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Somatic D816V KIT mutation in a case of adult-onset familial mastocytosis

2013; Elsevier BV; Volume: 131; Issue: 2 Linguagem: Inglês

10.1016/j.jaci.2012.11.040

1097-6825

Roberta Zanotti, Livio Simioni, Andrés C. García‐Montero, Omar Perbellini, Patrizia Bonadonna, Beatrice Caruso, María Jara‐Acevedo, Massimiliano Bonifacio, Giovanna De Matteis,

Coagulation, Bradykinin, Polyphosphates, and Angioedema

Familial occurrence of mastocytosis is unusual.1Metcalfe D.D. Mast cells and mastocytosis.Blood. 2008; 112: 946-956Crossref PubMed Scopus (440) Google Scholar Most of the clustered cases were pediatric cutaneous mastocytosis without KIT mutations, or presenting uncommon KIT lesions, not yet reported in sporadic cases (ie, A533D or K509I point mutation or deletion of exons 418 and 559-560, in association with familial gastrointestinal stromal tumors2Orfao A. Garcia-Montero A.C. Sanchez L. Escribano L. Recent advances in the understanding of mastocytosis: the role of KIT mutations.Br J Haematol. 2007; 138: 12-30Crossref PubMed Scopus (199) Google Scholar). These data suggest that familial mastocytosis comprises a subgroup with a different pathogenesis from the sporadic mastocytosis that is typically associated with the D816V KIT mutation.3Garcia-Montero A.C. Jara-Acevedo M. Teodosio C. Sanchez M.L. Nunez R. Prados A. et al.KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients.Blood. 2006; 108: 2366-2372Crossref PubMed Scopus (423) Google Scholar Here, we report a case of familial systemic mastocytosis (SM) without skin lesions presented in 2 adults, a mother and her son, both carrying the D816V mutation, and associated with systemic reaction to hymenoptera venom. Patients 1 and 2 had no personal or familial history of skin disorders, hematological diseases, gastrointestinal stromal tumor, or other cancer. The unique sister of patient 1 had normal serum tryptase levels and refused any other evaluation. Patient 1 (male, aged 32 years) came to the Allergy Service of Feltre, Belluno (Italy), in 2002 after a systemic reaction (Mueller III) subsequent to a hymenoptera sting, identified as a vespula. Skin prick tests and intradermal tests to Apis mellifera (I1), Vespa crabro (I75), Polistes dominulus (I77), Vespula species (I3), and Bombus terrestris were performed according to the recommendations of the European Academy of Allergology and Clinical Immunology; they evidenced positivity for the I3 venom, which was further confirmed by detection of specific IgE serum antibodies (CAP test, Pharmacia, Uppsala, Sweden). In July 2002, the patient started specific immunotherapy to Vespula species, which is still in course. From 2005 to 2009, he was sometimes stung by a vespid without any reaction. In 2006, a Bombus species field sting caused a Muller IV grade systemic reaction that determined his admission to the emergency room. Skin prick test and detection of specific serum IgE were repeated, and the tests confirmed a sensitization only to Vespula species. Furthermore, serum tryptase level was 12.5 ng/mL and he did not show any other mediator-related associated symptoms. Patient 2 (female, 57 years, mother of patient 1) had a history of osteoporosis, which was treated with alendronate 70 mg once a week. In 2002, she was stung by a vespid and had Muller I systemic reaction. Skin prick test and detection of specific IgE serum antibodies were positive for I3 and I4 (Polistes species). Vespula venom specific immunotherapy was started, but the patient suffered from Muller I systemic reaction after the dose of 20 μg. After a week, the serum tryptase level was 42 ng/mL. Some weeks later, she restarted the immunotherapy without any problems. She did not show any other mediator-related symptoms. The history of systemic reactions after hymenoptera sting and persistent raised tryptase serum levels led to the suspicion of SM.4Bonadonna P. Perbellini O. Passalacqua G. Caruso B. Colarossi S. Dal Fior D. et al.Clonal mast cell disorders in patients with systemic reactions to hymenoptera stings and increased serum tryptase levels.J Allergy Clin Immunol. 2009; 123: 680-686Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar Both patients were referred to the Multidisciplinary Outpatients Clinic for Mastocytosis of Verona, Italy, where they underwent physical examination, complete blood cell count, routine biochemistry, abdominal ultrasonography, bone densitometry evaluation with dual-energy x-ray absorptiometry, and bone marrow evaluation with histology/cytology and flow cytometric analysis, performed as previously described.4Bonadonna P. Perbellini O. Passalacqua G. Caruso B. Colarossi S. Dal Fior D. et al.Clonal mast cell disorders in patients with systemic reactions to hymenoptera stings and increased serum tryptase levels.J Allergy Clin Immunol. 2009; 123: 680-686Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar The D816V KIT mutation was demonstrated in both patients on total RNA from bone marrow samples by real-time PCR using mismatched forward primers for both mutated and wild-type sequence to control cDNA quality5Lawley W. Hird H. Mallinder P. McKenna S. Hargadon B. Murray A. et al.Detection of an activating c-kit mutation by real-time PCR in patients with anaphylaxis.Mutat Res. 2005; 572: 1-13Crossref PubMed Scopus (23) Google Scholar and by peptide nucleic acid-mediated PCR clamping and hybridization probes3Garcia-Montero A.C. Jara-Acevedo M. Teodosio C. Sanchez M.L. Nunez R. Prados A. et al.KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients.Blood. 2006; 108: 2366-2372Crossref PubMed Scopus (423) Google Scholar (the analyses were performed independently in Verona and Salamanca Laboratories). The presence of the D816V mutation was also investigated on genomic DNA from total peripheral blood (PB) and from fluorescence-activated cell sorting–purified populations of PB neutrophils, monocytes, and lymphocytes, by allele-specific real-time quantitative PCR.6Kristensen T. Vestergaard H. Møller M.B. Improved detection of the KIT D816V mutation in patients with systemic mastocytosis using a quantitative and highly sensitive real-time qPCR assay.J Mol Diagn. 2011; 13: 180-188Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar Genomic DNA from total PB sample of the son showed a slight positivity (2.5%-5%) of the D816V KIT mutation, whereas the mother was negative, which would confirm that it was not a case of germline but somatic mutation. Moreover, analysis of genomic DNA from purified PB cell populations of the son revealed that only monocytes and granulocytes carried the D816V KIT mutation while T lymphocytes were negative for this mutation. Clinical, laboratory, and bone marrow characteristics are reported in Table I. Both patients were diagnosed with indolent SM without skin lesions on the basis of 3 minor criteria (patient 1) or 1 major criteria and 4 minor criteria (patient 2) according to the current World Health Organization recommendations.7Horny H.P. Metcalfe D.D. Bennet J.M. Bain B.J. Akin C. Escribano L. et al.WHO classification of tumours of haematopoietic and lymphoid tissues. IARC, Lyon2008Google Scholar, 8Valent P. Horny H.P. Escribano L. Longley B.J. Li C.Y. Schwartz L.B. et al.Diagnostic criteria and classification of mastocytosis: a consensus proposal.Leuk Res. 2001; 25: 603-625Crossref PubMed Scopus (972) Google ScholarTable IClinical, laboratory, BM, and PB characteristics of 2 patients at diagnostic of SMPatient 1Patient 2SexMaleFemaleAge (y)3757Hemoglobin, median (gr/dL)16.114.2White cell count, median (×109/L)5.37.0Platelet count, median (×109/L)195212Tryptase level (ng/mL)12.442.0Skin lesionsAbsentAbsentHepatosplenomegalyAbsentAbsentLymphadenopathyAbsentAbsentBM histology Cellularity (%)4060 Multifocal, dense MC aggregatesNegative∗Small aggregates of atypical MCs.PositiveBM cytology % of atypical type I MC within all nucleated BM cells<1<1 (% of BM atypical MC type I of all BM MCs)7585BM flow cytometry % of CD25+ BM MCs within nucleated BM cells0.330.43D816V on BM cDNAPositivePositiveD816V on PB gDNAPositive (2.5%-5%)NegativeD816V on monocytes gDNAPositive–D816V on granulocytes gDNAPositive–D816V on T-lymphocytes gDNANegative–BM, Bone marrow; gDNA, genomic DNA; MC, mast cell.∗ Small aggregates of atypical MCs. Open table in a new tab BM, Bone marrow; gDNA, genomic DNA; MC, mast cell. To the best of our knowledge, this is the first report of a family (mother and son) with adult-onset SM associated with the occurrence of somatic D816V KIT mutation on both patients. Given the rarity of this disease, the simultaneous occurrence on both patients of the D816V KIT mutation by chance is negligible; therefore, SM onset is due to some type of parental inheritance. Nevertheless, the D816V mutation was somatic but not germline, as it has been shown to be restricted to a small part of the myeloid compartment of hematopoiesis. It is generally accepted that unlike familial mastocytosis, adult patients with sporadic mastocytosis usually express activating mutations in exon 17 of KIT, most commonly D816V,2Orfao A. Garcia-Montero A.C. Sanchez L. Escribano L. Recent advances in the understanding of mastocytosis: the role of KIT mutations.Br J Haematol. 2007; 138: 12-30Crossref PubMed Scopus (199) Google Scholar and this mutation has never been shown to be inherited.1Metcalfe D.D. Mast cells and mastocytosis.Blood. 2008; 112: 946-956Crossref PubMed Scopus (440) Google Scholar Indeed, a study performed on 50 pediatric cases showed that despite 36% of the cases being positive for the D816V KIT mutation, they were always somatic, including 2 brothers with a familial form of the disease without any history of KIT-related tumors (other than mastocytosis).9Bodemer C. Hermine O. Palmérini F. Yang Y. Grandpeix-Guyodo C. Leventhal P.S. et al.Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutation.J Invest Dermatol. 2010; 130: 804-815Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar The latter observation is consistent with a case of adult-onset familial SM in monozygotic twins with skin lesions and somatic D816V mutation.10Broesby-Olsen S. Kristensen T.K. Møller M.B. Bindslev-Jensen C. Vestergaard H. Mastocytosis Centre Odense University Hospital (MastOUH) Adult-onset systemic mastocytosis in monozygotic twins with KIT D816V and JAK2 V617F mutations.J Allergy Clin Immunol. 2012; 130: 806-808Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Therefore, the report of somatic D816V KIT mutation in familial cases of mastocytosis (either with children or adult onset) suggests the presence of other genetic factors predisposing to the acquisition of somatic-activating KIT mutation. Despite the fact that a great number of growth factor signal transduction pathways are closely related to KIT transduction pathways and may influence mast cell proliferation and survival (reviewed in Orfao et al2Orfao A. Garcia-Montero A.C. Sanchez L. Escribano L. Recent advances in the understanding of mastocytosis: the role of KIT mutations.Br J Haematol. 2007; 138: 12-30Crossref PubMed Scopus (199) Google Scholar), and polymorphism of genes encoding for mast cell growth factors and their receptors (eg, IL-13 and IL-4R) is described to influence different phenotypes in mastocytosis,11Daley T. Metcalfe D.D. Akin C. Association of the Q576R polymorphism in the interleukin-4 receptor alpha chain with indolent mastocytosis limited to the skin.Blood. 2001; 98: 880-882Crossref PubMed Scopus (53) Google Scholar, 12Nedoszytko B. Niedoszytko M. Lange M. van Doormaal J. Gleń J. Zabłotna M. et al.Interleukin-13 promoter gene polymorphism -1112C/T is associated with the systemic form of mastocytosis.Allergy. 2009; 64: 287-294Crossref PubMed Scopus (33) Google Scholar to the best of our knowledge there is still not enough scientific evidence to assume any potential genetic candidate predisposing the development of mastocytosis.