Clinical and genetic analysis of a patient with Mowat-Wilson syndrome / 中华医学遗传学杂志

OBJECTIVE@#To summarize the clinical phenotype and genotype of a Chinese child affected with Mowat-Wilson syndrome (MWS).@*METHODS@#Clinical data of the patient were collected. The patient was analyzed by whole-exome sequencing (WES) as well as Sanger sequencing.@*RESULTS@#The patient was a male infant with recurrent fever and slow growth. He also had characteristic facies, recurrent spasm, and growth retardation. WES revealed that he has carried a heterozygous nonsense c.2609C>G (p.Ser870X) variant of the ZEB2 gene (30% mosaicism). Based on the American College of Medical Genetics and Genomics standards and guidelines, the variant was predicted to be pathogenic (PVS1+PS1+PS2+PM2).@*CONCLUSION@#The c.2609C>G variant of the ZEB2 gene probably underlay the MWS in this child. The mosaicism of the variant may explain his mild symptoms.

Association of rs2435357 and rs1800858 polymorphisms in ret proto-oncogene with hirschsprung disease: systematic review and meta-analysis / Associação dos polimorfismos rs2435357 e rs1800858 no proto-oncogene ret com doença de hirschsprung: revisão sistemática e metanálise

ABSTRACT Introduction: Many published studies have estimated the association of rs2435357 and rs1800858 polymorphisms in the proto-oncogene rearranged during transfection (RET) gene with Hirschsprung disease (HSCR) risk. However, the results remain inconsistent and controversial. Aim: To perform a meta-analysis get a more accurate estimation of the association of rs2435357 and rs1800858 polymorphisms in the RET proto-oncogene with HSCR risk. Methods: The eligible literatures were searched by PubMed, Google Scholar, EMBASE, and Chinese National Knowledge Infrastructure (CNKI) up to June 30, 2018. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the susceptibility to HSCR. Results: A total of 20 studies, including ten (1,136 cases 2,420 controls) for rs2435357 and ten (917 cases 1,159 controls) for rs1800858 were included. The overall results indicated that the rs2435357 (allele model: OR=0.230, 95% CI 0.178-0.298, p=0.001; homozygote model: OR=0.079, 95% CI 0.048-0.130, p=0.001; heterozygote model: OR=0.149, 95% CI 0.048-0.130, p=0.001; dominant model: OR=0.132, 95% CI 0.098-0.179, p=0.001; and recessive model: OR=0.239, 95% CI 0.161-0.353, p=0.001) and rs1800858 (allele model: OR=5.594, 95% CI 3.653-8.877, p=0.001; homozygote model: OR=8.453, 95% CI 3.783-18.890, p=0.001; dominant model: OR=3.469, 95% CI 1.881-6.396, p=0.001; and recessive model: OR=6.120, 95% CI 3.608-10.381, p=0.001) polymorphisms were associated with the increased risk of HSCR in overall. Conclusions: The results suggest that the rs2435357 and rs1800858 polymorphisms in the RET proto-oncogene might be associated with HSCR risk.

RESUMO Introdução: Muitos estudos publicados estimaram a associação dos polimorfismos rs2435357 e rs1800858 do proto-oncogene rearranjado durante a transfecção (RET) com o risco de doença por Hirschsprung (HSCR). No entanto, os resultados permanecem inconsistentes e controversos. Objetivo: Realizar metanálise para obter estimativa mais precisa da associação dos polimorfismos rs2435357 e rs1800858 no proto-oncogene RET com risco de HSCR. Método: A literatura elegível foi pesquisada pelo PubMed, Google Scholar, EMBASE e CNKI até 30 de junho de 2018. Resultados: Um total de 20 estudos, incluindo dez (1.136 casos 2.420 controles) para rs2435357 e dez (917 casos 1.159 controles) para rs1800858 foram incluídos. Os resultados globais indicaram que o rs2435357 (modelo alelo: OR=0,230, IC 95% 0,178-0,298, p=0,001; modelo homozigoto: OR=0,079, IC 95% 0,048-0,130, p=0,001; modelo heterozigoto: OR=0,149 , IC 95% 0,048-0,130, p=0,001, modelo dominante: OR=0,132, IC 95% 0,098-0,179, p=0,001 e modelo recessivo: OR=0,239, IC 95% 0,161-0,353, p=0,001) e rs1800858 (modelo alelo: OR=5,594, IC 95% 3,653-8,877, p=0,001; modelo homozigoto: OR=8,453, IC 95% 3,783-18,890, p=0,001; modelo dominante: OR=3,469, IC 95% 1,881- 6,396, p=0,001 e modelo recessivo: OR=6,120, 95% CI 3,608-10,381, p=0,001) polimorfismos foram associados com o aumento do risco de HSCR em geral. Conclusões: Os resultados sugerem que os polimorfismos rs2435357 e rs1800858 no proto-oncogene RET podem estar associados ao HSCR.

Mowat-Wilson syndrome: neurological and molecular study in seven patients / Síndrome de Mowat-Wilson: estudo neurológico e molecular em sete pacientes

Objective To present a seven-cases serie of Mowat-Wilson syndrome (MWS). Method All patients with positive mutation for the ZEB2 were evaluated by a geneticist and a neurologist, with clinical and laboratorial characterization. Results A peculiar facies and mental retardation were present in all patients. The Denver II scale showed intense delay in all aspects, especially fine motor and adaptive. Acquired microcephaly was observed in five patients. Only one patient did not present epilepsy. Epilepsy was focal and predominating in sleep, with status epilepticus in three patients. The initial seizure was associated with fever in most patients (4/6). The EEG showed epileptic focal activity (5/7). The imaging studies revealed total agenesis (4/7) and partial agenesis of the corpus callosum (1/7). Conclusion Physicians who care for patients with mental retardation and epilepsy should be aware of SMW. .

Objetivo Apresentar uma série de sete casos da síndrome de Mowat-Wilson (SMW). Método Todos os pacientes com estudo positivo para a mutação ZEB2 foram avaliados por um geneticista e um neurologista, com a caracterização clínica e laboratorial. Resultados Todos apresentavam fácies peculiar e retardo mental. A escala de Denver II evidenciou intenso atraso em todos os aspectos, sobretudo motor fino e adaptativo. Microcefalia adquirida foi observada em cinco pacientes. Apenas um paciente não apresentava epilepsia, sendo esta focal e predominando no sono, sendo relatado estado de mal em três pacientes. A crise inicial estava associada à febre na maioria dos pacientes (4/6). O EEG evidenciou atividade epiléptica focal na maioria (5/7). Ao estudo de imagem foi observada agenesia total (4/7) e parcial do corpo caloso (1/7). Conclusão Médicos que lidam com pacientes com retardo mental e epilepsia devem saber distinguir as características peculiares da SMW. .

Síndrome de Mowat – Wilson, primer caso reportado en Colombia: Importancia de un estudio ampliado por genética / Mowat - Wilson syndrome, first case reported in Colombia: Importance of expanded by genetic study

El Síndrome de Mowat - Wilson (SMW), es una rara enfermedad genética con prevalencia desconocida, hasta el año 2010 habían sido descritos 180 casos en la literatura mundial indexada. Los pacientes con SMW presentan un fenotipo característico dado por: frente amplia y abombada, hipoplasia mediofacial, hipertelorismo ocular, nariz y columnela prominentes, asociado a compromiso neurológico (epilepsia, retardo en neurodesarrollo y mental) y enfermedad de Hirschsprung, que ha sido descrita solo en algunos casos. (1,2) El SMW se origina por mutaciones puntuales en el gen ZEB2 y hasta en el 17% de los casos se presenta por deleciones submicroscópicas que comprometen la región cromosómica 2q22.3 donde se localiza este gen (3). El gen ZEB2 es determinante en la diferenciación de las células derivadas de la cresta neural y sistema nervioso central lo cual explicaría el fenotipo neurológico. Los autores describimos el primer caso de SMW en población Colombiana, causado por microdeleción de novo de la región cromosómica 2q22.2, resaltando así la importancia de un completo estudio citogenético – molecular para pacientes con alta sospecha de síndromes de microdeleción (1,3).

Mowat – Wilson Syndrome (MWS), is a rare disease the prevalence is currently unknown approximately 180 cases had been reported until 2010. MWS patients exhibit a characteristic phenotype given by, high forehead, frontal bossing, midface hypoplasia, ocular hypertelorism, prominent nose and columella associated with neurological involvement (epilepsy and moderate to severe intellectual deficiency) and Hirschsprung disease, which has been described only in some cases (1,2). MWS is caused by mutations in the gene ZEB2 and up to 17% of the cases presented by submicroscopic deletions that compromise 2q22.3 chromosomal region where this gene is located (3). ZEB2 is critical for the differentiation of cells derived from the neural crest and central nervous system which would explain the neurological phenotype. We describe the first case of MWS in Colombian caused by de novo microdeletion of chromosome 2q22.2 region, We highlighted the importance of a complete cytogenetic and molecular study in patients with high suspected of microdeletion syndromes (1,3).

RET haplotype, not linked to the C620R activating mutation, associated with Hirschsprung disease in a novel MEN2 family

Hirschsprung disease is a congenital form of aganglionic megacolon that results from cristopathy. Hirschsprung disease usually occurs as a sporadic disease, although it may be associated with several inherited conditions, such as multiple endocrine neoplasia type 2. The rearranged during transfection (RET) proto-oncogene is the major susceptibility gene for Hirschsprung disease, and germline mutations in RET have been reported in up to 50% of the inherited forms of Hirschsprung disease and in 15-20% of sporadic cases of Hirschsprung disease. The prevalence of Hirschsprung disease in multiple endocrine neoplasia type 2 cases was recently determined to be 7.5% and the cooccurrence of Hirschsprung disease and multiple endocrine neoplasia type 2 has been reported in at least 22 families so far. It was initially thought that Hirschsprung disease could be due to disturbances in apoptosis or due to a tendency of the mutated RET receptor to be retained in the Golgi apparatus. Presently, there is strong evidence favoring the hypothesis that specific inactivating haplotypes play a key role in the fetal development of congenital megacolon/Hirschsprung disease. In the present study, we report the genetic findings in a novel family with multiple endocrine neoplasia type 2: a specific RET haplotype was documented in patients with Hirschsprung disease associated with medullary thyroid carcinoma, but it was absent in patients with only medullary thyroid carcinoma. Despite the limited number of cases, the present data favor the hypothesis that specific haplotypes not linked to RET germline mutations are the genetic causes of Hirschsprung disease.

The Hirschsprung's-multiple endocrine neoplasia connection

The risk of patients with Hirschsprung's disease later developing multiple endocrine neoplasia remains a matter of concern. The multiple endocrine neoplasia 2-Hirschsprung's disease association has been shown to cosegregate in Hirschsprung's disease patients with both short- and long-segment aganglionosis, although patients with long-segment aganglionosis a to carry the greatest risk. The Hirschsprung's disease-medullary thyroid carcinoma relationship also appears to be bi-directional, and activation or suppression of the rearranged during transfection gene appeared to vary over succeeding generations within the same family. Rearranged during transfection gene variations are associated with both conditions. The cosegregation of Hirschsprung's disease and multiple endocrine neoplasia 2 is particularly interesting as it involves both "switch off" and "switch on" of the rearranged during transfection proto-oncogene in the same patient. This cosegregation mostly relates to the cysteine-rich area on RET620 (the "Janus gene"). The mechanism whereby rearranged during transfection influences gene activation in multiple endocrine neoplasia 2 is complex, but genetic variations impair the rearranged during transfection tyrosine kinase response to tyrosine kinase activation, thus appearing to dictate downstream signaling cascade responses. Better understanding of the RET-620 relationship allows for a more cost-effective method of identifying those at risk by focusing rearranged during transfection gene testing to this specific area as a "hot spot". The clinical awareness of possible medullary thyroid carcinoma has led to timely intervention and early treatment of this chemo- and radioresistant tumor with poor prognosis. Establishment of "risk" by genetic testing has become a classic model of molecular medicine being integrated into patient care and offering rearranged during transfection directed prophylactic surgical management. In addition, novel approaches to treatment based on this genetic knowledge have already shown early promise in randomized clinical trials.

Genética e clínica da doença de hirschsprung: teoria e a prática no Instituto Fernandes Figueira / Genetics and clinic of the illness of hirschsprung: theory and the practical one in the Instituto Fernandes Figueira

O trabalho centra-se na doença de hirschsprung (DH). Para melhor recortar o objeto empreendeu-se: 1º) uma pesquisa bibliográfica na literatura médica internacional, de 1992 a 2003;2º) um estudo retrospectivo e descritivo, abarcando o levantamento de 55 prontuários relativos a pacientes atendidos pelos Departamentos de Cirurgia Pediátrica, Pediatria e Genética do IFF- FIOCRUZ, de 1993 a 2003, com o diagnóstico confirmado da doença, visando emoldurar o quadro da DH na instituição; 3º) estudos de caso referentes aos pacientes atendidos, tendo como objetivo avaliar aspectos correlacionados ao diagnóstico, à apresentação do quadro clínico, ao tratamento e às complicações.Os resultados mostraram: a) 9 genes já foram identificados como associados à DH, sendo o mais estudado o proto-oncogene RET; b) o padrão de herança é complexo e multigênico, influenciado pelo sexo e diferente para a forma de segmento curto e de segmento longo; c) portadores de DH podem apresentar só o fenótipo entérico ou co-ocorrer com síndromes complexas e anomalias congênitas isoladas; d) a DH é uma neurocristopatia decorrente de anormalidade da migração, diferenciação, ou perda in situ de células derivadas da crista neural; e) normalmente o pediatra é o primeiro profissional a se deparar com a criança portadora de DH. No IFF 54 crianças apresentaram sintomas no período neonatal, mas foram encaminhadas tardiamente para a cirurgia pediátrica, refletindo o desconhecimento sobre a doença; f) a taxa de letalidade no IFF foi de 9 por cento e todos os óbitos ocorreram na DH de segmento longo; g) a enterocolite é a principal causa de morbimortalidade e, há similitude entre os dados bibliográficos e os resultados do IFF;h) a tendência mundial é sempre que possível na DH clássica, realizar o abaixamento endoretal pela via transanal no período neonatal, mas no IFF as características da demanda dificultam esta condutai) distúrbios da defecção ocorrem com uma freqüência bem maior do que se supunha até recentemente, sendo fundamental o follow- up prolongado; j) a DH se associa a diversas síndromes, o que têm influência no manuseio e tratamento;l) a rara associação com neoplasias endócrinas múltiplas deve ser investigada devido a agressividade do fenótipo tumoral e, finalmente, m)a complexidade genética da DH se traduz na clínica, requerendo a atuação de uma equipe multidisciplinar muito bem integrada.

An experimental study on the expression of heme oxygenase-2 mRNA in Hirschsprung's disease / 华中科技大学学报（医学）（英德文版）

In order to investigate the relationship between the expression of heme oxygenase-2 (HO-2) mRNA and the pathogenesis of Hirschsprung's disease (HD), total ribonucleic acid (RNA) was extracted in the aganglionic and ganglionic segments of colon respectively from 15 cases of HD. The single-stranded cDNA of HO-2 was synthesized and further amplified by reverse transcription-polymerase chain reaction (RT-PCR). The expression of HO-2 mRNA was normal in ganglionic segments, but absent in aganglionic segments. It is concluded that the absence of HO-2 mRNA expression may be an important mechanism responsible for HD.

Chagas congénito en Bolivia: estudio comparativo de la eficacia y el costo de los métodos de diagnóstico / Congenital chagas in Bolivia: comparative study of the cost and efficasy of diagnostic methods

Ochocientos veinte recién nacidos (RN) de +- 2500g de la Maternidad percy Boland fueron examinados entre 1988 y 1989 por los diferentes métodos de diagnóstico de la enfermedad de chagas (Patología de placenta, serología, parasitología y clínica) con el propóeito de determinar su eficacia y costo. el exámen histopatológico permitió detectar 87 casos de infección placentaria, de este total, se observaron 43 (49) casos RN positovs al exámen parasitológico de la sangre del cordón. Este número aumentó con la repetición de la prueba durante el primer mes de vida del niño, alcanzando el mismo nivel que la histopatología. Con el exámen serológico se detectaron 2 casos positivos. el signo clínico de alta especificidad de la Enfermedad de Chagas en RN es la hepatoesplenomegalia. se discuten ventajas y desventajas en cuanto a costo y factibilidad de dos estrategias de detección de la enfermedad de Chagas congénito, la primera basada en la histopatilogía y otra en la parasitología. Se concluye que los programas de detección de la enfermedad de Chagas no pueden ser uniformes, que se deben tomar en cuenta aspectos de prevalencia de la enfermedad, existencia del vector y disponibilidad de técnicas de laboratorio