INTRODUCTION — Mastocytosis describes a group of disorders in which there is pathologic accumulation of mast cells in tissues. These diseases can be limited to the skin (cutaneous mastocytosis [CM]) or involve other tissues and organs in addition to the skin (systemic mastocytosis [SM]). In infants and pre-pubescent children, CM accounts for the majority of cases. The clinical manifestations, evaluation, and diagnosis of the different forms of CM and SM in infants and children are reviewed here. The clinical manifestations, pathogenesis, evaluation and diagnosis in adults, and the treatment and prognosis of mastocytosis in children and adults are discussed separately:
EPIDEMIOLOGY — Mastocytosis, in all its forms, is a rare disorder. The prevalence has been estimated at 1 per 10,000 persons . In children, males and females are affected, although there is a slight predominance in males . After puberty, more females are affected. The onset of mastocytosis in children follows a bimodal distribution with a peak in the first three years of life, a subsequent drop, and second much smaller peak after the age of 15 . Symptoms that develop or worsen after puberty are likely to represent systemic disease. Mastocytosis can be familial, although most cases are not [4,5].
Cutaneous mastocytosis — The most common form of mastocytosis in children is cutaneous mastocytosis (CM), which accounts for approximately 90 percent of mastocytosis cases in patients under the age of 18 years. In cutaneous disease, pathologic numbers of mast cells accumulate in the skin, causing cutaneous and systemic symptoms, but do not infiltrate other organs. Most affected children develop skin findings in the first year of life, although lesions can be present at birth. The diagnosis is usually made before the age of two years.
●The most prevalent form of CM is maculopapular cutaneous mastocytosis (MPCM), also called urticaria pigmentosa (UP) (picture 1) . MPCM/UP accounts for 70 to 90 percent of all pediatric cases of CM . It is referred to as "polymorphic" because the lesions vary in size and shape.
●The other forms of CM that present in young children are isolated cutaneous mastocytomas, which account for 10 to 15 percent of children with CM, and diffuse cutaneous mastocytosis (DCM), accounting for 1 to 3 percent (picture 2A-B).
Systemic mastocytosis — Systemic mastocytosis (SM) accounts for less than 10 percent of pediatric mastocytosis cases and involves the abnormal accumulation of mast cells in the skin and multiple organs. Children with SM nearly always have skin lesions that differ in appearance from those of typical pediatric MPCM/UP. Instead, the lesions are similar to those in patients with adult-onset disease. They are small and uniform, as shown in images H and I in the photo collection (picture 1). In systemic disease, the bone marrow, gastrointestinal tract, liver, spleen, and/or lymph nodes may be involved [8-10]. Most children with SM will prove to have indolent SM, rather than more aggressive (advanced) forms of the disease.
NATURAL HISTORY — There are important differences between the natural histories of pediatric and adult mastocytosis. Pediatric mastocytosis is confined to the skin in most cases, and although symptoms can be challenging to manage and occasionally associated with significant morbidity, the majority of children have a benign course and experience spontaneous improvement or resolution around the time of puberty [4,6,11]. In contrast, adults more often have systemic disease that persists throughout life. Prognosis in children is discussed in more detail separately. (See "Cutaneous mastocytosis: Treatment, monitoring, and prognosis", section on 'Prognosis'.)
PATHOGENESIS — Various KIT mutations have been identified in children with maculopapular cutaneous mastocytosis (MPCM), none of which predicts an association with systemic disease. In this way, pediatric and adult mastocytosis are similar. However, the pathogenesis of mastocytosis in infants and children may differ from that in adults in important ways. Based on research in mice, it has been proposed that mammalian mast cells may originate from at least two distinct sources during embryonic development and that the mast cells present in the skin at birth are gradually replaced by a different population as the individual matures . The presence of a defect in the population of mast cells that originates from the embryonic yolk sack and predominates in the neonatal period, but not in the population that is subsequently produced in the bone marrow, may explain the mechanism of resolution of the disease in most children.
A detailed discussion of the pathogenesis of mastocytosis, based largely on studies of adult disease, is found separately. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Pathogenesis'.)
●The most frequent presentation of cutaneous mastocytosis (CM) in children is the presence of polymorphic lesions of maculopapular cutaneous mastocytosis/urticaria pigmentosa (MPCM/UP), often located on the trunk, extremities, scalp, or neck. Lesions on the palms and soles are uncommon but do occur. Many children with skin lesions have minimal or no systemic symptoms. However, others may experience episodes of flushing, nausea/vomiting, or diarrhea. Infants may have episodic blistering. Nodular lesions, diffuse skin involvement, and mastocytomas are rare presentations. (See 'Skin' below.)
●The rare infant or child with systemic mastocytosis (SM) usually presents with numerous MPCM/UP lesions that are monomorphic and resemble the lesions seen in adults. Skin findings are accompanied by episodes of flushing, nausea/vomiting, and diarrhea. In older children, systemic disease may present as persistence of anaphylaxis-like symptoms and increasing numbers of skin lesions over time. In systemic disease, hepatosplenomegaly, abnormal liver function tests, or hematologic abnormalities are indicative of infiltration of organs by abnormal mast cells. (See 'Signs and symptoms of systemic disease' below.)
Signs and symptoms — Signs and symptoms of mastocytosis in infants and children may be grouped as follows (table 1):
●Skin findings (which may be present in both cutaneous and systemic forms of mastocytosis)
●Symptoms arising from mediator release (which may be present in both cutaneous and systemic forms of mastocytosis)
●Symptoms arising from (noncutaneous) organ infiltration (which are only present in systemic forms of mastocytosis)
Skin — There are three main variants of CM in infants and children: MPCM/UP, cutaneous mastocytoma, and diffuse cutaneous mastocytosis (DCM) [13,14]. Some children may be asymptomatic, but the most common complaint of children with skin involvement is pruritus . Pruritus associated with MPCM/UP may be exacerbated by changes in temperature, exercise, hot baths, local friction, emotional stress, or certain medications. (See 'Triggers for mediator release' below.)
Other common cutaneous symptoms include erythema, flushing, episodes of localized urticaria, swelling, dermatographism, or blister formation. In contrast, generalized urticaria and/or angioedema as isolated symptoms are not typical and should prompt consideration of chronic spontaneous urticaria or other allergic disorders. Bullous eruptions with hemorrhage can occur in children with MPCM/UP or DCM.
Darier's sign — Darier's sign is the development of localized urticaria and erythema (within about five minutes) following rubbing, scratching, or stroking skin or skin lesions that are heavily infiltrated with mast cells . Physical irritation triggers the localized release of mast cell mediators. Darier's sign can be seen in MPCM/UP, DCM, and mastocytomas; however, mastocytomas and DCM should not be purposefully rubbed, as this can precipitate severe symptoms.
●Maculopapular cutaneous mastocytosis/urticaria pigmentosa – MPCM/UP accounts for 70 to 90 percent of all pediatric cases of CM . It may also be a cutaneous manifestation in patients with SM. The lesions of MPCM/UP are macules or slightly raised papules, ranging in color from yellow-tan to reddish-brown (picture 3A-C). These may be mistaken for freckles initially. Plaque-like lesions (picture 4) and nodules (picture 5) may also occur. In children, the face and scalp may be involved. Lesions typically appear in the first six months of life and can be present at birth.
Skin lesions of MPCM can be distinguished in two major morphologies:
•Polymorphic lesions – Most children have "polymorphic" lesions that vary in size and shape and are larger than the monomorphic lesions seen in adults. Different types of polymorphic MPCM/UP are shown in images A through G of the photo collection (picture 1).
•Monomorphic lesions – A small number of children may have smaller (1 to 3 mm), "monomorphic" lesions that resemble the adult-onset lesions of MPCM/UP, as show in images H and I (picture 1). Children with monomorphic lesions have a greater risk of having SM and persistence into adulthood, particularly if the lesions develop later in childhood or increase in number after puberty.
●Mastocytomas – Solitary or multiple mastocytomas of the skin are usually present at birth or develop in the first months of life (picture 2A, 2C). Mastocytoma lesions are similar in quality to those of MPCM/UP but can be larger (up to several centimeters) . Three or fewer lesions are considered mastocytomas, while more than three lesions are classified as MPCM . Some mastocytomas have a yellow to orange coloration . Bullae may be present, with typical localization in the extremities, axillae or groin, or areas where the skin is rubbed or scratched. Pruritus is variable. Individual mastocytomas may grow or change in shape or appearance. Spontaneous involution is frequently observed by pre-adolescence. Flushing or even hypotension may also occur after physical irritation of the lesion, so mastocytomas should not be purposefully rubbed. Instead, the patient or caregiver can usually provide the history that flushing occurs if the lesions are disturbed.
●Diffuse cutaneous mastocytosis – Children with DCM generally present at birth or in the first year of life. They do not have individually discernible lesions but rather a diffuse thickening (peau d'orange) and slight darkening of the skin (picture 6A-B). Involvement of the whole skin, rather than discrete areas, is characteristic. Some have prominent dermatographism. Two subtypes of DCM have been proposed: one in which larger bullae form on deeply erythematous skin and a second characterized by yellow-orange skin infiltration with minimal small blisters . However, there are also case reports of mixed presentations [19,20].
Children with DCM may or may not experience itching but are prone to severe systemic symptoms (eg, anaphylaxis, gastrointestinal bleeding, coagulopathy), which can result in significant morbidity, especially if mast cell activating medications are administered before the condition is recognized [21,22]. DCM can also progress to aggressive forms of SM or to a rare type called well-differentiated SM [21,23,24].
Bullous eruptions with hemorrhage can occur in young children (usually under the age of three years) with DCM or MPCM (picture 7A-B). Blistering is not seen in older children or adults, possibly because the physical properties of infant skin are different from those of more mature skin. Eruptions can be spontaneous or triggered by physical triggers (eg, rubbing), infections, medications that activate mast cells (such as narcotics, nonsteroidal anti-inflammatory drugs [NSAIDs], or vancomycin) or, rarely, vaccinations (particularly with live vaccines or when several vaccines are given together) [25-28]. Blister fluid contains histamine, prostaglandins, and platelet-activating factor. Blisters can be present at birth, and CM should be considered in the differential of neonatal blistering disorders . (See "Vesicular, pustular, and bullous lesions in the newborn and infant".)
Symptoms arising from mediator release — Mast cells release histamine, prostaglandins, cytokines, and various other vasoactive mediators upon activation (table 2). In patients with either CM or SM, release of mast cell mediators may occur in explosive episodes, presenting as apparent "allergic" reactions and anaphylaxis or may occur on a more chronic basis, giving rise to problems such as chronic gastrointestinal complaints (table 1).
Anaphylaxis and episodic "allergic" symptoms — Acute mast cell activation presents as apparent "allergic" reactions and anaphylaxis. In over two-thirds of children with MPCM/UP, release of mast cell mediators may lead to episodes of multisystem symptoms, even when disease is limited to the skin. Acute release of mast cell mediators can result in episodes of flushing, pruritus, vasodilation, abdominal pain, nausea, vomiting, diarrhea, fatigue, and headache (table 2). Some children display apneic or cyanotic spells. (See "Anaphylaxis in infants", section on 'Clinical manifestations and diagnosis'.)
Infants and children tend not to have hypotension and syncopal episodes, which is a characteristic symptom in adults with SM. However, severe episodes of mast cell activation are seen in children with extensive skin involvement, increased basal serum tryptase values, and extensive blistering [30,31].
Anaphylaxis can be observed in both CM and SM and can result from either immunoglobulin E (IgE)-mediated allergy or nonspecific activation of mast cells. Adults can present with severe hypotension following insect stings, which is rare in infants and children. (See "Indolent and smoldering systemic mastocytosis: Management and prognosis", section on 'Insect stings'.)
Gastrointestinal complaints — Chronic mediator release can lead to gastrointestinal dysfunction, especially bloating and abdominal pain. Infants and children are often "picky eaters." In older children, diarrhea, reflux symptoms, and peptic ulcer disease are more typical problems. Gastrointestinal symptoms can be precipitated by spicy or strongly flavored foods and many of the same triggers that cause systemic symptoms (table 3).
Diarrhea can result from increased motility induced by prostaglandin D2 (PGD2) secretion. Histamine and other mediators released from local and distant mast cells increase gastric acid secretion. Serum histamine concentrations may be elevated, particularly in the setting of ulcer disease, suggesting that circulating histamine contributes to basal acid hypersecretion [32,33].
Neuropsychiatric symptoms — Neuropsychiatric manifestations may be easily overlooked in infants and children. Infants and young children may display anxiety and irritability. Older children can demonstrate anxiety, aggressive behavior, depression or other mood changes, or report headache. The precise cause of many of these manifestations is not known, although prostaglandin D2 (PGD2) is thought to increase somnolence . Histamine acts as a neurotransmitter and is important in wakefulness.
Musculoskeletal symptoms — Musculoskeletal symptoms are uncommon in children with mastocytosis. A small number may experience pain in the long bones, but the usual explanation for this is normal "growing pains." (See "Growing pains".)
Triggers for mediator release — The release of mast cell mediators in patients with CM and SM may be precipitated by a variety of stimuli, although not all triggers cause mast cell degranulation in all patients. A careful history is often helpful in determining what can or cannot be tolerated by individual patients.
Non-specific triggers — Potential triggers include the following (table 3):
●Physical factors, such as exercise, friction applied to the skin, extremes of temperature, sudden temperature changes, and spicy foods.
●Infections, including viral, bacterial, and parasitic. Of note, coronavirus disease 2019 (COVID-19) does not increase mast cell activation symptoms in most patients .
●Fever and febrile responses to vaccination. Note that most children with MPCM/UP tolerate vaccinations, but children with DCM can develop cutaneous blistering in response to febrile reactions following vaccinations . Children with mastocytosis should receive all vaccinations but can be premedicated with antihistamines and acetaminophen. In addition, administering vaccines one at a time is prudent.
●Surgical procedures or instrumentation (including biopsies or endoscopy), although many children with CM tolerate these without difficulty.
●Alcohol in medications.
●Other triggers seen less often in children than adults include insect stings and IgE-mediated allergies.
Allergic disorders — Children with mastocytosis may have concomitant IgE-mediated allergic diseases that trigger symptoms, including allergic rhinitis, food and drug allergies, and Hymenoptera allergy [37,38]. They may also have asthma. The prevalence of allergic disorders in patients with mastocytosis (both cutaneous and systemic) appears to be similar to that of the general population (ie, between 20 and 30 percent in Westernized nations) [37-39]. Total IgE levels are usually decreased in patients with mastocytosis, possibly due to binding to an increased number of mast cells .
Signs and symptoms of systemic disease — The organ systems most often affected are the bone marrow, lymph nodes, liver, and spleen, and gastrointestinal tract [8-10]. Involvement of these organ systems may give rise to a variety of symptoms, physical findings, and abnormalities on routine laboratories (table 1). In contrast, the respiratory, endocrine, and genitourinary systems are seldom involved in SM, although patients with SM may have concomitant asthma at rates similar to the general population. The incidence of bacterial, fungal, or viral infections is not increased, and patients are not immunocompromised unless there is an associated hematologic disorder affecting other cell lines (ie, neutrophils).
Most children who have SM have the indolent form, which carries a good long-term prognosis. Children with indolent SM usually present with monomorphic MPCM/UP that persists, accompanied by increasing tryptase levels. (See "Systemic mastocytosis: Determining the subtype of disease", section on 'Indolent systemic mastocytosis'.)
An even smaller number of children had advanced forms of SM and present similarly to adults. The most common signs and symptoms of systemic disease in infants and children with advanced forms of SM are:
●Hepatosplenomegaly – Enlargement of the liver, spleen, or both may be seen in children with SM . Alkaline phosphatase, transaminases, gamma-glutamyl transpeptidase (GGT), and/or bilirubin may be elevated.
●Unexplained lymphadenopathy – Lymphadenopathy in children is usually benign and is discussed in detail separately. Common causes, such as mononucleosis, should be considered initially. However, lymphadenopathy that is unexplained and persists beyond about four weeks may be a presentation of SM in children. (See "Peripheral lymphadenopathy in children: Etiology" and "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach".)
●Hematologic abnormalities – Various deviations from normal age-appropriate hematologic parameters may be seen in the rare child with SM. The most characteristic abnormalities on a complete blood count with differential are persistent and unexplained cytopenias and immature or abnormal myeloid and lymphoid leukocytes. Eosinophilia can be seen in both CM and SM.
Relationship to skin findings — Virtually all children with SM have skin lesions. SM presenting with symptoms of mast cell activation in children without skin lesions has not been reported. Monomorphic UP-like skin lesions are the most common type of skin finding in children with systemic disease. However, children with polymorphic MPCM can also have SM, and children with DCM have an increased risk of SM of a specific type called well-differentiated SM . The extent of skin involvement does not reliably correlate with the likelihood of systemic disease. Children with mastocytomas are not at risk for developing systemic disease.
Overview — The evaluation of a child with skin lesions suggestive of mastocytosis involves history and physical examination, measurement of serum total tryptase, laboratory tests to detect involvement of other organs, and biopsy of lesional skin (unless the clinician is experienced enough to diagnose mastocytosis skin lesions without a biopsy). Note that patients can have systemic symptoms due to mediator release from cutaneous mast cells, so it is often difficult to tell if the patient has systemic disease or disease limited to the skin based on systemic symptoms alone.
Because pediatric mastocytosis is usually limited to the skin and spontaneously improves, most infants and children will not require a bone marrow biopsy. However, children can have systemic disease and a small minority will have aggressive forms of systemic mastocytosis (SM) with poor prognoses. These children are usually detected by the presence of hepatosplenomegaly, abnormal liver function tests, or cytopenias.
If systemic symptoms are mild, there is no evidence of hepatosplenomegaly or lymphadenopathy on physical examination, and routine laboratories are normal, then no additional evaluation is needed initially and the child may be monitored. Further evaluation for systemic disease is indicated in children who have baseline levels of total tryptase >20 ng/mL on at least two occasions, hepatosplenomegaly, or persistent and significant abnormalities of the complete blood count with differential.
Diagnostic algorithm — An algorithmic approach to the evaluation and diagnosis of a child with skin lesions suggestive of mastocytosis is provided (algorithm 1).
History and physical examination — Daily and episodic symptoms should be reviewed in detail.
Skin examination — The skin should be examined for findings suggestive of the different forms of cutaneous mastocytosis (CM) . If lesions of maculopapular cutaneous mastocytosis/urticaria pigmentosa (MPCM/UP) are detected, then the examiner may lightly rub, scratch, or stroke a small area of the affected skin. The development of erythema, swelling, or urticaria over/around the lesion within a few minutes (Darier's sign) is pathognomonic for the presence of mast cells within the lesion. However, lesions consistent with mastocytomas should not be rubbed or scratched as this may lead to significant mast cell-mediator release that can result in generalized flushing and hives. Instead, the caretaker can usually report that these symptoms occur if the lesion is disturbed. In addition, pictures of the lesions at the time of flares are recommended to document Darier's sign.
Initial laboratory studies — The tests discussed in this section should be performed at least once in children with disease that appears to be limited to the skin, to ensure that there is no evidence of systemic involvement.
●Complete blood count with differential to evaluate for persistent and unexplained cytopenias and immature or abnormal myeloid and lymphoid leukocytes, which may be signs of systemic disease. In cutaneous forms of mastocytosis, the complete blood count and differential are typically normal, although a mild eosinophilia is sometimes noted. Lymphocytosis (which may be normal in young children) and thrombocytosis may be seen, although these findings usually normalize over time and should not prompt a bone marrow evaluation in the absence of other abnormalities.
●Liver function tests (including serum aminotransferases, alkaline phosphatase, gamma-glutamyl transpeptidase [GGT], and bilirubin) to evaluate for liver involvement in systemic disease. Liver function tests should be normal in CM.
Serum tryptase — A level of serum total tryptase should be obtained when the patient is in a baseline state (ie, not immediately following an episode of symptoms). Tryptase is a protease produced predominantly in mast cells, although a small amount is made by basophils and myeloid precursors as well. Total serum tryptase can be measured with a commercially available assay (ImmunoCAP tryptase), which is performed at many laboratories. Normal levels are between 1 and 11.4 ng/mL (some laboratories consider 15 ng/mL to be the upper limit of normal).
Tryptase is usually normal in children with CM and elevated in those with SM. The presence of serum tryptase >20 ng/mL is one of the minor criteria for the diagnosis of SM (table 4) . However, tryptase can be elevated in CM when the skin is diffusely involved, such as in diffuse cutaneous mastocytosis (DCM) or very extensive MPCM/UP, even in the absence of systemic disease [11,18,41-43]. Levels in excess of 100 ng/mL are not uncommon in the early stages of DCM, with gradual lowering over time [11,17,30]. In a study of 105 children with mastocytosis, tryptase levels were higher in patients with indolent SM and DCM, compared with those with MPCM/UP . Tryptase can also be elevated in patients with hereditary alpha tryptasemia (HaT), which can be present in patients with or without mastocytosis.
An elevated tryptase, in isolation, does not correlate with the presence of systemic symptoms or bone marrow involvement . Elevated tryptase values without other signs of systemic disease should be monitored every six months or yearly to assure that the level is stable or decreasing over time. In contrast, elevated tryptase in combination with organomegaly, should prompt further evaluation (ie, KIT mutational analysis of peripheral blood or a bone marrow biopsy), as described below .
In contrast, SM should be strongly suspected in patients with baseline levels of total tryptase >20 ng/mL on at least two occasions, liver or spleen enlargement, or abnormalities of the complete blood count with differential .
Shifting definition of normal tryptase — The level of tryptase that is considered elevated is evolving. The World Health Organization diagnostic criteria for SM specifies a level about 20 ng/mL as a minor criterion for SM. Different commercial laboratories set the upper limit of normal at either 11.4 or 15 ng/mL, as mentioned above. Patients with HaT have levels above 7.5 or 8 ng/mL and as high as 60 ng/mL. The inclusion of individuals with HaT in the general population may have skewed the previous definitions of normal upwards. There is growing evidence that individuals without HaT or any mast cell disorder have serum tryptase levels significantly lower (ie, typically <8 ng/mL). Because of these areas of uncertainty, the authors consider levels above 10 ng/mL to be potentially abnormal when considering which children to monitor more closely. (See 'Differential diagnosis' below.)
Skin biopsy (not always needed) — In most cases, cutaneous forms of mastocytosis are recognizable by inspection of the skin, and skin biopsy is not essential, particularly if the clinician is familiar with the appearance of CM. However, a 3 mm punch biopsy of lesional skin should be performed when the diagnosis of CM is in doubt. Skin biopsy does not provide information about systemic involvement.
Patients who are not already taking an H1 antihistamine regularly should take a dose prior to biopsy to reduce the effects of mediator release during the procedure. Specimens should be fixed in formalin and undergo histopathologic staining with Giemsa and/or immunohistochemical staining for tryptase and KIT (the receptor for stem cell factor, also called CD117). These stains identify both normal and abnormal mast cells. Degranulated mast cells can be difficult to identify without these specialized stains. Techniques for identifying mast cells in tissues are presented in more detail separately. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Skin biopsy (if needed)'.)
Skin biopsy may be submitted for mutational analysis of KIT. (See 'Other tests' below.)
Interpretation — Characteristic skin biopsy findings or detection of a KIT (the gene for KIT) mutation in the context of suggestive skin lesion(s) are diagnostic of CM [13,17]. Note that biopsy findings alone, without the characteristic skin lesions of various forms of CM, are not sufficient for diagnosis, because mast cells can accumulate in the skin in other disorders. (See 'Differential diagnosis' below.)
There is no specific cutoff value for numbers of mast cells in the skin that is considered abnormal. Mast cells in lesions of UP may have irregular shapes, sometimes with bilobed nuclei, which may be seen on light microscopy. Infiltrating eosinophils may also be present, but other types of inflammatory cells are usually absent.
●Perivascular infiltrates in the papillary and upper dermis
●Sheet-like infiltrates in the papillary body and upper reticular dermis
Other tests — Analysis of cutaneous mast cells for the presence of mutations in KIT is not a standard part of the evaluation of skin biopsies, although it was proposed in a consensus report to fulfill a minor diagnostic criterion  (see 'Cutaneous mastocytosis' below). Several studies have found a high rate (up to 80 percent) of KIT mutations in lesional skin samples obtained from children with CM. The prognostic significance of these findings is not clear. While approximately 40 percent of these mutations involved exon 17 (including D816V as seen in adult-onset disease), 40 percent had mutations in other exons. One study suggested that KIT mutations at codon 816 (in exon 17) may be associated with persistent disease in adulthood and SM, while other mutations in exons 8 and 9 were associated with remission of cutaneous disease at puberty . However, other studies did not find associations between specific mutations and prognosis, and further work is needed to clarify the prognostic significance of specific mutations [2,48].
KIT mutational analysis of peripheral blood — The presence of a mutation in KIT is one of the minor criteria for SM (table 4). All children suspected of having SM should undergo a mutational analysis of KIT, which can be performed on peripheral blood leukocytes or bone marrow (and occasionally on other tissues) [49,50]. The role of KIT analysis of peripheral blood is evolving . Testing is now performed routinely at some specialty centers and available through a limited number of commercial labs . Assays vary in sensitivity, and less sensitive assays may not detect mutations that are present at a low level. In addition to variations in sensitivity, the allele-specific polymerase chain reaction (PCR) tests performed by commercial laboratories for diagnosis of mastocytosis only detect the most common KIT mutation (D816V) and will miss less common mutations . Mutational assays using D816V allele-specific PCR primers have the highest sensitivity of detection and usually can detect <0.1 percent of the mutated allele in a sample, whereas sequencing-based techniques have poor sensitivity and should not be used for routine mutational analysis. Therefore, while a positive result on peripheral blood is helpful and may strengthen the need for bone marrow biopsy, a negative result does not exclude the possibility that an abnormal KIT mutation is present at low levels.
WHEN TO REFER — Pediatricians and dermatologists should perform a history and physical examination (with careful attention to the skin), obtain the initial laboratories mentioned above if possible, and obtain a biopsy of suggestive skin lesions if possible. Further evaluation usually requires specialty referral. When feasible, the following patients should be referred to an allergy/immunology or hematology expert with knowledge of mast cell disorders:
●Any child suspected of having cutaneous mastocytosis (CM) if the diagnosis could not be confirmed by skin examination or biopsy.
●Patients with physical exam or laboratory findings that could indicate the presence of systemic mast cell disease: unexplained and persistent lymphadenopathy, hepatosplenomegaly, abnormal liver function tests, or cytopenias.
●Patients with elevated tryptase levels but not in conjunction with acute anaphylaxis.
●Children with diffuse cutaneous mastocytosis (DCM).
●Patients who have a detectable D816V mutation in peripheral blood.
●Older children and adolescents with skin lesions that are not resolving, or ongoing episodes of anaphylaxis-like symptoms.
One clinical scenario that can cause concern is the child with typical maculopapular cutaneous mastocytosis/urticaria pigmentosa (MPCM/UP) who has an unexpectedly elevated tryptase. This is not common, because most children with MPCM/UP have disease limited to the skin and tryptase levels in the normal range. The finding of an elevated tryptase, without other signs of organ infiltration or cytopenias can be followed for a few years. If no other concerning symptoms for systemic mastocytosis (SM) develop aside from the elevated tryptase, and the skin lesions are stable or improving, then the child likely has cutaneous disease that will regress gradually. During this period of monitoring, additional testing may be reassuring. The authors' approach in a patient with increasing or persistently high tryptase level whose skin lesions have persisted into adolescence or a patient showing new symptoms such as recurrent anaphylaxis is to consider (through shared decision making with the patient and caregivers) testing for hereditary alpha tryptasemia (HaT), which could explain the elevation in tryptase but may not be reimbursed currently by third-party payors. If HaT is not present or testing is not feasible, high sensitivity allele-specific polymerase chain reaction (PCR) mutational analysis of KIT in the peripheral blood could be performed, although it is not as informative as a full bone marrow evaluation. Still, if there is a desire to avoid subjecting the child to a bone marrow analysis, then this strategy is often adequate and reassuring. The authors' approach is depicted in the algorithm (algorithm 2).
BONE MARROW EXAMINATION
Indications — Bone marrow examination is performed if systemic mastocytosis (SM) is suspected to determine if abnormal numbers and types of mast cells are present. Certain bone marrow findings constitute the major criterion for the diagnosis of SM (table 4).
Most children with findings of cutaneous mastocytosis (CM) do not require a bone marrow examination. The indications for bone marrow examination differ somewhat for children at different ages :
Infants and pre-adolescent children — Bone marrow biopsy is not routinely performed in infants and children with cutaneous manifestations of mastocytosis, because it is uncommon for the bone marrow to be involved. In particular, children with cutaneous mastocytomas are not at risk for SM. However, in children with maculopapular cutaneous mastocytosis/urticaria pigmentosa (MPCM/UP) or diffuse cutaneous mastocytosis (DCM), bone marrow biopsy is indicated if there are specific findings to suggest extracutaneous organ involvement [7,54]. These include:
●Unexplained abnormalities of the peripheral blood or liver function tests, such as unexplained cytopenias or increased immature forms.
●Hepatomegaly, splenomegaly, or unexplained and persistent lymphadenopathy .
●Severe systemic symptoms consistent with mast cell-mediator release that cannot be readily controlled with pharmacotherapy.
●D816V mutation detectable in peripheral blood.
●A possible indication for bone marrow examination is an elevated tryptase without other abnormalities suggestive of SM in a child with extensive skin involvement. In this setting, the elevated tryptase may be attributable to the mast cell burden in the skin or the child could have concomitant hereditary alpha tryptasemia (HaT). Children with isolated elevations of tryptase can be monitored over the course of several years. If the tryptase trends upward or does not normalize after puberty, then a bone marrow examination should be performed. If tryptase trends downward over time, and skin lesions are regressing, then a bone marrow examination is not necessary. The authors' approach to this specific scenario is depicted in the algorithm and a level of >10 ng/mL is considered as potentially abnormal (algorithm 2).
Adolescents — Cutaneous disease may initially be diagnosed in adolescents, although this is rare. The approach to evaluation is similar to that in younger children, except that adolescents have a higher likelihood of having SM compared with children whose lesions started within the first years of life. The indications for bone marrow evaluation are the same as those in young children. However, additional indications in adolescents are:
●Failure of skin lesions to begin to regress or baseline serum tryptase levels that remain above the normal range (usually >20 ng/mL) after puberty, in the absence of HaT .
●Continued episodes of anaphylaxis (ie, flushing/lightheadedness, tachycardia) with skin lesions that are not resolving.
Analysis — The bone marrow examination includes an evaluation of the histology of the core sample and of aspirated cells. Both types of samples should be examined for morphologically abnormal mast cells (eg, spindle-shaped, hypogranular forms). The components of bone marrow analysis are discussed in detail separately. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Additional evaluation and bone marrow biopsy'.)
A rare histopathologic variant termed "well-differentiated systemic mastocytosis" has been described, in which patients present in childhood with extensive MPCM/UP or DCM [55,56]. This variant is usually seen in patients with a history of pediatric-onset mastocytosis that persists into adulthood and elevated tryptase. Mast cells in the bone marrow have a mature, round, and fully granulated morphology, lack CD25, and do not generally carry the typical D816V KIT mutation. Clustering of mast cells in bone marrow and pathologic CD30 expression are usually detectable [24,55].
IMAGING AND ADDITIONAL EVALUATION — Children who appear to have lymphadenopathy, splenomegaly, or hepatomegaly on physical examination should have an abdominal ultrasound or computed tomography to evaluate these findings.
Other studies, such as gastrointestinal biopsies, biopsies of other organs, or imaging tests are sometimes obtained before the diagnosis of mastocytosis is considered or as part of an evaluation of specific signs and symptoms. Although these are not components of the diagnostic criteria for CM or SM, they are useful to determine the extent of disease and can be helpful if the diagnosis of SM has been made, to determine the degree of systemic involvement. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Other studies'.)
Cutaneous mastocytosis — The diagnosis of cutaneous mastocytosis (CM) is based upon the presence of characteristic cutaneous lesions combined with consistent findings on skin biopsy (table 4). In addition, features/criteria sufficient to establish the diagnosis of systemic mastocytosis (SM) must be absent.
"Mastocytosis in the skin" (MIS) is a term used to refer to the cutaneous findings that can occur in patients with all forms of mastocytosis. MIS describes the presence of skin findings in patients who have not yet been evaluated to determine if they have systemic disease.
A European and American consensus group published additional criteria for the diagnosis of MIS would require the following :
●The major criterion, which is the presence of typical skin lesions
●At least one of the following two minor criteria:
•Increased mast cell numbers in a biopsy from lesional skin (as determined by the judgement of the dermatopathologist)
•Activating KIT mutations in a biopsy from lesional skin
(See 'Skin biopsy (not always needed)' above.)
Thus, children with polymorphic MIS and no evidence of SM can be diagnosed with CM.
Systemic mastocytosis — According to the World Health Organization's (WHO) diagnostic criteria, the definitive diagnosis of SM requires either the presence of one major and one minor criteria OR three minor criteria for systemic mastocytosis (table 4) :
Major criterion — The major criterion for SM is the presence of multifocal, dense aggregates of greater than 15 mast cells in bone marrow (preferred) or other extracutaneous organs (eg, gastrointestinal tract, lymph nodes, liver, or spleen) as detected with antibodies for tryptase or other special stains.
Minor criteria — Four minor criteria for SM have been defined:
●Atypical morphology or spindle shapes in >25 percent of the mast cells in bone marrow sections, bone marrow aspirate, or other extracutaneous tissues.
●Mutational analysis of KIT (the gene for c-kit) showing a codon 816 mutation (eg, Asp816Val) in bone marrow, peripheral blood, or extracutaneous organs.
●Bone marrow or other extracutaneous mast cells expressing the surface markers CD2, CD25, or both.
●Serum tryptase levels >20 ng/mL (when the patient is in a baseline state). Values >11.4 ng/mL are considered elevated in most diagnostic laboratories. However, the WHO criterion is defined as a value >20 ng/mL. Of note, the serum tryptase criterion does not apply to patients with the subtype of SM called "systemic mastocytosis with an associated hematologic neoplasm," since tryptase in such patients can originate from myeloid precursor cells.
If criteria for the diagnosis of SM are met, the next step is to determine the type of systemic disease present. Most children with SM have indolent SM, and advanced forms of SM are rare. This evaluation is discussed separately. (See "Systemic mastocytosis: Determining the subtype of disease".)
Idiopathic anaphylaxis — Idiopathic anaphylaxis is usually diagnosed in adults but has been described in children . It is a diagnosis of exclusion, as discussed in detail separately. (See "Idiopathic anaphylaxis".)
Disorders with similar skin findings
●Epidermolysis bullosa (EB) simplex is an inherited disease characterized by skin fragility and blister formation following minor skin trauma (picture 9). It can mimic blistered CM [59,60]. EB is diagnosed by skin biopsy of a fresh blister analyzed by immunofluorescence microscopy. (See "Vesicular, pustular, and bullous lesions in the newborn and infant", section on 'Epidermolysis bullosa' and "Diagnosis of epidermolysis bullosa".)
●Diffuse CM with blistering can be mistaken for scalded skin syndrome (picture 10) or impetigo bullosa, and patients may receive antibiotics inappropriately . (See "Staphylococcal scalded skin syndrome" and "Impetigo", section on 'Bullous impetigo'.)
●Café-au-lait macules are pigmented lesions that appear during the first year of life. The presence of six or more is highly suggestive of neurofibromatosis type 1 (picture 11). Café-au-lait spots could be confused with MPCM but do not urticate when rubbed. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)
●Linear immunoglobulin A bullous dermatosis is a rare autoimmune blistering disease that can affect children or adults (picture 12). Most cases are idiopathic, although some are associated with drug exposure. (See "Linear IgA bullous dermatosis".)
●Increased mast cell numbers can be found in other inflammatory and neoplastic conditions of the skin, such as atopic dermatitis and nevi. However, these disorders are each associated with characteristic pathologic changes in the skin that differ from those of mastocytosis.
Solid mast cell tumors — Solid mast cell tumors are extremely rare and do not fulfill the criteria for either SM or CM. Benign and malignant variants of these tumors exist and can be difficult to distinguish from each other.
●Extracutaneous mastocytomas are benign lesions that are characterized by accumulation of mature mast cells in an organ other than the skin without aggressive features. These are typically detected accidentally or discovered because they can cause a mass effect and have been described in the skull and lungs . Surgical removal may be curative. Evolution of extracutaneous mastocytomas to mast cell sarcoma has not been described.
●Mast cell sarcoma are rare malignant tumors with few well-documented cases [63,64]. The sarcoma is a locally destructive lesion without systemic (bone marrow) involvement at the time of the diagnosis. Mast cell sarcomas may be located in skin, bone, extramedullary space, colon, larynx, and meninges [65-67]. Mast cell sarcomas can evolve to mast cell leukemia.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Mast cell disorders".)
SUMMARY AND RECOMMENDATIONS
●Definitions and epidemiology – Mastocytosis is a group of disorders caused by excessive mast cell proliferation and accumulation in tissues. Cutaneous mastocytosis (CM) describes disease limited to the skin. Systemic mastocytosis (SM) involves extracutaneous organ infiltration, with or without skin involvement. In children, cutaneous forms of disease account for approximately 90 percent of cases. Most affected children develop skin findings in the first year of life, although lesions can be present at birth. SM is uncommon in children, and aggressive forms of SM are rare. (See 'Epidemiology' above.)
●Natural history – Mastocytosis in children is confined to the skin in most cases, and although symptoms can be challenging to manage and occasionally associated with significant morbidity, the majority of children have a benign course and experience spontaneous improvement or resolution around the time of puberty. In contrast, adults more often have systemic disease that persists throughout life. (See 'Natural history' above.)
●Clinical manifestations – CM and SM have characteristic presentations in infants and children:
•The most frequent presentation of CM in children is the presence of characteristic accumulations of mast cells in the skin on the trunk, extremities, scalp, or neck. Most children have lesions that vary in size and shape (polymorphic) and are called maculopapular cutaneous mastocytosis, or urticaria pigmentosa (MPCM/UP). Polymorphic MPCM/UP is shown in images A to G (picture 1). Two other variants of CM include mastocytomas (picture 2A), and diffuse cutaneous mastocytosis (DCM) (picture 6A). Many children with skin lesions have minimal or no systemic symptoms, while others experience episodes of pruritus, flushing, nausea/vomiting, or diarrhea. Infants may have episodic blistering (picture 7B). (See 'Usual presentations' above and 'Signs and symptoms' above.)
•An infant or child with SM usually presents with numerous MPCM/UP lesions that are uniform in size and shape (monomorphic) and resemble the lesions seen in adult-onset mastocytosis. Monomorphic MPCM/UP is shown in images H and I (picture 1). Skin findings are often accompanied by episodes of flushing, nausea/vomiting, and diarrhea. Aggressive forms of SM are rare and present with hepato- or splenomegaly or lymphadenopathy, similar to other hematologic malignancies. (See 'Usual presentations' above and 'Signs and symptoms of systemic disease' above.)
Note that children with either CM or SM can have episodes of systemic symptoms (eg, pruritus, flushing, abdominal pain, diarrhea) resulting from the release of mediators from mast cells, so the presence of systemic symptoms does not distinguish between cutaneous and systemic disease (table 1). (See 'Clinical manifestations' above.)
●Physical examination – The evaluation of a child with suspected mastocytosis begins with a skin examination for characteristic lesions. Darier's sign is the development of localized urticaria and erythema (within about five minutes) following rubbing, scratching, or stroking skin or skin lesions that are heavily infiltrated with mast cells . Note that although Darier's sign can be seen in MPCM/UP, DCM, and mastocytomas, mastocytomas and DCM should not be purposefully rubbed, as this can precipitate severe symptoms. All patients should also be assessed for lymphadenopathy and hepatosplenomegaly, which indicate the possible presence of systemic disease. (See 'History and physical examination' above.)
●Initial laboratory studies – A complete blood count with differential, liver function tests, and a baseline serum tryptase should be obtained. Patients with persistent and unexplained abnormalities in any of these initial tests should be evaluated further for systemic forms of mastocytosis. If there is any doubt about whether skin lesions are consistent with CM, a punch biopsy should be obtained and analyzed with specific histopathologic stains. (See 'Initial laboratory studies' above and 'Skin biopsy (not always needed)' above.)
●Referral – Generalists should perform a history and physical examination, obtain the basic laboratories mentioned above if possible, and obtain a biopsy of suggestive skin lesions if needed. Further evaluation usually requires referral to either an allergy/immunology or hematology specialist with experience in mastocytosis. (See 'When to refer' above.)
●Further evaluation for systemic disease – The small minority of children with hepatosplenomegaly or lymphadenopathy on physical examination or abnormalities in initial laboratories (eg, unexplained cytopenias or liver function abnormalities, persistently elevated tryptase >20 ng/mL) should be evaluated further for systemic disease. This evaluation consists of imaging studies that may include an abdominal ultrasound or computed tomography (for hepatosplenomegaly) and a bone marrow biopsy (algorithm 1). In older children and adolescents, an additional indication for bone marrow biopsy is the failure of skin lesions to improve or regress after puberty or baseline serum tryptase levels that remain above the normal range (usually >20 ng/mL) after puberty. (See 'Bone marrow examination' above and 'Imaging and additional evaluation' above.)
•The diagnosis of CM is confirmed when the morphology of the skin lesions and the skin biopsy findings (if obtained) are consistent with CM and if the patient has no unexplained laboratory abnormalities or physical findings of systemic disease (table 4). (See 'Cutaneous mastocytosis' above.)
•The diagnosis of SM requires either the presence of the major criterion and one of the minor criteria or three of the minor criteria (in the absence of the major criterion) (table 4). (See 'Systemic mastocytosis' above.)
●Differential diagnosis – The differential diagnosis of CM or SM includes hereditary alpha tryptasemia (HaT), idiopathic anaphylaxis, and disorders with skin findings that can be mistaken for CM. (See 'Differential diagnosis' above.)
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