Ongoing research projects in CHARGE syndrome

CHD7 mutations in patients with AVSD en conotruncal heart defects

Patients with CHD7 mutations may have a mild phenotype. We hypothesized that CHD7 mutations may be identified by selecting patients with specific congenital heart defects and one other typical CHARGE feature. Based on the results of our study on heart defects in patients with a CHD7 mutation (see recently finished projects), we performed CHD7 analysis in 46 children with an AVSD or conotruncal heart defect, but without classical CHARGE syndrome. The aim of this study is to indicate if and when CDH7 mutation analysis should be recommended in newborns with a congenital heart defect. This project is being funded by Fonds NutsOhra.

Aortic arch anomalies in CHARGE syndrome

Aortic arch anomalies like aberrant subclavian arteries are overrepresented in patients with CHARGE syndrome and a proven CHD7 mutation. Although cardiologists often describe an aortic arch anomaly as a minor feature, it might be clinically important. In this study we will focus on the clinical importance of aortic arch anomalies.

Immunological problems in CHARGE syndrome

Immunological problems are occasionally reported in CHARGE syndrome. The largest published cohort of 25 CHARGE patients (Jyonouchi et al., 2009) showed that a greater proportion of CHARGE patients had immunological abnormalities than previously thought. The abnormalities are comparable to those seen in 22q11.2 deletion syndrome, a syndrome with clinical overlap with CHARGE syndrome (see finished projects ). However, screening for immunological problems in CHARGE syndrome will currently only be performed in children with clinical symptoms of immune dysfunction. Unnoticed immune dysfunction can contribute to the morbidity and maybe mortality in children with CHARGE syndrome (see finished projects ). In this study we are prospectively evaluating humoral and cellular immune function in children with CHARGE syndrome. We aim to learn more about the prevalence of immunological problems in CHARGE syndrome, to investigate the clinical presentation of immunological dysfunction, and to indicate whether further studies are needed to develop an evidence-based guideline for immunological tests in patients with CHARGE syndrome. This project (in combination with the project on adrenal function) is being funded by Fonds NutsOhra.

Central adrenal function in patients with CHARGE syndrome

Many children with CHARGE syndrome have endocrine problems, for example hypogonadotropic hypogonadism and growth hormone deficiency. Thus far, adrenal function has not been studied in CHARGE syndrome. Only one case report has been published on central adrenal insufficiency. Since children with CHARGE syndrome sometimes show an atypical response to infections and other stressful situations, e.g. surgery, a dysfunction of the hypothalamus-pituitary-adrenal axis may be present and contribute to the unexpected death of some children.

In this study we perform adrenal function tests in children with CHARGE syndrome. We aim to learn more about the prevalence of adrenal function in CHARGE syndrome and to provide a guideline for adrenal function testing in patients with CHARGE syndrome when adrenal dysfunction is present in our study cohort, since unnoticed central adrenal insufficiency has great impact on morbidity and mortality.

Hearing and swallowing in CHARGE syndrome

This research project focuses on the anatomical substrates of hearing and swallowing problems in CHARGE syndrome. Hearing problems can often be explained by anomalies of the middle and/or inner ear. However, sometimes the hearing deficit is worse than would be expected for the middle- and inner ear anomalies present. We therefore suspect that anomalies in the brainstem and/or cerebral cortex impair the hearing capability in CHARGE patients. We hypothesized that the feeding problems could also be explained by anomalies in the brainstem and/or cerebral cortex.

In this study, we will correlate the type and degree of brainstem anomalies, cortex anomalies and other features seen on CT- and MRI scans with the type and degree of hearing- and swallowing problems. This study is being performed in close collaboration with the Departments of Radiology and ENT Surgery of the UMCG.

Cochlear implants in CHARGE syndrome

Hearing loss is common in patients with CHARGE syndrome: 60-90% of them have a moderate to severe hearing loss. The loss is due to anomalies in the middle and inner ear, such as hypoplastic auditory canal, ossicular malformations, an absent or covered oval and round window, and an abnormal cochlea.

In most patients conventional hearing aids or bone conduction devices offer sufficient treatment. For patients in whom external hearing devices do not have the desired outcome, a cochlear implant can be considered. However, it can be difficult to place such an implant in a CHARGE syndrome patient, with complications due to anatomical anomalies of the middle and inner ear. And, as shown in the literature, learning to live with an implant can be difficult, and may be hampered by mental retardation or other handicaps.

Because the benefits of cochlear implantation in CHARGE syndrome patients are still unclear, we are reviewing the results of surgery and of speech and language development after implantation. We are also looking for predictive factors of patients’ speech and language results. The results of our study will provide support in deciding whether a cochlear implantation should be performed in a patient with CHARGE syndrome.

Brain anomalies/neurological dysfunction/cerebellar abnormalities

Currently a study is being set up in which cerebral MRI scans of over 40 CHARGE children will be systematically evaluated with special attention for cerebellar abnormalities. In a pilot series of 20 MRI scans, cerebellar abnormalities were found in half of the CHARGE patients. The neuroradiological symptoms will be correlated to the clinical features scored by a validated paediatric ataxia scoring list.

Growth charts for children with CHARGE syndrome

At the moment, the growth of children with CHARGE syndrome is recorded on growth charts designed for typical children. This is not ideal, since growth delay is part of CHARGE syndrome and these children may follow a specific growth curve under healthy conditions. In addition, the growth of children with CHARGE syndrome can be affected by other clinical features associated with the syndrome, like severe heart defects.

In ongoing work in our multidisciplinary CHARGE outpatient clinic, we have been collecting information to develop growth charts specifically for these children based on international case data. This project is being conducted in an international collaboration, coordinated by the UMCG. Moreover, we want to investigate the effect of several clinical features on the growth of patients with CHARGE.

Ultimately, we will make specific CHARGE syndrome growth charts available online as an interactive version for use by clinicians, patients and parents. Users will be able to print the individual patient’s growth curve for height, weight and head circumference on specific CHARGE syndrome growth diagrams. These growth charts will provide insight into children’s growth when they have CHARGE syndrome and help to reassure parents that their child’s growth is within the normal range for children with this syndrome.

Exome sequencing in CHARGE patients with no CHD7 mutation

No mutation in CHD7 can be found in 5-10% of clinically typical CHARGE patients. Non-detectable rearrangements in CHD7 might explain the syndrome in some of these patients, but other genes may also be involved. We are trying to find the cause of CHARGE syndrome in these patients by performing exome sequencing in patients and their parents.

Database for CHD7 mutations

In a rare syndrome like CHARGE syndrome, in which the mutations are often unique, it is important to know whether a mutation or variant has been described before. We therefore constructed an online database in which genomic CHD7 variants are being recorded. The database is accessible at http://www.CHD7.org and is being continually updated.