RESUMO
Recognition of distinct phenotypic features is an important component of genetic diagnosis. Although CHARGE syndrome, Kabuki syndrome, and a recently delineated KMT2D Ex 38/39 allelic disorder exhibit significant overlap, differences on neuroimaging may help distinguish these conditions and guide genetic testing and variant interpretation. We present an infant clinically diagnosed with CHARGE syndrome but subsequently found to have a de novo missense variant in exon 38 of KMT2D, the gene implicated in both Kabuki syndrome and a distinct KMT2D allelic disorder. We compare her brain and inner ear morphology to a retrospective cohort of 21 patients with classic Kabuki syndrome and to typical CHARGE syndrome findings described in the literature. Thirteen of the 21 Kabuki syndrome patients had temporal bone imaging (5/13 CT, 12/13 MRI) and/or brain MRI (12/13) which revealed findings distinct from both CHARGE syndrome and the KMT2D allelic disorder. Our findings further elucidate the spectrum of inner ear dysmorphology distinguishing Kabuki syndrome and the KMT2D allelic disorder from CHARGE syndrome, suggesting that these three disorders may be differentiated at least in part by their inner ear anomalies.
Assuntos
Anormalidades Múltiplas/genética , Síndrome CHARGE/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Predisposição Genética para Doença , Doenças Hematológicas/genética , Proteínas de Neoplasias/genética , Doenças Vestibulares/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Síndrome CHARGE/diagnóstico por imagem , Síndrome CHARGE/patologia , DNA Helicases/genética , Face/diagnóstico por imagem , Face/patologia , Feminino , Doenças Hematológicas/diagnóstico por imagem , Doenças Hematológicas/patologia , Histona Desmetilases/genética , Humanos , Lactente , Recém-Nascido , Masculino , Mutação/genética , Neuroimagem , Fenótipo , Estudos Retrospectivos , Doenças Vestibulares/diagnóstico por imagem , Doenças Vestibulares/patologiaRESUMO
To report ophthalmic findings of patients without colobomas, and with a clinical and molecular diagnosis of CHARGE Syndrome. Retrospective study of ophthalmic findings in 67 CHARGE patients-clinically confirmed diagnosis with positive CHD7 mutation-seen in the Ophthalmology department of Cincinnati Children's Hospital Medical Center between January 1, 2008 through September 25, 2018. Criteria for inclusion in this study was absence of any form of a coloboma in either eye. In our cohort, all patients had a positive CHD7 mutation, in addition to a clinical diagnosis. 19.4% (13/67) of CHARGE patients did not have a coloboma in either eye. 69.2% (9/13) had strabismus, 76.9% (10/13) had a refractive error that warranted refractive correction, 23.1% (3/13) had amblyopia, 38.5% (5/13) had nasolacrimal duct obstruction, 30.8% (4/13) had dry eye syndrome and exposure keratopathy, 15.4% (2/13) had ptosis, 15.4% (2/13) had blepharitis, 15.4% (2/13) had Cortical Visual Impairment, 7.7% (1/13) of patients had optic nerve drusen, 7.7% (1/13) had Marcus Gunn Jaw Winking, and 7.7% (1/13) with an eyelid nevus. There are numerous ophthalmic findings in individuals with CHARGE Syndrome without colobomas. No study to date has evaluated the ophthalmic findings in CHD7 positive CHARGE patients without colobomas. These findings need to be assessed and treated to ensure optimal vision in the CHARGE patient population. Absence of coloboma does not rule out a diagnosis of CHARGE syndrome, and if there is a clinical suspicion, clinical confirmation then genetic testing would be warranted.
Assuntos
Blefaroptose/genética , Síndrome CHARGE/genética , Coloboma/genética , Cardiopatias Congênitas/genética , Anormalidades Maxilomandibulares/genética , Obstrução dos Ductos Lacrimais/genética , Doenças do Sistema Nervoso/genética , Reflexo Anormal/genética , Adolescente , Blefaroptose/complicações , Blefaroptose/patologia , Síndrome CHARGE/complicações , Síndrome CHARGE/patologia , Criança , Pré-Escolar , Coloboma/complicações , Coloboma/patologia , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Feminino , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/patologia , Humanos , Lactente , Anormalidades Maxilomandibulares/complicações , Anormalidades Maxilomandibulares/patologia , Obstrução dos Ductos Lacrimais/complicações , Obstrução dos Ductos Lacrimais/patologia , Masculino , Mutação/genética , Ducto Nasolacrimal/metabolismo , Ducto Nasolacrimal/patologia , Doenças do Sistema Nervoso/complicações , Doenças do Sistema Nervoso/patologia , Nervo Óptico/metabolismo , Nervo Óptico/patologiaRESUMO
We present the case of a male who shortly after birth developed acute respiratory distress due to bilateral choanal atresia, following which he was found to have rectal stenosis. Genetic testing for CHARGE syndrome was negative, but whole genome sequencing identified heterozygosity for a pathogenic missense variant in TP63 (c.727C > T, p.(Arg243Trp). He also has partial cutaneous syndactyly of the third and fourth fingers of the right hand, and bilateral lacrimal duct stenosis/aplasia. A later maxillofacial review identified a palpable submucousal cleft and his scalp hair is blond and slightly sparse. Choanal atresia and rectal stenosis are recognized features of ectrodactyly-ectodermal dysplasia-clefting syndrome, but we believe this is the first report of a case presenting with these features in the absence of the cardinal features.
Assuntos
Atresia das Cóanas/genética , Fenda Labial/genética , Fissura Palatina/genética , Displasia Ectodérmica/genética , Doenças Retais/genética , Síndrome do Desconforto Respiratório/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Síndrome CHARGE/diagnóstico , Síndrome CHARGE/genética , Síndrome CHARGE/patologia , Atresia das Cóanas/complicações , Atresia das Cóanas/diagnóstico , Atresia das Cóanas/patologia , Fenda Labial/complicações , Fenda Labial/diagnóstico , Fenda Labial/patologia , Fissura Palatina/complicações , Fissura Palatina/diagnóstico , Fissura Palatina/patologia , Constrição Patológica/complicações , Constrição Patológica/diagnóstico , Constrição Patológica/genética , Constrição Patológica/patologia , Displasia Ectodérmica/complicações , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/patologia , Predisposição Genética para Doença , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/patologia , Heterozigoto , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto/genética , Doenças Retais/complicações , Doenças Retais/diagnóstico , Doenças Retais/patologia , Síndrome do Desconforto Respiratório/complicações , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/patologia , Sequenciamento Completo do GenomaRESUMO
Objective: CHARGE syndrome presents with a collection of congenital anomalies affecting multiple organs. Ear and temporal bone anomalies, including hearing loss are highly prevalent. We present an aid to management of this challenging condition and report the strategies and outcomes of cochlear implantation. Methods: Systematic review of Medline, EMBASE, Web of Science, CENTRAL and clinicaltrials.gov was performed up to 21/10/2018 The review and meta-analysis of studies were performed according to the PRISMA statement. Patient demographics, comorbidity, anatomical factors, details of cochlear implantation and audiological outcome were extracted and summarized. Anatomical and surgical factors were evaluated by meta-analysis. Audiological outcomes reported were too heterogeneous for meta-analysis. All statistics were calculated with SPSS v23.0 (IBM, New York, USA). Results: Thirty-one studies reported 165 cochlear implants in 156 patients with CHARGE syndrome. Temporal bone and facial nerve anomalies were common. Discussion: The assessment and management of patients with CHARGE syndrome undergoing cochlear implantation is challenging. Outcomes may be affected by cochlear nerve deficiency, inner ear anomalies, and developmental delay. Surgery is almost invariably complicated by abnormal anatomy, and increased incidence of complications. Conclusion: A careful, case-by-case assessment of an individual's requirements within a multi-disciplinary setup is essential for achieving the best possible outcome.
Assuntos
Síndrome CHARGE/cirurgia , Implante Coclear/métodos , Nervo Coclear/anormalidades , Orelha Interna/anormalidades , Nervo Facial/anormalidades , Osso Temporal/anormalidades , Síndrome CHARGE/patologia , Criança , Pré-Escolar , Implante Coclear/efeitos adversos , Nervo Coclear/cirurgia , Contraindicações de Procedimentos , Orelha Interna/cirurgia , Nervo Facial/cirurgia , Feminino , Humanos , Lactente , Masculino , Osso Temporal/cirurgia , Resultado do TratamentoRESUMO
Oligodendrocyte precursor cells (OPCs) constitute the main proliferative cells in the adult brain, and deregulation of OPC proliferation-differentiation balance results in either glioma formation or defective adaptive (re)myelination. OPC differentiation requires significant genetic reprogramming, implicating chromatin remodeling. Mounting evidence indicates that chromatin remodelers play important roles during normal development and their mutations are associated with neurodevelopmental defects, with CHD7 haploinsuficiency being the cause of CHARGE syndrome and CHD8 being one of the strongest autism spectrum disorder (ASD) high-risk-associated genes. Herein, we report on uncharacterized functions of the chromatin remodelers Chd7 and Chd8 in OPCs. Their OPC-chromatin binding profile, combined with transcriptome and chromatin accessibility analyses of Chd7-deleted OPCs, demonstrates that Chd7 protects nonproliferative OPCs from apoptosis by chromatin closing and transcriptional repression of p53 Furthermore, Chd7 controls OPC differentiation through chromatin opening and transcriptional activation of key regulators, including Sox10, Nkx2.2, and Gpr17 However, Chd7 is dispensable for oligodendrocyte stage progression, consistent with Chd8 compensatory function, as suggested by their common chromatin-binding profiles and genetic interaction. Finally, CHD7 and CHD8 bind in OPCs to a majority of ASD risk-associated genes, suggesting an implication of oligodendrocyte lineage cells in ASD neurological defects. Our results thus offer new avenues to understand and modulate the CHD7 and CHD8 functions in normal development and disease.
Assuntos
Montagem e Desmontagem da Cromatina , Proteínas de Ligação a DNA/metabolismo , Oligodendroglia/metabolismo , Células-Tronco/metabolismo , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/patologia , Síndrome CHARGE/genética , Síndrome CHARGE/metabolismo , Síndrome CHARGE/patologia , Sobrevivência Celular , Proteínas de Ligação a DNA/genética , Proteína Homeobox Nkx-2.2 , Proteínas de Homeodomínio , Camundongos , Camundongos Knockout , Proteínas Nucleares , Oligodendroglia/patologia , Células-Tronco/patologia , Fatores de TranscriçãoRESUMO
BACKGROUND AND PURPOSE: CHARGE syndrome is a multisystemic congenital disorder, most commonly including coloboma, heart malformations, choanal atresia, developmental delay, and genital and ear anomalies. The diagnostic criteria for CHARGE syndrome have been refined with time. However, limited reports describe skull base and craniocervical junction abnormalities. Recently, a coronal clival cleft has been identified in association with CHARGE syndrome. The aim of our study was to assess the prevalence of clival pathology in CHARGE syndrome. MATERIALS AND METHODS: In this retrospective study, the CT/MR imaging data base at a single academic children's hospital was queried for the phrase "CHARGE syndrome" during a 17-year period (2001-2017). Electronic medical records were reviewed to confirm the diagnosis. Images were assessed for skull base anomalies, specifically clival hypoplasia and dysplasia. RESULTS: The search yielded 42 examinations (21 CTs and 21 MRIs) from 15 distinct patients (mean age, 4.1 ± 5.6 years; range, 2 days to 19 years). CHARGE syndrome diagnosis was confirmed either by clinical and genetic testing (n = 6) or by clinical diagnosis only (n = 9). A coronal clival cleft was identified in 87% of patients (37 examinations, n = 13 patients), either partial (53%) or complete (33%). Clival hypoplasia without clefting was present in all 5 examinations from the remaining 2 patients. CONCLUSIONS: Clival pathology is universal in CHARGE syndrome. Coronal clival clefts are extremely common, representing a useful additional diagnostic finding. Detection of a clival cleft should alert the radiologist to examine the palate, choana, eyes, ears, and olfactory centers for other signs of CHARGE syndrome.
Assuntos
Síndrome CHARGE/patologia , Fossa Craniana Posterior/anormalidades , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética/métodos , Masculino , Estudos Retrospectivos , Adulto JovemRESUMO
CHD7, an ATP-dependent chromatin remodeler, is disrupted in CHARGE syndrome, an autosomal dominant disorder characterized by variably penetrant abnormalities in craniofacial, cardiac, and nervous system tissues. The inner ear is uniquely sensitive to CHD7 levels and is the most commonly affected organ in individuals with CHARGE. Interestingly, upregulation or downregulation of retinoic acid (RA) signaling during embryogenesis also leads to developmental defects similar to those in CHARGE syndrome, suggesting that CHD7 and RA may have common target genes or signaling pathways. Here, we tested three separate potential mechanisms for CHD7 and RA interaction: (a) direct binding of CHD7 with RA receptors, (b) regulation of CHD7 levels by RA, and (c) CHD7 binding and regulation of RA-related genes. We show that CHD7 directly regulates expression of Aldh1a3, the gene encoding the RA synthetic enzyme ALDH1A3 and that loss of Aldh1a3 partially rescues Chd7 mutant mouse inner ear defects. Together, these studies indicate that ALDH1A3 acts with CHD7 in a common genetic pathway to regulate inner ear development, providing insights into how CHD7 and RA regulate gene expression and morphogenesis in the developing embryo.
Assuntos
Aldeído Oxirredutases/metabolismo , Síndrome CHARGE/genética , DNA Helicases/deficiência , Proteínas de Ligação a DNA/deficiência , Regulação da Expressão Gênica no Desenvolvimento , Retinal Desidrogenase/metabolismo , Tretinoína/metabolismo , Aldeído Oxirredutases/genética , Animais , Síndrome CHARGE/patologia , Linhagem Celular Tumoral , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Orelha Interna/embriologia , Embrião de Mamíferos , Feminino , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Organogênese/genética , RNA Interferente Pequeno/metabolismo , Retinal Desidrogenase/genéticaRESUMO
CHARGE syndrome is an autosomal dominant malformation disorder caused by heterozygous loss of function mutations in the chromatin remodeler CHD7. Chd7 regulates the expression of Sema3a, which also contributes to the pathogenesis of Kallmann syndrome, a heterogeneous condition with the typical features hypogonadotropic hypogonadism and an impaired sense of smell. Both features are common in CHARGE syndrome suggesting that SEMA3A may provide a genetic link between these syndromes. Indeed, we find evidence that SEMA3A plays a role in the pathogenesis of CHARGE syndrome. First, Chd7 is enriched at the Sema3a promotor in neural crest cells and loss of function of Chd7 inhibits Sema3a expression. Second, using a Xenopus CHARGE model, we show that human SEMA3A rescues Chd7 loss of function. Third, to elucidate if SEMA3A mutations in addition to CHD7 mutations also contribute to the severity of the CHARGE phenotype, we screened 31 CHD7-positive patients and identified one patient with a heterozygous non-synonymous SEMA3A variant, c.2002A>G (p.I668V). By analyzing protein expression and processing, we did not observe any differences of the p.I668V variant compared with wild-type SEMA3A, while a pathogenic SEMA3A variant p.R66W recently described in a patient with Kallmann syndrome did affect protein secretion. Furthermore, the p.I668V variant, but not the pathogenic p.R66W variant, rescues Chd7 loss of function in Xenopus, indicating that the p.I668V variant is likely benign. Thus, SEMA3A is part of an epigenetic loop that plays a role in the pathogenesis of CHARGE syndrome, however, it seems not to act as a common direct modifier.
Assuntos
Síndrome CHARGE/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Epigênese Genética , Crista Neural/metabolismo , Semaforina-3A/genética , Animais , Síndrome CHARGE/metabolismo , Síndrome CHARGE/patologia , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Embrião não Mamífero , Teste de Complementação Genética , Células HEK293 , Proteína Homeobox Nkx-2.5/genética , Proteína Homeobox Nkx-2.5/metabolismo , Humanos , Síndrome de Kallmann/genética , Síndrome de Kallmann/metabolismo , Síndrome de Kallmann/patologia , Mutação , Crista Neural/patologia , Regiões Promotoras Genéticas , Semaforina-3A/metabolismo , Índice de Gravidade de Doença , Xenopus laevisRESUMO
OBJECTIVE: Identifying aspects for establishing cochlear implantation guidelines for patients with ocular coloboma, heart defects, atresia of the choanae, retardation (of growth and/or of development), genital anomalies, and ear anomalies (CHARGE) syndrome (CS). STUDY DESIGN: Explorative retrospective study. SETTING: Cochlear implant (CI)-centers of tertiary referral centers in The Netherlands. PATIENTS: Ten patients with CS who received a CI between 2002 and 2012. INTERVENTIONS: Describing the challenges and benefits of cochlear implantation in CS. MAIN OUTCOME MEASURES: Imaging and surgical findings, language development, and Quality-of-life (QoL), compared with two control groups: 1) 34 non-syndromic CI-users and 2) 13 patients with CS without CI because of sufficient hearing. RESULTS: Subjective and objective audiometry and magnetic resonance imaging were necessary to confirm the presence of the cochlear nerve. Surgery in CS was challenging because of enlarged emissary veins, semi-circular-canal aplasia, aberrant facial nerve, and dysplastic cochlear windows, making computed tomography indispensable in surgical preparations. No major intraoperative complications occurred. Despite additional handicaps, all patients showed auditory benefit and improvement in disease-specific QoL. Patients implanted at a relatively young age (≤37 months) followed by a long period of CI-use (>5 years) and with minor additional problems, developed spoken language at a basic level comparable to that of the control group of CS patients. CONCLUSION: A CI should be considered in all patients with CS and severe sensorineural hearing loss. A careful work-up is required, comprising computed tomography, magnetic resonance imaging, objective, and subjective audiometry and assessment by a specialized multidisciplinary team. Cochlear implantation in CS might be complicated by syndrome-related temporal-bone anatomy, and the outcome of the CI is more individually determined. Early implantation should be aimed for.
Assuntos
Síndrome CHARGE/complicações , Implante Coclear/métodos , Perda Auditiva Neurossensorial/cirurgia , Síndrome CHARGE/patologia , Implantes Cocleares/efeitos adversos , Feminino , Audição/fisiologia , Perda Auditiva Neurossensorial/etiologia , Testes Auditivos , Humanos , Imageamento por Ressonância Magnética , Países Baixos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Inactivating mutations in chromodomain helicase DNA binding protein 7 (CHD7) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2% of the IGD cohort (73% missense and 27% splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75% of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings (i) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, (ii) reiterate the emerging genetic complexity of this family of IGD disorders, and (iii) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems.
Assuntos
DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Deficiências Nutricionais/genética , Hormônio Liberador de Gonadotropina/deficiência , Síndrome de Kallmann/genética , Fenótipo , Peixe-Zebra/genética , Animais , Sequência de Bases , Síndrome CHARGE/genética , Síndrome CHARGE/patologia , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Técnicas de Silenciamento de Genes , Hormônio Liberador de Gonadotropina/genética , Humanos , Dados de Sequência Molecular , Mutação de Sentido Incorreto/genética , Membrana dos Otólitos/patologia , Estrutura Terciária de Proteína , Análise de Sequência de DNARESUMO
BACKGROUND: Congenital facial palsy can result in significant disfigurement. A potential treatment option is free functional muscle transfer to reanimate the face. For this to be possible, a suitable recipient artery and vein must be present in the affected hemiface. In this study, the authors aim to identify whether patients with syndromic congenital facial palsy have a higher rate of facial vessel agenesis than those with isolated congenital facial palsy. METHODS: Patients were identified between November of 2006 and October of 2013. Patients were stratified into two groups: those with syndromic congenital facial palsy and those with isolated congenital facial palsy. The presence or absence of facial vessels was determined intraoperatively. RESULTS: Forty-seven eligible patients were included in the study. Those with syndromic congenital facial palsy were significantly more likely to have an absent facial vein than patients with isolated congenital facial palsy (p = 0.015). There was a strong trend toward those with syndromic facial palsy lacking a facial artery (p = 0.08). Subgroup analysis of patients with Möbius syndrome revealed that these patients were significantly more likely to have facial artery agenesis than those with isolated congenital facial palsy (p = 0.03). CONCLUSIONS: Facial vessel agenesis is significantly more common in patients with syndromic congenital facial palsy compared with those with isolated congenital facial palsy. This must be considered in the preoperative planning for facial reanimation with free functional muscle transfer. The operating surgeon should consider vascular studies of the affected hemiface before undertaking the procedure.
Assuntos
Anormalidades Múltiplas/patologia , Face/irrigação sanguínea , Paralisia Facial/congênito , Malformações Vasculares/etiologia , Anormalidades Múltiplas/cirurgia , Adolescente , Síndrome CHARGE/patologia , Síndrome CHARGE/cirurgia , Estudos de Casos e Controles , Criança , Face/anormalidades , Face/cirurgia , Paralisia Facial/patologia , Paralisia Facial/cirurgia , Retalhos de Tecido Biológico , Síndrome de Goldenhar/patologia , Síndrome de Goldenhar/cirurgia , Humanos , Incidência , Síndrome de Möbius/patologia , Síndrome de Möbius/cirurgia , Síndrome de Poland/patologia , Síndrome de Poland/cirurgia , Procedimentos de Cirurgia Plástica/métodos , Estudos Retrospectivos , Malformações Vasculares/epidemiologia , Malformações Vasculares/patologia , Adulto JovemRESUMO
OBJECTIVE: To determine whether patients with semicircular canal dysplasia have mutations in CHD7. BACKGROUND: CHARGE syndrome is a nonrandom clustering of congenital anomalies, including ocular coloboma, heart defects, choanal atresia or stenosis, retarded growth and development, genital hypoplasia, and inner and outer ear anomalies including deafness. Semicircular canal dysplasia has been included as a major diagnostic criterion for CHARGE syndrome. Mutations in the gene CHD7 on chromosome 8q12.1 are a major cause of CHARGE syndrome, but the extent to which patients with semicircular canal dysplasia have CHD7 mutations is not fully understood. STUDY DESIGN: Cross-sectional analysis of CHD7 in 12 patients with semicircular canal dysplasia and variable clinical features of CHARGE syndrome. RESULTS: We identified 6 CHD7 mutations, 5 of which occurred in patients who fulfilled Verloes' diagnostic criteria for typical CHARGE syndrome, and three of which were previously unreported. Of the 3 remaining CHD7 mutation-positive patients, one had atypical CHARGE by diagnostic criteria. Four MRI records were available, which revealed 2 patients with cochlear nerve aplasia and 1 patient with Chiari 1 malformation. CONCLUSION: These data provide additional evidence that CHD7 mutations are a significant cause of semicircular canal atresia in children with full or partial CHARGE syndrome.
Assuntos
Síndrome CHARGE/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Doenças do Labirinto/genética , Canais Semicirculares/patologia , Adolescente , Sequência de Bases , Síndrome CHARGE/patologia , Criança , Pré-Escolar , Estudos Transversais , Análise Mutacional de DNA , Feminino , Furanos , Humanos , Doenças do Labirinto/patologia , Masculino , Dados de Sequência Molecular , Mutação , Fenótipo , TiofenosRESUMO
CHARGE syndrome is a complex developmental disorder caused by mutations in the chromodomain helicase DNA-binding gene CHD7. Kabuki syndrome, another developmental disorder, is characterized by typical facial features in combination with developmental delay, short stature, prominent digit pads and visceral abnormalities. Mutations in the KMT2D gene, which encodes a H3K4 histone methyltransferase, are the major cause of Kabuki syndrome. Here, we report a patient, who was initially diagnosed with CHARGE syndrome based on the spectrum of inner organ malformations like choanal hypoplasia, heart defect, anal atresia, vision problems and conductive hearing impairment. While sequencing and MLPA analysis of all coding exons of CHD7 revealed no pathogenic mutation, sequence analysis of the KMT2D gene identified the heterozygous de novo nonsense mutation c.5263C > T (p.Gln1755*). Thus, our patient was diagnosed with Kabuki syndrome. By using co-immunoprecipitation, immunohistochemistry and direct yeast two hybrid assays, we could show that, like KMT2D, CHD7 interacts with members of the WAR complex, namely WDR5, ASH2L and RbBP5. We therefore propose that CHD7 and KMT2D function in the same chromatin modification machinery, thus pointing out a mechanistic connection, and presenting a probable explanation for the phenotypic overlap between Kabuki and CHARGE syndromes.
Assuntos
Anormalidades Múltiplas/metabolismo , Síndrome CHARGE/metabolismo , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Face/anormalidades , Doenças Hematológicas/metabolismo , Proteínas de Neoplasias/metabolismo , Doenças Vestibulares/metabolismo , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Síndrome CHARGE/genética , Síndrome CHARGE/patologia , Criança , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Face/patologia , Células HeLa/citologia , Doenças Hematológicas/genética , Doenças Hematológicas/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Mutação , Proteínas de Neoplasias/genética , Proteínas Nucleares/metabolismo , Fenótipo , Proteínas/metabolismo , Fatores de Transcrição/metabolismo , Doenças Vestibulares/genética , Doenças Vestibulares/patologiaRESUMO
Any dysfunction in olfaction requires a radiological exploration comprising the nasal cavity, the anterior base of the skull, in particular the frontal and temporal lobes. MRI is the reference examination, due to the frontal plane and the T1, T2 volume maps. In the child, aplasia of the olfactory bulbs falls within a polymalformation (CHARGE) or endocrine (Kallman) context. In the adult, rhino sinus disease and meningiomas are the most common etiologies. Frontal or temporal impairment: tumoral or vascular and neurodegenerative disorders (Parkinson's disease) may accompany a loss of olfaction.
Assuntos
Neoplasias dos Nervos Cranianos/diagnóstico , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Transtornos do Olfato/diagnóstico , Doenças do Nervo Olfatório/diagnóstico , Nervo Olfatório/patologia , Adulto , Síndrome CHARGE/diagnóstico , Síndrome CHARGE/patologia , Criança , Neoplasias dos Nervos Cranianos/patologia , Diagnóstico Diferencial , Lobo Frontal/patologia , Humanos , Síndrome de Kallmann/diagnóstico , Síndrome de Kallmann/patologia , Transtornos do Olfato/patologia , Bulbo Olfatório/anormalidades , Bulbo Olfatório/patologia , Doenças do Nervo Olfatório/patologia , Doença de Parkinson/diagnóstico , Doença de Parkinson/patologia , Lobo Temporal/patologiaRESUMO
CHARGE (coloboma of the eye, heart defects, choanal atresia, retarded growth and development, genital hypoplasia and ear anomalies and/or hearing loss) syndrome is a rare genetic, multiple-malformation syndrome. About 80% of patients with a clinical diagnose, have a mutation or a deletion in the gene encoding chromodomain helicase DNA-binding protein 7 (CHD7). Genotype-phenotype correlation is only partly known. In this nationwide study, phenotypic characteristics of 18 Danish CHD7 mutation positive CHARGE individuals (N = 18) are presented. We studied patient records, clinical photographs, computed tomography, and magnetic resonance imaging (MRI). Information was not available for all traits in all subjects. Therefore, the results are presented as fractions. The following prevalence of cardinal symptoms were found: coloboma, 16/17; heart defects, 14/18; choanal atresia, 7/17; retarded growth and development, 11/13; genital abnormalities, 5/18; ear anomalies, 15/17 and sensorineural hearing loss, 14/15. Vestibular dysfunction (10/13) and swallowing problems (12/15) were other frequent cranial nerve dysfunctions. Three-dimensional reconstructions of MRI scans showed temporal bone abnormalities in >85%. CHARGE syndrome present a broad phenotypic spectrum, although some clinical features are more frequently occurring than others. Here, we suggest that genetic testing for CHD7 mutation should be considered in neonates with a specific combination of several clinical symptoms.
Assuntos
Síndrome CHARGE/patologia , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Estudos de Associação Genética , Adolescente , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/patologia , Síndrome CHARGE/genética , Criança , Pré-Escolar , Coloboma/genética , Coloboma/patologia , Dinamarca/epidemiologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Orelha Externa/anormalidades , Orelha Externa/patologia , Assimetria Facial/genética , Assimetria Facial/patologia , Feminino , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Humanos , Lactente , Masculino , Anormalidades da Boca/genética , Anormalidades da Boca/patologia , Mutação , Estudos Retrospectivos , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/patologiaRESUMO
CHARGE is a multiple congenital anomaly disorder and a common cause of pubertal defects, olfactory dysfunction, growth delays, deaf-blindness, balance disorders and congenital heart malformations. Mutations in CHD7, the gene encoding chromodomain helicase DNA binding protein 7, are present in 60-80% of individuals with the CHARGE syndrome. Mutations in CHD7 have also been reported in the Kallmann syndrome (olfactory dysfunction, delayed puberty and hypogonadotropic hypogonadism). CHD7 is a positive regulator of neural stem cell proliferation and olfactory sensory neuron formation in the olfactory epithelium, suggesting that the loss of CHD7 might also disrupt development of other neural populations. Here we report that female Chd7(Gt/+) mice have delays in vaginal opening and estrus onset, and erratic estrus cycles. Chd7(Gt/+) mice also have decreased circulating levels of luteinizing hormone and follicle-stimulating hormone but apparently normal responsiveness to gonadotropin-releasing hormone (GnRH) agonist and antagonist treatment. GnRH neurons in the adult Chd7(Gt/+) hypothalamus and embryonic nasal region are diminished, and there is decreased cellular proliferation in the embryonic olfactory placode. Expression levels of GnRH1 and Otx2 in the hypothalamus and GnRHR in the pituitary are significantly reduced in adult Chd7(Gt/+) mice. Additionally, Chd7 mutant embryos have CHD7 dosage-dependent reductions in expression levels of Fgfr1, Bmp4 and Otx2 in the olfactory placode. Together, these data suggest that CHD7 has critical roles in the development and maintenance of GnRH neurons for regulating puberty and reproduction.