Clinical aspects of paediatric mastocytosis: a review of 101 cases

Abstract

Background  Cutaneous mastocytosis (CM) is a typical presentation of mastocytosis in children. However, systemic mastocytosis may also occur in children.

Objective  We tried to characterize the clinical features of childhood-onset mastocytosis and estimate the value of the SCORMA (SCORing Mastocytosis) Index and serum tryptase levels as disease severity parameters.

Methods  In a survey of 101 children mastocytosis was diagnosed and classified according to World Health Organization criteria. In all the cases serum tryptase levels and the SCORMA Index were done to assess the extent and intensity of the disease.

Results  Cutaneous mastocytosis was diagnosed in 100 children; 84% of them presented maculopapular CM, 10% mastocytoma and 6% diffuse cutaneous mastocytosis. Moreover, systemic mastocytosis with bone marrow infiltration and associated with maculopapular CM was found in one case. There was a positive correlation of serum tryptase level to the SCORMA Index. Both the mean tryptase level and the mean SCORMA Index were elevated in diffuse cutaneous mastocytosis children when compared with other forms CM. A significantly higher mean tryptase level was found in children with flushing, hypotension, diarrhoea, extensive bullous lesions and osteoporosis or osteopenia.

Conclusion  Mastocytosis in children usually has a benign course. Nevertheless, severe mediator-related symptoms and systemic involvement may appear. Therefore, a multidisciplinary approach involving careful monitoring of the serum tryptase level, SCORMA Index and the organ function is recommended. Both tryptase levels and the SCORMA Index are of a great value as disease severity parameters and they should be assessed simultaneously in all mastocytosis patients.

Introduction

Mastocytosis is a rare disease characterized by a pathological increase and activation of mast cells in various tissues, particularly in the skin and internal organs such as the bone marrow, liver, spleen and the lymph nodes.^1–3 This explains the heterogeneity of clinical manifestations of mastocytosis ranging from a cutaneous disease to systemic forms with organ dysfunction.^4–6

The typical presentation of the condition in children is cutaneous mastocytosis (CM), in which mast cell infiltration is limited to the skin.^7,8 CM is often associated with systemic symptoms due to the release of mast cell mediators. Flushing, itching, blistering, diarrhoea, abdominal pain, vomiting, hypotension, headache and bone pain are the most frequently reported symptoms. These non-specific symptoms can be mimicked by other diseases.^3,6,9 Therefore, mastocytosis should be diagnosed according to the World Health Organization (WHO) criteria, including histological, immunohistochemical and molecular examinations.^1–4 The major systemic mastocytosis (SM) criterion is histological demonstration of compact mast cells infiltrates in the extra cutaneous tissue. Usually associated with an activating point mutation of the KIT gene (KIT D816V), SM is a very rare condition in children.^1–3,7

The WHO classification distinguishes three major clinical manifestations of CM: maculopapular type – MPCM, diffuse cutaneous mastocytosis – DCM and solitary mastocytoma of the skin.^1,10,11 Traditionally, MPCM has been named urticaria pigmentosa (UP) and the nodular lesions have been defined as multiple mastocytoma. Following recent suggestions concerning CM classification, we qualified small lesions type – UP and plaque type as subsets of MPCM.^1,10–13 The term mastocytoma was used only for the solitary skin lesion.^1,9 Mechanical irritation of skin lesions leads to a release of mast cell mediators and thus to reddening and urticarial swelling. This reaction is known as the Darier’s sign and is typical for all forms of CM.^2,7,10 For the assessment of the extent and activity of skin lesions, a method for scoring of CM (SCORMA Index) was designed and published.^12,13 The SCORMA Index is a clinical scoring system based on a semi-quantitative analysis of the extent (A), the intensity (B) and subjective complains (C). The SCORMA Index formula is A/5 + 5B + 2C/5, and it ranges from 5.2 to 100. This method provides a standardized and more accurate evaluation of the CM severity.^9,13

The published data show that about two-thirds of the patients suffering from mastocytosis are children.^3,7 The course of paediatric mastocytosis is usually benign and transient. However, systemic involvement and a fatal outcome have been reported in some paediatric cases, particularly in DCM.^14–16 Therefore, in DCM children with congenital and prominent bullae, a more guarded prognosis should be given.^14–17

The aim of our study was to characterize the clinical features of childhood-onset mastocytosis and estimate the value of the SCORMA Index and serum tryptase levels as disease severity parameters.

Materials and methods

A study was performed at the Gdansk Mastocytosis Center, which is a referral centre for Polish mastocytosis patients. A group of 101 children aged from 1 month to 16 years with various clinical forms of mastocytosis were examined between 2002 and 2009. All mastocytosis patients presenting within the study period have been included. The study group embraced 55 male patients and 46 female patients. The study was approved by the local ethics committee. The diagnosis of mastocytosis and assignment to the disease category was made according to the WHO criteria and classification. The diagnosis was based on clinical examination, including Darier’s sign, histopathological examination of the skin (both Giemsa staining and anti-c-kit CD117 staining were used), serum tryptase level, peripheral blood analysis, serum levels of transaminases, alkaline phosphatase and abdomen ultrasound. Skin biopsy was done in 78% of children. It was omitted only in cases with clinically typical manifestations or when biopsy was refused by the parents of the child. Serum tryptase levels, haematology, biochemistry abdomen ultrasound and SCORMA Index calculation were done in all cases. Bone marrow biopsy, flow cytometric patterns and genetic examination of KIT mutation at codon 816 were performed only in three cases, when systemic involvement was highly suspected. The organomegaly, clinically significant abnormalities in blood count and total tryptase levels higher than 100 ng/mL and/or rising, were the main indications to perform the bone marrow histological and molecular examinations.^1,9 Densitometry was done only in children with localized bone pain and/or tryptase levels higher than 20 ng/mL. Total serum tryptase levels were determined by a commercial fluorescent enzyme immunoassay (UniCAP assay and UniCAP 100 instrument; Phadia, Uppsala, Sweden).

All medical records were analysed retrospectively. We designed a standardized form on which the most important items were recorded, including: clinical form of CM, SCORMA Index, mast cell-related symptoms, Darier’s sign, provoking and aggravating factors, anaphylactic reactions, serum tryptase level and organ function tests. The results were expressed as the percentage of the patients, while the differences concerning the percentage values between groups were measured by chi-squared test. The data on continuous variables (tryptase level) were presented as means and standard deviations. The differences in tryptase levels and the SCORMA Index between groups were analysed using the Mann–Whitney U-test. Correlation between the SCORMA Index and tryptase levels was calculated with Pearson’s correlation test. A value of P < 0.05 was considered significant. statistica 8.0 PL (StatSoft, Tulsa, OK, USA) software was used.

Results

Mastocytosis was diagnosed in a group of 101 children containing 100 cases of CM and one case of SM associated with MPCM. Most skin lesions appeared during the first year of life (94%). CM was congenital in 31% of children (DCM – 2 cases, MPCM – 20 cases, mastocytoma – 9 cases). The onset of the disease occurred before the age of 6 months in 73% of children (DCM – 4 cases, MPCM – 20 cases, mastocytoma – 9 cases). Ninety-seven per cent of CM patients presented manifestations of the disease by the age of 2 years. As far as SM case is concerned, first skin symptoms appeared in a girl in her sixth year of life and progressed into a systemic form when she was eight.

The mean age of children in our series was 4 years; the range was 1 month–16 years. Only six children reached puberty (over 14 years) during the study period. Complete remission by puberty was observed in two of them, whereas a partial remission was found in 32% of CM children.

Maculopapular cutaneous mastocytosis appeared to be the most common clinical presentation of CM (84% of cases) to be followed by mastocytoma (10% of cases) and DCM (6% of cases). Plaque subset of MPCM was more frequent than MPCM with small lesions (UP) as it was shown in Table 1. Statistical analysis of skin symptoms revealed that the presence of bullous lesions was significantly more frequent in DCM when compared with MPCM (P = 0.002) and mastocytoma (P = 0.0028). All patients were positive to Darier’s sign.

Table 1.   Clinical presentation of cutaneous mastocytosis (CM) in children

Skin lesions	Total (n = 100)		MPCM (n = 84)		DCM (n = 6)		Mastocytoma (n = 10)
	%	(*)	%	(*)	%	(*)	%	(*)
Each form of CM can have more than one lesion. n– total cases; (*) – positive cases. MPCM, maculopapular CM; DCM, diffuse CM; ESI, entire skin infiltration.
Maculae and papules	37	37	44.0	37	0	0	0	0
Plaques	45	45	53.6	45	0	0	0	0
Nodules	2	2	2.4	2	50	3	100	10
ESI	6	6	0	0	100	6	0	0
Bullae	25	25	21.4	18	100	6	10	1
SCORMA Index mean ± SD	42.76 ± 16.1		41.61 ± 12.46		82.57 ± 4.06		28.5 ± 9.23

The mean SCORMA Index was higher in DCM when compared with MPCM (P = 0.00005) and mastocytoma (P = 0.0014). It was also higher in MPCM when compared with mastocytoma (P = 0.00023). There were no correlations of SCORMA Index with internal organs abnormalities, anaphylaxis and mediator-related symptoms.

Hepatomegaly, lymphadenopathy, osteoporosis (3% of cases) and osteopenia (3% of cases) were a rare finding in childhood CM as presented in Table 2. Splenomegaly was not present. No statistically significant differences were noted among the various types of CM in regard to organomegaly and osteoporosis/osteopenia. Results of further diagnostic procedures excluded SM in children with these symptoms.

Table 2.   Clinical features of CM in children

Symptoms	Total (n = 100)		MPCM (n = 84)		DCM (n = 6)		Mastocytoma (n = 10)
	%	(*)	%	(*)	%	(*)	%	(*)
n– total cases; (*) – positive cases. CM, cutaneous mastocytosis; MPCM, maculopapular CM; DCM, diffuse CM.
Hepatomegaly	10	10	9.5	8	33.6	2	0	0
Lymphadenopathy	5	5	4.8	4	16.7	1	0	0
Osteoporosis/osteopenia	6	6	4.8	4	33.3	2	0	0
Tryptase (ng/mL) mean ± SD	10.17 ± 20.08		7.94 ± 15.62		49.70 ± 42.64		4.63 ± 3.39

The frequency of mast cell mediator-related symptoms in children with CM was demonstrated in Table 3. Itching (P = 0.006), flushing (P = 0.0006), headache (P = 0,015) and anaphylactic shock (P = 0.0004) were significantly more frequent in DCM when compared with MPCM. Anaphylactic shock occurred in six children with CM; in one of the DCM patients three incidences were recorded. Anaphylactic shocks were due to: ketamin (six cases), clindamycin (one case) and magnetic resonance imaging-contrast media (one case). Flushing was more common in DCM than in mastocytoma (P = 0.009). There were no statistically significant differences between MPCM and mastocytoma as far as the frequency of mast cell mediator-inducted symptoms is concerned.

Table 3.   Mast cell mediator-related symptoms in paediatric CM

Symptoms	Total (n = 100)		MPCM (n = 84)		DCM (n = 6)		Mastocytoma (n = 10)
	%	(*)	%	(*)	%	(*)	%	(*)
n– total cases, (*) – positive cases. CM, cutaneous mastocytosis; MPCM, maculopapular CM; DCM, diffuse CM.
Flushing	29	29	25.0	21	100	6	20	2
Itching	68	68	65.5	55	100	6	70	7
Diarrhoea	22	22	22.6	19	50	3	0	0
Headache	18	18	16.7	14	66.7	4	0	0
Hypotension	16	16	15.5	13	50	3	0	0
Anaphylactic shock	6	6	3.6	3	50	3	0	0

The mean tryptase level was elevated in DCM children when compared with MPCM (P = 0.0002) and mastocytoma (P = 0.0014) as demonstrated in Table 2. A significantly higher mean tryptase level was found in children with flushing (P =  0.000002), hypotension (P =  0.00016), diarrhoea (P =  0.0078), extensive bullous lesions (P =  0.0000001) and osteoporosis/osteopenia (P =  0.00025) when compared with the mean tryptase level in children without these symptoms. The relation between tryptase levels and frequency of anaphylaxis was not revealed in our series. There was a positive correlation of serum tryptase levels to the SCORMA Index (r = 0.52; P < 0.05) what is presented in Fig. 1.

Figure 1.  The relationship between the SCORMA Index and serum tryptase levels.

Systemic mastocytosis was diagnosed in one 8-year-old girl with MPCM (small lesions type) limited to the chest, forehead and scalp. The SCORMA Index was 42 and serum tryptase was 65 ng/mL at first visit in the sixth year of life. In a 2-year period, the serum tryptase level increased to 200 ng/mL. Frequent episodes of flushing, anaphylaxis (unknown provoking factors), osteoporosis and eosinophilia (> 1500 total eosinophils) were found. Bone marrow biopsy revealed mast cells infiltration. Mast cells aggregates were found in bone marrow particles, in some constituting over 50% of cells. The KIT D816V mutation was negative. Fusion gene FIP1L1-PDGFR-α was not present and chronic eosinophilic leukaemia was excluded. Finally, SM with hypereosinophilic syndrome was diagnosed.

Discussion

Mastocytosis is an unusual disease in infants and children. In Spain, a prevalence of 5.4 cases per 1000 paediatric dermatology patients was found, whereas in Mexico the condition was seen in 1 : 500 first-time paediatric dermatology patients.^18,19 We managed to analyse a large group of 101 children with mastocytosis in a period of 7 years because we are a referral centre. Epidemiological data show that in approximately 50% of childhood mastocytosis cases first symptoms of the disease are noted by the age of 2 years and in about 25% skin lesions are congenital.^5,7,8 In our series, as many as 97% of CM children presented skin lesions within the first 2 years of life, although the frequency of congenital cases was similar to that reported by other authors.

The age of mastocytosis onset is very important because it has prognostic implications. Skin lesions demonstrate a tendency to partial or complete remission by puberty in a considerable number of children.^7,8,10 In our series, a low percentage of children underwent a spontaneous complete or partial resolution of skin symptoms, probably due to the fact that the majority of them were in prepubertal period. We will be able to estimate the real tendency towards CM remission in 10 years, because the mean age of our children is actually 4 years. Apart from one child with a bone marrow involvement, systemic alterations were rare, benign and transient in our study group similarly as it was reported in other paediatric studies.^17–19

The frequency of CM clinical forms in children is reported differently in the literature, which can be partially due to various classifications of CM.^{7,8,10,18–20} UP and mastocytoma are reported to be the most common clinical types in children (47–75% and 17–51%, respectively) in contrast to DCM, which is a rare finding (1–8%).^10,18–20 In comparison with the data in the literature, we found a higher frequency of MPCM and DCM and a lower frequency of mastocytoma. In our series, MPCM, particularly its plaque form was the most frequently diagnosed clinical presentation. Plaque form consists of slightly tan-to-orange, flat, slightly elevated plaques up to several centimetres in diameter and has tendency for spontaneous involution before puberty, whereas MPCM with small, brown maculae and papules (UP) tends to persist into adulthood.^10,11,21 DCM, the most severe form of CM, which presents as erythroderma involving almost the entire skin. This form usually occurs at birth or in early infancy.^10,11,22 We observed widespread, haemorrhagic blisters which were the first clinical presentation of DCM or occurred in the first year of life. It is noteworthy that bullous lesions do not represent a specific subset of the CM phenotype.^7,10 Bullae appeared in all forms of CM in our study group, particularly in infants. Due to a widespread and heavy mast cell load in the entire skin, children with DCM may have flushing, itching, hypotension, anaphylactic shock, diarrhoea and gastrointestinal bleeding.^10,11 Apart from bleeding, all these symptoms were found in our DCM cases and the majority of them were more intensive and more frequent than in other forms of CM. Systemic involvement and a fatal outcome have been reported in some DCM cases.^14–16 Nevertheless, in our DCM children systemic disease was excluded and some improvement of skin condition with age was observed.

Despite the morphology of skin lesions, CM cases differ in the extent and the activity of cutaneous symptoms. The SCORMA Index provides the standardized information on the severity of CM and imposes no burden on the patient, which is particularly important in children.^9,12,13 The SCORMA Index is comparable with that used for atopic dermatitis (SCORAD) and psoriasis (PASI) and its clinical applications have been published.^12,13 Statistical analysis of our data revealed that the mean SCORMA Index was higher in DCM when compared with MPCM and mastocytoma. We did not find positive correlation of SCORMA Index and mediator-related symptoms and internal organ abnormalities. However, it was a useful tool to evaluate and follow-up CM patients.

Serum tryptase levels closely correlate with the course of mastocytosis and are therefore used preferentially for the diagnosis and the following-up of mastocytosis patients.^23–27 The tryptase level higher than 20 ng/mL is one of the four minor criteria of SM.^1–3 Interestingly, in our series, the mean tryptase level was significantly higher in DCM patients (49.7 ng/mL; range of 18–106 ng/mL), than in those with other forms of CM, although the condition was limited to the skin. Tryptase levels were decreasing in all these cases during follow-up visits and no clinically significant abnormalities were found by organ function tests of these children. Our observations are consistent with findings presented by Heide et al. in the study of eight DCM cases.²⁸ In our study group, a significantly higher mean tryptase level was seen in children with flushing, hypotension, diarrhoea, extensive bullous lesions and osteoporosis/osteopenia than in children without these symptoms. These findings indicate that tryptase levels may correlate with mast cell numbers in the skin, osteoporosis and osteopenia, the extent of cutaneous lesions and the presence of mast cell mediator-related symptoms in children, as it has been reported by Sperr and Brockow.^27,29 There was no positive correlation of tryptase levels and anaphylaxis, what may suggest that the risk of this reaction is difficult to predict in CM children. On the other hand anaphylactic shock appeared in 50% of DCM and only in 3.6% of MPCM. This observation emphasizes that DCM is connected with increased risk of anaphylaxis.

A significant correlation of the SCORMA Index to serum tryptase levels was found in our series. We compared these parameters because the serum total tryptase level is widely employed as a surrogate marker of mastocytosis.^23–27 Interestingly, the relationship between serum tryptase levels and the SCORMA Index was also found by Heide et al. in a study of 64 children and adults with different variants of mastocytosis.¹³ The presented data may suggest that the combination of SCORMA Index and tryptase levels may be able to identify children at risk for SM in a better way than tryptase alone. Elevated serum tryptase levels correlated with high SCORMA Index, particularly in DCM cases, in which SM was excluded. Serum tryptase levels are considered to reflect the total body mast cell burden, so the extensive skin involvement may influence on serum tryptase levels. It is noteworthy, that low SCORMA Index and rising serum tryptase levels with time were found in SM child. Therefore, we consider the simultaneous assessment of both these parameters essential in all cases of paediatric mastocytosis. Moreover, our findings indicate that isolated elevation of serum tryptase level, without assessment of the skin lesions, is not a sufficient indication for bone marrow biopsy.

Systemic mastocytosis is a very rare finding in children and is usually presented as such in case reports.^7,14–17 In a large study of 173 children with mastocytosis, Hannaford and Rogers found only two cases of systemic involvement in children with DCM.²⁰ A highly elevated and rising tryptase level was the first symptom of systemic involvement and a marker of progression in the only SM patient in our series. This observation emphasizes the importance of tryptase level determination in monitoring mastocytosis children. The 8-year-old girl fulfilled diagnostic criteria including multifocal and dense infiltrates of mast cells in bone marrow (major) and serum tryptase levels higher than 20 ng/mL (minor), which are demanded to diagnose SM.^1–3 On the basis of clinical symptoms, eosinophilia and results of genetic examinations (lack of an activating point mutation of the KIT gene and fusion gene FIP1L1-PDGFR-α) SM with hypereosinophilic syndrome was diagnosed.

Despite the mild course of the disease in the majority of children, all variants of mastocytosis may occur. Therefore, a multidisciplinary approach is recommended, particularly when systemic involvement is suspected. In paediatric patients, a bone marrow biopsy is not recommended, unless persistently high (>100 ng/mL) or rising serum tryptase levels and other signs of SM are encountered.^2,7,9,28 Apart from diagnostic procedures, the follow-up including the physical examination, monitoring of mast cell mediator-related symptoms, organ function and the determination of serum tryptase level should be conducted at least once a year.⁹ The results of our study and the authors’ personal experience at the clinical care of mastocytosis patients confirm the benefit of using serum tryptase levels and the SCORMA. In conclusion, both these parameters, particularly assessed simultaneously, facilitate identification of patients with more severe mastocytosis who may require a more careful evaluation and more intensive management.