Hemophagocytic syndrome in a patient with Fanconi anemia and VACTERL association / Síndrome hemofagocítica em paciente com anemia de Fanconi e associação VACTERL

INTRODUCTION: Hemophagocytic syndrome results from hyperactivity of histiocytes and lymphocytes, triggered by infections, mainly viral by cytomegalovirus, Epstein-Barr and herpes. Fanconi anemia (FA) is a rare genetic disease with heterogeneous symptoms common to other diseases such as VACTERL, a disease of unknown etiology in which there are several congenital malformations. The concomitance of Fanconi and VACTERL anemia occurs in 5 to 30% of FA patients. REPORT: A 14-month-old male infant was admitted to investigate fever, hepatosplenomegaly, and granulopenia. The patient was diagnosed with hemophagocytic syndrome due to hyperferritinemia, bone marrow hemophagocytosis, transaminase elevation, decreased fibrinogen, and cytomegalovirus (CMV) infection confirmed by serology and PCR. The test with mitomycin C (MMC) showed chromosomal fragility. The patient was diagnosed with a VACTERL/FA association for having a clinic and a test compatible with both FA and VACTERL. CONCLUSION: The VACTERL/FA association is seldom described, but is present in pediatric medical practice. This study presented the main clinical-laboratory aspects and reviewed the main aspects of the concurrence of this pathology.

INTRODUÇÃO: A síndrome hemofagocítica decorre da hiperatividade de histiócitos e linfócitos e é desencadeada por infeções, principalmente virais por citomegalovírus, Epstein-barr e herpes. A anemia de Fanconi (AF) é uma doença genética rara com sintomas heterogêneos em comum a outras doenças como a associação VACTERL, uma doença de etiologia desconhecida na qual existe diversas mal formações congênitas. A concomitância da anemia de Fanconi e VACTERL é descrita em 5 a 30% dos pacientes AF. RELATO: Lactente de 14 meses, sexo masculino, admitido para investigar um quadro de febre, hepatoesplenomegalia e granulopenia. Os exames laboratoriais mostraram a hiperferritemia, elevação da transaminases, medula óssea com hemofagocitose e, sorologia e PCR positivos para citomegalovírus (CMV). O paciente foi diagnosticado com síndrome hemofagocítica por citomegalovírus. Como havia também hipoplasia do polegar esquerdo, presença de hemivértebra, agenesia renal e teste positivo de fragilidades cromossômicas com mitomicina C (MMC), o paciente foi diagnosticado com associação VACTERL/AF. CONCLUSÃO: O citomegalovírus quando infecta pacientes com problemas de imunidade como AF, apresenta risco de desencadear a síndrome hemofagocítica. A associação VACTERL/AF é pouco descrita, mas presente na prática médica da pediatria. Esse estudo descreveu os principais aspectos clínicos-laboratoriais e revisou os aspectos fundamenais descritos sobre a concomitância dessas patologias.

IL17A and IL17RA gene polymorphisms in Fanconi anemia

Abstract Fanconi anemia is a rare autosomal recessive disease. In this disease, cytokine pathways can induce the bone marrow failure that is observed in individuals with Fanconi anemia. Interleukin IL-17 exhibits a protective effect in organisms because it induces neutrophil recruitment and shows a pathological role in several models of autoimmune diseases, periodontal disease, cancer, allograft rejection, and graft versus host disease. Polymorphisms in the IL17A and IL17RA genes were evaluated from DNA in saliva, comparing individuals with or without Fanconi anemia, using models of genotypic transmission (additive, dominant, and recessive). Polymorphisms in the IL17A and IL17RA genes (rs2241044 [C allele], rs879577 [C allele], rs9606615 [T allele], and rs2241043 [C allele]) were risk factors for developing Fanconi anemia. We also performed an analysis of gene markers with clinical variables in the Fanconi group. Polymorphisms in the IL17A gene (rs3819025 [A allele] and rs2275913 [G allele], respectively) were associated with an age of less than 20 years (p = 0.026; RP 0.65) and the female sex (p = 0.043; RP 0.88). The IL17RA gene was also associated with age and the presence of leukoplakia (a potentially malignant oral disorder). An age of less than 20 years was associated with rs917864 (T allele; p = 0.036; RP 0.67). The presence of leukoplakia was associated with rs17606615 (T allele; p = 0.042; RP 0.47). To our knowledge, this is the first study that associates IL17A and IL17RA gene polymorphisms with Fanconi anemia and examines rs2241044 polymorphisms in scientific literature thus far.

Graft-versus-host disease and other cutaneous manifestations in pediatric patients transplanted for Fanconi anemia / Doença do enxerto contra o hospedeiro e outras manifestações cutâneas em pacientes pediátricos transplantados por anemia de Fanconi

ABSTRACT Objective: The aim of this study was to elaborate a specific protocol for the assessment and early identification of skin lesions in pediatric patients with Fanconi anemia undergoing hematopoietic stem cell transplantation. Methods: This is a longitudinal, retrospective, and descriptive study. The medical records of 136 pediatric patients with Fanconi anemia who underwent hematopoietic stem cell transplantation between 2008 and 2018 at the Clinical Hospital of the Federal University of Paraná were reviewed. A specific protocol was created for data collection, which included age, sex, skin color, age at diagnosis of Fanconi anemia, transplantation data, family history of consanguinity, and pre- and post-transplant complications. In addition, the data included the presence of graft-versus-host disease of the skin and other organs, its classification, type of lesion, location, and also skin lesions not related to graft-versus-host disease. Results: Among the skin manifestations in pre-transplant period, café-au-lait spots stood out (32.4%). At least one organ was affected by graft-versus-host disease in 55.1% of patients; the most common involvement being the mouth, followed by the skin. Rash and erythema were the most frequently observed cutaneous manifestations of graft-versus-host disease. Conclusion: A high prevalence of cutaneous manifestations of the disease was observed, as well as cutaneous manifestations of graft-versus-host disease. The protocol developed gathers relevant and standardized information for the follow-up of patients with Fanconi anemia undergoing hematopoietic stem cell transplantation, ensuring greater reliability of the information, and its implementation will allow the prospective evaluation of patients.

RESUMO Objetivo: Elaborar um protocolo específico para a avaliação e identificação precoces de lesões de pele em pacientes pediátricos com anemia falciforme submetidos ao transplante de células-tronco hematopoiéticas. Métodos: Estudo longitudinal, retrospectivo e descritivo. Foram revisados os prontuários dos pacientes pediátricos com anemia de Fanconi submetidos a transplante de células-tronco hematopoiéticas entre os anos de 2008 e 2018 no Hospital de Clínicas da Universidade Federal do Paraná, totalizando 136 pacientes. Foi criado um protocolo específico para a coleta de dados, que incluiu: idade, sexo, cor, idade ao diagnóstico da anemia de Fanconi, dados do transplante, história familiar de consanguinidade e complicações pré e pós-transplante. Além disso, foram verificados a presença de doença do enxerto contra o hospedeiro da pele e de outros órgãos, sua classificação, tipo de lesão, localização e, também, lesões de pele não relacionadas à doença. Resultados: Entre as manifestações de pele no período pré-transplante, destacaram-se as manchas café com leite (32,4%). Pelo menos um órgão foi afetado pela doença do enxerto contra o hospedeiro em 55,1% dos pacientes, sendo o acometimento mais comum o de boca, seguido pelo de pele. Exantema e eritema foram as manifestações cutâneas mais frequentemente observadas. Conclusões: Observou-se alta prevalência de manifestações cutâneas próprias da doença, bem como de manifestações cutâneas de doença do enxerto contra o hospedeiro. O protocolo elaborado reúne informações relevantes e padronizadas para o acompanhamento dos pacientes com anemia de Fanconi submetidos ao transplante, garantindo maior confiabilidade das informações, e sua implementação permitirá a avaliação prospectiva dos pacientes.

Disulfiram enhances the antitumor activity of cisplatin by inhibiting the Fanconi anemia repair pathway / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

A series of chemotherapeutic drugs that induce DNA damage, such as cisplatin (DDP), are standard clinical treatments for ovarian cancer, testicular cancer, and other diseases that lack effective targeted drug therapy. Drug resistance is one of the main factors limiting their application. Sensitizers can overcome the drug resistance of tumor cells, thereby enhancing the antitumor activity of chemotherapeutic drugs. In this study, we aimed to identify marketable drugs that could be potential chemotherapy sensitizers and explore the underlying mechanisms. We found that the alcohol withdrawal drug disulfiram (DSF) could significantly enhance the antitumor activity of DDP. JC-1 staining, propidium iodide (PI) staining, and western blotting confirmed that the combination of DSF and DDP could enhance the apoptosis of tumor cells. Subsequent RNA sequencing combined with Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis and cell biology studies such as immunofluorescence suggested an underlying mechanism: DSF makes cells more vulnerable to DNA damage by inhibiting the Fanconi anemia (FA) repair pathway, exerting a sensitizing effect to DNA damaging agents including platinum chemotherapy drugs. Thus, our study illustrated the potential mechanism of action of DSF in enhancing the antitumor effect of DDP. This might provide an effective and safe solution for combating DDP resistance in clinical treatment.

Nursing diagnosis after hematopoietic stem cell transplant due to Fanconi anemia / Diagnósticos de enfermería en trasplantados de células madre hematopoyéticas por anemia de Fanconi / Diagnósticos de enfermagem em transplantados de células-tronco hematopoéticas por anemia de Fanconi

ABSTRACT Objectives: to identify nursing diagnoses in patients who underwent hematopoietic stem-cell transplants due to Fanconi anemia, according to the NANDA-I taxonomy. Methods: exploratory study using a retrospective analysis of 85 records from patients who underwent hematopoietic stem-cell transplants due to Fanconi anemia, developed in a specialize transplant center in the South of Brazil. The results were analyzed using descriptive statistics. Results: 73 different diagnoses were found in 9 out of the 13 domains from the NANDA-I taxonomy. From these, 22 were in 50% or more of the patients investigated, and most of them are related to the domain Safety/Protection. Conclusions: it was possible to identify the nursing diagnosis in the patients who underwent hematopoietic stem cell transplants due to Fanconi anemia, contributing to design a plan for the care of these patients. The same was true for those with other syndromes of chromosomal instability that need to undergo this transplant.

RESUMEN Objetivos: identificar diagnósticos de enfermería en pacientes sometidos a trasplante de células madre hematopoyéticas por anemia de Fanconi, segundo la taxonomía NANDA-I. Métodos: estudio exploratorio mediante análisis retrospectivo de registros de 85 prontuarios de pacientes sometidos a trasplante de células madre hematopoyéticas por anemia de Fanconi, desarrollado en un centro trasplantador de referencia del Sur Brasileño. Analizados los datos utilizándose estadística descriptiva. Resultados: identificaron 73 diferentes diagnósticos en 9 de los 13 dominios de la taxonomía NANDA-I. De estos, 22 diagnósticos atingieron 50% o más de los pacientes investigados, y el mayor número está relacionado al dominio de Seguridad y Protección. Conclusiones: fue posible identificar los diagnósticos de enfermería presentes en pacientes sometidos a un trasplante de células madre hematopoyéticas por anemia de Fanconi, contribuyendo para el delineamento del plan de cuidados de esos pacientes, incluso para aquellos con otros síndromes de inestabilidad cromosómica que necesitan ser sometidos al trasplante.

RESUMO Objetivos: identificar diagnósticos de enfermagem em pacientes submetidos a transplante de células-tronco hematopoéticas por anemia de Fanconi, segundo a taxonomia da NANDA-I. Métodos: estudo exploratório mediante análise retrospectiva dos registros de 85 prontuários de pacientes submetidos a transplante de células-tronco hematopoéticas por anemia de Fanconi, desenvolvido em um centro transplantador de referência do Sul do Brasil. Analisaram-se os dados utilizando-se estatística descritiva. Resultados: identificaram-se 73 diferentes diagnósticos em 9 dos 13 domínios da taxonomia da NANDA-I. Destes, 22 diagnósticos atingiram 50% ou mais dos pacientes investigados, e o maior número está relacionado ao domínio de Segurança e Proteção. Conclusões: foi possível identificar os diagnósticos de enfermagem presentes em pacientes submetidos a um transplante de células-tronco hematopoéticas por anemia de Fanconi, contribuindo para o delineamento do plano de cuidados desses pacientes, assim como para aqueles com outras síndromes de instabilidade cromossômica que necessitam ser submetidos ao transplante.

Fanconi anemia gene-associated germline predisposition in aplastic anemia and hematologic malignancies / 医学前沿

Whether Fanconi anemia (FA) heterozygotes are predisposed to bone marrow failure and hematologic neoplasm is a crucial but unsettled issue in cancer prevention and family consulting. We retrospectively analyzed rare possibly significant variations (PSVs) in the five most obligated FA genes, BRCA2, FANCA, FANCC, FANCD2, and FANCG, in 788 patients with aplastic anemia (AA) and hematologic malignancy. Sixty-eight variants were identified in 66 patients (8.38%). FANCA was the most frequently mutated gene (n = 29), followed by BRCA2 (n = 20). Compared with that of the ExAC East Asian dataset, the overall frequency of rare PSVs was higher in our cohort (P = 0.016). BRCA2 PSVs showed higher frequency in acute lymphocytic leukemia (P = 0.038), and FANCA PSVs were significantly enriched in AA and AML subgroups (P = 0.020; P = 0.008). FA-PSV-positive MDS/AML patients had a higher tumor mutation burden, higher rate of cytogenetic abnormalities, less epigenetic regulation, and fewer spliceosome gene mutations than those of FA-PSV-negative MDS/AML patients (P = 0.024, P = 0.029, P = 0.024, and P = 0.013). The overall PSV enrichment in our cohort suggests that heterozygous mutations of FA genes contribute to hematopoietic failure and leukemogenesis.

Self-perception of periodontal health status among individuals with Fanconi anemia

ABSTRACT Introduction: Fanconi anemia (FA) is a rare genetic disease characterized by congenital malformations and bone marrow failure. One of the most common oral diseases in individuals with FA is periodontitis and adequate self-perception of periodontal status could contribute to its prevention and early detection. Aim: To compare oral health self-perception, measured by a questionnaire, with the clinical oral condition of patients with FA. Methods and Results: Fifty-six patients with FA, over 11 years of age, answered a questionnaire about dental history and self-reported oral health. Decayed, missing, and filled teeth (DMFT), Visible Plaque Index (VPI) and Gingival Bleeding Index (GBI) were measured. The median age of participants was 21 years (min 11, max 44), 31 (55%) were females and 25 (45%) males. Thirty-five (62.5%) participants rated their oral condition as satisfactory and 7 (12.5%) participants reported tooth mobility, 10 (17.9%) exposed roots and 21 (37.5%) gingival bleeding. Clinical examination detected average DMFT = 5.23, VPI = 31.36% and GBI = 33.77%. The gingival bleeding report was more frequent among individuals with higher GBI (p = 0.014). The DMFT was higher in those who had already undergone dental treatments (p = 0.031). There was an association between participants who presented dental caries and who rated their oral health as poor (p = 0.03). The question "Do your gums bleed easily?" had good accuracy in the evaluation of periodontal disease (p = 0.68). Conclusion: Oral health self-perception of individuals with FA about gingival inflammation was associated with their gingival bleeding index.

Diagnóstico citogenético de la anemia de Fanconi en pacientes cubanos con sospecha clínica de la enfermedad / Cytogenetic diagnosis of Fanconi anemia in Cuban patients with clinical suspicion of the disease

Introducción: La anemia de Fanconi es una enfermedad genética rara, de herencia autosómica o ligada al X, caracterizada por inestabilidad genómica e hipersensibilidad a los agentes de entrecruzamiento del ADN, como el diepoxibutano y la mitomicina C (MMC). La respuesta anormal a estas sustancias, que constituye un marcador celular único y se manifiesta como un incremento de la frecuencia de roturas cromosómicas, es la base de su diagnóstico. Objetivo: Realizar el análisis de roturas cromosómicas inducidas por la mitomicina C en linfocitos de sangre periférica de pacientes cubanos con sospecha de anemia de Fanconi. Métodos: Se realizó estudio de roturas cromosómicas inducidas por la mitomicina C a diferentes concentraciones en cultivos de linfocitos T provenientes de sangre venosa periférica en 32 pacientes con sospecha clínica de anemia de Fanconi e igual cantidad de sujetos controles. Resultados: Al finalizar el análisis seis pacientes (20 por ciento) fueron diagnosticados con anemia de Fanconi. De ellos, cuatro presentaron alto porcentaje de rupturas y dos un mosaicismo somático. Desde el punto de vista clínico, cuatro mostraban anemia aplásica y dos exhibían únicamente rasgos dismórficos típicos de la enfermedad. Conclusiones: El ensayo de roturas cromosómicas inducidas por la mitomicina C permitió el diagnóstico definitivo de anemia de Fanconi en pacientes con antecedentes de anemia aplásica, aún sin anomalías congénitas. Este constituye el primer estudio de este tipo en un grupo de pacientes cubanos(AU)

Introduction: Fanconi anemia is a rare genetic disease of autosomal inheritance or X-linked, characterized by genomic instability and hypersensitivity to DNA cross-linking agents like diepoxybutane and mitomycin C (MMC). The basis for its diagnosis is an abnormal response to these substances, which constitutes a unique cell marker and manifests as an increased chromosomal breakage rate. Objective: To perform the analysis of the chromosomal breakages induced by mitomycin C in peripheral blood lymphocytes of Cuban patients with suspicion of Fanconi anemia. Methods: A study was conducted of chromosomal breakages induced by mitomycin C at various concentrations in cultures of T lymphocytes from venous peripheral blood of 32 patients with clinical suspicion of Fanconi anemia and an equal number of control subjects. Results: At the end of the analysis, six patients (20 percent) were diagnosed with Fanconi anemia. Of these, four showed a high percentage of breakages and two had somatic mosaicism. From a clinical point of view, four had aplastic anemia and two only presented dysmorphic features typical of the disease. Conclusions: Evaluation of the chromosomal breakages induced by mitomycin C led to the definitive diagnosis of Fanconi anemia in patients with a history of aplastic anemia, even in the absence of congenital anomalies. This is the first study of its type in a group of Cuban patients(AU)

Desenlace de los pacientes pediátricos con falla medular tratados en un centro de alta complejidad / Outcomes in pediatrics patients diagnosed with bone marrow failure disorders treated in a tertiary care center

INTRODUCCIÓN: Los síndromes de falla medular (SFM) son trastornos infrecuentes, con una incidencia anual de 2-4 casos por millón. Las opciones de tratamiento incluyen terapia de inmunosupresión (TIS) y restaura ción de la hematopoyesis con trasplante de progenitores hematopoyéticas (TPH). OBJETIVO: Analizar los desenlaces de pacientes pediátricos diagnosticados con SFM tratados en una institución de alta complejidad. PACIENTES Y MÉTODO: Estudio retrospectivo de pacientes pediátricos con diagnóstico de SFM que consultaron a la Fundación Valle del Lili, Cali. Se realizo análisis estadístico descriptivo según SFM adquirida (SFMA) y SFM congénita (SFMC). Los desenlaces incluyeron: tratamiento, complicaciones, supervivencia global (SG) en los trasplantados, calculada con el método Kaplan Meier. RESULTADOS: Se incluyeron 24 pacientes con SFM, edad 6,5 ± 4 años, 50% mujeres. El 58% fue ron SFMC, 9 con anemia de Fanconi, 2 disqueratosis congénita, 2 trombocitopenia amegacariocítica congénita, uno anemia Diamond-Blackfan. Doce pacientes con TPH tuvieron SG a 5 años de 83%. SFMA correspondió al 42%, 6 recibieron TIS-TPH, 3 TIS y 1 TPH, la SG del grupo con TIS-TPH fue 86%. Seis pacientes fallecieron, 4/6 relacionadas con infección. CONCLUSIONES: En esta serie fue mayor el número de casos con SFMC. La SG de los pacientes llevados a TPH es comparable con la reportada en estudios recientes. La causa de muerte predominante fue infecciosa que también se ha reportado previamente. El tratamiento instaurado en los pacientes de esta serie mostró resultados favorables en un centro de alta complejidad en un país latinoamericano.

INTRODUCTION: Bone marrow failure (BMF) syndromes are rare disorders with an annual incidence of 2-4 cases per million. Treatment options include immunosuppressive therapy (IST) and hematopoietic stem cell transplantation (HSCT). OBJECTIVE: To analyze the outcomes of pediatric patients diagnosed with BMF treated in a tertiary care center. PATIENTS AND METHODP: Retrospective study of pediatric patients diagnosed with BMF who consulted at Fundación Valle de Lili, Cali. Descriptive statistical analysis was performed according to Acquired BMF (ABMF) and Inherited BMF (IBMF). The outcomes include treatment, complications, overall survival (OS) in transplant patients, calculated using the Kaplan Meier method. RESULTS: We included 24 patients with BMF, average age 6.5 ± 4 years, and 50% were women. 58% presented IBMF, 9 with Fanconi anemia (FA), 2 dyskeratosis congenita, 2 congenital amegakaryocytic thrombocytopenia, and 1 presented Diamond-Blackfan anemia. 12 patients treated with HSCT had a 5-year OS of 83%. ABMF represented 42%. 6 patients received IST-HSCT, 3 received IST, and 1 received HSCT. The OS of the IST-HSCT group was 86%. Six patients died, four of them related to infection. CONCLUSIONS: In this series, there was a higher number of cases with IBMF. The OS of patients treated with HSCT is similar to that reported in recent studies. The most frequent cause of death was of infectious origin which has also been previously reported. The treatment esta blished in the patients showed favorable results in a Latin American tertiary care center.

FANCA Gene in Pakistani Fanconi Anemia Patients: Screening of Mutations in Exon 28 and Exon 29

Objective: This kind of study was conducted first time in Pakistan. Its objective was to ascertain the associated clinical features and analyze the FANCA exon 28 and exon 29 mutations in Pakistani Fanconi anemia (FA) patients. Methods: A total of 38 patients with Fanconi anemia were recruited presenting in the Armed forces institute of pathology (AFIP) Rawalpindi Pakistan. They were enrolled in this study on the basis of comprehensive clinical evaluation and positive Diepoxybutane (DEB)/Mitomycin C Chromosomal breakage test. Genomic DNA was extracted from peripheral blood of patients and age and gender-matched controls. Mutation analysis of FANCA gene was done by conventional Polymerase chain reaction (PCR) and DNA sequencing. Various online tools and software were used for analysis of the obtained data and identification of the sequence alterations in FANCA gene in exon 28 and exon 29 of FA patients. Results and Discussion: The current study on screening of FANCA mutational analysis in exon 28 and exon 29 revealed four novel mutations. These include three missense variants (p.F876L, p.L883H, and p.K921I) in exon 28 and a novel homozygous frameshift variant (p.S947FfsX950) in exon 29. In addition two new intronic variants were also found in this set of patients. Conclusion: The sequence variants identified in this study in 10 (26.31%) FA patients in two out of forty-three FANCA gene exons (i.e., exon 28 and exon 29) strongly emphasize the importance of large-scale molecular studies on FANCA gene in Pakistani population.

Inactivation of the NHEJ Activity of DNA-PKcs Prevents Fanconi Anemia Pre-Leukemic HSC Expansion

Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure and high risk of cancer particularly leukemia. Here we show that inactivation of the non-homologous end-joining (NHEJ) activity of DNA-PKcs prevented DNA damage-induced expansion of FA pre-leukemic hematopoietic stem cells (HSCs). Furthermore, we performed serial BM transplantation to demonstrate that the DNA damage-induced expanded FA HSC compartment contained pre-leukemic stem cells that required the NHEJ activity of DNA-PKcs to induce leukemia in the secondary recipients. These results suggest that NHEJ may collaborate with FA deficiency to promote DNA damage-induced expansion of pre-leukemic HSCs.

Pediatric Dental Care in Fanconi Anemia: A Case Report / Cuidado dental pediátrico en paciente con anemia de Fanconi: Reporte de un caso

ABSTRACT Fanconi Anemia (FA) is an autosomal-recessive genetic disease that is linked to Chromosome X, which is reported in studies with pancytopenia, congenital malformations, and a predisposition to develop cancer. FA 1,360,000 births, and is a condition that occurs in heterozygous subjects in 0.5% of the population. In Mexico, there are, to our knowledge, no epidemiological data on FA, and it is thought that many cases are underdiagnosed. This document reports the clinical case of a patient diagnosed with FA who the cardinal signs of this rare pathology. The pediatric approach involved was performed with a preventive and restorative approach, in addition to the design and placement of a palatal shutter. After a follow-up of more than 12 months, a significant reduction in the recurrence of infections, such as otitis, tonsillitis, and pharyngitis, was observed, suggesting a positive influence of the use of the obturator. In turn with the latter, there was a lower need for transfusions, which may also be related to control of the foci of the infection. The pediatric approach employed in to patients with FA may have significant repercussions on both quality of life and on their patients' general systemic condition, although this is scarcely verifiable due to the rarity of this pathology.

RESUMEN La anemia de Fanconi es una enfermedad genética, autosómica recesiva, ligada al cromosoma X, la cual cursa con pancitopenia, malformaciones congénitas y predisposición a desarrollar cáncer. Afecta a 1:360,000 nacimientos, es un padecimiento que se presenta en sujetos heterocigotos en el 0.5% de la población, en México no existen datos epidemiológicos y se cree que muchos casos se encuentran sub diagnosticados. En el presente documento se reporta el caso clínico de una paciente con diagnóstico de Anemia de Fanconi, que presenta los signos cardinales de esta rara patología. Se realizó el abordaje odontopediátrico con un enfoque preventivo y restaurador, además del diseño y colocación de un obturador palatino. Tras un seguimiento mayor a 12 meses se logró observar una reducción importante en la recurrencia de infecciones como otitis, amigdalitis y faringitis, lo que sugiere una influencia positiva del uso del obturador, y a su vez se pudo constatar una menor necesidad de transfusiones, lo cual puede también estar relacionado con el control de los focos de infección. El abordaje odontopediátrico dirigido a pacientes con Anemia de Fanconi puede tener repercusiones importantes tanto en la calidad de vida como en su condición sistémica general, aunque esto es difícilmente comprobable debido la rareza de dicha patología.

Anemia de Fanconi / Fanconi anemia

Resumen: La anemia de Fanconi es una enfermedad hereditaria con patrón de transmisión autosómico recesivo, asociada con múltiples mutaciones en al menos 20 genes cuyos productos forman parte de los mecanismos de reparación del material genético en las células. Estas mutaciones generan inestabilidad cromosomal que resulta en manifestaciones clínicas muy diversas, las más características son la insuficiencia de médula ósea, anormalidades congénitas y alta predisposición a neoplasias. El diagnóstico clínico de este trastorno es difícil, no sólo por su heterogeneidad, sino también porque es poco sospechado, se necesitan pruebas de laboratorio específicas para poder confirmarlo. De la misma manera, el tratamiento de la enfermedad es difícil porque está enfocado principalmente al manejo de los síntomas y a la prevención de afecciones asociadas, por lo que la anemia de Fanconi debe ser conocida para poder dar a los pacientes el seguimiento correcto.

Abstract Fanconi anemia is a hereditary disease with an autosomal recessive transmission pattern, associated with multiple mutations on at least 20 genes whose products are part of the cell's genetic material repair mechanisms. These mutations produce chromosomal instability, which results in diverse clinical manifestations; the most characteristic is bone marrow failure, congenital abnormalities and a high predisposition to neoplasms. Clinical diagnosis of this disorder is difficult, not only due to its heterogeneity but also because is little suspected, being necessary laboratory test to allow confirmation. In like manner, treatment of the disease is difficult as its mainly focused on symptoms management and prevention of associated conditions, therefore Fanconi anemia needs to be known in order to be able to give patients a correct follow up.

Outcomes of alternative donor allogeneic hematopoietic stem cell transplantation for Fanconi anemia:a five cases report / 中华内科杂志

Five patients with Fanconi anemia who received hematopoietic cell transplantation were retrospectively analyzed. The conditioning regimens included fludarabine, cyclophosphamide and anti-thymocyte globulin. Two patients received both bone marrow and peripheral blood stem cells as the source of stem cell grafts from haploidentical matched related donors, while the others received peripheral blood stem cells from unrelated donors.All patients tolerated well and reached hematopoietic reconstitution. One patient died of intracranial infection.During follow-up,4 patients survived independent of transfusion with full donor chimerism.

Treatment of four cases of Fanconi anemia by allogeneic hematopoietic stem cell transplantation with low intensity conditional regimen / 中华血液学杂志

Objective@#To evaluate the efficiency and safety of low intensity conditional regimen for children with Fanconi anemia (FA) receiving allogenic hematopoietic stem cells transplantation (allo-HSCT).@*Methods@#Four patients diagnosed as Fanconi anemia were enrolled in this study. One patient received HLA-identical sibling donor hematopoietic stem cell transplantation, two patients underwent unrelated donor matched (UD) HSCT, and one patient received unrelated cord blood transplantation. The conditional regimen consisted of Busulfan with low dose of cyclophosphamide.@*Results@#All 4 cases succeeded in allo-HSCT. The median time for neutrophils engraftment was 11(9-15) day, median time to platelets (PLT) engraftment was 12 (8-28) day. One case occurred with grade I of aGVHD, 1 case with hemorrhagic cystitis. No patient happened with hepatic veno-occlusive disease (VOD).@*Conclusion@#Low intensity of conditional regimen is efficient and safe which should be recommended for FA patients with HSCT.

A never-ending story: the steadily growing family of the FA and FA-like genes

Abstract Among the chromosome fragility-associated human syndromes that present cancer predisposition, Fanconi anemia (FA) is unique due to its large genetic heterogeneity. To date, mutations in 21 genes have been associated with an FA or an FA-like clinical and cellular phenotype, whose hallmarks are bone marrow failure, predisposition to acute myeloid leukemia and a cellular and chromosomal hypersensitivity to DNA crosslinking agents exposure. The goal of this review is to trace the history of the identification of FA genes, a history that started in the eighties and is not yet over, as indicated by the cloning of a twenty-first FA gene in 2016.

Treatment of Tongue Cancer in Patient with Fanconi's Anemia / 대한이비인후과학회지

Fanconi's anemia is a rare autosomal recessive genetic disorder characterized by congenital abnormalities and anaplastic anemia. Patients with this disorder has predisposition for leukemia, specifically acute myeloid leukemia. Risk for head and neck solid tumors are also increased. Head and neck cancers in patients with Fanconi's anemia are significantly different from those in patients without Fanconi's anemia in frequency, distribution, clinical course, and treatment. Therefore, we report a case of 23-year-old male with Fanconi's anemia, who presented with an oral tongue cancer treated with radical excision, bilateral neck dissection and careful postoperative radiation therapy.

Fanconi Anemia Genes and Reactive Oxygen Species in Cancer Development.

Fanconi Anemia (FA) is an autosomal recessive disease of childhood. However, the FA pathway is responsible for the development of leukemia and the other cancers. It has been also demonstrated that FA, an only human genomic instability syndrome is very sensitive to oxidative stress and ROS overproduction. In the present work, we consider major mechanisms of antioxidant protection in FA cells. We showed that there are two types of such mechanisms: the suppression of ROS overproduction by FA genes through the activation of basic FA anemia proteins under the conditions of oxidative stress and the application of free radical scavengers able to react with iron-dependent ROS such as flavonoids rutin and quercetin. The last nontoxic compounds of vitamin P group might be recommended for the treatment of FA anemia patients. Then, we discussed the role of FA anemia proteins in cancer development.

Aspergilosis pulmonar invasiva: reporte de un caso / Invasive pulmonary aspergillosis: A case report

El hongo Aspergillus spp. causa infecciones oportunistas en huéspedes inmunocomprometidos. Cursa con una variedad de síndromes clínicos en el pulmón, que incluyen aspergilosis invasiva, aspergilosis pulmonar necrótica crónica, aspergilosis broncopulmonar alérgica y aspergiloma, cuya manifestación depende del tipo de relación con el huésped. El aspergiloma resulta de lesiones colonizadas por Aspergillus spp. en el árbol bronquial, en tanto que las formas invasivas se caracterizan por la presencia de hifas por debajo de la membrana basal del árbol bronquial. El objetivo de este trabajo es describir el caso de una paciente con aspergilosis pulmonar invasiva en su forma de traqueobronquitis seudomembranosa, considerando el curso clínico, el diagnóstico y el manejo paraclínico. Se trató de una paciente de cinco años de edad con antecedentes de anemia de Fanconi, que fue llevada a consulta con neutropenia febril y neumonía. Se inició el tratamiento antibiótico con cefepime, sin mejoría clínica. La tomografía computadorizada (TC) de tórax reveló opacidades parenquimatosas en ambas bases pulmonares. En una fibrobroncoscopia se encontró una lesión exofítica blanquecina en el bronquio principal derecho, que se sometió a biopsia, y se practicó un lavado broncoalveolar. En el examen de histopatología se hallaron hifas tabicadas a 45°, y el resultado del cultivo reveló la presencia del complejo Aspergillus flavi, por lo que se inició la administración de voriconazol. Se revisaron los reportes en la literatura científica sobre la infección pulmonar por Aspergillus spp. en niños, con énfasis en los síndromes clínicos, y en su manejo y tratamiento. Ante la presencia de síntomas respiratorios en pacientes pediátricos con enfermedades hematológicas que cursen con neutropenia febril, es indispensable considerar como agentes etiológicos los hongos, entre los cuales Aspergillus spp. se presenta frecuentemente causando diferentes síndromes clínicos.

The fungus Aspergillus spp. causes infections in immunocompromised hosts and produces a variety of clinical syndromes including lung tracheobronchial, chronic necrotizing pulmonary and allergic bronchopulmonary manifestations, as well as aspergilloma, depending on the type of host-fungus relationship involved. Aspergilloma is usually colonized by Aspergillus spp. lesions in the bronchial tree, while invasive forms are characterized by the presence of hyphae below its basement membrane. The objective of the present study was to describe the case of a pediatric patient with invasive pulmonary aspergillosis in the form of pseudomembranous tracheobronchitis, including the clinical course, diagnostic approach and paraclinical care provided. The patient was a 5-year-old female with a history of Fanconi anemia who presented with febrile neutropenia and pneumonia. Antibiotic treatment with cefepime provided no improvement in the patient´s condition and computed tomography of the thorax revealed bibasilar pulmonary opacities. Bronchoalveolar lavage and a lesion biopsy were performed after diagnostic bronchoscopy showed a white exophytic lesion. Since pathologic examination revealed numerous septate fungal hyphae exhibiting 45° branching compatible with Aspergillus spp., the patient was treated with voriconazole. Bronchoalveolar lavage culture produced fungi of the Aspergillus flavi complex. A review of pulmonary Aspergillus spp. infection in children is also included, with emphasis on the management and treatment of clinical syndromes. In pediatric patients with hematological diseases who present with febrile neutropenia and respiratory symptoms, it is essential to consider fungi as potential etiologic agents including Aspergillus spp., which is common and causes a variety of clinical syndromes.

Clinical and cytogenetic features of a Brazilian sample of patients with phenotype of oculo-auriculo-vertebral spectrum: a cross-sectional study / Características clínicas e citogenéticas de uma amostra brasileira de pacientes com fenótipo de espectro óculo-aurículo-vertebral: um estudo transversal

CONTEXT AND OBJECTIVE: Oculo-auriculo-vertebral spectrum (OAVS) is considered to be a defect of embryogenesis involving structures originating from the first branchial arches. Our objective was to describe the clinical and cytogenetic findings from a sample of patients with the phenotype of OAVS. DESIGN AND SETTING: Cross-sectional study in a referral hospital in southern Brazil. METHODS: The sample consisted of 23 patients who presented clinical findings in at least two of these four areas: orocraniofacial, ocular, auricular and vertebral. The patients underwent a clinical protocol and cytogenetic evaluation through high-resolution karyotyping, fluorescence in situ hybridization for 5p and 22q11 microdeletions and investigation of chromosomal instability for Fanconi anemia. RESULTS: Cytogenetic abnormalities were observed in three cases (13%) and consisted of: 47,XX,+mar; mos 47,XX,+mar/46,XX; and 46,XX,t(6;10)(q13; q24). We observed cases of OAVS with histories of gestational exposition to fluoxetine, retinoic acid and crack. One of our patients was a discordant monozygotic twin who had shown asymmetrical growth restriction during pregnancy. Our patients with OAVS were characterized by a broad clinical spectrum and some presented atypical findings such as lower-limb reduction defect and a tumor in the right arm, suggestive of hemangioma/lymphangioma. CONCLUSIONS: We found a wide range of clinical characteristics among the patients with OAVS. Different chromosomal abnormalities and gestational expositions were also observed. Thus, our findings highlight the heterogeneity of the etiology of OAVS and the importance of these factors in the clinical and cytogenetic evaluation of these patients. .

CONTEXTO E OBJETIVO: O espectro oculoauriculovertebral (EOAV) é considerado um defeito de embriogênese envolvendo estruturas originadas a partir dos primeiros arcos branquiais. Nosso objetivo foi descrever os achados clínicos e citogenéticos de uma amostra de pacientes com fenótipo de EOAV. TIPO DE ESTUDO E LOCAL: Estudo transversal em um hospital de referência no sul do Brasil. MÉTODOS: A amostra foi composta de 23 pacientes que apresentaram achados clínicos em pelo menos duas das quatro áreas: orocraniofacial, oculares, auriculares e vertebrais. Os pacientes foram submetidos a um protocolo clínico e avaliação citogenética através do cariótipo de alta resolução, hibridização in situ fluorescente para as microdeleções 5p e 22q11 e pesquisa de instabilidade cromossômica para anemia de Fanconi. RESULTADOS: Alterações citogenéticas foram observadas em três casos (13%) e consistiam de: 47,XX,+mar; mos 47,XX,+mar/46,XX e 46,XX,t(6;10)(q13;q24). Observamos casos de EOAV com história de exposição gestacional à fluoxetina, ácido retinoico e crack. Um dos nossos pacientes foi um gêmeo monozigótico discordante que teve restrição de crescimento assimétrica durante a gravidez. Nossos pacientes com EOAV foram caracterizados por um amplo espectro clínico e alguns apresentaram achados clínicos atípicos como um defeito de redução de membro inferior e um tumor do braço direito, sugestivo de hemangioma/linfangioma. CONCLUSÕES: Verificamos grande variedade de características clínicas entre os pacientes com EOAV. Também foram observadas diferentes anomalias cromossômicas e exposições gestacionais. Assim, nossos achados salientam a heterogeneidade da etiologia do EOAV e a importância desses fatores na avaliação clínica e citogenética desses pacientes. .