ABSTRACT
Fanconi anemia (FA) is a chromosome instability syndrome with congenital abnormalities, cancer predisposition and bone marrow failure (BMF). Although hematopoietic stem and progenitor cell (HSPC) transplantation is the recommended therapy, new therapies are needed for FA patients without suitable donors. BMF in FA is caused, at least in part, by a hyperactive growth-suppressive transforming growth factor ß (TGFß) pathway, regulated by the TGFß1, TGFß2, and TGFß3 ligands. Accordingly, the TGFß pathway is an attractive therapeutic target for FA. While inhibition of TGFß1 and TGFß3 promotes blood cell expansion, inhibition of TGFß2 is known to suppress hematopoiesis. Here, we report the effects of AVID200, a potent TGFß1- and TGFß3-specific inhibitor, on FA hematopoiesis. AVID200 promoted the survival of murine FA HSPCs in vitro. AVID200 also promoted in vitro the survival of human HSPCs from patients with FA, with the strongest effect in patients progressing to severe aplastic anemia or myelodysplastic syndrome (MDS). Previous studies have indicated that the toxic upregulation of the nonhomologous end-joining (NHEJ) pathway accounts, at least in part, for the poor growth of FA HSPCs. AVID200 downregulated the expression of NHEJ-related genes and reduced DNA damage in primary FA HSPC in vitro and in in vivo models. Collectively, AVID200 exhibits activity in FA mouse and human preclinical models. AVID200 may therefore provide a therapeutic approach to improving BMF in FA.
Subject(s)
Fanconi Anemia/drug therapy , Hematopoiesis/drug effects , Transforming Growth Factor beta1/antagonists & inhibitors , Transforming Growth Factor beta3/antagonists & inhibitors , Adolescent , Adult , Animals , Cell Survival/drug effects , Cells, Cultured , Child , Child, Preschool , Fanconi Anemia/metabolism , Fanconi Anemia/physiopathology , Female , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/pathology , Humans , Male , Mice , Transforming Growth Factor beta1/metabolism , Transforming Growth Factor beta3/metabolismABSTRACT
Fanconi anemia is a rare autosomal recessive inherited bone marrow failure syndrome with congenital and hematological abnormalities. Literature regarding the anesthetic management in these patients is limited. A management of a developmental dislocation of the hip was described in a patient with fanconi anemia. Because of the heterogeneous nature, a patient with fanconi anemia should be established thorough preoperative evaluation in order to diagnose on clinical features. In conclusion, we preferred caudal anesthesia in this patient with fanconi anemia without thrombocytopenia, because of avoiding from N2O, reducing amount of anesthetic, existing microcephaly, hypothyroidism and elevated liver enzymes, providing postoperative analgesia, and reducing amount of analgesic used postoperatively.
Subject(s)
Anesthesia, Caudal/methods , Fanconi Anemia/surgery , Hip Dislocation, Congenital/surgery , Analgesics/administration & dosage , Analgesics/therapeutic use , Child, Preschool , Fanconi Anemia/physiopathology , Female , Hip Dislocation, Congenital/etiology , Humans , Pain, Postoperative/drug therapyABSTRACT
Fanconi anemia is a rare autosomal recessive inherited bone marrow failure syndrome with congenital and hematological abnormalities. Literature regarding the anesthetic management in these patients is limited. A management of a developmental dislocation of the hip was described in a patient with fanconi anemia. Because of the heterogeneous nature, a patient with fanconi anemia should be established thorough preoperative evaluation in order to diagnose on clinical features. In conclusion, we preferred caudal anesthesia in this patient with fanconi anemia without thrombocytopenia, because of avoiding from N2O, reducing amount of anesthetic, existing microcephaly, hypothyroidism and elevated liver enzymes, providing postoperative analgesia, and reducing amount of analgesic used postoperatively.
A anemia de Fanconi é uma síndrome hereditária autossômica recessiva rara, caracterizada por deficiência da medula óssea e anomalias congênitas e hematológicas. A literatura sobre o manejo anestésico dos pacientes é limitada. O manejo de uma displasia do desenvolvimento do quadril foi descrito em um paciente com anemia de Fanconi. Por causa da natureza heterogênea, um paciente com anemia de Fanconi deve ser submetido à avaliação pré-operatória para diagnosticar as características clínicas. Em conclusão, o bloqueio caudal foi a nossa escolha para esse paciente com anemia de Fanconi, sem trombocitopenia, para evitar o N2O, reduzir a quantidade de anestésico, a microcefalia existente, o hipotireoidismo e o aumento das enzimas hepáticas, proporcionar analgesia pós-operatória e reduzir a quantidade de analgésico usada no pós-operatório.
La anemia de Fanconi es un síndrome hereditario autosómico recesivo raro, caracterizado por deficiencia de la médula ósea y por anomalías congénitas y hematológicas. La literatura sobre el manejo anestésico de esos pacientes es limitada. El manejo de una displasia del desarrollo de la cadera fue descrito en un paciente con anemia de Fanconi. Debido a la naturaleza heterogénea, un paciente con anemia de Fanconi debe ser sometido a la evaluación preoperatoria para diagnosticar las características clínicas. En conclusión, el bloqueo caudal fue nuestra elección para ese paciente con anemia de Fanconi sin trombocitopenia para evitar el N2O, reducir la cantidad de anestésico, microcefalia existente, hipotiroidismo y aumento de las enzimas hepáticas, proporcionar analgesia postoperatoria y reducir la cantidad de analgésico usado en el postoperatorio.
Subject(s)
Child, Preschool , Female , Humans , Anesthesia, Caudal/methods , Fanconi Anemia/surgery , Hip Dislocation, Congenital/surgery , Analgesics/administration & dosage , Analgesics/therapeutic use , Fanconi Anemia/physiopathology , Hip Dislocation, Congenital/etiology , Pain, Postoperative/drug therapyABSTRACT
Fanconi's anemia (FA) is a genetic autosomal recessive disorder, characterized by progressive bone marrow failure, congenital abnormalities, growth retardation, and predisposition to leukemia and solid tumors. The purpose of this study was to compare the chronological age (CA), bone age (BA), and dental age (DA) of FA patients and to determine whether the therapy received influenced the BA or DA. Thirty FA patients were evaluated and divided into three groups according to the therapy received. Hand and wrist radiographs for BA estimation and panoramic radiographs for DA estimation were taken. Statistical analysis demonstrated that mean values for CA, BA, and DA were 8.91 years old, 7.90 years old, and 7.75 years old, respectively, indicating low mean values for BA and DA in comparison with CA (P<0.01). The therapy given to the patient did not influence the BA or DA. BA and DA are delayed and are not influenced by the therapy given.
Subject(s)
Age Determination by Skeleton/methods , Age Determination by Teeth/methods , Fanconi Anemia/physiopathology , Child , Humans , Reproducibility of ResultsABSTRACT
La Anemia de Fanconi es un síndrome de fragilidad cromosómica, autosómico recesivo, caracterizado por presentar malformaciones congénitas muy diversas y en diferentes órganos en el 70 por ciento de los casos; insuficiencia medular progresiva y tendencia a enfermedades malignas: sobre todo leucemia mieloide aguda y tumores sólidos. La afección fue descrita en 1927 por el pediatra suizo, Guido Fanconi, en tres hermanos con diferentes malformaciones congénitas, astenia, infecciones de repetición y sangrados espontáneos por fallo en la función de la médula ósea. El diagnóstico precoz permite un buen control del compromiso hematológico; la realización de los tratamientos quirúrgicos antes de la instauración de la trombopenia; consejo genético para la familia; la identificación presintomática de hermanos afectados o de embarazos cuyos fetos sean posibles donantes de progenitores hematopoyéticos para un hermano comprometido.
Subject(s)
Humans , Child , Fanconi Anemia/diagnosis , Fanconi Anemia/physiopathology , Fanconi Anemia/therapy , Androgens/therapeutic use , Fanconi Anemia/complications , Fanconi Anemia/genetics , Blood Transfusion , Bone Marrow Transplantation , Epoxy Compounds , Adrenal Cortex Hormones/therapeutic use , Diagnosis, Differential , Hematopoietic Stem Cell Transplantation , MitomycinSubject(s)
Bone Marrow Diseases/genetics , Anemia, Aplastic/genetics , Bone Marrow Diseases/physiopathology , Bone Marrow Diseases/therapy , Bone Marrow Transplantation , Fanconi Anemia/epidemiology , Fanconi Anemia/genetics , Fanconi Anemia/physiopathology , Fanconi Anemia/therapy , Female , Hematopoietic Cell Growth Factors/therapeutic use , Humans , Infant , Infant, Newborn , Male , SyndromeSubject(s)
Humans , Male , Female , Infant, Newborn , Infant , Anemia, Aplastic/genetics , Bone Marrow Transplantation , Bone Marrow Diseases/physiopathology , Bone Marrow Diseases/therapy , Hematopoietic Cell Growth Factors/therapeutic use , Fanconi Anemia , Fanconi Anemia/genetics , Fanconi Anemia/physiopathology , Fanconi Anemia/therapySubject(s)
Humans , Male , Female , Infant, Newborn , Infant , Child, Preschool , Child , Adolescent , Adult , Middle Aged , Aged , Bone Marrow Diseases , Fanconi Anemia/physiopathology , Fanconi Anemia/diagnosis , beta-Thalassemia , ThrombocytopeniaABSTRACT
La anemia de Fanconi, entidad autosómica recesiva se caracteriza por pancitopenia, malformaciones congénitas e inestabilidad cromosómica; las manifestaciones clínicas suelen iniciarse a los seis años de edad. Se presenta un paciente de 19 meses de edad cuyo diagnóstico se estableció en fase preanémica. Se discuten aspectos génicos y cromosómicos de la entidad y la importancia de establecer el diagnóstico en etapa temprana.
Subject(s)
Humans , Male , Infant , Fanconi Anemia/physiopathology , Fanconi Anemia/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/geneticsABSTRACT
Se presentan tres casos de anemia de Fanconi, atendidos en la Unidad de Hematologia del Hospital Universitario Ramon Gonzalez Valencia con edades al momento de diagnostico entre 6 y 13 anos, dos de sexo femenino, dos eran hermanos. Todos presentaban baja talla para la edad y malformaciones congenitas diversas. Todos los pacientes recibieron tratamiento con esteroides y androgenos. Un paciente fallecio despues de diez anos de evolucion, por sepsis y otro fallecio tras ocho anos de evolucion, por hemorragia masiva. El tercer paciente se encuentra actualmente en control. Se hace una breve revision de la literatura