RESUMEN
PAX3/7-FOXO1 fusion-negative alveolar rhabdomyosarcoma (ARMS) developed in a patient presenting with intellectual disability and dysmorphic facial features. Whole exome sequencing analysis of a germline sample identified a PACS1 c.607 C>T de novo variant and the patient was diagnosed with Schuurs-Hoeijmakers syndrome (SHS). SHS is a rare disease characterized by intellectual disability and dysmorphic facial features, among various physical abnormalities, due to PACS1 c.607 C>T de novo variant. Due to the rarity of the SHS, diagnosis based on phenotypic information is difficult. To date, there have been no previous reports describing malignancy associated with SHS. Comprehensive somatic mutation analysis revealed a unique pattern of genetic alterations in the PAX3/7-FOXO1 fusion-negative ARMS tumor, including mutations in the oncogene, HRAS; MYOD1, a molecule essential for muscle differentiation; and KMT2C and TET1, genes encoding factors involved in epigenetic regulation. Although the role of PACS1 in tumorigenesis is unclear, it is reported to function in apoptosis regulation. Our case suggests that PACS1 could have a novel role in oncogenesis.
Asunto(s)
Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Predisposición Genética a la Enfermedad , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Rabdomiosarcoma Alveolar/diagnóstico , Rabdomiosarcoma Alveolar/etiología , Alelos , Proteína Forkhead Box O1/genética , Estudios de Asociación Genética , Genotipo , Humanos , Proteínas de Fusión Oncogénica/genética , Factor de Transcripción PAX3/genética , Fenotipo , SíndromeRESUMEN
BACKGROUND: Gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) cause susceptibility to a range of infections, autoimmunity, immune dysregulation, and combined immunodeficiency. Disease manifestations can be mild or severe and life-threatening. Hematopoietic stem cell transplantation (HSCT) has been used in some patients with more severe symptoms to treat and cure the disorder. However, the outcome of HSCT for this disorder is not well established. OBJECTIVE: We sought to aggregate the worldwide experience of HSCT in patients with GOF-STAT1 mutations and to assess outcomes, including donor engraftment, overall survival, graft-versus-host disease, and transplant-related complications. METHODS: Data were collected from an international cohort of 15 patients with GOF-STAT1 mutations who had undergone HSCT using a variety of conditioning regimens and donor sources. Retrospective data collection allowed the outcome of transplantation to be assessed. In vitro functional testing was performed to confirm that each of the identified STAT1 variants was in fact a GOF mutation. RESULTS: Primary donor engraftment in this cohort of 15 patients with GOF-STAT1 mutations was 74%, and overall survival was only 40%. Secondary graft failure was common (50%), and posttransplantation event-free survival was poor (10% by 100 days). A subset of patients had hemophagocytic lymphohistiocytosis before transplant, contributing to their poor outcomes. CONCLUSION: Our data indicate that HSCT for patients with GOF-STAT1 mutations is curative but has significant risk of secondary graft failure and death.
Asunto(s)
Mutación con Ganancia de Función , Predisposición Genética a la Enfermedad , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/mortalidad , Trasplante de Células Madre Hematopoyéticas , Factor de Transcripción STAT1/genética , Aloinjertos , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/inmunología , Humanos , Masculino , Estudios Retrospectivos , Factores de Riesgo , Factor de Transcripción STAT1/inmunología , Tasa de SupervivenciaAsunto(s)
Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/etiología , Citomegalovirus , Laringitis/diagnóstico , Laringitis/etiología , Inmunodeficiencia Combinada Grave/complicaciones , Adolescente , Antivirales/uso terapéutico , Biopsia , Niño , Fosfatidilinositol 3-Quinasa Clase Ia/genética , Infecciones por Citomegalovirus/tratamiento farmacológico , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Humanos , Lactante , Laringitis/tratamiento farmacológico , Masculino , Mutación , Inmunodeficiencia Combinada Grave/etiología , Inmunodeficiencia Combinada Grave/inmunología , Evaluación de Síntomas , Resultado del TratamientoRESUMEN
We encountered a case of neonatal acute megakaryoblastic leukemia not associated with Down syndrome (DS). Molecular cytogenetic analysis of leukemic blast cells indicated that increased blast cell status was caused by transient abnormal myelopoiesis with trisomy 21 and GATA1 mutation. Based on these molecular cytogenetic data, intensive chemotherapy was avoided, and the patient was successfully cured with low-dose cytarabine. Morphologically, leukemic blast cells of acute megakaryoblastic leukemia in a non-DS neonate are indistinguishable from a blast cell of transient abnormal myelopoiesis. The possibility of transient abnormal myelopoiesis should be carefully considered before intensive chemotherapy is adopted.
Asunto(s)
ADN/genética , Síndrome de Down/genética , Factor de Transcripción GATA1/genética , Reacción Leucemoide/genética , Mutación , Western Blotting , Síndrome de Down/metabolismo , Factor de Transcripción GATA1/metabolismo , Humanos , Recién Nacido , Reacción Leucemoide/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Hematopoietic stem cell transplantation (HSCT) for dyskeratosis congenita (DC) is challenging due to severe treatment-related adverse effects. Development of pulmonary fibrosis or veno-occlusive disease is well described in DC. However, neurological complication after HSCT has not been reported. A 9-year-old Japanese male with DC harboring the TINF2 mutation received reduced-intensity HSCT. Unfortunately, patient developed posterior reversible encephalopathy syndrome-like symptoms plausibly result by combination of thrombotic microangiopathy, graft-versus-host disease, and persistent hypertension and has been persisted mental retardation. Therefore, to decrease risk in DC cases after HSCT, strict control of hypertension, graft-versus-host disease, and thrombotic microangiopathy is required.
Asunto(s)
Disqueratosis Congénita/cirugía , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucoencefalopatías/etiología , Mutación , Proteínas de Unión a Telómeros/genética , Preescolar , Disqueratosis Congénita/sangre , Disqueratosis Congénita/genética , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Leucoencefalopatías/sangre , Leucoencefalopatías/genética , MasculinoAsunto(s)
Displasia Ectodérmica/terapia , Infecciones por Virus de Epstein-Barr/inmunología , Enfermedad Injerto contra Huésped/inmunología , Herpesvirus Humano 4/inmunología , Síndromes de Inmunodeficiencia/terapia , Inhibidor NF-kappaB alfa/genética , Trasplante de Células Madre/métodos , Preescolar , Displasia Ectodérmica/genética , Antígenos HLA/inmunología , Humanos , Síndromes de Inmunodeficiencia/genética , Terapia de Inmunosupresión , Lactante , Desnutrición , Mutación/genética , Quimera por Trasplante , Acondicionamiento Pretrasplante , Resultado del TratamientoRESUMEN
We retrospectively analyzed 60 cases of pediatric patients who received allogeneic stem cell transplantation (SCT) between 2000 and 2008, using the tentative scoring system for evaluation of early (<30 days) coagulation disorders. In the 41 patients who survived, D-dimer levels showed a transient increase 2 weeks after SCT and normalized thereafter, but these levels were persistently elevated in the 19 patients who died. Of 19 patients with a positive score, 11 died of transplantation-related complications [transplantation-related mortality (TRM) = 0.579] within 1 year, while none of the 41 with a negative score died during the same period. Since 2009, 12 of 30 patients had positive scores within 30 days after SCT. Intervention with recombinant human thrombomodulin (rhTM) was introduced for patients with a positive score, and 10 of these patients survived (TRM = 0.167) along with a dramatic improvement of D-dimer level. Although the effects of this treatment were observed in a limited number of patients, our observations suggest that early coagulation disorder after allogeneic SCT is a strong prognostic factor for TRM, and that intervention with rhTM improves TRM.