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1.
Dermatol Online J ; 25(1)2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30710899

RESUMO

A 26-year-old man with a history of congenital bilateral microtia, unilateral renal agenesis, left aural atresia, and right external auditory canal occlusion admitted for right rib cartilage graft harvest and left ear re-construction. Following surgery, an ulceration with violaceous borders and a yellow fibrinous base unresponsive to broad-spectrum antibiotics developed at the harvest site. The wound was expanding and not responsive to systemic broad-spectrum antibiotics. Biopsy revealed a dense dermal infiltrate of neutrophils with negative tissue cultures consistent with pyoderma gangrenosum (PG). He was treated with systemic, intralesional, and topical steroids, as well as doxycycline. Three weeks after the diagnosis of PG, he was found to have persistent anemia and leukopenia. Bone marrow aspiration analysis was consistent with hypocellular myelodysplastic syndrome and genetic testing was consistent with Fanconi anemia. There is a well-known association of PG with hematological disorders. Fanconi anemia is a rare genetic hematologic disorder with congenital defects leading to bone marrow failure and malignancy in long-standing disease. In our patient, we consider his development of PG a paraneoplastic sign associated with the onset of his hypocellular myelodysplastic syndrome.


Assuntos
Anemia de Fanconi/diagnóstico , Síndromes Mielodisplásicas/patologia , Síndromes Paraneoplásicas/patologia , Complicações Pós-Operatórias/patologia , Pioderma Gangrenoso/patologia , Corticosteroides/uso terapêutico , Adulto , Cartilagem/transplante , Anormalidades Congênitas/cirurgia , Microtia Congênita/complicações , Orelha/anormalidades , Orelha/cirurgia , Anemia de Fanconi/complicações , Humanos , Masculino , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/diagnóstico , Neutrófilos/patologia , Síndromes Paraneoplásicas/diagnóstico , Síndromes Paraneoplásicas/etiologia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Pioderma Gangrenoso/diagnóstico , Pioderma Gangrenoso/tratamento farmacológico , Pioderma Gangrenoso/etiologia , Costelas/cirurgia , Rim Único/complicações
2.
Dig Liver Dis ; 51(2): 242-246, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30249500

RESUMO

BACKGROUND AND AIMS: The primary clinical characteristics of Fanconi Anemia (FA) include typical physical features, progressive bone marrow failure, and an increased incidence of neoplasms, including esophageal carcinoma. Currently, there are no data regarding endoscopic findings or the interval time to malignancy in these patients. Data about the contribution of Human Papilloma Virus (HPV) to esophageal carcinoma is conflicting. Our objective is to document the upper gastrointestinal (GI) findings at baseline, document cancer incidence, and evaluate the role of HPV among these cancers. METHODS: We reviewed endoscopic and clinical data of FA subjects who participated in active surveillance before cancer diagnosis. Incident esophageal cancers were stained for HPV p16 protein. RESULTS: Eight FA patients were included (men 62.5%; median age at first endoscopy 20 years, median endoscopies number: 5.5). At baseline, 8/8 had endoscopic evidence for reflux esophagitis. In 3/8 the reflux esophagitis was mild and in 5/8 it was moderate or severe. During the follow up time (median time 4.5 years 2/8 developed Barrett's esophagus and 2/8 patients had incident esophageal squamous cell carcinoma during follow up, at intervals of eight and eighteen months from the previous upper endoscopy. Both cancers stained negative for HPV P16. CONCLUSIONS: FA subjects have both an extremely high risk for esophageal cancer within short intervals and a very high prevalence of reflux esophagitis with various severities. Active surveillance programs in specialized centers including annual upper endoscopies should be considered in these patients.


Assuntos
Endoscopia Gastrointestinal , Neoplasias Esofágicas , Esofagite Péptica , Anemia de Fanconi , Infecções por Papillomavirus , Adulto , Endoscopia Gastrointestinal/métodos , Endoscopia Gastrointestinal/estatística & dados numéricos , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/patologia , Esofagite Péptica/diagnóstico , Esofagite Péptica/epidemiologia , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/epidemiologia , Anemia de Fanconi/fisiopatologia , Feminino , Humanos , Incidência , Israel/epidemiologia , Masculino , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/epidemiologia , Prevalência , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
3.
Genet Med ; 21(1): 189-194, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29904161

RESUMO

PURPOSE: In about 10% of patients affected by Fanconi anemia (FA) the diagnosis is delayed until adulthood, and the presenting symptom in these "occult" FA cases is often a solid cancer and cancer treatment-related toxicity. Highly predictive clinical parameter(s) for diagnosing such an adult-onset cases are missing. METHODS: (1) Exome sequencing (ES), (2) Sanger sequencing of FANCA, (3) diepoxybutane (DEB)-induced chromosome breakage test. RESULTS: ES identified a pathogenic homozygous FANCA variant in a patient affected by Sertoli cell-only syndrome (SCOS) and in his azoospermic brother. Although they had no overt anemia, chromosomal breakage test revealed a reverse somatic mosaicism in the former and a typical FA picture in the latter. In 27 selected SCOS cases, 1 additional patient showing compound heterozygous pathogenic FANCA variants was identified with positive chromosomal breakage test. CONCLUSION: We report an extraordinarily high frequency of FA in a specific subgroup of azoospermic patients (7.1%). The screening for FANCA pathogenic variants in such patients has the potential to identify undiagnosed FA before the appearance of other severe clinical manifestations of the disease. The definition of this high-risk group for "occult" FA, based on specific testis phenotype with mild/borderline hematological alterations, is of unforeseen clinical relevance.


Assuntos
Azoospermia/genética , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Anemia de Fanconi/genética , Síndrome de Células de Sertoli/genética , Adulto , Idade de Início , Azoospermia/sangue , Azoospermia/complicações , Azoospermia/patologia , Quebra Cromossômica , Exoma/genética , Anemia de Fanconi/sangue , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/patologia , Feminino , Regulação da Expressão Gênica/genética , Humanos , Masculino , Mutação , Linhagem , Fenótipo , Síndrome de Células de Sertoli/sangue , Síndrome de Células de Sertoli/complicações , Síndrome de Células de Sertoli/patologia , Testículo/metabolismo , Testículo/patologia , Sequenciamento Completo do Exoma
5.
Vnitr Lek ; 64(5): 488-500, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30193517

RESUMO

This review summarizes the pathophysiology, genetic background and clinical symptoms of anemias belonging to the group of inherited bone marrow failure syndromes with unilineage failure of erythropoiesis. It sums up the current knowledge of three diseases: Diamond-Blackfan anemia, congenital dyserythropoietic anemia and Fanconi anemia whose pathophysiology was elucidated in detail during the last decade, owing to the rapid development of new molecular-genetic techniques, especially next-generation sequencing. Fanconi anemia is included in this overview because of macrocytosis and/or anemia detected in the majority of the patients before they develop bone marrow failure. The paper also aims at pointing out typical associated anomalies in these diseases which might be overlooked and which can lead to early diagnosis. Unfortunately, the correct diagnosis is often established later in adulthood and, in some cases, as late as at the time of manifestation of malignant disease. Accurate and timely diagnosis of these conditions is extremely important for the determination of appropriate treatment approach, diagnosis of affected family members (especially in the process of bone marrow donor search), and genetic counselling, which can substantially influence the prognosis of these diseases. Key words: congenital dyserythropoietic anemia - Diamond-Blackfan anemia - DNA repair - dyserythropoiesis - Fanconi anemia - inherited bone marrow failure - ribosomopathies.


Assuntos
Anemia Aplástica , Doenças da Medula Óssea , Anemia de Fanconi , Hemoglobinúria Paroxística , Anemia Aplástica/complicações , Anemia Aplástica/diagnóstico , Doenças da Medula Óssea/complicações , Doenças da Medula Óssea/diagnóstico , Anemia de Fanconi/diagnóstico , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/diagnóstico , Humanos
6.
Pediatr Blood Cancer ; 65(12): e27371, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30070008

RESUMO

Hematopoietic cell transplantation (HCT) remains until now the only curative modality for hematological manifestations in patients with Fanconi anemia (FA). The doses of alkylating agents used in the conditioning of this patient population before HCT are usually significantly decreased due to the genomic instability of the FA cells. FA patients with renal impairment represent a dilemma because of the need to further modify the conditioning regimen according to the degree of renal impairment to avoid additional toxicity. At our institution, we successfully transplanted three FA patients using an ultra-modified regimen.


Assuntos
Ciclofosfamida/administração & dosagem , Anemia de Fanconi/terapia , Transplante de Células-Tronco Hematopoéticas , Nefropatias/terapia , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Anemia de Fanconi/complicações , Anemia de Fanconi/diagnóstico , Feminino , Humanos , Nefropatias/complicações , Nefropatias/diagnóstico , Masculino , Vidarabina/administração & dosagem
7.
Med Hypotheses ; 119: 29-31, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30122487

RESUMO

Currently one of the greater challenges is the diagnosis and treatment of cancer. Many studies address the genetic and metabolic aspects to support in early diagnosis and increase the survival of individuals at high risk. Individuals with Fanconi anemia can be included in this high risk group because they have a predisposition to develop head and neck cancer. The use of salivary enzymes as biomarkers to detect the changes in oral tissue at the initial phase seems viable, because saliva is easy to obtain, it moisture oral mucosa and cells metabolic compounds can be found on it. Due to the metabolic characteristics of the cancer cell, an increase in Lactate Dehydrogenase (LDH) may indicate a carcinogenesis process. The hypothesis of this study is to use of salivary LDH as a tool in the early diagnosis of oral cancer on a high risk group such as Fanconi anemia's patients.


Assuntos
Anemia de Fanconi/diagnóstico , Anemia de Fanconi/enzimologia , L-Lactato Desidrogenase/análise , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/enzimologia , Saliva/enzimologia , Biomarcadores Tumorais/metabolismo , Carcinogênese/metabolismo , Progressão da Doença , Detecção Precoce de Câncer , Anemia de Fanconi/complicações , Neoplasias de Cabeça e Pescoço , Humanos , Neoplasias Bucais/complicações , Oxigênio/metabolismo , Fosforilação
8.
Hum Gene Ther ; 29(10): 1114-1123, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30117331

RESUMO

Fanconi anemia (FA) is a rare inherited disease that is associated with bone marrow failure and a predisposition to cancer. Previous clinical trials emphasized the difficulties that accompany the use of gene therapy to treat bone marrow failure in patients with FA. Nevertheless, the discovery of new drugs that can efficiently mobilize hematopoietic stem cells (HSCs) and the development of optimized procedures for transducing HSCs, using safe, integrative vectors, markedly improved the efficiency by which the phenotype of hematopoietic repopulating cells from patients with FA can be corrected. In addition, these achievements allowed the demonstration of the in vivo proliferation advantage of gene-corrected FA repopulating cells in immunodeficient mice. Significantly, new gene therapy trials are currently ongoing to investigate the progressive restoration of hematopoiesis in patients with FA by gene-corrected autologous HSCs. Further experimental studies are focused on the ex vivo transduction of unpurified FA HSCs, using new pseudotyped vectors that have HSC tropism. Because of the resistance of some of these vectors to serum complement, new strategies for in vivo gene therapy for FA HSCs are in development. Finally, because of the rapid advancements in gene-editing techniques, correction of CD34+ cells isolated from patients with FA is now feasible, using gene-targeting strategies. Taken together, these advances indicate that gene therapy can soon be used as an efficient and safe alternative for the hematopoietic treatment of patients with FA.


Assuntos
Proteína do Grupo de Complementação C da Anemia de Fanconi/genética , Anemia de Fanconi/genética , Anemia de Fanconi/terapia , Terapia Genética , Animais , Modelos Animais de Doenças , Anemia de Fanconi/diagnóstico , Edição de Genes , Regulação da Expressão Gênica , Técnicas de Transferência de Genes , Terapia Genética/métodos , Vetores Genéticos/genética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Humanos , Lentivirus/genética , Mutação , Retroviridae/genética , Transdução Genética , Resultado do Tratamento
9.
Int J Lab Hematol ; 40(6): 630-636, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29989348

RESUMO

INTRODUCTION: Fanconi anemia (FA), as one of the congenital bone marrow failure syndromes, is characterized by severe bone marrow hypocellularity and pancytopenia which is similar with acquired aplastic anemia (AAA). However, patients with FA or AAA need an accurate diagnose, as the two syndromes differ significantly in both treatment and prognosis. FA results from gene mutations of the FA pathway genes specifically required for DNA repair, and the mutation of these genes contributes to the genome instability of FA cells. Based on this feature, chromosome aberration (CA) has been used as a "golden standard" to the auxiliary diagnosis of FA from AAA. However, CA diagnose calls for more technical requirements and a long time for the subsequent statistical analysis. METHODS: In our study, another two genome instability examination tools, cytokinesis-block micronucleus (CBMN) and single-cell gel electrophoresis (SCGE), were used to distinguish FA patients from AAA patients, compared with CA. RESULTS: The results suggested that significant differences were observed in the FA patients compared with the AAA patients and the controls using all of the three genomic instability examination tools. However, CBMN is the most cost-effective method to distinguish FA patients from AAA patients among the three genome instability examination tools, when the time costs, instrument costs, and technical costs were compared. CONCLUSION: In areas with economic and technical limitations, CBMN is an alternative assay to help distinguish FA patients from AAA patients.


Assuntos
Ensaio Cometa/métodos , Anemia de Fanconi/diagnóstico , Instabilidade Genômica , Micronúcleos com Defeito Cromossômico , Adolescente , Criança , Pré-Escolar , China , Feminino , Humanos , Masculino
10.
Immun Inflamm Dis ; 6(4): 428-434, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30028084

RESUMO

INTRODUCTION: Dickkopf-1 (DKK1) is a soluble protein and antagonist of the Wnt/ß-catenin signaling pathway. DKK1 is found elevated in serum from patients affected with various types of cancers and in some instances, it is considered a diagnostic and prognostic biomarker. Elevated serum levels of DKK1 have also been detected in animal models of chronic inflammatory diseases. Previous work from our laboratory has demonstrated upregulation of DKK1 in cells and mouse models of the bone marrow failure (BMF) and cancer-prone disease Fanconi anemia (FA). The present study aimed to investigate whether DKK1 blood levels in patients are associated with FA or inflammatory responses to acute infections. METHODS: Plasma samples were collected from 58 children admitted to the Centre Mère-Enfant Soleil du Centre Hospitalier de Québec-Université Laval with signs of acute infections. Blood plasma specimens were also collected from healthy blood donors at the Héma-Québec blood donor clinic. Plasmas from patients diagnosed with FA were also included in the study. DKK1 levels in blood plasmas were assessed by standard ELISA. RESULTS: Patients with acute infections showed dramatically high levels of DKK1 (6072 ± 518 pg/ml) in their blood compared to healthy blood donors (1726 ± 95 pg/ml). No correlations were found between DKK1 levels and C reactive protein (CRP) concentration, platelet numbers, or white blood cell counts. Patients with FA showed higher DKK1 plasma levels (3419 ± 147.5 pg/ml) than healthy blood donors (1726 ± 95 pg/ml) but significantly lower than patients with acute infections. CONCLUSION: These findings suggest that blood DKK1 is elevated in response to infections and perhaps to inflammatory responses.


Assuntos
/sangue , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Doença Aguda , Adolescente , Adulto , Doadores de Sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Anemia de Fanconi/sangue , Anemia de Fanconi/diagnóstico , Feminino , Humanos , Lactente , Recém-Nascido , Inflamação/sangue , Inflamação/diagnóstico , Masculino , Pessoa de Meia-Idade , Via de Sinalização Wnt , Adulto Jovem
11.
Exp Hematol ; 66: 32-41.e8, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30031030

RESUMO

Fanconi anemia (FA) is a rare recessive disease characterized by progressive bone marrow failure, congenital abnormalities, and increased incidence of cancers. To date, mutations in 22 genes can cause FA or an FA-like phenotype. In China, in addition to clinical information, FA diagnosis primarily relies on genetic sequencing because the chromosome breakage test is rarely performed. Here, we employed multiple genetic diagnostic tools (DNA sequencing, multiplex ligation-dependent probe amplification, and chromosome microarray) and a variant-based functional assay platform to investigate the genetic cause in 25 Chinese suspected FA patients. A total of 45 distinct candidate variants were detected in six FA genes (FA-A, FA-B, FA-C, FA-D2, FA-G, and FA-J), of which 36 were novel. Eight missense variants and one indel variant were unable to restore FANCD2 mono-ubiquitination and mitomycin C resistance in a panel of FA indicator cell lines, indicating that these mutations are deleterious. Three missense variants (FANCA-L424V, FANCC-E273K, and FANCG-A153G) were harmless. Finally, 23 patients were molecularly diagnosed with FA, consistent with their clinical phenotype. In the FA-A subgroup, large deletions accounted for 14% of the disease-causing variants. We have established a comprehensive molecular diagnostic workflow for Chinese FA patients that can substitute for standard FA cytogenetic analysis.


Assuntos
Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Proteína do Grupo de Complementação C da Anemia de Fanconi/genética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Proteína do Grupo de Complementação G da Anemia de Fanconi/genética , Anemia de Fanconi/genética , Mutação , Sequência de Bases , Criança , Pré-Escolar , China , Éxons , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/etnologia , Anemia de Fanconi/patologia , Feminino , Expressão Gênica , Humanos , Lactente , Íntrons , Masculino , Reação em Cadeia da Polimerase Multiplex , Análise de Sequência de DNA , Sequenciamento Completo do Exoma
12.
S Afr Med J ; 108(5): 393-398, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29843852

RESUMO

Fanconi anaemia (FA) is an inherited genetic disorder characterised by somatic anomalies, bone marrow failure and an increased predisposition to solid tumours and haematological malignancies. South African (SA) black and Afrikaner individuals are at higher than average risk for this condition owing to genetic founder mutations in certain Fanconi-associated genes. This review explores the epidemiology, clinical presentation, diagnostic modalities and recommended care of affected patients, focusing on the founder population groups in SA. The early diagnosis of FA is important and provides improved opportunities for early intervention, but remains challenging.


Assuntos
Anemia de Fanconi , Neoplasias , Diagnóstico Precoce , Intervenção Médica Precoce , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/epidemiologia , Anemia de Fanconi/genética , Anemia de Fanconi/terapia , Humanos , Neoplasias/epidemiologia , Neoplasias/prevenção & controle , Prognóstico , África do Sul
14.
Pediatr Nephrol ; 33(9): 1547-1551, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29651604

RESUMO

BACKGROUND: Fanconi anaemia (FA) is an inherited disease with bone marrow failure, variable congenital and developmental abnormalities, and cancer predisposition. With improved survival, non-haematological manifestations of FA become increasingly important for long-term management. While renal abnormalities are recognized, detailed data on patterns and frequency and implications for long-term management are sparse. METHODS: We reviewed clinical course and imaging findings of FA patients with respect to renal complications in our centre over a 25-year period to formulate some practical suggestions for guidelines for management of renal problems associated with FA. RESULTS: Thirty patients including four sibling sets were reviewed. On imaging, 14 had evidence of anatomical abnormalities of the kidneys. Two cases with severe phenotype, including renal abnormalities, had chronic kidney disease (CKD) at diagnosis. Haematopoietic stem cell transplantation was complicated by significant acute kidney injury (AKI) in three cases. In three patients, there was CKD at long-term follow-up. All patients had normal blood pressure. CONCLUSIONS: Evaluation of renal anatomy with ultrasound imaging is important at diagnostic workup of FA. While CKD is uncommon at diagnosis, our data suggests that the incidence of CKD increases with age, in particular after haematopoietic stem cell transplantation. Monitoring of renal function is essential for management of FA. Based on these long-term clinical observations, we formulate some practical guidelines for assessment and management of renal abnormalities in FA.


Assuntos
Lesão Renal Aguda/terapia , Anemia de Fanconi/terapia , Rim/anormalidades , Assistência de Longa Duração/normas , Insuficiência Renal Crônica/terapia , Lesão Renal Aguda/diagnóstico , Lesão Renal Aguda/epidemiologia , Lesão Renal Aguda/etiologia , Criança , Pré-Escolar , Progressão da Doença , Anemia de Fanconi/complicações , Anemia de Fanconi/diagnóstico , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Incidência , Lactente , Rim/diagnóstico por imagem , Assistência de Longa Duração/métodos , Masculino , Guias de Prática Clínica como Assunto , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologia , Estudos Retrospectivos , Ultrassonografia
15.
J Pediatr Hematol Oncol ; 40(5): e299-e304, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29702541

RESUMO

Fanconi anemia (FA) is a rare autosomal recessive or X-linked disorder with highly variable clinical manifestations and an incidence of ∼1 to 5 in 1 million births. To date, 15 bona fide FA genes have been reported to be responsible for the known FA complementation groups and the FANCA gene accounts for almost 60%. In the present study, we report a special Chinese family, which has 2 children with classic FA characteristics. Via 2-step analysis of the whole-exome sequencing data and verification using multiplex ligation-dependent probe amplification test, one child was found to have a novel compound heterozygous mutation of a splicing variant (c.1471-1G>A) and a large intragenic deletion (exons 23-30 del) of the FANCA gene. The other child had the same splicing variant and another novel large deletion (exons 1-18 del) in the FANCA gene. Clone sequencing showed the c.1471-1G>A variant generate an altered transcript with 1 cryptic splice site in intron 15, resulting in a premature termination codon (p.Val490HisfsX6). This study not only shows the complexity of FA molecular diagnosis via comprehensively studying the FA pathogenic genes and the mutational spectrum, but also has significant reference value for the future molecular diagnosis of FA.


Assuntos
Família , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Mutação , Sítios de Splice de RNA , Grupo com Ancestrais do Continente Asiático , Criança , China , Códon de Terminação , Humanos , Masculino
16.
BMC Med Genet ; 19(1): 7, 2018 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-29325523

RESUMO

BACKGROUND: Fanconi anemia (FA) is an inherited genomic instability disorder with congenital and developmental abnormalities, bone marrow failure and predisposition to cancer early in life, and cellular sensitivity to DNA interstrand crosslinks. CASE PRESENTATION: A fifty-one-year old female patient, initially diagnosed with FA in childhood on the basis of classic features and increased chromosomal breakage, and remarkable sun-sensitivity is described. She only ever had mild haematological abnormalities and no history of malignancy. To identify and characterise the genetic defect in this lady, who is one of the oldest reported FA patients, we used whole-exome sequencing for identification of causative mutations, and functionally characterized the cellular phenotype. Detection of the novel splice site mutation c.793-2A > G and the previously described missense mutation c.1765C > T (p.Arg589Trp) in XPF/ERCC4/FANCQ assign her as the third individual of complementation group FA-Q. Ectopic expression of wildtype, but not mutant, XPF/ERCC4/FANCQ, in patient-derived fibroblasts rescued cellular resistance to DNA interstrand-crosslinking agents. Patient derived FA-Q cells showed impaired nuclear excision repair capacity. However, mutated XPF/ERCC4/FANCQ protein in our patient's cells, as in the two other patients with FA-Q, was detectable on chromatin, in contrast to XP-F cells, where missense-mutant protein failed to properly translocate to the nucleus. CONCLUSIONS: Patients with FA characteristics and UV sensitivity should be tested for mutations in XPF/ERCC4/FANCQ. The missense mutation p.Arg589Trp was previously detected in patients diagnosed with Xeroderma pigmentosum or Cockayne syndrome. Hence, phenotypic manifestations associated with this XPF/ERCC4/ FANCQ mutation are highly variable.


Assuntos
Proteínas de Ligação a DNA/genética , Anemia de Fanconi/genética , Mutação de Sentido Incorreto , Transtornos de Fotossensibilidade/genética , Sequência de Aminoácidos , Linhagem Celular , Linhagem Celular Tumoral , Dano ao DNA , Reparo do DNA , Anemia de Fanconi/diagnóstico , Feminino , Fibroblastos , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Transtornos de Fotossensibilidade/diagnóstico , Sistema Solar
17.
Hematology ; 23(7): 405-412, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29307285

RESUMO

OBJECTIVES: Fanconi anaemia (FA) is a rare inherited bone marrow failure and autosomal recessive blood disorder. FA patients have a higher risk of cancer, including acute myeloid leukaemia and squamous cell carcinoma. Maximum, but not all, affected individuals have one or more somatic abnormalities, including skin, skeletal, genitourinary, gastrointestinal, cardiac and neurological anomalies, etc. Positive stress cytogenetics has immense implications for the treatment and management of FA. The aim of our study was to find out the incidence of FA in the population of phenotypically normal aplastic anaemia (AA) patients in West Bengal. METHODS: Ethical clearances were obtained from the corresponding institutional committees. A total of 117 AA cases was selected. Stress cytogenetics was performed from peripheral venous blood (PVB) samples of 63 AA patients (age ≤ 50 years) and 63 age- and sex-matched healthy individual (control) using Mitomycin C (MMC). RESULTS: Out of 63 AA patients, 6 (9.25%) cases showed positive stress cytogenetics suggestive of FA, which is statistically significant (p-value - 0.000532), analysed by chi-square test. DISCUSSION: A considerable percentage of patients showing sensitivity towards MMC, even if they are phenotypically normal and did not have any distinguishable features which are generally found in FA. CONCLUSION: This observation may indicate that stress cytogenetics analysis of phenotypically normal AA patients (≤50 years) is essential for the improvement of the treatment procedure.


Assuntos
Anemia Aplástica/complicações , Anemia Aplástica/epidemiologia , Anemia de Fanconi/complicações , Anemia de Fanconi/epidemiologia , Anemia Aplástica/diagnóstico , Biomarcadores , Criança , Pré-Escolar , Aberrações Cromossômicas/efeitos dos fármacos , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Feminino , Humanos , Incidência , Masculino , Mitomicina/farmacologia , Fenótipo , Vigilância da População , Avaliação de Sintomas
18.
Br J Haematol ; 180(1): 100-109, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29094350

RESUMO

The outcomes of adult patients transplanted for Fanconi anaemia (FA) have not been well described. We retrospectively analysed 199 adult patients with FA transplanted between 1991 and 2014. Patients were a median of 16 years of age when diagnosed with FA, and underwent transplantation at a median age of 23 years. Time between diagnosis and transplant was shortest (median 2 years) in those patients who had a human leucocyte antigen identical sibling donor. Fifty four percent of patients had bone marrow (BM) failure at transplantation and 46% had clonal disease (34% myelodysplasia, 12% acute leukaemia). BM was the main stem cell source, the conditioning regimen included cyclophosphamide in 96% of cases and fludarabine in 64%. Engraftment occurred in 82% (95% confidence interval [CI] 76-87%), acute graft-versus-host disease (GvHD) grade II-IV in 22% (95% CI 16-28%) and the incidence of chronic GvHD at 96 months was 26% (95% CI 20-33). Non-relapse mortality at 96 months was 56% with an overall survival of 34%, which improved with more recent transplants. Median follow-up was 58 months. Patients transplanted after 2000 had improved survival (84% at 36 months), using BM from an identical sibling and fludarabine in the conditioning regimen. Factors associated with improved outcome in multivariate analysis were use of fludarabine and an identical sibling or matched non-sibling donor. Main causes of death were infection (37%), GvHD (24%) and organ failure (12%). The presence of clonal disease at transplant did not significant impact on survival. Secondary malignancies were reported in 15 of 131 evaluable patients.


Assuntos
Anemia de Fanconi/terapia , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Causas de Morte , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/mortalidade , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Pessoa de Meia-Idade , Segunda Neoplasia Primária/etiologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Doadores de Tecidos , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
19.
DNA Repair (Amst) ; 61: 17-24, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29154021

RESUMO

Fanconi Anaemia (FA) is an autosomal recessive disorder characterised by defects in DNA repair, associated with chromosomal instability and cellular hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC). The FA repair pathway involves complex DNA repair mechanisms crucial for genomic stability. Deficiencies in DNA repair genes give rise to chromosomal radiosensitivity. FA patients have shown increased clinical radiosensitivity by exhibiting adverse normal tissue side-effects. The study aimed to investigate chromosomal radiosensitivity of homozygous and heterozygous carriers of FA mutations using three micronucleus (MN) assays. The G0 and S/G2MN assays are cytogenetic assays to evaluate DNA damage induced by ionising radiation in different phases of the cell cycle. The MMC MN assay detects DNA damage induced by a crosslinking agent in the G0 phase. Patients with a clinical diagnosis of FA and their parents were screened for the complete coding region of 20 FA genes. Blood samples of all FA patients and parents were exposed to ionising radiation of 2 and 4Gy. Chromosomal radiosensitivity was evaluated in the G0 and S/G2 phase. Most of our patients were homozygous for the founder mutation FANCG c.637_643delTACCGCC; p.(Tyr213Lysfs*6) while one patient was compound heterozygous for FANCG c.637_643delTACCGCC and FANCG c.1379G > A, p.(Gly460Asp), a novel missense mutation. Another patient was compound heterozygous for two deleterious FANCA mutations. In FA patients, the G0- and S/G2-MN assays show significantly increased chromosomal radiosensitivity and genomic instability. Moreover, chromosomal damage was significantly elevated in MMC treated FA cells. We also observed an increase in chromosomal radiosensitivity and genomic instability in the parents using 3 assays. The effect was significant using the MMC MN assay. The MMC MN assay is advantageous as it is less labour intense, time effective and has potential as a reliable alternative method for detecting FA patients from parents and controls.


Assuntos
Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Micronúcleos com Defeito Cromossômico/efeitos da radiação , Testes para Micronúcleos , Mitomicina/farmacologia , Radiação Ionizante , Adolescente , Adulto , Estudos de Casos e Controles , Ciclo Celular , Criança , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Análise Mutacional de DNA , Reparo do DNA , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Proteína do Grupo de Complementação G da Anemia de Fanconi/genética , Feminino , Instabilidade Genômica , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Tolerância a Radiação/genética , Adulto Jovem
20.
Genet Med ; 20(4): 452-457, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28837162

RESUMO

PurposeMonoallelic germ-line mutations in the BRCA1/FANCS, BRCA2/FANCD1 and PALB2/FANCN genes confer high risk of breast cancer. Biallelic mutations in these genes cause Fanconi anemia (FA), characterized by malformations, bone marrow failure, chromosome fragility, and cancer predisposition (BRCA2/FANCD1 and PALB2/FANCN), or an FA-like disease presenting a phenotype similar to FA but without bone marrow failure (BRCA1/FANCS). FANCM monoallelic mutations have been reported as moderate risk factors for breast cancer, but there are no reports of any clinical phenotype observed in carriers of biallelic mutations.MethodsBreast cancer probands were subjected to mutation analysis by sequencing gene panels or testing DNA damage response genes.ResultsFive cases homozygous for FANCM loss-of-function mutations were identified. They show a heterogeneous phenotype including cancer predisposition, toxicity to chemotherapy, early menopause, and possibly chromosome fragility. Phenotype severity might correlate with mutation position in the gene.ConclusionOur data indicate that biallelic FANCM mutations do not cause classical FA, providing proof that FANCM is not a canonical FA gene. Moreover, our observations support previous findings suggesting that FANCM is a breast cancer-predisposing gene. Mutation testing of FANCM might be considered for individuals with the above-described clinical features.


Assuntos
Alelos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Fragilidade Cromossômica , DNA Helicases/genética , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Predisposição Genética para Doença , Mutação , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Consanguinidade , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Estudos de Associação Genética , Genótipo , Mutação em Linhagem Germinativa , Humanos , Masculino , Linhagem , Fenótipo , Medição de Risco , Fatores de Risco
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