Scientific Letters
Diffuse cutaneous mastocytosis in a girl with M541L polymorphism in KIT gene: Response to treatment with imatinib
Mastocitosis cutánea difusa en una niña con polimorfismo M541L en el gen KIT: respuesta al tratamiento con imatinib
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BMJ. 2021;372:n71.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Pilar Aizpurua Galdeano, Paz González Rodríguez, María Aparicio Rodrigo, Nieves Balado Insunza, Elena Pérez González, Juan Ruiz-Canela Cáceres, Eduardo Ortega Páez" "autores" => array:8 [ 0 => array:2 [ "nombre" => "Pilar" "apellidos" => "Aizpurua Galdeano" ] 1 => array:2 [ "nombre" => "Paz" "apellidos" => "González Rodríguez" ] 2 => array:2 [ "nombre" => "María" "apellidos" => "Aparicio Rodrigo" ] 3 => array:2 [ "nombre" => "Nieves" "apellidos" => "Balado Insunza" ] 4 => array:2 [ "nombre" => "Elena" "apellidos" => "Pérez González" ] 5 => array:2 [ "nombre" => "Juan" "apellidos" => "Ruiz-Canela Cáceres" ] 6 => array:2 [ "nombre" => "Eduardo" "apellidos" => "Ortega Páez" ] 7 => array:1 [ "colaborador" => "en representación del Grupo de Trabajo de Pediatría Basada en la Evidencia de la AEPap y el Comité de Pediatría Basada en la Evidencia de la AEP" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S1695403323001972" "doi" => "10.1016/j.anpedi.2023.09.005" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1695403323001972?idApp=UINPBA00005H" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2341287923002272?idApp=UINPBA00005H" "url" => "/23412879/0000009900000005/v1_202311240521/S2341287923002272/v1_202311240521/en/main.assets" ] "en" => array:15 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Scientific Letters</span>" "titulo" => "Diffuse cutaneous mastocytosis in a girl with M541L polymorphism in <span class="elsevierStyleItalic">KIT</span> gene: Response to treatment with imatinib" "tieneTextoCompleto" => true "saludo" => "Dear Editor." "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "350" "paginaFinal" => "351" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Aniza Giacaman, José Antonio Salinas Sanz, Mercedes Guibelalde, Iván Álvarez-Twose, Ana Martín-Santiago" "autores" => array:5 [ 0 => array:4 [ "nombre" => "Aniza" "apellidos" => "Giacaman" "email" => array:1 [ 0 => "anizagiacaman@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "José Antonio" "apellidos" => "Salinas Sanz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Mercedes" "apellidos" => "Guibelalde" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "Iván" "apellidos" => "Álvarez-Twose" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 4 => array:3 [ "nombre" => "Ana" "apellidos" => "Martín-Santiago" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital Universitari Son Espases, Palma de Mallorca, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Hemato-Oncología Infantil, Hospital Universitari Son Espases, Palma de Mallorca, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Instituto de Estudios de Mastocitosis de Castilla-La Mancha, Hospital Virgen del Valle, Toledo, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Mastocitosis cutánea difusa en una niña con polimorfismo M541L en el gen <span class="elsevierStyleItalic">KIT</span>: respuesta al tratamiento con imatinib" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1459 "Ancho" => 1274 "Tamanyo" => 116692 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0615" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">(A) The same girl with multiple infiltrative plaques on her skin before treatment with imatinib; (B) The same patient on treatment with imatinib at 20 months of follow-up.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Over the last few years, growing knowledge of the pathogenesis of mastocytosis has allowed advances in the diagnosis, treatment and outcomes of these patients.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Patients with mastocytosis and D816V variants in the <span class="elsevierStyleItalic">KIT</span> gene can benefit from treatment with midostaurin, an oral multi-targeted tyrosine kinase inhibitor (TKI).<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Variants other than KIT D816V are more frequent in children with mastocytosis, and these patients have been found to respond to other TKIs such as imatinib, nilotinib and masitinib.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Paediatric patients with severe mastocytosis refractory to conventional therapy have been successfully treated with imatinib.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">We present the case of a girl with diffuse cutaneous mastocytosis (DCM) who had onset in the first month of life with large plaques and bullous lesions on the face and body (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) associated with flushing, abdominal pain and diarrhoea. A skin biopsy confirmed the diagnosis. Tryptase levels were elevated in the early months of life. The patient exhibited a limited response to treatment with steroids, antihistamines, cromoglycate and ketotifen. At age 4 years, her condition worsened, with development of frequent headaches and episodes of hypotension. She was treated with psoralen plus ultraviolet A (PUVA) phototherapy twice a week, which achieved an improvement in her symptoms and cutaneous lesions initially but became decreasingly effective over 10 months of treatment.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">At age 8 years (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A), the symptoms associated with heat, exercise and emotional triggers worsened. The tryptase levels were normal. A new skin biopsy revealed an infiltrate of mast cells with a granular cytoplasm that were c-KIT<span class="elsevierStyleSup">+</span>, tryptase<span class="elsevierStyleSup">+</span>, CD30<span class="elsevierStyleSup">+</span> and CD25<span class="elsevierStyleSup">−</span>. A bone marrow biopsy and examination was performed, revealing normal cell counts and morphology. The allele-specific oligonucleotide real-time quantitative PCR (ASOqPCR) assay (TaqMan) did not detect the D816V variant in the <span class="elsevierStyleItalic">KIT</span> gene. However, fluorescence-activated cell sorting (FACS) isolated 0.0012% of mast cells with a c-KIT<span class="elsevierStyleSup">+</span>, tryptase<span class="elsevierStyleSup">+</span>, CD25<span class="elsevierStyleSup">−</span> and CD30<span class="elsevierStyleSup">−</span> immunophenotype. Sanger sequencing of genetic material from FACS-purified bone marrow mast cells did not find the D816V variant, but rather the M541L polymorphism in the <span class="elsevierStyleItalic">KIT</span> gene. Based on this finding, treatment with imatinib 100<span class="elsevierStyleHsp" style=""></span>mg per day was initiated combined with the ongoing treatment with cromoglycate 200<span class="elsevierStyleHsp" style=""></span>mg twice a day and ketotifen 1<span class="elsevierStyleHsp" style=""></span>mg twice a day, with addition of oral antihistamines and steroids during mast cell flares.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">During the 4 years of follow-up, the response to treatment has been satisfactory, with good tolerance of imatinib, an attenuation of infiltration in the cutaneous lesions (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B) and improvement in systemic symptoms. Occasional episodes of dizziness have resolved with oral dexchlorpheniramine maleate. The patient’s growth has been normal, no adverse events have been detected, and laboratory test results and tryptase levels have remained normal.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Activating mutations of the KIT receptor tyrosine kinase have been reported in different types of cancer and in diffuse cutaneous mastocytosis. Imatinib is an oral TKI approved for treatment of systemic mastocytosis in patients with <span class="elsevierStyleItalic">KIT</span> mutations outside exon 17, but is generally not effective for D816V-associated disease.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The M541L polymorphism found in our patient has been associated with paediatric mastocytosis and a greater sensitivity to imatinib therapy.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The adverse events associated with the use of imatinib include nausea, vomiting, diarrhoea, transaminase elevation, cardiomyopathy, anaemia, thrombocytopenia, granulocytopenia, oedema, skin rash and decreased growth velocity in children.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,5</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Although there is limited experience in the use of imatinib in children with mastocytosis, it could be an alternative option for patients with DCM and severe symptoms refractory to conventional therapies.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 678 "Ancho" => 1274 "Tamanyo" => 136934 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0610" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">(A) Girl aged 1 month with diffuse cutaneous mastocytosis; (B) diffuse infiltrated plaques with a peau d’orange appearance, focal blisters and rough thickening of skin.</p>" ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1459 "Ancho" => 1274 "Tamanyo" => 116692 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0615" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">(A) The same girl with multiple infiltrative plaques on her skin before treatment with imatinib; (B) The same patient on treatment with imatinib at 20 months of follow-up.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "P. Valent" 1 => "C. Akin" 2 => "D.D. Metcalfe" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2016-09-731893" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2017" "volumen" => "129" "paginaInicial" => "1420" "paginaFinal" => "1427" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28031180" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pediatric mastocytosis: recognition and management" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "J.V. Schaffer" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s40257-020-00581-5" "Revista" => array:6 [ "tituloSerie" => "Am J Clin Dermatol" "fecha" => "2021" "volumen" => "22" "paginaInicial" => "205" "paginaFinal" => "220" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33492611" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association of paediatric mastocytosis with a polymorphism resulting in an amino acid substitution (M541L) in the transmembrane domain of c-KIT" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R. Foster" 1 => "E. Byrnes" 2 => "C. Meldrum" 3 => "R. Griffith" 4 => "G. Ross" 5 => "E. Upjohn" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2133.2008.08827.x" "Revista" => array:6 [ "tituloSerie" => "Br J Dermatol" "fecha" => "2008" "volumen" => "159" "paginaInicial" => "1160" "paginaFinal" => "1169" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18795925" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Imatinib mesylate in the treatment of diffuse cutaneous mastocytosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.A. Morren" 1 => "A. Hoppe" 2 => "M. Renard" 3 => "M.D. Rychter" 4 => "A. Uyttebroeck" 5 => "P. Dubreuil" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jpeds.2012.08.035" "Revista" => array:6 [ "tituloSerie" => "J Pediatr" "fecha" => "2013" "volumen" => "162" "paginaInicial" => "205" "paginaFinal" => "207" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23069194" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Update on mastocytosis (part 2): categories, prognosis, and treatment" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J.M. Azana" 1 => "A. Torrelo" 2 => "A. Matito" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ad.2015.09.009" "Revista" => array:6 [ "tituloSerie" => "Actas Dermosifiliogr" "fecha" => "2016" "volumen" => "107" "paginaInicial" => "15" "paginaFinal" => "22" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26525106" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack705964" "titulo" => "Acknowledgements" "texto" => "<p id="par0040" class="elsevierStylePara elsevierViewall">We thank the patient and the family who collaborated in the publication of this case, thus contributing to furthering the knowledge of this condition.</p><p id="par0045" class="elsevierStylePara elsevierViewall">We also thank Dr Victor J. Asensio and Dr María Carmen Vidal of the Department of Genetics for their comments on the manuscript and Dr Ana Bauzá for providing the photographs of the patient in the early months of life.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/23412879/0000009900000005/v1_202311240521/S2341287923002211/v1_202311240521/en/main.assets" "Apartado" => array:4 [ "identificador" => "38181" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Scientific letters" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23412879/0000009900000005/v1_202311240521/S2341287923002211/v1_202311240521/en/main.pdf?idApp=UINPBA00005H&text.app=https://analesdepediatria.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2341287923002211?idApp=UINPBA00005H" ]
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