CHARGE syndrome in a neonate with esophageal atresia / 中华围产医学杂志

This article reported a case of neonatal CHARGE syndrome complicated by congenital esophageal atresia. A prenatal ultrasound examination at 30 weeks of gestation revealed polyhydramnios and a small magenblase of the fetus, then fetal MRI suggested congenital esophageal atresia. The infant was born with severe asphyxia at 37 +5 gestational weeks by cesarean section due to placental abruption with a birth weight of 2 310 g. Gastric tube could not be placed after resuscitation. Congenital esophageal atresia complicated by tracheoesophageal fistula was diagnosed by esophageal imaging. Bilateral choanal atresia was detected by electronic nasopharyngoscopy and MRI. Moreover, skull defect, suspected meningocele were also observed. CHARGE syndrome was confirmed by whole exome sequencing, revealing a frameshift deletion of c.2155delA (p.Thr719GlnfsTer9) in the CHD7 gene. The infant died after withdrawing treatment.

Síndrome CHARGE: reporte de caso / CHARGE syndrome: case report

El síndrome CHARGE es un trastorno genético raro que generalmente se diagnostica durante el período prenatal o neonatal, con la identificación de numerosas anomalías dismórficas y congénitas, como coloboma, defectos cardiacos, atresia de coanas, retraso del crecimiento, hipogonadismo y defectos auditivos, con una incidencia de 1 por cada 12.000 a 15.000 nacidos vivos. Presenta un patrón de herencia autosómico dominante, y entre el 60% y el 70% de los casos se deben a mutaciones que alteran la secuencia del gen CHD7 en el cromosoma 8, las cuales en su mayoría (>90%) son mutaciones de novo. Se describe el caso de una paciente de 6 años con sospecha de síndrome de malformaciones múltiples, que presentó al examen físico talla baja, pabellones de baja implantación, frente amplia, antecedentes de atresia esofágica, hipoacusia neurosensorial, coloboma y riñón en herradura, los cuales son criterios mayores y menores para el diagnóstico clínico de la entidad. Posteriormente, se realizó secuenciación del exoma completo, detectándose alteración del gen CHD7, que confirmó el diagnóstico de síndrome CHARGE. Se debe tener presente que, aunque la prueba molecular confirma el diagnóstico, un gran porcentaje de los pacientes con diagnóstico clínico de síndrome CHARGE no presentan alteraciones en la secuencia de este gen; por lo tanto, el diagnóstico clínico, basado en las alteraciones fenotípicas, continúa demostrando su relevancia

CHARGE syndrome is a rare genetic disorder, which is usually diagnosed during the prenatal or neonatal period with the identification of numerous dysmorphic and congenital abnormalities, characterized by coloboma, heart defects, choanal atresia, retarded growth and development, hypogonadism, and hearing defects, with an incidence of 1 in every 12,000 to 15,000 live births. It has an autosomal dominant inheritance pattern, and between 60% and 70% of cases are caused by mutations in the CHD7 gene at chromosome 8, with the majority (>90%) of mutations occurring de novo. The case of a 6-year-old patient with a multiple malformation syndrome is described, who presented during the physical examination with short stature, ear abnormalities, prominent forehead, a history of esophageal atresia, sensorineural hearing loss, coloboma and horseshoe kidney, which are major and minor criteria for the clinical diagnosis of this condition. Subsequently, complete exome sequencing was performed, detecting a mutation in the CHD7 gene, that confirmed the diagnosis of CHARGE syndrome. It should be noted that although the molecular test confirms the diagnosis, a large percentage of patients with a clinical diagnosis of CHARGE syndrome do not have mutations in this gene sequence; therefore, clinical diagnosis, based on phenotypic features, continues demonstrating its relevance

Espectro fenotípico de Síndrome de CHARGE neonatal / Phenotypic spectrum of neonatal CHARGE syndrome

INTRODUCCIÓN: El Síndrome de CHARGE (SCH), es un síndrome genético de amplia variabilidad fenotípica, de he rencia autosómica dominante, causado por variantes patogénicas en el gen CHD7. OBJETIVO: Descri bir el amplio espectro fenotípico de un SCH neonatal, heterocigoto para el gen CDH7 y la utilidad de la secuenciación en la confirmación diagnóstica, considerando los diagnósticos diferenciales. CASO CLÍNICO: recién nacida prematura de 34 semanas, con antecedentes prenatales de polihidroamnios severo, translucencia nucal aumentada y foco hiperecogénico cardiaco, con estudio de TORCH antenatal, que descartó infección congénita. Al nacer se pesquisó parálisis facial periférica, atresia de coanas, dismorfias múltiples, cardiopatía congénita y coloboma retinocoroideo bilateral. Las neuroimágenes mostraron hipoplasia de cóclea y de canales semicirculares bilaterales e hipoplasia pontocerebelosa. Los potenciales evocados auditivos mostraron hipoacusia sensorioneural profunda derecha y anacusia izquierda. Evolucionó con hipocalcemia y alteraciones en la inmunidad, confirmándose un hipoparatiroidismo e hipoplasia de timo. El cariograma fue normal y la amplificación de sondas dependiente de ligandos múltiples (MLPA) excluyó microdeleción 22q11.2. La sospecha clínica de SCH se confirmó con la detección de una variante patogénica en el gen CHD7. CONCLUSIONES: La su perposición de características clínicas del SCH con otros síndromes genéticos requiere confirmación genética molecular considerando diferencias en evolución, terapias y riesgos de recurrencia.

INTRODUCTION: CHARGE syndrome is a genetic disorder of wide phenotypic variability, of autosomal dominant in heritance, caused by pathogenic variants in the CHD7 gene. OBJECTIVE: To describe the broad pheno typic spectrum of neonatal CHARGE syndrome, heterozygous for the CHD7 gene, and the usefulness of genome sequencing in diagnostic confirmation, considering differential diagnoses. CLINICAL CASE: 34-week preterm newborn, with severe prenatal history of polyhydramnios, increased nuchal trans- lucency, and hyperechogenic cardiac focus, with a TORCH study that ruled out congenital infection. Peripheral facial paralysis, choanal atresia, multiple dysmorphisms, congenital heart disease, and bilateral retinochoroidal coloboma were observed at birth. The neuroimaging study showed hypo plasia of the cochlea and bilateral semicircular canals, and pontocerebellar hypoplasia. The auditory evoked potentials showed deep right-sided sensorineural hearing loss and left anacusis. The patient developed hypocalcemia and immunological alterations, confirming hypoparathyroidism and thy mus hypoplasia. The karyogram was normal and 22q11.2 microdeletion was excluded through mul tiplex ligation-dependent probe amplification (MPLA). A pathogenic variant in the CHD7 gene was detected that confirmed the clinical suspicion of CHARGE syndrome. CONCLUSIONS: The overlap of clinical characteristics of CHARGE syndrome requires molecular genetic confirmation, considering differences in evolution, therapies, and recurrence risks with other genetic syndromes.

Successful intubation using video laryngoscope in a child with CHARGE syndrome: A case report

CHARGE syndrome is a rare genetic disorder with CHD7 gene mutation. CHARGE is an acronym for coloboma (C), heart disease (H), atresia of choanae (A), retardation of growth (R), genitourinary malformation (G), and ear abnormalities (E). Patients with CHARGE syndrome need to undergo many surgeries due to their various congenital anomalies. Since airway abnormalities frequently accompany CHARGE syndrome, general anesthesia remains a challenge. Here we report a case of difficult intubation in a 35-month-old boy with CHARGE syndrome during general anesthesia and the experience of successful intubation using D-blade of C-MAC® video laryngoscope.

New progress in diagnosis and treatment of CHARGE syndrome / 中华实用儿科临床杂志

CHARGE syndrome is a rare autosomal dominant genetic disease, which involves the structure and function of multiple organs.The clinical manifestations are complex and diverse, it can be hereditary, but most cases was sporadic.While, the representation of disease is too much overlap with other diseases, it can be difficult to make a diagnosis only by clinical data.With the discovery of the pathogenic gene-CHD7, it can be further enhanced the knowledge and diagnosis of disease.Prompt diagnosis and treatment is not only beneficial to reduce mortality, but also can help to the prognosis of the patients.Through reviewing the literature, the progress of diagnosis and treatment of CHARGE syndrome were summarized in order to diagnose and treat the disease.

NeW progress in diagnosis and treatment of CHARGE syndrome / 中华实用儿科临床杂志

CHARGE syndrome is a rare autosomal dominant genetic disease,which involves the structure and function of multiple organs. The clinical manifestations are complex and diverse,it can be hereditary,but most cases was sporadic. While,the representation of disease is too much overlap with other diseases,it can be difficult to make a diag-nosis only by clinical data. With the discovery of the pathogenic gene-CHD7,it can be further enhanced the knowledge and diagnosis of disease. Prompt diagnosis and treatment is not only beneficial to reduce mortality,but also can help to the prognosis of the patients. Through reviewing the literature,the progress of diagnosis and treatment of CHARGE syn-drome were summarized in order to diagnose and treat the disease.

A novel CHD7 mutation in an adolescent presenting with growth and pubertal delay

Mutations in the CHD7 gene, encoding for the chromodomain helicase DNA-binding protein 7, are found in approximately 60% of individuals with CHARGE syndrome (coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia, ear abnormalities and/or hearing loss). Herein, we present a clinical case of a 14-year-old male presenting for evaluation of poor growth and pubertal delay highlighting the diagnostic challenges of CHARGE syndrome. The patient was born full term and underwent surgery at 5 days of life for bilateral choanal atresia. Developmental milestones were normally achieved. At age 14 his height and weight were

Clinical data and mutation analysis of two cases of CHARGE syndrome / 中华内分泌代谢杂志

Objective To analyze the clinical manifestations and possible gene mutation sites of Chinese patients in order to improve the clinician's understanding of CHARGE syndrome. Methods Clinical data were collected and blood samples were obtained from the proband of CHARGE syndrome and their relatives. The peripheral blood DNA was extracted and sequenced by PCR amplification. Mutation sites were verified by Sanger sequencing. Results For the first proband, a heterozygous mutation was detected in the intron 10 of CHD7 gene. His parents and brother did not have mutation. For the second proband, total repeat sequence in exon 7 of CHD7 gene was detected. His father carried the same mutation and his mother did not have mutation. Conclusion For the patients who are diagnosed with CHARGE syndrome based on the clinical manifestations, genetic mutation detection should be proceeded. It is useful for studying possible genetic pathogenesis and enhancing the awareness of clinicians.

CHARGE syndrome: a review of the literature / 中华整形外科杂志

CHARGE (Coloboma, Heart defects, Atresia of the choanal, Retarded growth and development, Genital abnormalities, Ear anomalies and deafness) syndrome is a combination of multiple congenital abnormality. With the previous data which has been reported, most cases of CHARGE syndrome were liked to heterozygous mutations in the gene CHD7, encoding the CHD (chromodomain helicase DNA binding domain) member CHD7. Owing to the misleading by common features with other anomaly syndromes and the insufficient CHARGE syndrome, the diagnostic rate of this disease is quite low. In this review authors summarize the recent developments in phenotypic features, diagnosis, aetiology and clinical management of CHARGE syndrome.

Non-Homologous End Joining Repair Mechanism-Mediated Deletion of CHD7 Gene in a Patient with Typical CHARGE Syndrome

CHARGE syndrome MIM #214800 is an autosomal dominant syndrome involving multiple congenital malformations. Clinical symptoms include coloboma, heart defects, choanal atresia, retardation of growth or development, genital hypoplasia, and ear anomalies or deafness. Mutations in the chromodomain helicase DNA binding protein 7 (CHD7) gene have been found in 65-70% of CHARGE syndrome patients. Here, we describe a 16-month-old boy with typical CHARGE syndrome, who was referred for CHD7 gene analysis. Sequence analysis and multiplex ligation-dependent probe amplification were performed. A heterozygous 38,304-bp deletion encompassing exon 3 with a 4-bp insertion was identified. There were no Alu sequences adjacent to the breakpoints, and no sequence microhomology was observed at the junction. Therefore, this large deletion may have been mediated by non-homologous end joining. The mechanism of the deletion in the current case differs from the previously suggested mechanisms underlying large deletions or complex genomic rearrangements in the CHD7 gene, and this is the first report of CHD7 deletion by this mechanism worldwide.

Retrospective Study of a Series of Choanal Atresia Patients

Introduction: Although it has been more than 250 years since the first description of choanal atresia (CA), there are still doubts about this abnormality. The differences between unilateral and bilateral forms are seldom discussed. Objectives: Aggregate data from patients diagnosed with CA, grouping patients with unilateral and bilateral forms. Methods: Retrospective study. Results  Eighteen patients were included: 12 (66.6%) presented bilateral atresia, of which 77.8% were mixed bony-membranous type and 22.2% were pure bony type. From the 12 patients with bilateral atresia, 10 presented related malformations, 3 of whom had CHARGE syndrome (coloboma, heart defects, choanal atresia, retardation of growth and development, genitourinary problems, ear abnormalities). From the remaining 6 patients with unilateral atresia, only 2 showed malformations, 1 renal and 1 cardiac. All patients with unilateral atresia needed only 1 surgical procedure, and patients with the bilateral form needed a median of 2.85 interventions (p = 0.003). The median age of surgical procedure in the unilateral group was 6 years, ranging from 6 months to 18 years, and in the bilateral group was 25 days, ranging from 6 days to 6 years (p = 0.003). The median interval between diagnosis and surgery was 9 months in the unilateral group, ranging from 1 month to 18 years, and in the bilateral group was 1 day, ranging from 1 day to 2 months (p = 0.001). Discussion and Conclusions:  Success rates with the endoscopic approach vary from 62 to 100%. Nonetheless, most of these reports present results without considering the number of compromised sides. In our opinion, unilateral and bilateral cases involve distinct patients (taking into account the related malformations), have diverging clinical presentations, and show discrepant restenosis rates and therefore could be considered in different groups of analysis...

Analysis of respiratory problems in CHARGE syndrome: a single center study

PURPOSE: CHARGE syndrome consists of multiple malformation including coloboma, heart defect, choanal atresia, growth or developmental retardation, genital anomalies, and ear anomalies. The aim of this study was to evaluate the respiratory problems in children with CHARGE syndrome. METHODS: Out of 9 patients with CHARGE syndrome, medical records from 8 patients showing respiratory distress or respiratory failure were retrospectively reviewed. We investigated the causes of respiratory problems by physical examination, endoscopy, echocardiogram, computed tomography, rigid bronchoscopy, swallowing test, and 24-hour impedence monitoring. RESULTS: Five patients required endotracheal intubation soon after birth due to bilateral choanal atresia (n=2) and congenital heart diseases (n=3). Three patients were intubated within a month because of surgery for complex heart diseases (n=2) or recurrent apnea (n=1). Tracheostomy was performed in 3 patients who showed primary or secondary subglottic stenosis. Among 8 patients who had aspiration or respiratory distress after feeding, cricopharyngeal incoordination and gastroesophageal reflux disease were found in 7 and 2 children, respectively. One patient died of aspiration during oral feeding. CONCLUSION: Patients with CHARGE syndrome manifest respiratory distress or failure due to various causes including congenital anomaly in the airway, cardiac anomaly, neurologic or gastrointestinal problems. Therefore, pediatricians should be alert to the respiratory symptoms and signs in CHARGE syndrome and take active intervention from the birth to improve their long-term prognosis.

Identification of a novel mutation in the CHD7 gene in a patient with CHARGE syndrome / 소아과

CHARGE syndrome has been estimated to occur in 1:10,000 births worldwide and shows various clinical manifestations. It is a genetic disorder characterized by a specific and a recognizable pattern of anomalies. The major clinical features are ocular coloboma, heart malformations, atresia of the choanae, growth retardation, genital hypoplasia, and ear abnormalities. The chromodomain helicase DNA-binding protein 7 (CHD7) gene, located on chromosome 8q12.1, causes CHARGE syndrome. The CHD7 protein is an adenosine triphosphate (ATP)-dependent chromatin remodeling protein. A total of 67% of patients clinically diagnosed with CHARGE syndrome have CHD7 mutations. Five hundred twenty-eight pathogenic and unique CHD7 alterations have been identified so far. We describe a patient with a CHARGE syndrome diagnosis who carried a novel de novo mutation, a c.3896T>C (p. leu1299Pro) missense mutation, in the CHD7 gene. This finding will provide more information for genetic counseling and expand our understanding of the pathogenesis and development of CHARGE syndrome.

Cochlear Implants in Children Diagnosed with CHARGE Syndrome

The CHARGE association (coloboma of the eyes; heart disease; atresia of the choanae; retarded growth and development; genital hypoplasia/genitourinary anomalies; ear anomalies and/or hearing loss) was first described in 1979 by Hall, and among its main features is hearing loss. This study presents a case aiming to establish relationships between performance on Infant Toddler Meaningful Auditory Integration Scale (IT-MAIS) and Meaningful Use of Speech Scales (MUSS) tests and the analysis of hearing and language categories of a patient diagnosed with CHARGE syndrome, before and after cochlear implant (CI) surgery. Case Report: A 7-year-old girl was diagnosed with CHARGE. She had severe sensorineural hearing loss and was a prelingual unilateral CI user. We analyzed data from the patient's medical records regarding therapies and video recordings. Results: The patient showed positive results in all evaluations after CI. IT-MAIS rose from 5 to 90% following the use of CI. MUSS also rose, from 75 to 72.5%, after use of CI. Classification of Auditory Skills changed from category 1 before use of CI to category 6 after use of CI. Classification of Language Skills changed from category 1 before use of CI to category 3 after use of CI. The CI is an aid but there are many factors in the therapeutic process, and great heterogeneity in individuals diagnosed with CHARGE should be investigated. Conclusion: The development of listening and language skills after CI use was demonstrated by IT-MAIS and MUSS tests, and categorization of speech and hearing in this child with a diagnosis of CHARGE syndrome shows that CI can be an effective technological resource to provide information on hearing as one source for language construction...

Malformaciones Congénitas: Aspectos Generales y Genéticos / Congenital Malformations: General and Genetic Aspects

Los defectos del desarrollo se pueden deber a malformaciones congénitas, deformaciones o disrupciones. El 10% de las malformaciones se atribuyen a causas ambientales el 25% a factores genéticos y el 65% a factores desconocidos probablemente de orden multifactorial. Existe un período de mayor susceptibilidad frente a los teratógenos que corresponde a la etapa donde se están formando la mayoría de los órganos y sistemas. La ingestión de plantas teratogénicas puede dar lugar a anomalías congénitas en los fetos de animales. Los pesticidas como DDT, la contaminación de las aguas por mercurio y los disruptores endocrinos afectan la embriogénesis de las distintas especies del reino animal. También se consideran como factores causantes de malformaciones a los agentes ambientales infecciosos y a algunos medicamentos. Los agentes físicos como los aumentos de temperatura, las condiciones de hipoxia y las radiaciones afectan a distintos organismos, desde los peces al ser humano. La genética de las malformaciones ha sido difícil de establecer, principalmente porque la mayor parte de ellas se caracteriza por presentar manifestaciones fenotípicas diversas, que en muchos casos aparentemente no están relacionadas y que son variables para los individuos afectados. Por otra parte, los estudios realizados indican que frecuentemente, en la determinación genética de las malformaciones participan varios genes y las interacciones de éstos con el ambiente, aunque determinaciones monogénicas se han podido establecer para unos pocos casos. Ilustramos aquí estos dos tipos contrastantes de determinación genética, a través de la descripción de los factores genéticos que estarían involucrados en los defectos del tubo neural y en el síndrome de CHARGE, respectivamente.

Developmental defects may be due to congenital malformations, deformations or disruptions; 10% of malformations are caused by environmental factors, 25% by genetics factors and 65% are due to unknown multifactorial problems. There is a developmental period of greater susceptibility to teratogens, which corresponds to the stages when most organs and systems are being formed. Ingestions of teratogenics plants may result in congenital anomalies in animal foetuses. Pesticide such as DDT, water contamination with the Hg and the endocrine disrupters affect embryogenesis of different animal species. As factors that provoke malformations there are environmental agents, infections and some drugs. Physical agents such as increased temperature, hypoxic conditions and radiation, affect different organisms from fishes to human. Genetic of malformations have been difficult to establish, mainly because most of them are characterized by diverse phenotypic aspects, apparently not related and variable for the different affected organisms. On the other hand, studies realized indicate that frequently in the genetic determination of malformations several genes and their interactions with the environment are involved, although it has been possible to establish monogenic determination for a few cases. Here we contrast these two types of genetic determination, describing the genetic factors involved in the neural tube defects and the CHARGE syndrome, respectively.

Novel CHD7 and FBN1 mutations in an infant with multiple congenital anamolies.

The first case of an infant with a dual genetic diagnosis of CHARGE and Marfan syndrome is reported here. The patient had multiple congenital anamolies, many of them consistent with CHARGE syndrome and genetic testing identified a heterozygous mutation c.3806_11del6insA in the CHD7 gene. In addition, his father had physical features consistent with Marfan syndrome. Fibrillin-1 (FBN1) mutation screening identified a heterozygous c.3990insC mutation in both father and the patient.

Hypogonadotropic Hypogonadism and Abnormal Olfactory Bulb Development in CHARGE Syndrome with CHD7 Mutation / 대한소아내분비학회지

CHARGE syndrome is a congenital malformation disorder that includes Coloboma, Heart defect, Atresia of the choanae, Retarded growth and development, Genital hypoplasia, and Ear abnormalities. Recently hypogonadotropic hypogonadism and abnormal olfactory bulb development are occasionally described in CHARGE syndrome with chromodomain helicase DNA-binding protein 7 (CHD7) gene mutation. We report the case of Korean female patient with CHARGE syndrome and CHD7 mutation who had hypogonadotropic hypogonadism and abnormal olfactory bulb as manifested by delayed puberty and growth retardation at 13 years of age. She had both optic nerve coloboma, external ear abnormalities and bilateral agenesis of the semicircular canals. She had severe mental retardation and autistic-like behavior. We identified a heterozygous nonsense mutation at exon 20 of the CHD7 gene (c.4601G>A; Trp1534X).

A case of CHARGE syndrome diagnosed after delivery: A case report / 대한산부인과학회지

The acronym CHARGE (Coloboma, Heart defects, Atresia choanae, Retarded growth and development, Genital hypoplasia, and Ear abnormalities) was coined by Pagon et al. in 1981. The prevalence of CHARGE syndrome was estimated to be approximately 1/10,000 - 1/15,000. The cause of the CHARGE syndrome remains unknown but several observations support the role of genetic factors and a significantly higher paternal age at conception and several chromosomal abnormalities. The clinical spectrum of this multiple congenital anomaly and mental retardation is broad and variable, therefore the treatment of the CHARGE syndrome was not definitive and conservative. We hereby report, with reviewing other literature, a case of CHARGE syndrome diagnosed after delivery.

Síndrome de Charge: relato de caso / Charges's syndrome: case report

A síndrome de CHARGE é um conjunto especifico de malformações congênitas que podem comprometer o crescimento e o desenvolvimento da criança. O objetivo deste trabalho e relatar o caso de uma criança portadora desta síndrome e comparar suas características com aquelas apontadas na literatura. Para a execução do estudo foi solicitada a autorização do responsável pela criança e foram coletados os dados referentes ao exame físico e neurológico, incluindo resultados dos exames laboratoriais e radiológicos. Ao comparar o quadro da criança com os dados da literatura verificou-se a presença de quatro características mais freqüentes e quatro características menos freqüentes, as quais fornecem critérios para o diagnostico clinico da síndrome.

CHARGE syndrome it is a specific group of congenital malformations that can commit the child's growth and development. The objective of this paper was the presentation of a child with this syndrome and to compare its characteristics with those pointed in the literature. For the execution of the study it was requested the authorization of the responsible by the child and the referring data from physical and neurological exam were collected, including the results of laboratorial and radiological tests. When comparing the child's features with the data of the literature it was verified the presence of four more frequent characteristics and four less frequent characteristics, which supply the criteria for the clinical diagnosis of the syndrome.