Sandra L. H. Davenport

CHARGE Association: An Update and Review for the Primary Pediatrician

CHARGE association is a nonrandom pattern of congenital anomalies that occurs together more frequently than one would expect on the basis of chance. This common multiple anomaly condition has an estimated prevalence of 1:10,000. The number of children diagnosed with CHARGE association is increasing, owing presumably to greater awareness of this condition and advances in the care of complex, chronically ill children, resulting in improved survival and outcome. This review of ClHARGE association presents diagnostic criteria that may define a concise, recognizable syndrome with a single pathogenetic basis. This review also summarizes our current understanding of the management for this complex and chronic multiple congenital anomaly condition and discusses the pathogenetic basis for this condition.

Spectrum of CHD7 Mutations in 110 Individuals with CHARGE Syndrome and Genotype-Phenotype Correlation

CHARGE syndrome is a well-established multiple-malformation syndrome with distinctive consensus diagnostic criteria. Characteristic associated anomalies include ocular coloboma, choanal atresia, cranial nerve defects, distinctive external and inner ear abnormalities, hearing loss, cardiovascular malformations, urogenital anomalies, and growth retardation. Recently, mutations of the chromodomain helicase DNA-binding protein gene CHD7 were reported to be a major cause of CHARGE syndrome. We sequenced the CHD7 gene in 110 individuals who had received the clinical diagnosis of CHARGE syndrome, and we detected mutations in 64 (58%). Mutations were distributed throughout the coding exons and conserved splice sites of CHD7. Of the 64 mutations, 47 (73%) predicted premature truncation of the protein. These included nonsense and frameshift mutations, which most likely lead to haploinsufficiency. Phenotypically, the mutation-positive group was more likely to exhibit cardiovascular malformations (54 of 59 in the mutation-positive group vs. 30 of 42 in the mutation-negative group; P=.014), coloboma of the eye (55 of 62 in the mutation-positive group vs. 30 of 43 in the mutation-negative group; P=.022), and facial asymmetry, often caused by seventh cranial nerve abnormalities (36 of 56 in the mutation-positive group vs. 13 of 39 in the mutation-negative group; P=.004). Mouse embryo whole-mount and section in situ hybridization showed the expression of Chd7 in the outflow tract of the heart, optic vesicle, facio-acoustic preganglion complex, brain, olfactory pit, and mandibular component of the first branchial arch. Microarray gene-expression analysis showed a signature pattern of gene-expression differences that distinguished the individuals with CHARGE syndrome with CHD7 mutation from the controls. We conclude that cardiovascular malformations, coloboma, and facial asymmetry are common findings in CHARGE syndrome caused by CHD7 mutation.

The spectrum of clinical features in CHARGE syndrome

Fifteen patients with CHARGE syndrome are described, nine sporadic and six familial. A recognizable pattern of malformations is present which appears to constitute a syndrome rather than a non‐random association. In addition to acronymic features of Coloboma, ifeart disease, Atresia of the choanae,.Retarded growth and development, Genital hypoplasia, and Ear anomalies, other important diagnostic features include facial paralysis and feeding problems suggestive of velopharyngeal incompetency. A square facial appearance with asymmetry and malar flattening is characteristic, and long philtrum or prominent nasal columella may be present. Characteristic external ear anomalies and a ‘wedge’‐shaped audiogram may be unique to this syndrome. Short stature and hypogonadism with genital hypoplasia is pituitary or possibly hypothalamic in origin. Each feature varies from normal to severe involvement including mental function, and no single feature appears to be necessary for diagnosis.

Duchenne muscular dystrophy, glycerol kinase deficiency, and adrenal insufficiency associated with Xp21 interstitial deletion

We report an interstitial deletion in the short arm of the X chromosome in a 6-year-old boy with Duchenne muscular dystrophy, glycerol kinase deficiency, adrenal insufficiency, intermittent hypoglycemia, spasticity, psychomotor retardation, and growth delay. His mother also has this deletion in an X chromosome. From our findings, we propose that the human glycerol kinase locus and the human X-linked adrenal hypoplasia locus are in the Xp21 band.

CHARGE Syndrome. Part II. Hearing loss

CHARGE is a mnemonic for a syndrome with multiple congenital anomalies that occurs with normal chromosomes. The unique external ear anomalies have been described in CHARGE Syndrome Part I in this journal. This report describes the distinctive middle ear and sensorineural losses that occur in the syndrome, both of which can be progressive and, in most cases, are moderate to severe. There is evidence to indicate that these losses are due to congenital ossicular anomalies, eustachian tube dysfunction from craniofacial malformation, and cochlear involvement that is greatest for high frequencies.

Alu-specific microhomology-mediated deletions in CDKL5 in females with early-onset seizure disorder

Mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene in Xp22.13 have been associated with infantile spasms, early-onset intractable epilepsy, and a Rett syndrome (RTT)-like phenotype. Using array comparative genomic hybridization, we identified variable-sized microdeletions involving exons 1–4 of the CDKL5 gene in three females with early-onset seizures. Two of these deletions were flanked by Alu repetitive elements and may have resulted from either non-allelic homologous recombination or the microhomology-mediated Fork Stalling and Template Switching/Microhomology-Mediated Break-Induced Replication mechanism. Our findings demonstrate the first instance of genomic deletion as the molecular basis of CDKL5 deficiency in females and highlight the importance of exon targeted array-CGH analysis for this gene in females with drug-resistant early-onset seizures.

Toward a genetic etiology of CHARGE syndrome: I. A systematic scan for submicroscopic deletions

CHARGE syndrome is a distinctive subgroup within the more heterogeneous group of patients with CHARGE association. While significant progress has been made in the clinical delineation of this syndrome, the molecular basis of the disorder remains unknown. Based on the complex phenotype, some overlap with DiGeorge/velocardiofacial syndrome (DGS/VCFS), and its estimated population incidence, we hypothesized that CHARGE syndrome could be caused by an unidentified genomic microdeletion. In order to address this hypothesis, we carried out a genome‐wide screen for loss of expected heterozygosity using 811 microsatellite markers in ten CHARGE syndrome subjects and their unaffected parents. Eight markers gave results suggestive of failure to inherit one parental allele. These loci were tested with fluorescence in situ hybridization (FISH), but none showed evidence of deletion. This screen sets upper limits on the length of a CHARGE‐related microdeletion, should that be the genetic mechanism underlying the phenotype.

Postoperative airway events of individuals with CHARGE syndrome

OBJECTIVE CHARGE syndrome is a heterogeneous genetic disorder comprising multiple congenital anomalies. Major clinical diagnostic criteria include ocular coloboma, choanal atresia/stenosis, characteristic ear abnormalities, and cranial nerve abnormalities. CHARGE syndrome is caused by a mutation in the gene CHD7 located on chromosome 8. Patients with CHARGE syndrome require multiple anesthetics for surgical and otorhinolaryngology procedures. This study describes the postoperative anesthetic related airway events (i.e. re-intubations for apneas and desaturations, airway obstruction due to excessive secretions) of nine individuals with CHARGE syndrome. METHODS Detailed chart audits were performed on nine patients diagnosed clinically with CHARGE syndrome who had undergone surgery at a single tertiary health centre. The CHARGE characteristics present in each individual, the number and types of surgeries and anesthetics, and the related postoperative airway events were determined. RESULTS The mean+/-age of the population at chart review was 11.8 years (+/-8.0). The total number of anesthetics was 147, with a mean of 16.2(+/-8.4). Of the 215 surgical procedures (mean 21.9, +/-12.2), 30% were otorhinolaryngological. Postoperative airway events occurred after 35% of anesthetics. Surgeries resulting in the most airway events involved the heart (65%), the gastrointestinal tract (39%), and airway diagnostic scopes, i.e., bronchoscopy, laryngoscopy, and nasopharyngoscopy (36%). Combining multiple surgical procedures under one anesthetic did not increase the risk of postoperative airway events. As individuals aged, they had fewer surgeries and anesthetics, as well as a lower risk of postoperative airway events. CONCLUSION Individuals with CHARGE syndrome face a significant risk of postoperative airway events with anesthesia, and this is exacerbated by the high number of surgeries they require. Surgeons and anesthesiologists should be aware of potential for postoperative airway events in individuals with CHARGE syndrome and plan accordingly.

Use of an expert model to test diagnostic criteria in CHARGE syndrome

AI/GEN is an expert model of the diagnosis of deaf-blind syndromes that uses the EXPERT system developed by Rutgers University. Its knowledge structure employs criteria tables for diagnosis of the three types of CHARGE syndrome. The system has been used to test the published diagnostic criteria against the revised expert criteria, the latter being significantly more accurate than the former. The two sets of criteria are also compared with respect to the specificity and sensitivity of diagnosis. Expert systems can be of direct use to experts in refining and revising their diagnostic criteria.