Association of adult mastocytosis with M541L in the transmembrane domain of KIT

Editor Mastocytosis is a disorder characterized by mast cell (MC) proliferation and accumulation within various organs, most commonly the skin. Multiple KIT mutations have been reported in patients with adult mastocytosis, but the potential association of specific KIT mutations with specific subtypes of mastocytosis remains to be clarified. We present the case of a 32-year-old caucasian woman who came to the Dermatology Department complaining of a 12-year history of multiple, generalized and reddish-brown macules and papules with positive Darier’s sign. These lesions were more numerous in the trunk and limbs, and absent from face, palms and soles. She had no systemic symptoms and physical examination was unremarkable. Skin biopsy showed MC infiltrates in the dermis (Fig. 1), confirming the diagnosis of cutaneous mastocytosis. Full blood count, white blood cell differential and routine serum biochemistry tests were within normal range. Serum tryptase level was 17.9 ng ⁄ mL (normal: 0.1–11.4 ng ⁄ mL). The patient had a 46,XX karyotype. Abdominal ultrasound, PET scan and bone densitometry were all normal. Complete bone marrow study showed normal percentage of bone marrow MCs (BMMCs) (0.04%) which showed aberrant coexpression of CD25+, CD2+ and also CD33+, CD35+, CD45+, CD63+, CD69+ and CD59+. Analysis of coding exons 8, 9, 10, 11 and 17 of the KIT gene revealed the presence of a heterozygous substitution in exon 10, resulting in the substitution of leucine for methionine at codon 541 (M541L) (Fig. 2). The sequencing of KIT exon 10, using DNA extracted from oral mucosa cells, confirmed that this was a germline mutation. Human KIT is a protooncogene located at chromosome 4q12 that contains 21 exons, which encode a transmembrane receptor (kit) with tyrosine kinase (TK) activity. Binding of kit ligand stem cell factor (SCF) to kit receptor is known to activate kit TK, which results in different biological effects depending on the activated cell. In MCs, these effects include, among others, cell proliferation and suppression of apoptosis. Mutations of KIT are considered to play a key role in the pathogenesis of mastocytosis. Most frequently, KIT mutations occur at exon 11 and 17, resulting in aminoacid changes at the juxtamembrane and TK domain of kit respectively. Furitsu et al. showed that point mutations in KIT (Asp816Val and Val560Asp) are capable of inducing constitutive activation of kit. Multiple other activating KIT mutations have been reported in patients with adult mastocytosis, but few are described in the transmembrane domain of KIT, encoded by exon 10. In our patient, we detected a heterozygous substitution (germline mutation) in exon 10, resulting in the substitution of leucine for methionine at codon 541 (M541L). This mutation was described in general population, in a family with piebaldism and in two unrelated pairs of apparently identical twin children with mastocytosis. To the best of our knowledge, however, this is the first time it is reported in an adult patient with mastocytosis. According to Foster et al., cells expressing M541L displayed a significantly heightened response to low levels of SCF, suggesting that these cells may have a proliferative and ⁄ or survival advantage. Although our patient had elevated serum tryptase levels, coexpression of both CD2 and CD25 by BMMCs and a KIT Figure 2 Analysis of coding exons 8, 9, 10, 11 and 17 of the KIT gene revealed the presence of a heterozygous substitution in exon 10, resulting in the substitution of leucine for methionine at codon 541 (M541L).