RESUMO
BACKGROUND: KRAS (KRAS proto-oncogene, GTPase; OMIM: 190,070) encodes one of three small guanosine triphosphatase proteins belonging to the RAS family. This group of proteins is responsible for cell proliferation, differentiation and inhibition of apoptosis. Gain-of-function variants in KRAS are commonly found in human cancers. Non-malignant somatic KRAS variants underlie a subset of RAS-associated autoimmune leukoproliferative disorders (RALD). RALD is characterized by splenomegaly, persistent monocytosis, hypergammaglobulinemia and cytopenia, but can also include autoimmune features and lymphadenopathy. In this report, we describe a non-malignant somatic variant in KRAS with prominent clinical features of massive splenomegaly, thrombocytopenia and lymphopenia. CASE PRESENTATION: A now-11-year-old girl presented in early childhood with easy bruising and bleeding, but had an otherwise unremarkable medical history. After consulting for the first time at 5 years of age, she was discovered to have massive splenomegaly. Clinical follow-up revealed thrombocytopenia, lymphopenia and increased polyclonal immunoglobulins and C-reactive protein. The patient had an unremarkable bone marrow biopsy, flow cytometry showed no indication of expanded double negative T-cells, while malignancy and storage disorders were also excluded. When the patient was 8 years old, whole exome sequencing performed on DNA derived from whole blood revealed a heterozygous gain-of-function variant in KRAS (NM_004985.5:c.37G > T; (p.G13C)). The variant was absent from DNA derived from a buccal swab and was thus determined to be somatic. CONCLUSIONS: This case of idiopathic splenomegaly in childhood due to a somatic variant in KRAS expands our understanding of the clinical spectrum of RAS-associated autoimmune leukoproliferative disorder and emphasizes the value of securing a molecular diagnosis in children with unusual early-onset presentations with a suspected monogenic origin.
Assuntos
Transtornos Linfoproliferativos , Esplenomegalia , Biópsia , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Mutação , Proto-Oncogene Mas , Esplenomegalia/etiologiaAssuntos
Mutação com Ganho de Função , Genes Dominantes , Síndrome Hipereosinofílica/diagnóstico , Síndrome Hipereosinofílica/etiologia , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/etiologia , Janus Quinase 1/genética , Alelos , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Mutação em Linhagem Germinativa , Humanos , Síndrome Hipereosinofílica/tratamento farmacológico , Doenças do Sistema Imunitário/tratamento farmacológico , Imunomodulação/genética , Janus Quinase 1/química , Masculino , Linhagem , Fenótipo , Sequenciamento do ExomaAssuntos
Caspases , Homozigoto , Mutação , Proteínas de Neoplasias , Imunodeficiência Combinada Severa/genética , Adolescente , Caspases/genética , Caspases/imunologia , Feminino , Humanos , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologiaRESUMO
This FOCIS Centers of Excellence Short Analytical Review is based on the clinical vignette of two boys from the same family with very different outcomes following hematopoietic stem cell transplantation (HSCT) for X-linked severe combined immunodeficiency (SCID). We review the kinetics of immune reconstitution following HSCT in SCID and emphasize the latest information regarding optimizing transplant outcomes for this disorder. The cases illustrate the difficulties and controversies surrounding the optimal strategies for planning SCID transplants. Specifically, we will focus on 3 areas of current debate and investigation: (i) factors involved in donor selection; (ii) the role of pretransplant conditioning; and (iii) benefits of early HSCT for SCID.