Mastocytosis, Cutaneous

A number sign (#) is used with this entry because of evidence that some cases of cutaneous mastocytosis (MASTC) are caused by heterozygous germline mutation in the KIT gene (164920) on chromosome 4q12. Systemic mastocytosis and some cases of cutaneous mastocytosis are caused by somatic mutation in the KIT gene.

Description

Mastocytosis, or mast cell disease, is a heterogeneous group of clinical disorders characterized by the abnormal accumulation of mast cells in various tissues, especially in the skin and hematopoietic organs. Mastocytosis usually appears in infancy or early adulthood. In most pediatric cases, the disease is limited to the skin, but it can be associated with systemic symptoms due to the release of mediators from mast cells, even when there is no systemic infiltration. It usually has a good prognosis, with substantial improvement or spontaneous resolution before puberty. In rare cases, the disease may remain active through adolescence as a systemic adult mastocytosis. Cutaneous mastocytosis is characterized by macules, papules, nodules, or diffuse infiltration of the skin, often associated with localized hyperpigmentation. Gentle rubbing of the lesions induces histamine release from mechanically activated mast cells, causing local wheals, erythema, and often pruritus, a phenomenon termed the 'Darier sign.' In contrast to childhood-onset mastocytosis, adult-onset mastocytosis often persists for the lifetime of the patient and is also more likely to be a severe and systemic disease involving numerous organs. In some cases, it is associated with a clonal hematologic non-mast-cell lineage disease, such as a myelodysplastic or myeloproliferative disorder. Adult-onset mastocytosis can also lead to the rare mast cell leukemia, which carries a high risk of mortality (summary by Bodemer et al., 2010 and Kambe et al., 2010).

Clinical Features

Burgoon et al. (1968) observed cutaneous mastocytosis in association with diffuse infiltration of mast cells in other organs in a father and daughter and an unrelated girl.

Bazex et al. (1971) reviewed 35 families reported between 1891 and 1971. Fowler et al. (1986) added 14 further families.

Oku et al. (1990) described bullous mastocytosis in a mother and 2 daughters and a son. The appearance of the mast cells differed in the adult from that in the children, and improvement in the clinical features occurred spontaneously over time.

Clark et al. (1990) described urticaria pigmentosa in a sister and brother and in their maternal grandfather who had a daughter (aunt of the sibs) who had histologically diagnosed urticaria pigmentosa. An unusual feature was the marked diversity of the skin disease: classic lesions, telangiectasia macularis eruptiva perstans, and clinically normal skin with positive dermal infiltrates of excess mast cells.

Anstey et al. (1991) described a woman and her daughter who both developed diffuse cutaneous mastocytosis in early infancy. Mast-cell granules in both cases were found on electron microscopy to have an abnormal ultrastructure. Similar giant granules had been noted in familial cases by James and Eady (1981).

Longley et al. (1996) studied a patient who had aggressive systemic mastocytosis with massive splenic involvement who first noted the pigmented macules of urticaria pigmentosa on his thighs at age 40. The lesions were initially asymptomatic, but over the next 2 years the lesions progressively involved his trunk and upper limbs and the diagnosis of cutaneous mastocytosis was made. He required antihistamines for pruritus, and at age 42, splenomegaly was first noted. The following year mild anemia developed, paratrabecular mast cell infiltrates with fibrosis and eosinophils were identified in his bone marrow, and he required a gluten-free diet and type I and II histamine receptor antagonists to control cramps and diarrhea. Because of hematologic hypersplenism with the progressively enlarging spleen and his need to travel to remote areas, he successfully underwent elective splenectomy at age 47 with concurrent biopsies of liver, mesenteric lymph nodes, and skin, all of which showed infiltration by mast cells.

Pignon et al. (1997) reported a 44-year-old man who presented with a 2-month history of asthenia, gastric pain, and flushes. He was found to have moderate splenomegaly. Although there were no circulating mast cells, bone marrow aspirates showed 40% abnormal mast cells, often arranged in clusters. Despite chemotherapy followed by a familial HLA-matched bone marrow transplant that appeared to achieve engraftment, the patient relapsed 4 months later and died from massive multivisceral involvement of the mastocytosis.

Tang et al. (2004) studied a family in which 5 individuals over 3 generations had diffuse cutaneous mastocytosis. The proband developed generalized pruritus and blistering on the scalp at 4 months of age, and at 9 months exhibited dermatographism on his trunk. He had intermittent groups of blisters on the scalp and posterior trunk, and a single yellow-brown papule on his arm, similar in appearance to a solitary mastocytoma, that remained unchanged over 2 years. He had no cutaneous pigmentary abnormalities or organomegaly. Biopsy of both clinically normal and involved skin revealed a dense infiltrate of mature mast cells in the upper dermis. His father also had developed blisters on his trunk and scalp at age 4 months, which resolved by 2 years of age. His skin remained itchy, dry, and diffusely thickened with ill-defined flexural pigmentation. At age 25, he had appendicitis, at which time he was found to have mast cell infiltration of the appendix and bone marrow. Since that time he had no further hematologic or gastrointestinal symptoms. The proband's paternal uncle, paternal grandfather, and a paternal great aunt were also diagnosed with cutaneous mastocytosis in infancy, presenting with blistering of the trunk and scalp; they had diffuse cutaneous thickening and pigmentation of flexural areas associated with dermatographism, but no evidence of systemic involvement. None of the affected family members was known to have a gastrointestinal stromal tumor (GIST; 606764).

Zhang et al. (2006) described a mother and daughter with mastocytosis. The mother, who had an undiagnosed childhood skin complaint, presented at age 26 years with hepatosplenomegaly, ichthyotic skin, and dermatographism. Bone marrow examination confirmed a diagnosis of mastocytosis, which was designated 'smoldering systemic mastocytosis' according to the WHO classification for mast cell disorders. Five years later she underwent splenectomy for abdominal pain, and she had progressive hepatomegaly with extensive necrosis, fibrosis, and mast cell infiltration. Her daughter presented at age 16 years with lichenified skin and a history of blistering and weals on minor trauma in infancy, blotchy skin on exposure to cold, and raised red-brown discoid maculopapular lesions over her neck and back since age 8 years. Skin biopsy was consistent with urticaria pigmentosa. She did not develop organomegaly during more than a decade of follow-up; thus her diagnosis remained cutaneous mastocytosis. The daughter gave birth to a son who had unusual skin symptoms since birth, with rashes and blistering, but he had not been evaluated for mast cell disease.

Wasag et al. (2011) reported a Polish father and 2 children who exhibited urticaria pigmentosa as the only manifestation of mastocytosis. The 33-year-old father had mildly itchy skin lesions on his trunk and lower extremities from early childhood. He had no other symptoms and chest x-ray and abdominal ultrasound showed no abnormalities. His 5-year-old daughter and 1-year-old son had similar skin lesions present since infancy, without systemic symptoms or any food intolerance or allergy. Skin biopsy confirmed the clinical diagnosis of urticaria pigmentosa in all 3 patients, and bone marrow analysis in the father was negative for mastocytosis. Over a 3-year follow-up period, none of the affected family members showed any symptoms of mastocytosis other than urticaria pigmentosa.

Inheritance

Selmanowitz et al. (1970) described cutaneous mastocytosis in 8 females in 3 generations with a male carrier representing a 'skipped generation.' They also reviewed experience in twins. Selmanowitz and Orentreich (1970) stated that about 40 familial cases and 6 concordant pairs of monozygotic twins are known. Both dominant and recessive inheritance had been postulated (Shaw, 1968). Fowler et al. (1986) reported urticaria pigmentosa in 4 persons

in 2 generations (father and son and 2 sisters of the father). No consistent HLA haplotypes were found; the affected boy and his unaffected brother, for instance, were of identical haplotype.

Rockoff (1978) compiled 11 sets of twins and 1 set of triplets with urticaria pigmentosa to which he added his own report. Boyano et al. (1990) described monozygotic male twins who simultaneously developed urticaria pigmentosa. Boyano et al. (1990) suggested that this was the tenth such pair to be reported. Noto et al. (1995) gave a 5-year follow-up on identical twins strikingly concordant for specific clinical features of urticaria pigmentosa.

Of 50 reported families with familial cutaneous mastocytosis, Anstey et al. (1991) found that 22 had 2 or more generations affected; in 20 families, only females were affected, and in 17 families, members of both sexes were affected.

Mapping

Tang et al. (2004) genotyped 5 affected and 3 unaffected members of a 3-generation family segregating autosomal dominant diffuse cutaneous mastocytosis for 7 tandem repeat markers spanning 8 cM of chromosome 4q12 around the KIT locus, and obtained a maximum nonparametric lod score of 2.3 (p = 0.03).

Molecular Genetics

Germline Mutations

In 5 affected members of a 3-generation family segregating autosomal dominant diffuse cutaneous mastocytosis mapping to chromosome 4q12, Tang et al. (2004) identified heterozygosity for a missense mutation in the KIT gene (A533D; 164920.0026). The mutation was not present in 3 unaffected family members or in 56 controls. The germline nature of the mutation was confirmed by the presence of A533D in DNA extracted from buccal washings of the proband and his affected father. Tang et al. (2004) also screened the affected individuals for a Q576R gain-of-function variant in the IL4R gene (147781.0001) that had been associated with atopy and detected the variant in 2 of the 5 affected individuals in this family; however, there was no clear difference in disease severity between those with and without Q576R, and the only individual with known systemic disease did not carry the polymorphism.

In a Polish father and 2 children with urticaria pigmentosa as the only manifestation of mastocytosis, Wasag et al. (2011) identified heterozygosity for a germline missense mutation in the KIT gene (N822I; 164920.0027). Functional analysis demonstrated that N822I is an activating mutation that results in predominantly immature KIT isoforms and is resistant to the tyrosine kinase-inhibitor imatinib.

Somatic Mutations

In the human mast cell leukemia line HMC-1, Furitsu et al. (1993) identified a missense mutation in the KIT gene (D816V; 164920.0009) that they determined plays a major role in constitutive activation of c-Kit product in HMC-1 cells.

In peripheral blood mononuclear cells (PBMCs) from 4 patients with mastocytosis associated with a hematologic disorder with predominantly myelodysplastic features, Nagata et al. (1995) identified the D816V mutation in the KIT gene.

In mast cells from a patient with aggressive systemic mastocytosis with massive splenic involvement, Longley et al. (1996) identified heterozygosity for the D816V substitution in KIT. The somatic mutation was not found in ectodermally-derived epithelial cells of the buccal mucosa or in non-mast cell leukocytes.

In a 44-year-old man with aggressive mast cell disease, who did not carry the D816V mutation, Pignon et al. (1997) identified a different somatic mutation in the KIT gene (D820G; 164920.0010).

In PBMCs from 16 (25%) of 65 patients with systemic mastocytosis, Worobec et al. (1998) identified the D816V KIT mutation. Patients carrying D816V manifested a more severe disease pattern and commonly had osteosclerotic bone involvement as well as immunoglobulin dysregulation and peripheral blood abnormalities. Pedigree analysis of 3 families provided evidence that the mutation was somatic.

Longley et al. (1999) analyzed the KIT gene in 25 patients with cutaneous mastocytosis and identified heterozygosity for a somatic D816V mutation in the lesions of 11 sporadic adult patients with progressive or persistent urticaria pigmentosa, 3 of whom had systemic involvement and 8 without systemic involvement. In addition, 4 childhood-onset cases with clinically unusual disease also had somatic codon 816 activating mutations: D816Y (164920.0018) was detected in 2 patients with extensive cutaneous disease with systemic involvement of the bone marrow, liver, and spleen; D816V in 1 patient with progressive cutaneous disease without systemic involvement; and D816F in 1 patient with extensive cutaneous disease, including papules, nodules, and plaques. In 3 unrelated children with typical urticaria pigmentosa, the authors detected heterozygosity for a somatic E839K mutation in KIT (164920.0020). No KIT mutations were detected in 3 members of a family with persistent urticaria pigmentosa; Longley et al. (1999) suggested that additional pathologic mechanisms exist in some patients with mastocytosis, which in this kindred were inherited.

Yanagihori et al. (2005) screened lesions from 16 sporadic Japanese patients with indolent cutaneous mastocytosis, including 12 with urticaria pigmentosa, 2 with solitary mastocytoma, and 2 with diffuse cutaneous mastocytosis, for the most common KIT mutations at codons 816, 560, 820, and 839. Ten (83.3%) of the 12 children and all 4 adult patients had missense mutations at codon 816, including 9 with D826V and 5 with D816F. It appeared that the children with D816F developed cutaneous mastocytosis at an earlier age compared to those with D816V (mean age of onset, 1.3 months vs 5.9 months). No other mutations were detected.

Tefferi et al. (2009) sequenced the TET2 gene (612839) in bone marrow cells from 42 patients who met the WHO criteria for systemic mastocytosis (SM) and identified 17 different mutations in 12 patients (29%), including 13 frameshift, 2 nonsense, and 2 missense mutations. Of the mutation-positive patients, 2 had indolent SM, 2 had aggressive SM, and 8 had SM associated with a clonal non-mast cell-lineage hematopoietic disease. Tefferi et al. (2009) also analyzed for the D816V mutation in the KIT gene (164920.0009) and the V617F mutation in the JAK2 gene (147796.0001), and found that 6 of the TET2-mutated patients also displayed D816V in KIT and that 1 TET2-mutated patient had V617F in JAK2. Tefferi et al. (2009) concluded that TET2 mutations are frequent in systemic mastocytosis and segregate with the D816V mutation in KIT.

Bodemer et al. (2010) analyzed the entire c-KIT sequence from cutaneous biopsies of 50 children with mastocytosis, and identified heterozygosity for somatic activating mutations in 43 (86%). In 21 (42%) of the children, the mutation involved codon 816, including 18 with D816V, 2 with D816Y, and 1 with D816I. Unexpectedly, half of the mutations were located in the fifth Ig loop of the KIT extracellular domain, encoded by exons 8 and 9, including 9 changes involving codon 419. Of 4 children with familial mastocytosis, 2 carried the D816V mutation without any history of KIT-related tumors, and the other 2 lacked c-KIT mutations. Overall, there was no clear genotype/phenotype correlation and no significant change in the relative expression of the short (GNNK) or long (GNNK+) isoforms of KIT, which have been shown (Caruana et al., 1999) to signal through different pathways and to have distinct transforming activities. Bodemer et al. (2010) concluded that most cases of childhood-onset mastocytosis are clonal in nature and are associated with activating mutations in c-KIT.

Exclusion Studies

Rosbotham et al. (1999) identified 3 sibs with urticaria pigmentosa. They pointed out that sporadic nonfamilial cases of urticaria pigmentosa had been related to mutations in the KIT gene (164920). Using 7 microsatellite repeat markers spanning an 8-cM interval encompassing the KIT gene, they constructed haplotypes that excluded KIT as the cause of urticaria pigmentosa in this kindred. Two affected individuals had inherited different maternal haplotypes with the same paternal haplotype. Autosomal dominant inheritance with incomplete penetrance was assumed in this family, as had been suggested by Clark et al. (1990). SSCP analysis detected no mutations in exon 17 of the KIT gene in this family.