Lack of c-kit mutation in familial urticaria pigmentosa

Somatic mutations within c-kit have been reported in individuals with mastocytoses, including urticaria pigmentosa (UP). We have identified three siblings with UP. We aimed to determine whether the c-kit proto-oncogene was playing a part in the aetiology of UP in these three siblings. Using seven microsatellite repeat markers spanning an 8-cM interval encompassing the c-kit gene we followed the transmission of the c-kit gene in this family. Furthermore, single-strand conformation polymorphism analysis was used to scan exon 17 of the c-kit gene for mutations in genomic DNA of all family members and somatic DNA extracted from skin of the eldest affected sibling, the proband. No mutations were found in exon 17 in either genomic DNA of all family members or somatic DNA of the proband. Patients with UP have been shown to possess somatic mutations of the c-kit gene. However, this locus has been excluded as playing a part in the three siblings examined here in whom a second gene locus must be determining their UP. Therefore, this study emphasizes genetic heterogeneity in UP. Future study to identify primary molecular determinants of UP should include affected sib-pair studies.     

Urticaria pigmentosa in two pairs of monozygotic twins.

Urticaria pigmentosa occurred in both members of two pairs of twins. Identical blood typings, HLA histocompatibility and appearance strongly indicate that each pair of twins is monozygotic. Except for cutaneous lesions, there were no clinical or roentgenologic evidences of systemic mastocytosis. But latent diabetes mellitus was found in one member. Literature reporting monozygotic twins with urticaria pigmentosa will be discussed in this paper.     

Evidence for altered mast cell proliferation and apoptosis in cutaneous mastocytosis

BACKGROUND: Mastocytosis presents as a focal or generalized increase of mast cells, particularly in the skin, but also in other organs. Activating mutations of KIT (formerly c-kit), the receptor of the mast cell growth factor stem cell factor (SCF), appear to play a key role in the pathogenesis of sporadic adult onset mastocytosis. However, these mutations are not present in childhood-onset and familial mastocytosis and also fail to explain the heterogeneity of adult-onset disease. Other factors such as prolonged survival of mast cells may therefore participate in causing and modulating the pathological increase of mast cells in mastocytosis. OBJECTIVES: To examine the expression of proliferation and apoptosis markers in the mast cells of cutaneous mastocytosis lesions in order to gain further insight into the pathogenesis of mastocytosis. METHODS: Lesional cutaneous biopsies from eight infants with solitary mastocytomas, five children with multiple mastocytomas, 11 children with generalized urticaria pigmentosa, 12 adults with urticaria pigmentosa, and skin from seven normal controls were used in this study. Serial sections were stained with toluidine blue to quantify mast cell numbers and with antibodies against the proliferation marker Ki67 protein, the tumour suppressor protein p53, and the inhibitor of cyclins and cyclin-dependent kinases p21WAF1/CIP1, using the alkaline phosphatase antialkaline phosphatase technique. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labelling (TUNEL) method was used to assess apoptosis. RESULTS: Cutaneous mast cell counts were significantly increased in all patient sections, particularly in childhood lesions, and similarly, a small but significant increase of proliferation was found in the lesional mast cells of all patients. Enhanced mast cell numbers and proliferation was associated with a significant decrease of TUNEL staining, particularly in mastocytomas. p53 expression was highly variable, with an overall significant increase in all patient skin mast cells, whereas p21 expression was barely observed at all. CONCLUSIONS: These findings further support the concept that an imbalance of mast cell proliferation and apoptosis is prevalent in mastocytosis lesions that may account in part for the increased focal mast cell accumulation in this condition.     

183例儿童皮肤型肥大细胞增生症临床及预后分析

目的 探讨儿童皮肤型肥大细胞增生症的临床特征及预后。 方法 回顾分析183例儿童皮肤型肥大细胞增生症患者的临床资料,并随访部分患者。 结果 183例患者中,色素性荨麻疹136例（74.3%）,肥大细胞瘤43例（23.5%）,弥漫性肥大细胞增生症4例（2.2%）;生后2岁内发病者179例（97.8%）。43例肥大细胞瘤患者中出生即发病者21例（48.8%）,出生后至6个月发病者17例（39.5%）,136例色素性荨麻疹患者中出生即发病者35例（25.7%）,出生至6个月发病者78例（57.3%）。伴随症状记录详细的33例患者中,10例出现伴随症状,其中9例为潮红发作。对45例患者随访3 ~ 6年（平均4年）,色素性荨麻疹患者1例于11岁时皮损完全消退,18例皮损部分消退;肥大细胞瘤患者1例皮损于8岁时完全消退,7例行皮肤活检后1年内皮损消退。口服抗组胺药可控制患者潮红、风团及水疱等症状;口服糖皮质激素可有效控制弥漫性肥大细胞增生症患儿反复发生的泛发水疱、大疱。 结论 儿童皮肤型肥大细胞增生症以色素性荨麻疹最常见,其次为肥大细胞瘤。肥大细胞瘤多于出生即发病,而色素性荨麻疹以出生后至6个月发病多见。口服抗组胺药可控制介质释放相关症状。严重的弥漫性肥大细胞增生症患者可口服糖皮质激素控制症状。     

Cutaneous mastocytosis in children: a clinical analysis of 71 cases

OBJECTIVE: To characterize the clinical features, response to therapy, evolution and prognosis of cutaneous mastocytosis in children. BACKGROUND: Mastocytosis in children, instead of being induced by a potentially oncogenic c-kit mutation, is probably a clonal disease with benign prognosis. METHODS: The clinicopathological features, evolution and response to treatment were analysed in 71 children with mastocytosis. RESULTS: There were 53 (75%) cases of urticaria pigmentosa, 12 (17%) cases of mastocytoma, and six (8%) cases of diffuse cutaneous mastocytosis. In 92% of cases disease onset was in the first year of life. There was a male predominance 1.8 : 1. Treatment did not modify the disease evolution. Eighty per cent of patients improved or had spontaneous resolution of the disease. CONCLUSION: The most frequent clinical form of mastocytosis was urticaria pigmentosa followed by mastocytoma and diffuse cutaneous mastocytosis. Darier's sign was present in 94% of cases. A negative Darier's sign does not rule out mastocytosis. In contrast to adults, mastocytosis in children usually has a benign course making sophisticated or invasive diagnostic tests unnecessary. A classification of paediatric cutaneous mastocytosis is proposed.     

Cutaneous mastocytosis in twins: multiple mastocytomas and urticaria pigmentosa in two pairs of monozygotic twins

We report two sets of monozygotic twins with cutaneous mastocytosis: one set with urticaria pigmentosa and the other set with multiple mastocytomas. This is the first report of multiple mastocytomas in twins to our knowledge.     

Expression of stem cell factor in cutaneous mastocytosis

Stem cell factor has recently been identified as a potent growth factor for bone marrow stem cells, melanocytes and mast cells. In order to evaluate its possible role in human mastocytosis, skin lesions from 13 patients with urticaria pigmentosa and five patients with mastocytomas, and normal skin specimens from five healthy donors were studied by immunohistochemistry, using polyclonal and monoclonal (hkl-12) antibodies against stem cell factor, and a monoclonal antibody (YB5.B8) against its receptor, the c-kit proto-oncogene product. Stem cell factor expression was noted in all sections studied, with an equal distribution pattern for both antibodies, but a weaker intensity with the hkl-12 reagent. Cytoplasmic staining was noted in keratinocytes, Langerhans cells, sweat gland ductal lining cells, mast cells, endothelial cells and spindle-shaped dermal stromal cells. An intense, diffusely granular reaction pattern was noted in all cells, except for a sparse, coarsely granular pattern in mast cells and stromal cells. In urticaria pigmentosa, staining was weaker in keratinocytes, but more prominent in Langerhans cells. In all sections, toluidine blue-positive mast cells and TA 99-positive basal epidermal melanocytes were the only cells to react with the c-kit antibody. Mastocytomas and urticaria pigmentosa lesions thus exhibit different patterns of stem cell factor expression. However, a possible pathogenetic role of this factor in mastocytosis remains to be determined.     

Immunohistochemical demonstration of migration inhibitory factor in different types of urticaria

Because urticarial lesions can persist for extended periods of time, we have investigated the histochemical expression of an antibody against the cytokine macrophage inhibitory factor in 23 patients with different types of urticaria. Positive staining of upper and middermal dendritic cells was noted in sections from all three biopsy specimens of acute urticaria, eight of chronic urticaria, and all six of urticaria pigmentosa lesions. In all but one biopsy specimen, endothelial cells reacted as well. In three sections (two chronic urticaria, one urticaria pigmentosa), luminal lining cells of sweat glands were also noted to stain positively. In contrast, lesional skin from all eight patients with pressure urticaria was negative, as was the clinically normal skin of all patients, with the exception of one patient with urticaria pigmentosa. The data suggest that cytokines may be involved in lesions of acute type immunologic processes and that they need not be expressed in delayed type reactions.     

Urtikaria

Although the etiology of urticaria is mostly unclear, there are a number of recent new insights into the underlying pathomechanisms and causes. Dermal mast cell numbers and endothelial cell adhesion molecule and cytokine expression are also increased in uninvolved skin, while serum P-selectin levels are elevated, suggesting a systemic activation of the cutaneous inflammatory system in urticaria. In all adults, but not children with indolent mastocytosis, we found activating point mutations of c-kit, the mast cell growth factor receptor, in lesional cutaneous mast cells. In acute urticaria, IgE-dependent mechanisms are only rarely involved (0.9%), in contrast to generally held beliefs, whereas acute upper respiratory infections (39.3%) and drug intolerance (9.2%) are more frequent. In chronic urticaria, pseudoallergies to food (73%) and more rarely chronic inflammatory gastrointestinal diseases (11%) play a major role, with avoidance or elimination of the eliciting factors leading to long term remission. On the basis of recent findings, autoantibodies must be viewed mostly as secondary rather than causative in chronic urticaria.     

Urticaria Pigmentosa: A Review of 67 Pediatric Cases

Abstract: Mastocytosis is a disorder of mast cell proliferation that may appear during infancy, childhood, or adulthood. We studied 67 consecutive patients (33 males, 34 females) with urticaria pigmentosa and assessed them fully to determine the presence of systemic involvement. Ages at onset of lesions ranged from birth to 11 years, with most developing in the first year of life. Pruritus was the primary symptom. Hematologic and serum chemistry profile, radiologic skeletal surveys, and bone marrow aspirations were performed. Slight anemia was present in three patients. Radiologic bone lesions were observed in eight. Bone marrow aspirates showed slight changes in six patients, with only an increased number of mast cells in an additional patient. The disease tended to resolve spontaneously. This prospective study emphasizes the benign nature of pediatric urticaria pigmentosa.     

Macrophage subsets in different types of urticaria

Summary Biopsy specimens from lesional and uninvolved skin of nine patients with delayed pressure urticaria, three patients with acute urticaria, six patients with chronic recurrent urticaria, and four patients with urticaria pigmentosa were analyzed by routine histology and by immunochemistry for their reactivity with monoclonal antibodies to three different subsets of macrophages. Skin from 12 healthy volunteers served as control. Uninvolved skin of patients did not differ from that of healthy volunteers. An antibody against activated macrophages (27E10) was reactive to a marked extent with macrophages in wheals of pressure urticaria, more variably in acute and chronic urticaria, and practically not at all in urticaria pigmentosa. Antibodies with specificities for macrophages in healing (RM3/1) and normal (25F9) tissue reacted more markedly in all but pressure urticaria lesions, compared with normal skin. These findings indicate an active involvement of inflammatory macrophages in whealing reactions while these cells play apparently no role in cutaneous mast cell proliferation (urticaria pigmentosa).     

Urticaria pigmentosa associated with Wilms tumor

Urticaria pigmentosa is the most common manifestation of mastocytosis, with the majority of cases undergoing spontaneous resolution, especially in children. Several reports have documented hematologic malignancies developing in patients with urticaria pigmentosa. We present a 4.5-year-old boy with urticaria pigmentosa who developed Wilms tumor. To our knowledge, coexisting urticaria pigmentosa and Wilms tumor have not previously been described.     

No detection of c-kit gene mutations in exons 9, 11, 13 and 17 and low CD117 expression in plaque-stage mycosis fungoides

The growth factor receptor c-kit (CD117) is expressed in immature T-cells and in some advanced forms of mycosis fungoides. c-kit gene mutation results in unrestricted neoplastic proliferation. We aimed to detect by PCR the most frequent exon mutations in seventeen plaque-stage MF patients, in their perilesional skin and in healthy skin donors. We secondarily evaluated CD117 expression by immunohistochemistry in plaque-stage and tumor-stage MF. We detected no mutation in c-kit gene and low CD117 expression was confirmed on atypical cells in one patient. Complete c-kit exon and intron sequences should be assessed and more sensitive sequencing method could be also applied.     

c-kit Mutation in generalized lentigines associated with gastrointestinal stromal tumor

We describe the case of a 59-year-old Japanese woman presenting with generalized lentigines without systemic anomalies. She had a medical history of gastrointestinal stromal tumors (GISTs), in which gain-of-function mutations of the c-kit gene had recently been found. We detected a point mutation at codon 557 in exon 11 of leukocyte DNA from the patient. The stem cell factor-type III receptor tyrosine kinase pathway plays important roles in the regulation of melanocyte proliferation and differentiation. We speculate that the generalized lentigines of the patient may be caused by melanocyte proliferation due to the c-kit gene mutation.     

Cutaneous mastocytosis exacerbated by pinworms in a young boy

Cutaneous mastocytosis in children has an indolent course and undergoes spontaneous regression. Many triggering factors may cause mast cell degranulation and clinical manifestations. Knowledge of these factors is important for patients and their families. We report a case of exacerbation of urticaria pigmentosa due to mast cell degranulation caused by Enterobius vermicularis, which has not been reported before as a triggering factor.     

31例维吾尔族黏膜黑素瘤临床与c-kit基因突变研究

目的 分析维吾尔族黏膜黑素瘤临床特点,检测c-kit基因突变,探讨与黏膜黑素瘤临床特征之间的关系。 方法 收集经病理确诊的31例维吾尔族黏膜黑素瘤患者的临床资料,采用PCR及DNA直接测序法进行c-kit基因突变检测。 结果 维吾尔族黏膜黑素瘤男女性别比为1 ∶ 1.2,平均年龄61.35岁。60 ~ 70岁为高发年龄段,51 ~ 59岁为次高发年龄段。头颈部为最常见的发病部位,其中以鼻腔黏膜居多;其次为泌尿生殖道和直肠黏膜。31例黏膜黑素瘤有4例发生c-kit基因突变（12.9%,4/31）,突变均位于11外显子,以L576P突变为主。4例突变中,3例发生于直肠黏膜,1例发生于尿道黏膜。直肠黏膜与其他黏膜部位c-kit基因突变率分别为3/7、4.17%（1/24）。发生淋巴结转移患者c-kit基因突变率高于无淋巴结转移者（P = 0.043）。c-kit基因突变与性别、年龄无相关性（P > 0.05）。 结论 维吾尔族黏膜黑素瘤好发于老年人,发病部位以头颈部黏膜为主。c-kit基因突变与黏膜黑素瘤发生部位、有无淋巴结转移密切相关。     

Photochemotherapy (PUVA) in the treatment of urticaria pigmentosa

Eight patients received PUVA for mastocytosis. Five women had typical adult-onset urticaria pigmentosa, without evidence of systemic disease. Another woman had suspected hepatic involvement while the remaining female had early-onset familial urticaria pigmentosa with morphologically atypical mast cells. The only male patient had cirrhosis with hepatic deposits of mast cells in addition to polycythaemia rubra vera. In all patients, except the man with systemic disease, there was reduced pruritus and wealing and partial to almost complete fading of the macules. The manifestations of urticaria pigmentosa recurred after treatment was discontinued. In both lesional and uninvolved skin there was no significant change in either the mean mast cell counts or mast cell ultrastructure after an average of twenty-seven PUVA exposures. In addition, PUVA did not cause a significant alteration in the histamine content of the skin. The beneficial effect of PUVA in urticaria pigmentosa therefore does not appear to be directly related to a change in mast cell numbers or morphology, or to the histamine concentration in the skin. Urticaria pigmentosa usually presents as a generalized maculo-papular rash which urticates on rubbing (Darier's sign). Many patients are troubled only by the unsightliness of the rash while some complain of pruritus, wealing or flushing. These symptoms are attributed to the release of histamine by mast cells which characteristically occur in increased numbers in the dermis. Symptomatic treatment is often unrewarding, but favourable results have been claimed for cimetidine with or without Hi blockers (Hirschowitz & Groarke, 1979; O'Laughlin & Bredfeldt, 1980) and for oral disodium cromoglycate (Soter, Austen & Wasserman, 1979; Czarnetski & Behrendt, 1981). In 1978, Christophers and colleagues reported that photochemotherapy (PUVA) produced symptomatic relief in all of ten adult patients with typical urticaria pigmentosa. Similarly encouraging results were subsequently reported from other centres (Ortonne et al., 1980; Allevato, Donatti & Cordero, 1980; Granerus, Roupe & Swanbeck, 1981; Väätäinen, Hannuksela & Karvonen, 1981). In this study we examined the effects of PUVA in eight adult patients with urticaria pigmentosa. Although PUVA produced a moderately good clinical response in seven out of these eight patients (reduced pruritus, reduced wealing and faded macules) quantitative studies failed to reveal a consistent effect of PUVA on either the mast cell population density or the histamine concentration in both lesional and clinically uninvolved skin. The findings arc discussed in relation to existing information concerning the effect of ultraviolet radiation (U VR) on mast cells and other constituents of the skin.     

斑驳病一家系c-kit基因突变检测及共聚焦激光扫描显微镜皮损观察

目的 报告一例斑驳病家系，运用共聚焦激光扫描显微镜对先证者进行实时在体组织学检查和诊断，并检测该家系患者c-kit基因突变位点。方法 应用Vivascope 1500TM皮肤在体共聚焦成像系统对患者皮损进行扫描成像和诊断。采集患者及表型正常者静脉血，提取其外周血白细胞DNA，PCR扩增c-kit基因编码区21对外显子，DNA直接测序，确定点突变的位点。结果 患者白斑处共聚焦激光扫描成像结果显示基底层几乎无黑素细胞分布，白斑与色素斑交杂区扫描显示基底层及真皮乳头周围黑素细胞呈灶性或区域性聚集。家系中患者 c-kit基因均于17号外显子的2362 位碱基发生T > C突变，密码子TGT突变为CGT，导致高度保守区的Cys 788 Arg （C788R）错义突变。表型正常者及100例正常人对照未见此突变。结论 皮肤在体共聚焦激光扫描显微镜具有实时、无创的特点，在斑驳病等色素缺失性疾病中可作为传统组织病理之外可供选择的新型诊断手段。Cys 788 Arg突变可能为此家系斑驳病的主要原因。     

荨麻疹外周血细胞因子表达模式研究进展

荨麻疹的类型多样,发病机制也各不相同.细胞因子在外周血中的水平充分反应疾病的炎症水平及发病机制所牵涉的效应细胞.在急性荨麻疹中,Th2系列因子的高表达证实了急性荨麻疹的过敏性,大量促炎症因子的高表达反映出急性荨麻疹的炎症性.在慢性荨麻疹中,透过外周血细胞因子的表达水平可以发现,不仅Th1/Th2失衡、还有Th17、Tc17和Th9的活化、促炎症因子和趋化因子的广泛激活和非炎症非免疫系统等均参与了慢性荨麻疹的发生发展过程.自体血清皮肤试验不同反应性的慢性荨麻疹的细胞因子表达模式差异也逐渐被证实.除此之外,可诱导性荨麻疹,如寒冷性荨麻疹和延迟压力性荨麻疹等在部分细胞因子表达上也存在差异.