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.

Análisis de roturas cromosómicas en un paciente con sospecha clínica de anemia de Fanconi / Chromosomal breakage analysis in a patient with presumptive diagnosis of Fanconi anemia

La anemia de Fanconi (AF) es un síndrome de inestabilidad cromosómica caracterizado por diversos rasgos dismórficos, pancitopenia progresiva y predisposición a neoplasias hematológicas. El ensayo de sensibilidad a la mitomicina C (MMC) proporciona un marcador celular único para el diagnóstico de la enfermedad. Con el objetivo de introducir este ensayo de roturas cromosómicas, se aplicó la técnica en dos muestras procedentes de un paciente con sospecha clínica de AF y un sujeto control. Las muestras de sangre periférica fueron cultivadas según los protocolos establecidos para los estudios citogenéticos. Se prepararon cuatro frascos de cultivo por cada muestra. A uno de ellos se le añadió solo cloruro de sodio (cultivo control) y a los restantes se les añadieron concentraciones crecientes de MMC (50, 150 y 300 nM). Fueron analizadas cincuenta metafases por cada frasco. La exposición de los linfocitos del paciente a todas las concentraciones de MMC provocó diferencias significativas en el número de células con roturas cromosómicas respecto a la misma exposición en el control (p <0.005). Se comprobó el éxito del ensayo teniendo en cuenta que a 300 nM en el control sano solo aparece el 32 por ciento de células con roturas. Es interesante resaltar que en la muestra del paciente a la concentración más elevada, se apreció la presencia de 2 líneas celulares, una con pocas o ninguna rotura (38 por ciento) similar a las que aparecen en las células no-AF; y otra con múltiples roturas (62 por ciento) típicas de las células AF. Esto indicó la presencia de mosaicismo somático en los linfocitos T del paciente. De acuerdo con los resultados obtenidos se confirmó la sospecha clínica de que se trata de un paciente AF, por la hipersensibilidad a la acción de la MMC que presenta mosaicismo somático en linfocitos T...

Fanconi anemia (FA) is a chromosomal instability syndrome characterized by various dysmorphic features, progressive pancytopenia and predisposition to hematological malignancies. The assay sensitivity to mitomycin C (MMC) provides a unique cell marker for the diagnosis of the disease. In order to introduce this chromosomal breakage test the technique was applied in two samples from a patient with clinical suspicion of AF and a control subject. Peripheral blood samples were cultured by protocols established for cytogenetic studies. Four flasks were prepared for each sample culture. Only sodium chloride was added to one of the flasks (control) and to the remaining flasks increasing concentrations of MMC (50, 150 and 300 nM) were added. Fifty metaphases were analyzed for each bottle. Exposure of lymphocytes from the patient at all concentrations of MMC caused significant differences in the number of cells with chromosome breaks with respect to the same exposure in the control (p <0.005). Assay success was proved considering that in 300 nM in healthy control only 32 percent shows cell breakage. It is interesting to remark that in the patient sample with highest concentration, the presence of two cell lines were observed, one with little or no breakage (38 percent) similar to those found in no-F cells and other with multiple breaks (62 percent), typical of AF cells. These results indicated the presence of somatic mosaicism in patient´s T lymphocytes. The results obtained confirmed the clinical suspicion that this is an AF patient, due to the hypersensitivity to the action of MMC and the presence of somatic mosaicism in T lymphocytes...

A Case Report of Fanconi Anemia Diagnosed by Genetic Testing Followed by Prenatal Diagnosis

Fanconi anemia (FA) is a rare genetic disorder affecting multiple body systems. Genetic testing, including prenatal testing, is a prerequisite for the diagnosis of many clinical conditions. However, genetic testing is complicated for FA because there are often many genes that are associated with its development, and large deletions, duplications, or sequence variations are frequently found in some of these genes. This study describes successful genetic testing for molecular diagnosis, and subsequent prenatal diagnosis, of FA in a patient and his family in Korea. We analyzed all exons and flanking regions of the FANCA, FANCC, and FANCG genes for mutation identification and subsequent prenatal diagnosis. Multiplex ligation-dependent probe amplification analysis was performed to detect large deletions or duplications in the FANCA gene. Molecular analysis revealed two mutations in the FANCA gene: a frameshift mutation c.2546delC and a novel splice-site mutation c.3627-1G>A. The FANCA mutations were separately inherited from each parent, c.2546delC was derived from the father, whereas c.3627-1G>A originated from the mother. The amniotic fluid cells were c.3627-1G>A heterozygotes, suggesting that the fetus was unaffected. This is the first report of genetic testing that was successfully applied to molecular diagnosis of a patient and subsequent prenatal diagnosis of FA in a family in Korea.

Evaluation of concentration and storage effects of mitomycin C in the diagnosis of Fanconi anemia among idiopatic aplastic anemia patients.

BACKGROUND: Fanconi anemia (FA) is a rare autosomal recessive genetic disorder that shows an increased sensitivity to the intercalating agents such as mytomycin C (MMC), measured as chromosomal aberrations. This study was conducted to differentiate between FA and “idiopathic” aplastic anemia on the basis of induced chromosomal breakage study with MMC. MATERIALS AND METHODS: MMC stress tests in different final concentrations of 20 and 50 ng/ml of MMC were conducted on peripheral blood lymphocytes from 32 patients with aplastic anemia and 13 healthy controls. Fifty nanograms per milliliter of MMC from old, fresh and frozen stocks was used to check the sensitivity of diagnosis on FA-diagnosed patients. Statistical analysis was used for the assessment of aberrations, including chromatid and chromosome breaks and exchanges. RESULTS: Eight patients (25%) with a very high percentage of chromosomal breakage were diagnosed as FA on the basis of the chromosomal breakage study. Six of these patients exhibited congenital anomalies at presentation, while another two lacked such anomalies or had minor physical problems. Freshly made MMC has shown more sensitivity to detect FA patients compared with frozen or 1-week-old MMC stock. CONCLUSIONS: The study indicates that freshly made MMC stress test provides an unequivocal means of differentiation between FA and “idiopathic” aplastic anemia. Further, the study, the first of its kind from Iran, stresses on the need for conducting this test in all aplastic anemia cases, even those without congenital anomalies, for accurate and timely diagnosis of FA to implement appropriate therapy.

Características clínicas de pacientes com anemia de Fanconi / Clinical characteristics of patients with Fanconi anemia

OBJETIVO: Verificar as características clínicas de pacientes com anemia de Fanconi (AF) diagnosticados em um Serviço de Genética Clínica. MÉTODOS: O estudo incluiu todos os pacientes atendidos no Serviço de Genética Clínica da Universidade Federal de Ciências da Saúde de Porto Alegre e Complexo Hospitalar Santa Casa de Porto Alegre, entre 1975 e 2008, com suspeita clínica de AF submetidos ao estudo de quebras cromossômicas com o uso de diepoxi-butano (DEB) a partir do sangue periférico. Realizou-se uma análise retrospectiva das características clínicas dos pacientes, a partir de um levantamento sistemático dos seus prontuários médicos. RESULTADOS: A amostra foi composta de 17 pacientes, sendo que em sete o diagnóstico de AF foi confirmado. Os pacientes com AF caracterizaram-se por um fenótipo amplo, oscilando desde um quadro de pancitopenia sem dismorfias até a presença de múltiplas malformações sem alterações hematológicas. Certos achados, como face triangular, orelhas em abano e manchas café com leite foram frequentes e encontrados apenas nos indivíduos com AF. História de equimoses, hematomas, petéquias, infecções e linfadenopatias foi comum entre os indivíduos desse grupo. Por outro lado, alterações neurológicas foram observadas apenas em pacientes sem AF. Consanguinidade foi verificada em apenas um paciente, que apresentava AF. CONCLUSÕES: Apesar das limitações do estudo, os achados ilustram a grande variabilidade fenotípica observada na AF, o que torna seu diagnóstico clínico um desafio. No entanto, alguns achados específicos podem servir de pistas para sua detecção. A identificação precoce desses indivíduos é fundamental para o seu manejo adequado.

OBJECTIVE: To investigate the clinical characteristics of Fanconi anemia (FA) patients diagnosed in a Clinical Genetics Service. METHODS: The study included all patients assisted in an university genetics service in Southern Brazil, between 1975 and 2008, with clinical suspicious of FA and submitted to the study of chromosomal breakage with diepoxybutane (DEB) from peripheral blood. A retrospective analysis of the clinical characteristics of the patients was carried out by a systematic survey of their medical records. RESULTS: 17 patients were studied and seven had a confirmed diagnosis of FA. Patients with FA were characterized by a broad phenotype, ranging from pancytopenia without dysmorphisms to multiple malformations and absence of hematological alterations. Certain findings, such as triangular face, prominent ears and café-au-lait spots were common and found only among individuals with FA. History of bruises, hematomas, petechiae, infections and lymphadenopathies was also common among individuals of this group. However, neurological alterations were observed only in patients without FA. Consanguinity was verified in one patient who presented FA. CONCLUSIONS: Despite the limitations of this study, thefindings show the great phenotypical variability observed in patients with FA, which makes the diagnosis a clinical challenge. Nevertheless, some specific findings can serve as clues for FA detection. The early identification of these individuals is essential for their proper clinical management.

FANCD2 Western blot as a diagnostic tool for Brazilian patients with Fanconi anemia

Fanconi anemia is a rare hereditary disease showing genetic heterogeneity due to a variety of mutations in genes involved in DNA repair pathways, which may lead to different clinical manifestations. Phenotypic variability makes diagnosis difficult based only on clinical manifestations, therefore laboratory tests are necessary. New advances in molecular pathogenesis of this disease led researchers to develop a diagnostic test based on Western blot for FANCD2. The objective of the present study was to determine the efficacy of this method for the diagnosis of 84 Brazilian patients with Fanconi anemia, all of whom tested positive for the diepoxybutane test, and 98 healthy controls. The FANCD2 monoubiquitinated isoform (FANCDS+/FANCD2L-) was not detected in 77 patients (91.7 percent). In 2 patients (2.4 percent), there was an absence of both the monoubiquitinated and the non-ubiquitinated proteins (FANCD2S-/FANCD2L-) and 5 patients (5.9 percent) had both isoforms (FANCD2S+/FANCD2L+). This last phenotype suggests downstream subtypes or mosaicism. All controls were diepoxybutane negative and were also negative on the FANCD2 Western blot. The Western blot for FANCD2 presented a sensitivity of 94 percent (79/84) and specificity of 100 percent (98/98). This method was confirmed as an efficient approach to screen Brazilian patients with deleterious mutations on FANCD2 (FANCD2S-/FANCD2L-) or other upstream genes of the FA/BRCA pathway (FANCDS+/FANCD2L-), to confirm the chromosome breakage test and to classify patients according to the level of FA/BRCA pathway defects. However, patients showing both FANCD2 isoforms (FANCD2S+/FANCD2L+) require additional studies to confirm mutations on downstream Fanconi anemia genes or the presence of mosaicism.

Fanconi's anemia in monozygotic twins.

Fanconi's anemia is one of the inherited causes of bone marrow failure. It is inherited in autosomal recessive fashion. It presents as aplastic anemia usually at the age of 7-8 yr. Leukemias and solid tumours are complications in those who manage to survive beyond two decades. Though it has been seen in siblings, reports in monozygotic twins have been very few.

Fanconi anemia presenting as acute myeloid leukemia: a case report.

Fanconi anemia is an autosomal recessive disorder characterized by phenotypic abnormalities, increased chromosomal breaks and predisposition to various hematological and non-hematological malignancies. We present case report of a paediatric patient with Fanconi anemia presenting as acute myeloid leukemia. The presence of dysplastic features in this marrow suggests the possibility of a prior stage of myelodysplasia progressing to leukemia.

Differentiation of Nijmegen breakage syndrome from Fanconi anemia

Nijmegen breakage syndrome (NBS) is a rare auto-somal recessive condition with chromosomal instability. Clinical and biological overlap between Fanconi anemia and ataxia telangiectasia has been reported. We report two cases of NBS born to consanguineous parents. Case one had NBS and Falconi anemia clinical features but relatively little chromosome breakage. The second case had mild NBS features, while cytogenetic evaluation with mitomycin C induction showed chromosome damage. Chromosomal analysis of bone marrow cells revealed tetraploidy, which indicates progression towards leukemia. On the basis of clinical and cytogenetic evaluation, these two cases were confirmed as NBS. However, detailed molecular studies are essential for accurate diagnosis and management of this disease.

Fanconi's anemia in newborn.

Fanconi's anemia (FA) is a paradigm for congenital anomalies, aplastic anemia and predisposition to malignancies. Identification of the disease at birth is based on characteristic physical malformations, as hematologic manifestations at birth are extremely rare. We report a case of FA in a newborn who presented with anophthalmia, unilateral radial ray defect, hemivertebrae and thrombocytopenia.

Anemia de Fanconi: revisión / Fanconi anemia: review

La Anemia de Fanconi es un síndrome de fragilidad cromosómica, autosómico recesivo, caracterizado por presentar malformaciones congénitas muy diversas y en diferentes órganos en el 70 por ciento de los casos; insuficiencia medular progresiva y tendencia a enfermedades malignas: sobre todo leucemia mieloide aguda y tumores sólidos. La afección fue descrita en 1927 por el pediatra suizo, Guido Fanconi, en tres hermanos con diferentes malformaciones congénitas, astenia, infecciones de repetición y sangrados espontáneos por fallo en la función de la médula ósea. El diagnóstico precoz permite un buen control del compromiso hematológico; la realización de los tratamientos quirúrgicos antes de la instauración de la trombopenia; consejo genético para la familia; la identificación presintomática de hermanos afectados o de embarazos cuyos fetos sean posibles donantes de progenitores hematopoyéticos para un hermano comprometido.

Differentiation of Fanconi anemia from idiopathic aplastic anemia by induced chromosomal breakage study using mitomycin-C (MMC).

This study was conducted to differentiate between Fanconi anemia (FA) and "idiopathic" aplastic anemia on the basis of induced chromosomal breakage study with mitomycin C (MMC). MMC-stress test was conducted on peripheral blood lymphocytes from 29 patients with aplastic anemia. Ten patients with very high percentage of chromosomal breakage and four patients exhibiting somatic mosaicism were diagnosed as FA on the basis of chromosomal breakage study. Six of these patients exhibited congenital anomalies at presentation while another eight lacked such anomalies or had minor physical problems.The present study illustrates that MMC stress test provides an unequivocal means of differentiation between Fanconi anemia and 'idiopathic' aplastic anemia. Further, the study, first of its kind from India, stresses on the need for conducting this test in all aplastic anemia cases, even those without congenital anomalies, for accurate and timely diagnosis of Fanconi anemia to implement appropriate therapy.

Recent advances in chromosome breakage syndromes and their diagnosis.

Chromosome instability is a characteristic cytogenetic feature of a number of genetically determined disorders collectively called as the chromosome breakage syndromes or DNA-repair disorders. They are characterized by susceptibility to chromosomal breakages, increased frequency of breaks and interchanges occurring either spontaneously or following exposure to various DNA-damaging agents. These diseases are a group of genetic disorders sharing a number of features. They are all autosomal recessive, show an increased tendency for chromosomal aberrations and to develop malignancies. The principal diseases in this group having a diverse etiology and clinical manifestations include Fanconi anemia (FA), ataxia telangiectasia (AT), Nijmegen breakage syndrome (NBS), Bloom syndrome (BS), xeroderma pigementosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). The underlying defect in these syndromes is the inability to repair a particular type of DNA damage. A number of repair disorder phenotypes are caused by more than one gene. The diagnosis of these syndromes is made by the characteristic clinical features specific to each disease, but the definitive diagnosis is achieved by laboratory investigations such as cytogenetic, biochemical and molecular methods. The importance of prenatal diagnosis and our experience are discussed in this article.

Anemia de Diamond Blackfan: experiencia clínica en 20 pacientes 1968-1998 / Diamond Blackfans anemia: clinical experience in 20 patients 1968-1998

La anemia de Diamond-Blackfan es una causa poco frecuente de anemia en el recién nacido y el lactante menor. Analizamos retrospectivamente las características clínicas y de laboratorio en 20 pacientes controlados en un período de 30 años. Encontramos que en el 85 por ciento de los casos el diagnóstico se planteó antes del año de edad y la mayoría eran de sexo femenino. En 45 por ciento existía el antecedente de bajo peso de nacimiento. El principal hallazgo al examen físico, además de la palidez, fue la talla baja y no se encontraron otras malformaciones asociadas en la mayoría de los pacientes. El 100 por ciento presentaba valores de hemoglobina por debajo de los valores normales para su edad, con macrocitosis y reticulocitopenia, sin compromiso del resto de las series hematológicas. La respuesta adecuada a corticoides se observó en 85 por ciento. De los 3 pacientes refractarios, 2 fallecieron y 1 sobrevive con dependencia a transfusiones de glóbulos rojos y hemosiderosis secundaria, ya que no fue posible efectuar trasplante de médula ósea por falta de donante. El trasplante debe ser considerado precozmente como alternativa terapéutica en el grupo no respondedor a corticoides, si existe donante compatible, ya que otros tratamientos son poco exitosos

Variabilidad clínica citogenética en doce familias mexicanas con anemia de Fanconi y su relación con el grupo de complementación al que pertenecen / Clinical and cytogenetic variability on twelve Fanconi anemia families and its relationship with complementation group assignment

Objetivo. Describir las caractetísticas clínica y citogenéticas en pacientes mexicanos con anemia de Fanconi y determinar si la variabilidad fenotípica se relaciona con el grupo de complementación. Material y métodos. Se hizo el diagnóstico citogenético por exposición de linfocitos de sangre periférica a mitomicina C y a diepoxibutano. Se clasificaron, la gravedad de la anemia y las manifestaciones clínica utilizando las puntuaciones de alter y Auerbach respectivamente. Se establecieron líneas linfoblastoides de ocho individuos y se determinó el grupo de complementación mediante fusión celular en cuatro casos índices. Resultados. se estudiaron 12 familias con 25 afectados. Los pacientes mostraron frecuencias elevadas de aberraciones cromosómicas espontáneas e inducidas; no existió relación con la gravedad clínica o estado anémico. El cuadro clínico se clasificó como grave en 12 pacientes y como leve en 13. La anemia no se presentó en tres enfermos, fue leve en 13, moderadas en siete y grave en uno. La mortalidad fue del 32 por ciento (8/25). No hubo relación entre puntuación clínica, grado de anemia y defunción. Once pacientes se asignaron al grupo de complementación A con cuadro clínico y anemia leves; sus resultados citogenéticos mostraron variabilidad. Un paciente fue asignado al grupo C, obtuvo una puntuación clínica grave, anemia dependiente de transfusión y alta sensibilidad a mutágenos. Trece sujetos no fueron clasificados, en tres pacientes se obtuvo una línea linfoblastoide resistente a mitomicina C, que sugirió mosaicismo somático. Conclusiones. El grupo de complementación no explica la variabilidad; existen otros factores como el mosaicismo somático que modifica el fenotipo celular

Anemia de fanconi: presentación de un caso / Fanconi's anemia: presentation of a case

La anemia de Fanconi es un desorden cromosómico caracterizado por una anemia aplástica familiar de carácter autosómico recesivo, que se manifiesta clínicamente con lesiones de piel, anormalidades congénitas de tipo esquelético, genitourinario y neuroocular, de baja prevalencia mundial. Se presenta un caso de anemia de Fanconi diagnósticado en un preescolar masculino de 33 meses de edad, hospitalizado en el Servicio de Pediatría del Hospital General "Patrocinio Peñuela Ruíz" de San Cristóbal. Se analizan los hallazgos clínicos y aspectos diagnósticos y terapéuticos de esta enfermedad