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1.
Ir J Med Sci ; 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31414326

RESUMO

BACKGROUND/AIMS: Application of evidence-based guidelines in the management of cellulitis is poorly studied in Ireland and it is observed that current admission and prescription practices in this country vary widely from internationally accepted standards of care. We aimed to examine the management of cellulitis with regard to hospital admission and initial antibiotic therapy. METHODS: A retrospective audit of patients admitted with cellulitis from 2013 to 2017 in an Irish district general hospital. Exclusion criteria included specialist regions of the body and surgical site infections. Appropriateness of admission and management was compared against international guidelines (Clinical Research Efficiency Support Team (CREST) and Infectious Disease Society of America (IDSA)). RESULTS: Five hundred twenty emergency admissions with cellulitis were analysed. Thirty-five percent (n = 182) were deemed inappropriate admissions compared with CREST and IDSA guidelines, with an estimated cost of €152,203 per annum. Ninety-six percent (n = 501) of patients with cellulitis were treated with a combination of flucloxacillin and benzylpenicillin, despite level 1 evidence showing combination therapy to provide no benefit over appropriate monotherapy. CONCLUSIONS: There is a significant discrepancy between current clinical practice and international guidelines for the management of cellulitis in Ireland; local guidelines are not in keeping with newer evidence and there is a lack of national guidelines for this common condition. Closer adherence to international guidelines would significantly reduce costs by reducing unnecessary admissions and initial monotherapy would improve antibiotic stewardship. This study shows a clear need for local institutions to re-examine antibiotic guidelines to ensure the HSE provides effective evidence-based treatment in the correct setting.

2.
3.
Sleep Med ; 61: 44-51, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31285160

RESUMO

OBJECTIVE: Sleep disturbances are frequently reported in Mowat-Wilson Syndrome (MWS). The current study aimed to evaluate clinical and video-polysomnographic (VPSG) characteristics of the sleep architecture and abnormal electroencephalogram (EEG) patterns during sleep in MWS. METHODS: Sixteen individuals with MWS (range 16 months-25 years), attending the Department of Child Neurology and Psychiatry of the University of Bologna, were included. The "Sleep Disturbances Scale for Children (SDSC)" questionnaire was administered to all parents of MWS patients, and all patients underwent a VPSG recording. RESULTS: The analysis of the SDSC questionnaire revealed disturbances mainly at the sleep-wake transition and in initiating and maintaining sleep. Evaluation of sleep structure in MWS patients showed a significant reduction of total sleep time, an increase of wake after sleep onset and arousal index as compared to normal controls. An EEG pattern characterized by slowing of background activity and poverty of physiological sleep characterisitcs was observed in all patients. Moreover, in patients aged >7 years, anteriorly predominant spike and waves were observed, markedly activated by sleep configuring a sub-continuous or continuous activity. CONCLUSION: Our data (both clinical and VPSG) documented the presence of significant and clinically relevant sleep disturbances in MWS patients. Moreover, we identified a characteristic age-dependent sleep EEG pattern that could provide a new element to assist in the management of MWS.

4.
Genet Med ; 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31164752

RESUMO

PURPOSE: Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists. METHODS: Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds. RESULTS: The additional use of similarity scores from computer-assisted analysis of frontal photos improved the top 1 accuracy rate by more than 20-89% and the top 10 accuracy rate by more than 5-99% for the disease-causing gene. CONCLUSION: Image analysis by deep-learning algorithms can be used to quantify the phenotypic similarity (PP4 criterion of the American College of Medical Genetics and Genomics guidelines) and to advance the performance of bioinformatics pipelines for exome analysis.

6.
Am J Med Genet A ; 176(9): 1991-1995, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30088855

RESUMO

KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat-containing cofactors. After the advent of whole exome sequencing, the number of clinical reports with KBG diagnosis has increased, leading to a revision of the phenotypic spectrum associated with this syndrome. Here, we report a female child showing clinical features of the KBG syndrome in addition to a caudal appendage at the coccyx with prominent skin fold and a peculiar calcaneus malformation. Exons and exon-intron junctions targeted resequencing of SH3PXD2B and MASP1 genes, known to be associated with prominent coccyx, gave negative outcome, whereas sequencing of ANKRD11 whose mutations matched the KBG phenotype of the proband showed a de novo heterozygous frameshift variant c.4528_4529delCC in exon 9 of ANKRD11. This report contributes to expand the knowledge of the clinical features of KBG syndrome and highlights the need to search for vertebral anomalies and suspect this condition in the presence of a prominent, elongated coccyx.

7.
Am J Med Genet A ; 176(5): 1166-1174, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29681106

RESUMO

Biallelic variants in FAT4 are associated with the two disorders, Van Maldergem syndrome (VMS) (n = 11) and Hennekam syndrome (HS) (n= 40). Both conditions are characterized by a typical facial gestalt and mild to moderate intellectual disability, but differ in the occurrence of neonatal hypotonia and feeding problems, hearing loss, tracheal anomalies, and osteopenia in VMS, and lymphedema in HS. VMS can be caused by autosomal recessive variants in DCHS1 as well, and HS can also be caused by autosomal recessive variants in CCBE1 and ADAMTS3. Here we report two siblings with VMS and one girl with HS, all with FAT4 variants, and provide an overview of the clinical findings in all patients reported with FAT4 variants. Our comparison of the complete phenotypes of patients with VMS and HS indicates a resemblance of several signs, but differences in several other main signs and symptoms, each of marked importance for affected individuals.

9.
Genet Med ; 20(9): 965-975, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29300384

RESUMO

PURPOSE: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS. METHODS: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. RESULTS: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations. CONCLUSION: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.

10.
World J Gastroenterol ; 23(44): 7930-7938, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-29209134

RESUMO

The underlying pathophysiology of liver dysfunction in urea cycle disorders (UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle (UC) intermediates are toxic for hepatocyte mitochondria. It is possible that liver injury is directly caused by the toxicity of ammonia. The rarity of UCDs, the lack of checking of iron level in these patients, superficial knowledge of UC and an underestimation of the metabolic role of fumaric acid, are the main reasons that are responsible for the incomprehension of the mechanism of liver injury in patients suffering from UCDs. Owing to our routine clinical practice to screen for iron overload in severely ill neonates, with the focus on the newborns suffering from acute liver failure, we report a case of citrullinemia with neonatal liver failure and high blood parameters of iron overload. We hypothesize that the key is in the decreased-deficient fumaric acid production in the course of UC in UCDs that causes several sequentially intertwined metabolic disturbances with final result of liver iron overload. The presented hypothesis could be easily tested by examining the patients suffering from UCDs, for liver iron overload. This could be easily performed in countries with a high population and comprehensive national register for inborn errors of metabolism. CONCLUSION: Providing the hypothesis is correct, neonatal liver damage in patients having UCD can be prevented by the supplementation of pregnant women with fumaric or succinic acid, prepared in the form of iron supplementation pills. After birth, liver damage in patients having UCDs can be prevented by supplementation of these patients with zinc fumarate or zinc succinylate, as well.


Assuntos
Citrulinemia/metabolismo , Hepatócitos/metabolismo , Hiperamonemia/metabolismo , Hepatopatias/etiologia , Fígado/fisiopatologia , Amônia/sangue , Amônia/toxicidade , Sistema Nervoso Central/fisiopatologia , Citrulinemia/sangue , Citrulinemia/diagnóstico , Citrulinemia/terapia , Enterobacter/isolamento & purificação , Evolução Fatal , Humanos , Hiperamonemia/sangue , Hiperamonemia/diagnóstico , Hiperamonemia/terapia , Recém-Nascido , Letargia/etiologia , Letargia/metabolismo , Letargia/fisiopatologia , Letargia/terapia , Fígado/citologia , Fígado/metabolismo , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Hepatopatias/terapia , Masculino , Sepse/microbiologia , Sepse/terapia , Ureia/sangue , Ureia/metabolismo , Ureia/toxicidade
11.
Genet Med ; 19(6): 691-700, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27831545

RESUMO

PURPOSE: Mowat-Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined. METHODS: Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations. RESULTS: Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical, and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis. CONCLUSION: This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016.


Assuntos
Encéfalo/diagnóstico por imagem , Doença de Hirschsprung/diagnóstico por imagem , Deficiência Intelectual/diagnóstico por imagem , Imagem por Ressonância Magnética , Microcefalia/diagnóstico por imagem , Neuroimagem , Encéfalo/patologia , Criança , Pré-Escolar , Estudos de Coortes , Epilepsia/patologia , Facies , Feminino , Genótipo , Haploinsuficiência , Doença de Hirschsprung/genética , Doença de Hirschsprung/patologia , Humanos , Lactente , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Estudos Longitudinais , Masculino , Microcefalia/genética , Microcefalia/patologia , Fenótipo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética
12.
Mol Syndromol ; 7(6): 337-343, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27920637

RESUMO

To date, 5 cases of 17p13.1 microduplications have been described in the literature. Intellectual disability was reported as the core feature, together with minor facial dysmorphisms and obesity, but a characteristic phenotype for 17p13.1 microduplication has not been delineated. Here, we describe a patient with a 1.56-Mb de novo duplication in 17p13.1, affected by mild intellectual disability, facial dysmorphisms, obesity, and diabetes. By comparing the different phenotypes of currently described cases, we delineated the main clinical features of 17p13.1 microduplication syndrome. All patients described to date had variable facial dysmorphisms; therefore, it was difficult to define a common facial gestalt. Furthermore, we stress endocrinological abnormalities as important features and the need to monitor these over time.

13.
Eur J Pediatr ; 175(10): 1307-15, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27562837

RESUMO

UNLABELLED: Myhre syndrome (OMIM 139210) is a rare developmental disorder inherited as an autosomal dominant trait and caused by a narrow spectrum of missense mutations in the SMAD4 gene. The condition features characteristic face, short stature, skeletal anomalies, muscle pseudohypertrophy, restricted joint mobility, stiff and thick skin, and variable intellectual disability. While most of the clinical features manifest during childhood, the diagnosis may be challenging during the first years of life. We report on the evolution of the clinical features of Myhre syndrome during childhood in a subject with molecularly confirmed diagnosis. The clinical records of 48 affected patients were retrospectively analysed to identify any early clinical signs characterizing this disorder and to better delineate its natural history. We also note that pericarditis and laryngotracheal involvement represent important life-threatening complications of Myhre syndrome that justify the recommendation for cardiological and ENT follow-up for these patients. CONCLUSION: Short length/stature, short palpebral fissures, and brachydactyly with hyperconvex nails represent signs/features that might lead to the correct diagnosis in the first years of life and direct to the proper molecular analysis. We underline the clinical relevance of pericarditis and laryngotracheal stenosis as life-threatening complications of this disorder and the need for careful monitoring, in relation to their severity. WHAT IS KNOWN: • The clinical and radiological signs of the disease in children older than 7-8 years. • Pericarditis, sometimes occurring with constrictive pericardium requiring pericardiectomy, has been reported as a recurrent feature but has not been adequately stressed in previous literature. What is New: • Short length/stature, short palpebral fissures, brachydactyly with hyperconvex nails represent clinical signs that might lead to diagnosis in the first years of life. • Review of the literature showed that pericarditis and laryngotracheal complications represent major recurrent issues in patients with Myhre syndrome.


Assuntos
Criptorquidismo/diagnóstico , Transtornos do Crescimento/diagnóstico , Deformidades Congênitas da Mão/diagnóstico , Deficiência Intelectual/diagnóstico , Mutação de Sentido Incorreto/genética , Proteína Smad4/genética , Braquidactilia , Criança , Criptorquidismo/complicações , Criptorquidismo/genética , Facies , Dedos/anormalidades , Dedos/diagnóstico por imagem , Transtornos do Crescimento/complicações , Transtornos do Crescimento/genética , Deformidades Congênitas da Mão/complicações , Deformidades Congênitas da Mão/genética , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Masculino , Unhas Malformadas/fisiopatologia , Pericardite/etiologia , Fenótipo , Radiografia , Estudos Retrospectivos
14.
Am J Med Genet A ; 170(9): 2408-15, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27277385

RESUMO

Biallelic defects in the RIN2 gene, encoding the Ras and Rab interactor 2 protein, are associated with a rare autosomal recessive connective tissue disorder, with only nine patients from four independent families reported to date. The condition was initially termed MACS syndrome (macrocephaly, alopecia, cutis laxa, and scoliosis), based on the clinical features of the first identified family; however, with the expansion of the clinical phenotype in additional families, it was subsequently coined RIN2 syndrome. Hallmark features of this condition include dysmorphic facial features with striking, progressive facial coarsening, sparse hair, normal to enlarged occipitofrontal circumference, soft redundant and/or hyperextensible skin, and scoliosis. Patients with RIN2 syndrome present phenotypic overlap with other conditions, including EDS (especially the dermatosparaxis and kyphoscoliosis subtypes). Here, we describe a 10th patient, the first patient of Caucasian origin and the oldest reported patient so far, who harbors the previously identified homozygous RIN2 mutation c.1878dupC (p. (Ile627Hisfs*7)). Besides the hallmark features, this patient also presents problems not previously associated with RIN2 syndrome, including cervical vertebral fusion, mild hearing loss, and colonic fibrosis. We provide an overview of the clinical findings in all reported patients with RIN2 mutations and summarize some of the possible pathogenic mechanisms that may underlie this condition. © 2016 Wiley Periodicals, Inc.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Proteínas de Transporte/genética , Estudos de Associação Genética , Fatores de Troca do Nucleotídeo Guanina/genética , Mutação , Fenótipo , Anormalidades Múltiplas/terapia , Adolescente , Adulto , Alelos , Biópsia , Éxons , Facies , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia , Síndrome , Adulto Jovem
15.
Pediatr Med Chir ; 37(2): pmc.2015.112, 2015 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-26429121

RESUMO

TEL-AML1 (ETV6-RUNX1) fusion gene which is formed prenatally in 1% of the newborns, is a common genetic abnormality in childhood Bcell precursor acute lymphoblastic leukemia. But only one child out of a hundred children born with this fusion gene develops leukemia (bottleneck phenomenon) later in its life, if contracts the second mutation. In other words, out of a hundred children born with TEL-AML1 only one child is at risk for leukemia development, which means that TEL-AML1 fusion gene is not sufficient for overt leukemia. There is a stringent requirement for a second genetic abnormality for leukemia development and this is the real or the ultimate cause of the leukemia bottleneck phenomenon. In most cases of TEL-AML1+ leukemia, the translocation t(12;21) is complemented with the loss of the normal TEL gene, not involved in the translocation, on the contralateral 12p. The loss of the normal TEL gene, i.e. loss of heterozygosity at 12p, occurs postnatally during the mitotic proliferation of TEL-AML1+ cell in the mitotic crossing over process. Mitotic crossing over is a very rare event with a frequency rate of 10-6 in a 10 kb region. The exploration and identification of the environmental exposure(s) that cause(s) proliferation of the TELAML1+ cell in which approximately 106 mitoses are generated to cause 12p loss of heterozygosity, i.e. TEL gene deletion, may contribute to the introduction of preventive measures for leukemia.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Troca Genética/genética , Leucemia/genética , Proteínas de Fusão Oncogênica/genética , Criança , Meio Ambiente , Predisposição Genética para Doença , Humanos , Leucemia/epidemiologia , Perda de Heterozigosidade , Mitose , Leucemia-Linfoma Linfoblástico de Células Precursoras B/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Translocação Genética
16.
Am J Med Genet A ; 167A(8): 1902-7, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25846317

RESUMO

Noonan-like syndrome with loose anagen hair (NSLH), also known as Mazzanti syndrome, is a RASopathy characterized by craniofacial features resembling Noonan syndrome, cardiac defects, cognitive deficits and behavioral issues, reduced growth generally associated with GH deficit, darkly pigmented skin, and an unique combination of ectodermal anomalies. Virtually all cases of NSLH are caused by an invariant and functionally unique mutation in SHOC2 (c.4A>G, p.Ser2Gly). Here, we report on a child with molecularly confirmed NSLH who developed a neuroblastoma, first suspected at the age 3 months by abdominal ultrasound examination. Based on this finding, scanning of the SHOC2 coding sequence encompassing the c.4A>G change was performed on selected pediatric cohorts of malignancies documented to occur in RASopathies (i.e., neuroblastoma, brain tumors, rhabdomyosarcoma, acute lymphoblastic, and myeloid leukemia), but failed to identify a functionally relevant cancer-associated variant. While these results do not support a major role of somatic SHOC2 mutations in these pediatric cancers, this second instance of neuroblastoma in NSLAH suggests a possible predisposition to this malignancy in subjects heterozygous for the c.4A>G SHOC2 mutation.


Assuntos
Neuroblastoma/complicações , Síndrome de Noonan/fisiopatologia , Humanos , Recém-Nascido , Masculino , Síndrome de Noonan/complicações
17.
Ital J Pediatr ; 40: 86, 2014 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-25516103

RESUMO

Multiple Sulfatase Deficiency (MSD; OMIM 272200) is a rare autosomal recessive inborn error of metabolism caused by mutations in the sulfatase modifying factor 1 gene, encoding the formylglycine-generating enzyme (FGE), and resulting in tissue accumulation of sulfatides, sulphated glycosaminoglycans, sphingolipids and steroid sulfates. Less than 50 cases have been published so far. We report a new case of MSD presenting in the newborn period with hypotonia, apnoea, cyanosis and rolling eyes, hepato-splenomegaly and deafness. This patient was compound heterozygous for two so far undescribed SUMF1 mutations (c.191C > A; p.S64X and c.818A > G; p.D273G).


Assuntos
DNA/genética , Doença da Deficiência de Múltiplas Sulfatases/genética , Mutação , Sulfatases/genética , Análise Mutacional de DNA , Feminino , Humanos , Recém-Nascido
18.
World J Gastroenterol ; 20(35): 12522-5, 2014 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-25253953

RESUMO

Mitotic crossover is a natural mechanism that is a main source of the genetic variability of primitive organisms. In complex organisms such as mammals, it represents an evolutionary rudiment which persisted as one of the numerous DNA repair mechanisms, and results in the production of homozygous allele combinations in all heterozygous genes located on the chromosome arm distal to the crossover. This event is familiar as loss of heterozygosity, which is one of the key mechanisms responsible for the development and progression of almost all cancers. We propose the hypothesis in which mitotic crossover is a principal source of the increased loss of heterozygosity that leads to the initiation and progression of colorectal carcinoma. The hypothesis could be tested by in vitro inhibition of Rad51 protein, orthotopic grafting of human colon cancer tissue into the gut of mice, and treatment with potential inhibitors. After these procedures, the frequency of mitotic crossover would be estimated. The development of selective inhibitors of mitotic crossover could stop further carcinogenesis of colorectal carcinoma, as well as many other neoplastic events. Loss of heterozygosity is an event responsible for carcinogenesis, its reduction by selective inhibitors of mitotic crossover could have a positive effect on cancer chemoprevention, as well as on growth reduction and a cessation in the progression of earlier developed tumors.


Assuntos
Carcinoma/genética , Transformação Celular Neoplásica/genética , Neoplasias Colorretais/genética , Evolução Molecular , Regulação Neoplásica da Expressão Gênica , Perda de Heterozigosidade , Mitose/genética , Recombinação Genética , Animais , Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Carcinoma/metabolismo , Carcinoma/patologia , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Variação Genética , Heterozigoto , Homozigoto , Humanos , Mitose/efeitos dos fármacos , Terapia de Alvo Molecular , Recombinação Genética/efeitos dos fármacos
19.
Chin Med J (Engl) ; 125(6): 1182-5, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22613552

RESUMO

Childhood leukemia bottleneck phenomenon is the most mysterious corollary of the prenatal origin discovery of leukemogenic chromosome translocations. The bottleneck is evidence that leukemia initiation, by in utero acquired chromosome translocations that generate functional fusion genes, is far more common than the incidence rate of corresponding leukemia. For childhood TEL-AML1(+) acute lymphoblastic leukemia (ALL) this equates to approximately 100 times. Practically this means that among a hundred children born with TEL-AML1 fusion gene, only one child will later in its life develop ALL. The key data necessary for unraveling of this mystery were discovered in 2002. It was the level of TEL-AML1(+) cells' frequency. The bottleneck is caused by the very low body TEL-AML1(+) cell count. Only one out of a thousand B cells carries TEL-AML1 fusion gene. TEL-AML1(+) body cell count is low because TEL-AML1 fusion is generated at cell level of 10(-3) to 10(-4) just during the late fetal lymphopoiesis i.e. after the 36th gestational week.


Assuntos
Cromossomos Humanos Par 12 , Cromossomos Humanos Par 21 , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética , Criança , Subunidade alfa 2 de Fator de Ligação ao Core/análise , Humanos , Recém-Nascido , Modelos Genéticos , Proteínas de Fusão Oncogênica/análise , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia
20.
World J Gastroenterol ; 16(44): 5647-50, 2010 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-21105201

RESUMO

Celiac disease (CD) is a common autoimmune condition. Previously it was considered to be a rare childhood disorder, but is actually considered a relatively common condition, present at any age, which may have multiple complications and manifestations. Hematological disorders of the disease are not uncommon. Among these disorders, the most frequently reported are anemias as a result of iron deficiency, often associated with folate and/or B12 deficiency. Anemias caused by hemolysis are very rarely reported in celiac patients. An 11-year-old girl with a previous uneventful medical history presented with severe hemolytic anemia. Hemolysis was Coombs negative, accompanied by inappropriate low reticulocyte count, despite exaggerated bone marrow hyperplasia of the erythroid precursors which showed normal maturation. Serology for recent infections, including Epstein-Barr virus, parvovirus B19, cytomegalovirus and mycoplasma, were all negative. Levels of serum IgA, IgG and IgM, were all within normal ranges for age. Screening for anti-DNA, antinuclear, antineutrophil cytoplasmic, antimicrosomal, antithyroglobulin, and antimitochondrial antibodies and lupus anticoagulants, was negative. She was also negative for human immunodeficiency virus. Conventional therapy with corticosteroids and intravenous immunoglobulin failed. CD was serendipitously discovered upon screening for anti-tissue transglutaminase autoantibodies. The disease was confirmed by biopsy of the small intestine mucosa. The patient recovered with gluten-free diet. A unique case of CD is presented. CD should be serologically screened in each patient with Coombs negative "immune" hemolytic anemia, particularly if accompanied by "reticulocytopenia". A new hemolytic mechanism and very speculative explanation for "reticulocytopenia" are discussed.


Assuntos
Anemia Hemolítica Autoimune/etiologia , Autoanticorpos/sangue , Doença Celíaca/diagnóstico , Eritrócitos/enzimologia , Transglutaminases/imunologia , Anemia Hemolítica Autoimune/sangue , Anemia Hemolítica Autoimune/imunologia , Anemia Hemolítica Autoimune/terapia , Biópsia , Doença Celíaca/complicações , Doença Celíaca/dietoterapia , Doença Celíaca/imunologia , Criança , Dieta Livre de Glúten , Transfusão de Eritrócitos , Feminino , Proteínas de Ligação ao GTP , Humanos , Reticulocitose , Resultado do Tratamento
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