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.

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.

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)

Manifestações orofaciais associadas aos diferentes tipos de anemias / Orofacial manifestations associated with different types of anemia

Introduction: Anemias correspond to hematological disorders that can present in the oral cavity and face. Objective: To review the literature on the main types of anemic disorders and their orofacial manifestations, considering the aspects of interest to dentists. Methodology: This is a literature review, in which articles were selected in Portuguese and English, indexed in the Scielo, Medline/Pubmed and Lilacs databases with the descriptors: Anemia, Oral Manifestations, Jaw Abnormalities and their correspondents in Portuguese language. Literature review: Anemic disorders associated with orofacial signs and symptoms include mainly Iron-Deficiency, Megaloblastic, Fanconis, Sickle Cell, Thalassemia and Aplastic Anemia. The manifestations vary from burning and painful symptoms in the tongue, pallor of lips and mucosa, stomatitis, atrophic glossitis, angular cheilitis, susceptibility to candidiasis and peri-odontal disease. Also, dental changes, hyposalivation, malocclusion, osteomyelitis of the jaw, paraesthesia of the mental nerve and orofacial pain are included. Conclusion: These manifestations can be the first signs of the presence of anemia, which gives the dentist an important role in early diagnosis and proper management of dental treatment.

Introdução: As anemias correspondem a distúrbios hematológicos que podem apresentar manifestações na cavidade oral e face. Objetivo: Revisar a literatura acerca dos principais tipos de distúrbios anêmicos e suas manifestações orofaciais, considerando os aspectos de interesse aos cirurgiões-dentistas. Metodologia: Trata-se de uma revisão de literatura, em que foram selecionados artigos em português e inglês, indexados nas bases de dados do Scielo, Medline/Pubmed e no Lilacs, com os descritores: Anemia, Oral Manifestations, Jaw Abnormalities e seus correspondentes na língua portuguesa. Revisão de literatura: Os distúrbios anêmicos associados aos sinais e sintomas orofaciais incluem principalmente a Anemia Ferropriva, Megaloblástica, de Fanconi, Falciforme, Talassemia e Anemia Aplástica. As manifestações variam de ardência e sintomatologia dolorosa em língua, palidez de lábios e mucosa, estomatite, glossite atrófica, queilite angular, suscetibilidade a candidíase e doença periodontal. Ainda, englobam-se as alterações dentárias, hipossalivação, má oclusão, osteomielite da mandíbula, parestesia do nervo mental e dor orofacial. Conclusão: Essas alterações podem ser os primeiros sinais da presença da anemia, o que confere ao cirurgião-dentista um importante papel no seu diagnóstico precoce e condução adequada ao tratamento odontológico.

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.

Fanconi Anaemia in South African Patients with Afrikaner Ancestry

Background. Fanconi anaemia (FA) is a rare genetic disorder of impaired DNA repair that results in physical and haematological consequences in affected individuals. In South Africa (SA), individuals with Afrikaner ancestry are at an increased risk of inheriting disease-causing FA mutations, owing to the three common FANCA (FA, complementation group A) founder mutations present in this population subgroup.Objectives. To describe the physical phenotype of SA patients with FANCA mutations for the purpose of recommending appropriate care for affected individuals.Methods. A structured clinical examination and file-based review were used to evaluate the physical phenotype of 7 patients with compound heterozygous and homozygous FANCA founder mutations, and 1 patient with confirmed FANCA complementation analysis. Descriptive statistical analysis was used to determine the frequency of physical anomalies in Afrikaner patients and to compare the described phenotype to other FA cohorts, including a previously clinically characterised black SA FA cohort.Results. An earlier age of diagnosis of FA in Afrikaner patients, a high frequency of somatic anomalies and a higher-than-expected incidence of the VACTERL/H phenotype were noted.Conclusions. Based on our findings, recommendations for the care of FA patients with Afrikaner ancestry are made, including renal ultrasound evaluation at diagnosis and hearing screening

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.

Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Genetic Rare Diseases in Children / 임상소아혈액종양

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) has been established as an important curative method in genetic rare diseases in children. However, adverse effects have been obstacles for successful outcomes. This study aims to review the transplant outcomes of genetic rare diseases over the last 2 decades, to analyze the prognostic factors that may affect outcome, and to suggest future perspective of HSCT in these diseases.METHODS: Seventeen patients younger than 18 years who were transplanted at Department of Pediatrics, Chonnam National University Hospital and Chonnam National University Hwasun Hospital from 1996 to 2015 were retrospectively reviewed. Outcomes were analyzed by donor source, intensity of conditioning [myeloablative conditioning (MAC) vs. reduced-intensity conditioning (RIC)], and disease type.RESULTS: The 5-year Kaplan-Meier overall survival (OS), and event-free survival (EFS) was 64.7±14.3% and 52.9±12.9%, respectively. Among subgroups, the 5-year OS was 61.5±15.8% after RIC as compared to 28.6±17.1% after MAC (P=0.27). The 5-year EFS was 60.0±25.0% after matched sibling donor transplants, 62.5±20.4% after mismatched related/unrelated bone marrow/peripheral blood stem cell transplants, and 28.6±17.1% after unrelated umbilical cord blood transplants, respectively. The 5-year OS according to disease type was as follows: 60.0±21.9% for Fanconi anemia, 50.0±25.0% for familial hemophagocytic lymphohisticytosis. All patients with primary immunodeficiency survived, but none with adrenoleukodystrophy.CONCLUSION: Although definitive conclusions cannot be drawn due to the limited number of cases, RIC may be preferred in select, genetic rare diseases. Better strategies are required to improve outcomes after cord blood transplantation. Moreover, special attention should be given to minimize late complications in children.

Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Genetic Rare Diseases in Children / 임상소아혈액종양

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) has been established as an important curative method in genetic rare diseases in children. However, adverse effects have been obstacles for successful outcomes. This study aims to review the transplant outcomes of genetic rare diseases over the last 2 decades, to analyze the prognostic factors that may affect outcome, and to suggest future perspective of HSCT in these diseases. METHODS: Seventeen patients younger than 18 years who were transplanted at Department of Pediatrics, Chonnam National University Hospital and Chonnam National University Hwasun Hospital from 1996 to 2015 were retrospectively reviewed. Outcomes were analyzed by donor source, intensity of conditioning [myeloablative conditioning (MAC) vs. reduced-intensity conditioning (RIC)], and disease type. RESULTS: The 5-year Kaplan-Meier overall survival (OS), and event-free survival (EFS) was 64.7±14.3% and 52.9±12.9%, respectively. Among subgroups, the 5-year OS was 61.5±15.8% after RIC as compared to 28.6±17.1% after MAC (P=0.27). The 5-year EFS was 60.0±25.0% after matched sibling donor transplants, 62.5±20.4% after mismatched related/unrelated bone marrow/peripheral blood stem cell transplants, and 28.6±17.1% after unrelated umbilical cord blood transplants, respectively. The 5-year OS according to disease type was as follows: 60.0±21.9% for Fanconi anemia, 50.0±25.0% for familial hemophagocytic lymphohisticytosis. All patients with primary immunodeficiency survived, but none with adrenoleukodystrophy. CONCLUSION: Although definitive conclusions cannot be drawn due to the limited number of cases, RIC may be preferred in select, genetic rare diseases. Better strategies are required to improve outcomes after cord blood transplantation. Moreover, special attention should be given to minimize late complications in children.

Association between clinical outcome and gene mutation in children with Fanconi anemia / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the association between clinical outcome and gene mutations in children with Fanconi anemia (FA).</p><p><b>METHODS</b>A retrospective analysis was performed for the clinical data of six children with the same severity of FA and receiving the same treatment. At first, single cell gel electrophoresis and chromosome breakage induced by mitomycin C were performed for diagnosis. Then the gene detection kit for congenital bone marrow failure diseases or complementation test was used for genotyping of FA. Finally the association between the clinical outcome at 3, 6, 9, or 12 months after treatment and gene mutation was analyzed.</p><p><b>RESULTS</b>Of all the six FA children, five had FANCA type disease, and one had FANCM type disease; four children carried two or more FA gene mutations. Among the children with the same severity of FA, those with more FA mutations had a younger age of onset and poorer response to medication, and tended to progress to a severe type.</p><p><b>CONCLUSIONS</b>Children carrying more than two FA mutations have a poor clinical outcome, and hematopoietic stem cell transplantation should be performed as soon as possible.</p>

Manejo estomatológico de anemia de Fanconi en odontología pediátrica. Reporte de caso / Stomatological management of Fanconi anemia in pediatric dentistry. Case report

La anemia de Fanconi (FA) es una enfermedad autos6mica recesiva que se caracteriza por presentar anemia aplasica, además de malformaciones congénitas renales, cardiacas, esqueléticas, dermatológicas, y aumento en la incidencia de neoplasias malignas. Los pacientes con FA son más susceptibles de presentar sangrado e infecciones, síntomas relacionados con trombocitopenia y neutropenia. El prop6sito del presente reporte es describir el manejo estomato16gico proporcionado a un niño de 9 años y 9 meses de edad con diagn6stico de Anemia de Fanconi, en la Clínica del Posgrado en Estomatología Pediátrica...

Fanconi Anemia (FA) is an autosomal recessive disorder, characterized by aplastic anemia, congenital malformations in kidney, heart, skeletal and skin structures, and with increased incidence to malignancies. FA patients are likely to have bleeding and infections, which are associated with thrombocytopenia and neutropenia symptoms. The purpose of this paper is to report the stomatological management delivered to a child of 9 years and 9 months of age, diagnosed with Fanconi Anemia, in the clinic of Pediatric Dentistry...

Prevalencia de intento de suicidio adolescente y factores de riesgo asociados en una comuna rural de la provincia de Concepción / Suicide attempts among Chilean adolescents

Background: Suicide mortality rates are increasing among teenagers. Aim: To study the prevalence and predictive factors of suicide attempts among Chilean adolescents. Material and Methods: A random sample of 195 teenagers aged 16 ± 1 years (53% males) answered an anonymous survey about their demographic features, substance abuse, the Osaka suicidal ideation questionnaire, Smilksten familial Apgar. Beck hopelessness scale, Beck depression scale and Coppersmith self-esteem inventory. Results: Twenty five percent of respondents had attempted suicide at least in one occasion during their lives. These attempts were significantly associated with female gender, absent parents, family dysfunction, drug abuse, smoking, low self-esteem, hopelessness, depression and recent suicidal ideation. A logistic regression analysis accepted female gender, smoking and recent suicidal ideation as significant independent predictors of suicide attempt. Conclusions: Suicide attempted is common among teenagers and its predictors are female sex, smoking and previous suicidal ideation.

Diagnosis and Treatment of Pediatric Acute Myeloid Leukemia / 임상소아혈액종양

Acute myeloid leukemia (AML) is a heterogeneous malignancy that comprises 25-30% of pediatric leukemias in Korea. Several inherited diseases, such as Down syndrome and Fanconi anemia, predispose towards AML leukemogenesis. Subgrouping of AML is a key diagnostic step, previously done with the French-American-British (FAB) classification and recently complemented by that of the World Health Organization (WHO). An important feature of AML is the possibility of chloroma at diagnosis, which, if detected, requires follow-up evaluation to determine treatment response. Numerous genetic abnormalities with prognostic relevance have recently been found, the most important of which include those of the core-binding factor (CBF) leukemias, and FLT3-ITD mutation. These genetic abnormalities, combined with patient response to initial treatment, allow for a scheme of risk stratification, and the current consensus is to treat low risk patients with chemotherapy only, whereas high risk patients may receive allogeneic transplant in first remission, although the benefits of transplant remain inconclusive. Overall, the outcome of children and adolescents with AML has improved significantly so that many clinical trials now report event-free survival of around 60%. However, much of this improvement stems from better supportive care and transplant methods, and the genetics-based diagnostic advances in AML have yet to result in enhanced treatment. New therapeutics, including possibly targeted therapy, are necessary to further improve the outcome of pediatric AML.

Molecular and prenatal diagnosis of a family with Fanconi anemia by next generation sequencing / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To provide prenatal diagnosis for a pregnant woman who had given birth to a child with Fanconi anemia with combined next-generation sequencing (NGS) and Sanger sequencing.</p><p><b>METHODS</b>For the affected child, potential mutations of the FANCA gene were analyzed with NGS. Suspected mutation was verified with Sanger sequencing. For prenatal diagnosis, genomic DNA was extracted from cultured fetal amniotic fluid cells and subjected to analysis of the same mutations.</p><p><b>RESULTS</b>A low-frequency frameshifting mutation c.989_995del7 (p.H330LfsX2, inherited from his father) and a truncating mutation c.3971C>T (p.P1324L, inherited from his mother) have been identified in the affected child and considered to be pathogenic. The two mutations were subsequently verified by Sanger sequencing. Upon prenatal diagnosis, the fetus was found to carry two mutations.</p><p><b>CONCLUSION</b>The combined next-generation sequencing and Sanger sequencing can reduce the time for diagnosis and identify subtypes of Fanconi anemia and the mutational sites, which has enabled reliable prenatal diagnosis of this disease.</p>

The study of genetic instability in patients with Dyskeratosis congenital / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the genetic instability in patients with Dyskeration congenita.</p><p><b>METHODS</b>The spontaneous chromosome instability of lymphocytes from 4 DC patients, 29 FA patients and 24 healthy volunteers was assessed with comet assay. The percent of DNA in comet head (HeadDNA%）, the percent of DNA in comet tail (TailDNA%）, tail moment (TM), olive tail moment (OTM), the comet cell percentage (CCP) were compared between groups. And the results of MMC test, PNH clones and karotype were analysed additionally. The correlation between TM, OTM, CCP and the severity degree of bone marrow failure in DC group were evaluated.</p><p><b>RESULTS</b>①PNH clones and karotype abnormalities were not found in 4 DC patients. ②TM (6.77 ± 0.90), OTM（6.19 ± 0.80) and CCP [(46.00 ± 5.03) %] in DC were significantly higher than those in normal control group [0.61 ± 0.49, 0.66 ± 0.42, (5.91 ± 3.19)%, P<0.05], however, not distinguished from FA patients [7.81 ± 3.58, 6.65 ± 2.21, (56.03 ± 13.47) %, P ≥ 0.05]. The aberrant cell percent at the MMC concentration of 80 μg/L in DC group was significantly lower than that in FA group [(21.00 ± 3.16) % vs (31.97 ± 6.33)%, P=0.003]. ③The correlation between TM, OTM, CCP and the severity of bone marrow failure in DC group were not found (P>0.05).</p><p><b>CONCLUSION</b>DC patients were of significantly increased genetic instability and normal DNA repair, which was different from that in FA patients. And there was no correlation between the degree of genetic instability and the severity of bone marrow failure in DC patients presenting as aplastic anemia.</p>