sulfate glycosaminoglycans, leukotrienes, prostaglandin D2, vascular endothelial growth factor, platelet activating factor, cytokines (tumor necrosis factor and interleukins), and chemokines. These mediators related symptoms are flushing, itching, blistering, diarrhea, abdominal pain, vomiting, hypotension, headache, and bone pain. 
| Clinical features|| |
The most common form of mastocytosis is the cutaneous form. Approximately, two-thirds of children present with CM. In 90% cases, only skin is involved. CM can be classified into UP (maculopapular form), solitary mastocytoma, diffuse CM (DCM), and telangiectasia macularis eruptiva perstans (TMEP). TMEP is very rare in children and seen mostly in adults and is not recognized in WHO classification.  Nodular and plaque type of CM have also been reported. In children, CM typically presents as UP or solitary mastocytoma.  Diffuse form is rare in children. There is mild to moderate pruritus in all cutaneous forms. Stroking the skin lesions produce erythema, swelling, and blister formation, and this is seen after 5-10 min. This reaction pattern is called Darier's sign and is pathognomonic of all forms of CM. 
UP is the most common type of mastocytosis seen in children. It is seen in 70-90% of cases. Lesions can present at birth or usually within 2 years of age. Familial cases of UP have been reported. They occur as multiple, monomorphic red to brown papules or ill-defined gray-brown macules distributed on the face, trunk, and extremities [Figure 1]. Lesions can be generalized but tend to be concentrated more on the trunk. Scalp, palms, soles, and sun exposed areas are less commonly affected. The lesions heal without scarring. UP lesions usually resolve by the age of 10 years, if they persist they tend to be symptomatic and involves systemic features.  Darier's sign is positive in one-third of cases [Figure 2]. Diarrhea, wheezing, and syncope may be associated with UP. Flushing is seen in 36% cases of UP. Rarely, hepatosplenomegaly and skeletal lesions may occur.
|Figure 1: Urticaria pigmentosa showing multiple well-defined hyperpigmented plaques on the trunk|
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Mastocytoma is seen in 10-30% cases. It can occur at birth or in infancy. They present as asymptomatic solitary or up to 5 lesions, round to oval, reddish-brown, pink or yellow nodule on neck, arms or trunk.  The surface of the skin is smooth or resembles pitted skin ('peau d'orange' appearance) [Figure 3].  Urticaria or bullous lesions do occur. There is a classical history of intermittent bullae occurring at the same region. Systemic involvement like flushing, abdominal colic is rarely seen. Persistence of solitary mastocytoma for many years may develop into UP.
|Figure 3: Solitary mastocytoma showing ill-defined hypopigmented plaque with peau d'orange appearance|
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Diffuse Cutaneous Mastocytosis
Diffuse CM is a rare variant and accounts to 1-3% cases of CM. There is diffuse infiltration of MCs in the skin. DCM presents at birth or during infancy during the neonatal period with diffuse blisters or hemorrhagic bullae. The first sign is the presence of extensive bullae which ruptures to form crusting and erosions. Diffuse papules and nodules occur making the skin thickened, lichenified, and doughy. , DCM can present with minimal blistering with erythema evolving into erythroderma.  Pseudoxanthomatous mastocytosis is a variant of DCM characterized by multiple, flat, yellowish papules, and nodules from birth resembling xanthomatosis. ,
Systemic symptoms are often associated with DCM and include flushing, hemorrhage, nausea, vomiting, diarrhea, hypotension, dyspnea, headache, dizziness, irritability, tachycardia, hypotension, abdominal pain, melena, sepsis, and overt shock leading to death.  These symptoms are more pronounced and are episodic and occur during the release of MC mediators.
Other Variants of Mastocytosis
Atypical variants of mastocytosis include bullous, anetoderma, giant inguinal and suprapubic masses.  Rarely, two variants of mastocytosis can be present in the same child. Recently, a new variant of mastocytosis called blaschkoid pattern of mastocytosis has been described in the literature in a child where the lesions occur along the Lines of Blaschko More Details. 
Systemic mastocytosis is more common in adults and is rarely seen in children. It is defined as mastocytosis occurring in at least 2 organs. In a study involving 173 children with mastocytosis, only 2 children had systemic involvement.  SM is diagnosed based on organ involvement and histopathological examination of bone marrow [Table 2]. Gastrointestinal and skeletal system is more commonly involved. Other organs involved are lungs, kidney, liver, spleen, lymph nodes, and bone marrow. The incidence of the skeletal system involved in children is 15%. Radiographic features include sclerotic, lytic or mixed lesions, osteoporosis or osteosclerosis. Gastrointestinal involvement is seen in 4% of children. Symptoms include nausea, vomiting, abdominal pain, gastrointestinal hemorrhage, diarrhea, steatorrhea, malabsorption, perforation, and peptic ulceration.  The hematopoietic and reticuloendothelial system is rarely seen in children. Mastocytosis syndrome results from the massive release of mediators resulting in sudden shock and may lead to death.
| Histopathology|| |
All types of mastocytosis show increased number of MCs in the dermis. In UP and mastocytoma, there is diffuse infiltration of MCs in upper one-third of dermis along with perivascular aggregates.  There is increased melanin in the basal layer and melanophages in the upper dermis which explains the pigmentation in UP [Figure 4]a and b]. It is important to choose a biopsy site that has not been traumatized as there will be degranulation of MCs and histopathology may not be evident of mastocytosis. Precautions must be taken while doing skin biopsy in diffuse involvement to prevent mediator related symptoms, and one should have an emergency kit before starting the procedure. Special stains are required to demonstrate MCs. Giemsa stain, toluidine blue or leder's stain are special stains that identify metachromatic cytoplasmic granules in MCs. Geimsa and toluidine blue stain metachromatic granules purple and leders stain used stain red color.
|Figure 4: (a) Epidermis showing increased basal layer pigmentation with perivascular lymphohistiocytic infiltrate in the dermis (H and E, ×10), (b) Giemsa stain showing multiple perivascular mast cells in the dermis|
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Bone marrow involvement present as accumulation of dense aggregates of spindle-shaped or round MCs adjacent to paratrabecular and perivascular areas.  At least 15 MC aggregates should be present to fulfill the criteria for SM.
| Diagnosis|| |
The diagnosis of mastocytosis is mainly clinical. The diagnostic work up in a child with mastocytosis is outlined in [Table 3]. A high index of suspicion is necessary to recognize the skin lesions of mastocytosis, and this should be corroborated with other features like positive Darier's sign and investigations. All children with mastocytosis baseline investigations should be performed as shown in [Table 3], only if systemic involvement is suspected further investigations must be done [Table 4]. Serum tryptase levels correlate with the MC numbers in the skin, and increased levels are seen in severe disease.  There is a positive correlation between the extent of skin involved, physical appearance of the lesions, associated symptoms such as pruritus, flushing, positive Darier's sign, bone pain, diarrhea, and tryptase levels. Serum levels > 20 ng/ml are seen in 80% of patients with SM. Urinary histamine metabolite N-methylhistamine and N-methylimidazylacetic acid have been correlated with increased MC numbers in the skin.  Skeletal radiographic survey and bone scan are done if there is bone pain, hepatosplenomegaly, anemia or failure to thrive.
| Differential diagnosis|| |
Mastocytoma should be differentiated from juvenile xanthogranuloma, naevocellular nevus, connective tissue nevi, spitz nevus, angioma, histiocytoma, bullous insect bites, bullous urticaria or nodular scabies. Differential diagnosis of UP includes lentigines, pigmented nevi, eruptive xanthomas, neurofibromatosis, histiocytosis, and fixed drug eruption. Bullous forms of UP are differentiated from chronic bullous dermatoses of childhood, bullous pemphigoid, and epidermolysis bullosa.  Diffuse erythrodermic forms can mimic staphylococcal scalded skin syndrome.
| Treatment|| |
Treatment of UP is aimed at three aspects: Counseling, avoidance of triggers known to stimulate MC degranulation and suppressing skin and MC mediator related symptoms.
Education of parents about the disorder and the natural history is important. As most the CM has a benign course, only symptomatic treatment is necessary. There is a tendency for spontaneous resolution before puberty. Caregivers must be informed about the trigger factors that can cause a sudden release of MC mediators and induce symptoms. Information brochures regarding trigger factors and frequently asked questions about the disorder should be given to parents that will help to prevent life-threatening complications.
Avoidance of Triggers
MCs can be activated due to trigger factors that are listed in [Table 5].  Children should avoid bathing in extreme temperature, prevent insect bites, and any physical trauma. Over the counter cough medications should be avoided as they contain dextromethorphan and codeine which can activate MCs. All precautions must be taken while doing surgical procedures and giving general anesthesia. Literature review regarding pediatric anesthesia in mastocytosis has revealed that anesthetic medications can be given with precaution and meticulous preparation to treat complications. Propofol, vecuronium, and fentanyl are safe to use in mastocytosis patients undergoing surgery. 
Treatment of Symptoms
Solitary mastocytoma can be treated with emollients, moderate potent topical corticosteroids or topical calcineurin inhibitors. ,, Single lesions of nodular mastocytosis can be treated with intralesional steroids (5-10 mg/ml). H 1 -receptor antagonist like diphenhydramine, hydroxyzine, loratadine, cetirizine, desloratadine, levocetirizine can control pruritus and flushing. H 2 -receptor antagonist (cimetidine, ranitidine) can be given if gastrointestinal symptoms are present. MC stabilizers disodium cromoglycate (200-800 mg/day) and ketotifen (1-2 mg twice daily) is effective in the treatment of cutaneous and gastrointestinal symptoms. Antileukotrienes are used only in refractory cases. Ultraviolet A or oral psoralen is effective for bullous DCM in children. 
Oral corticosteroids and epinephrine are given only if there is anaphylactic storm and in SM. , Anaphylactic reactions occur in 30% of patients with mastocytosis and in 50% of cases with SM. Sudden symptoms leading to flushing, abdominal cramps, hypotension, shock, and death resulting from massive mediator release may be seen in DCM and SM due to the high MC load. Other modes of therapy for systemic involvement include interferon-alfa therapy, cyclosporine, hydroxyurea, cladribine, and imatinib. Recently, newer biological therapies for mastocytosis are in clinical trials.
| Prognosis|| |
Prognosis depends on age, severity, and clinical subtype. There are limited data regarding long-term follow-up in childhood group. Childhood mastocytosis has a good prognosis. 50-60% of children improve by adolescence. If mastocytosis persists beyond adolescence, 10% of them go for systemic involvement with guarded prognosis. UP, mastocytoma and only cutaneous involvement have a good prognosis. Solitary mastocytoma resolves spontaneously in the majority of cases. 
| FOLLOW-UP|| |
CM should be followed once in 6 months to 1 year, and investigations must be repeated. SM must be followed up to 5 years with regular monitoring.
| Conclusions|| |
Mastocytosis in children has varied manifestations. The course of childhood mastocytosis is different from adult onset. Treatment strategies are not standardized. It requires a lot of research in understanding the heterogeneity of this disorder and still today remains a big challenge for treating dermatologists.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]