RESUMO
Seizures are one of the clinical hallmarks of Wolf-Hirschhorn syndrome (WHS), causing a significant impact on the life quality, still in the first years of life. Even that the knowledge about WHS-related seizure candidate genes has grown, cumulative evidence suggests synergic haploinsufficiency of distinct genes within cellular networks that should be better elucidated. Herein, we evaluated common mechanisms between candidate genes from WHS seizure-susceptibility regions (SSR) and genes globally associated with epilepsy. For this purpose, data from 94 WHS patients delineated by chromosomal microarray analysis were integrated into a tissue-specific gene network with gene expression, drugs, and biological processes. We found functional modules and signaling pathways involving candidate and new genes with potential involvement in the WHS-related seizure phenotype. The proximity among the previous reported haploinsufficient candidate genes (PIGG, CPLX1, CTBP1, LETM1) and disease genes associated with epilepsy suggests not just one, but different impaired mechanisms in cellular networks responsible for the balance of neuronal activity in WHS patients, from which neuron communication is the most impaired in WHS-related seizures. Furthermore, CTBP1 obtained the largest number of drug associations, reinforcing its importance for adaptations of brain circuits and its putative use as a pharmacological target for treating seizures/epilepsy in patients with WHS.
Assuntos
Epilepsia , Síndrome de Wolf-Hirschhorn , Epilepsia/complicações , Epilepsia/genética , Haploinsuficiência/genética , Humanos , Fenótipo , Convulsões/complicações , Convulsões/genética , Síndrome de Wolf-Hirschhorn/complicações , Síndrome de Wolf-Hirschhorn/genéticaRESUMO
El síndrome de Wolf-Hirschhorn es una entidad polimalformativa debida a la microdeleción en la región distal del brazo corto del cromosoma 4 (4p16.3), el cual produce una serie de manifestaciones clínicas, que pueden variar dependiendo del tipo y tamaño del defecto genético en este síndrome de genes contiguos. Se presentan cinco pacientes, tres de ellos de sexo femenino, todos con los hallazgos clínicos primordiales, con rasgo facial característico de "apariencia en casco de guerrero griego", retraso en el crecimiento y del desarrollo psicomotor. Además de la deleción parcial en la región distal del brazo corto del cromosoma 4, en dos pacientes, se encontraron alteraciones genéticas adicionales, mediante el uso de microarrays de polimorfismos de nucleótido único. Se resaltan las características clínicas del síndrome de Wolf-Hirschhorn con la finalidad de orientar el diagnóstico, brindar una atención médica interdisciplinaria y, a través de su confirmación, brindar un adecuado asesoramiento genético familiar.
Wolf-Hirschhorn syndrome is a polymalformative entity due to the microdeletion in the distal region of the short arm of chromosome 4 (4p16.3), which produces a series of clinical manifestations that can vary depending on the type and size of the genetic defect in this contiguous gene syndrome. Five patients are presented, three of them female, all with the primary clinical findings, characterized by "Greek warrior helmet appearance" facial feature, growth retardation and psychomotor development delay. In addition to the partial deletion in the distal region of the short arm of chromosome 4, two additional genetic alterations were found in two patients, through the use of single nucleotide polymorphism arrays. The clinical characteristics of Wolf-Hirschhorn syndrome are highlighted in order to guide the diagnosis, provide interdisciplinary medical care and, through its confirmation, provide adequate family genetic counseling.
Assuntos
Humanos , Masculino , Feminino , Lactente , Síndrome de Wolf-Hirschhorn , Equipe de Assistência ao Paciente , Anormalidades Múltiplas , Análise em Microsséries , Aconselhamento GenéticoRESUMO
Wolf-Hirschhorn syndrome is a polymalformative entity due to the microdeletion in the distal region of the short arm of chromosome 4 (4p16.3), which produces a series of clinical manifestations that can vary depending on the type and size of the genetic defect in this contiguous gene syndrome. Five patients are presented, three of them female, all with the primary clinical findings, characterized by "Greek warrior helmet appearance" facial feature, growth retardation and psychomotor development delay. In addition to the partial deletion in the distal region of the short arm of chromosome 4, two additional genetic alterations were found in two patients, through the use of single nucleotide polymorphism arrays. The clinical characteristics of Wolf-Hirschhorn syndrome are highlighted in order to guide the diagnosis, provide interdisciplinary medical care and, through its confirmation, provide adequate family genetic counseling.
El síndrome de Wolf-Hirschhorn es una entidad polimalformativa debida a la microdeleción en la región distal del brazo corto del cromosoma 4 (4p16.3), el cual produce una serie de manifestaciones clínicas, que pueden variar dependiendo del tipo y tamaño del defecto genético en este síndrome de genes contiguos. Se presentan cinco pacientes, tres de ellos de sexo femenino, todos con los hallazgos clínicos primordiales, con rasgo facial característico de "apariencia en casco de guerrero griego", retraso en el crecimiento y del desarrollo psicomotor. Además de la deleción parcial en la región distal del brazo corto del cromosoma 4, en dos pacientes, se encontraron alteraciones genéticas adicionales, mediante el uso de microarrays de polimorfismos de nucleótido único. Se resaltan las características clínicas del síndrome de Wolf-Hirschhorn con la finalidad de orientar el diagnóstico, brindar una atención médica interdisciplinaria y, a través de su confirmación, brindar un adecuado asesoramiento genético familiar.
Assuntos
Polimorfismo de Nucleotídeo Único , Síndrome de Wolf-Hirschhorn/genética , Feminino , Humanos , Lactente , Masculino , Análise em Microsséries , FenótipoRESUMO
Deletions in the 4p16.3 region are associated with Wolf-Hirschhorn syndrome (WHS), a contiguous gene deletion syndrome involving variable size deletions. In this study, we perform a cytogenomic integrative analysis combining classical cytogenetic methods, fluorescence in situ hybridization (FISH), chromosomal microarray analysis (CMA), and systems biology strategies, to establish the cytogenomic profile involving the 4p16.3 critical region and suggest WHS-related intracellular cell signaling cascades. The cytogenetic and clinical patient profiles were evaluated. We characterized 12 terminal deletions, one interstitial deletion, two ring chromosomes, and one classical translocation 4;8. CMA allowed delineation of the deletions, which ranged from 3.7 to 25.6 Mb with breakpoints from 4p16.3 to 4p15.33. Furthermore, the smallest region of overlapping (SRO) encompassed seven genes in a terminal region of 330 kb in the 4p16.3 region, suggesting a region of susceptibility to convulsions and microcephaly. Therefore, molecular interaction networks and topological analysis were performed to understand these WHS-related symptoms. Our results suggest that specific cell signaling pathways including dopamine receptor, NAD+ nucleosidase activity, and fibroblast growth factor-activated receptor activity are associated with the diverse pathological WHS phenotypes and their symptoms. Additionally, we identified 29 hub-bottlenecks (H-B) nodes with a major role in WHS.
Assuntos
Deleção Cromossômica , Coloração Cromossômica , Cromossomos Humanos Par 4/genética , Redes Reguladoras de Genes , Síndrome de Wolf-Hirschhorn/genética , Feminino , Humanos , Masculino , Estudos RetrospectivosRESUMO
El síndrome de Wolf Hirschhorn, también conocido como monosomía del brazo corto del cromosoma 4 (4p) o síndrome 4p-, es una rara enfermedad genética descrita por primera vez en el año 1961 por los doctores Cooper y Hirschhorn. El objetivo del trabajo es presentar un caso clínico sobre el síndrome de Wolf-Hirschhorn, que es un trastorno genético raro y aún bastante desconocido que cursa con múltiples anomalías morfológicas congénitas, así como con un retraso neurológico e intelectual de grado variable. La prevalencia de este síndrome es extremadamente baja, teniendo en cuenta que la cifra puede estar infraestimada, dada las pérdidas gestacionales precoces y la dificultad en el diagnóstico prenatal. Reportamos el caso de una paciente con gestación gemelar bicorial biamniótica tras un ciclo de FIV-ICSI, en el que al segundo gemelo se diagnosticó un Síndrome de Wolf-Hirschhorn, luego del estudio por una discordancia de pesos estimados y crecimiento intrauterino restringido de este segundo feto. El patrón clásico de presentación clínica se caracteriza por el desarrollo de alteraciones craneofaciales importantes, retraso en el crecimiento normal tanto prenatal como posnatal y deficiencia mental e intelectual de grado variable. El diagnóstico prenatal debe ser realizado por expertos. Puede sospecharse por un crecimiento intrauterino restringido, ya que se da en 80-90 por ciento de los fetos con esta patología. Una vez diagnosticado, se recomienda el estudio genético de los padres, dado que hasta 15 por ciento de los progenitores pueden padecer un reordenamiento cromosómico equilibrado en el brazo corto del cromosoma 4(AU)
Wolf Hirschhorn syndrome, also known as monosomy of the short arm of chromosome 4 (4p) or 4p-syndrome, is a rare genetic disorder first described in 1961 by doctors Cooper and Hirschhorn. The prevalence of this syndrome is extremely low, taking into account that the figure may be underestimated given the early gestational losses and the difficulty in prenatal diagnosis. The objective of the study is to present a clinical case of Wolf-Hirschhorn syndrome, presenting with multiple congenital morphological anomalies, as well as a neurological and intellectual retardation of variable degree. We report the case of a patient with a bicorial biamniotic twin gestation after a cycle of IVF-ICSI. The second twin was diagnosed with a Wolf-Hirschhorn syndrome, after performing the corresponding study due to a discordance of estimated weights and restricted intrauterine growth of this second fetus. The development of important craniofacial alterations, delay of normal prenatal and postnatal growth, and mental and intellectual deficiency of variable degree characterize the classic clinical presentation. Experts must make prenatal diagnosis. Wolf-Hirschhorn syndrome can be suspected by a restricted intrauterine growth, as it occurs in 80-90 percent of fetuses with this pathology. Once diagnosed, the genetic study of the parents is recommended, since up to 15 percent of the parents can suffer a balanced chromosomal rearrangement in the short arm of chromosome 4(AU)
Assuntos
Humanos , Feminino , Gravidez , Síndrome de Wolf-Hirschhorn/epidemiologia , Síndrome de Wolf-Hirschhorn/diagnóstico por imagem , Retardo do Crescimento Fetal/diagnóstico por imagemRESUMO
TITLE: Sindrome de Wolf-Hirschhorn: simple omision al citar?
Assuntos
Cromossomos Humanos Par 4 , Síndrome de Wolf-Hirschhorn/genética , Deleção Cromossômica , HumanosRESUMO
Wolf-Hirschhorn syndrome (WHS) is a contiguous gene and multiple malformation syndrome that results from a deletion in the 4p16.3 region. We describe here a 6-month-old girl that presented with WHS features but also displayed unusual findings, such as epibulbar dermoid in the left eye, ear tags, and left microtia. Although on G-banding her karyotype appeared to be normal, chromosomal microarray analysis revealed an â¼13-Mb 4p16.3p15.33 deletion and an â¼9-Mb Xp22.33p22.31 duplication, resulting from a balanced maternal t(X;4)(p22.31;p15.33) translocation. The patient presented with functional Xp disomy due to an unbalanced X-autosome translocation, a rare cytogenetic finding in females with unbalanced rearrangements. Sequencing of both chromosome breakpoints detected no gene disruption. To the best of our knowledge, this is the first patient described in the literature with WHS and epibulbar dermoid, a typical characteristic of the oculoauriculovertebral spectrum (OAVS). Our data suggest that possible candidate genes for OAVS may have been deleted along with the WHS critical region.
Assuntos
Deleção Cromossômica , Duplicação Cromossômica/genética , Cromossomos Humanos Par 4/genética , Cromossomos Humanos X/genética , Cisto Dermoide/genética , Translocação Genética/genética , Síndrome de Wolf-Hirschhorn/genética , Adulto , Criança , Bandeamento Cromossômico , Pontos de Quebra do Cromossomo , Feminino , Humanos , Lactente , Idade MaternaRESUMO
Wolf-Hirschhorn syndrome (WHS) is a syndrome with craniofacial and systemic abnormalities, which is related to 4p deletion. A 3-month old girl with an undiagnosed syndrome was referred for evaluation of the cleft lip and palate. Hypotonia, short stature, cardiac malformation, hypertrophied clitoris, and atypical thumb of both hands was observed. Microcephaly, low-set ear, prominent glabella, downslanting palpebral fissures, a characteristic "Greek warrior helmet" appearance, micrognathia, ears with pits/tags and bilateral incomplete cleft lip apart from incomplete cleft palate were observed as craniofacial findings. With clinical diagnosis of WHS, blood was subjected to karyotyping, which showed a 4p15.2 deletion, consistent with the condition. Here is reported the case of this WHS patient with an uncommon oral cleft extending the phenotypic spectrum of the disorder. The child was referred to a multidisciplinary team to reparative surgery of the cleft lip and palate. The patient is on regular medical follow-up and will be further assisted by dentists, physical therapists, occupational therapists and psychologists. The genotype-phenotype correlation of the affected patient with previous WSH syndrome reports is described.