Histology and synchrotron radiation-based microtomography of the inner ear in a molecularly confirmed case of CHARGE syndrome
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Rudolf Glueckert1, Helge Rask-Andersen, Consolato Sergi
1Department of Otolaryngology, Medical University Innsbruck, Innsbruck, Austria.
Insights
CHARGE syndrome, often caused by CHD7 mutations, frequently involves inner ear defects. This study details the temporal bone malformations in a CHARGE patient, revealing severe vestibular and cochlear abnormalities.
Area of Science:
- Otolaryngology
- Genetics
- Developmental Biology
Background:
- CHARGE syndrome is a rare genetic disorder associated with multiple congenital anomalies, frequently including inner ear malformations.
- Mutations in the CHD7 gene are the primary cause of CHARGE syndrome.
- Vestibular and cochlear abnormalities, specifically semicircular canal (SCC) hypoplasia/aplasia and Mondini malformation, are characteristic features.
Observation:
- A temporal bone from a 3-month-old CHARGE syndrome patient with a confirmed de novo CHD7 mutation was analyzed.
- Synchrotron radiation-based micro computed tomography and light microscopy were used to assess the temporal bone structure.
- The patient presented with a rudimentary vestibule, agenesis of SCCs, and a hypoplastic cochlea with Mondini dysplasia.
Findings:
- The study observed severe malformations of the inner ear, including absent semicircular canals and a dysplastic cochlea.
- The organ of Corti showed near-normal structure and innervation, despite cochlear hypoplasia.
- Hypoplasia of the modiolus and Rosenthal's canal was noted, with displaced neuronal cell bodies.
Implications:
- Understanding the specific inner ear malformations in CHARGE syndrome is crucial for clinical management.
- The findings may inform the potential benefits and surgical considerations for cochlear implantation in affected individuals.
- The observed neural preservation in the organ of Corti suggests potential for auditory function restoration.
Abstract:
CHARGE (Coloboma of the iris or retina, heart defects, atresia of the choanae, retardation of growth and/or development, genital anomalies, ear anomalies) syndrome (OMIM #214800) affects about 1 in 10,000 children and is most often caused by chromodomain helicase DNA-binding protein-7 (CHD7) mutations. Inner ear defects and vestibular abnormalities are particularly common. Specifically, semicircular canal (SCC) hypoplasia/aplasia and the presence of a Mondini malformation can be considered pathognomonic in the context of congenital malformations of the CHARGE syndrome. We obtained a temporal bone (TB) of a patient with CHARGE syndrome who died from bacteremia at 3 months of age. The clinical diagnosis was confirmed in the patient by direct DNA sequencing and the detection of a de novo, truncating CHD7 mutation, c.6169dup (p.R2057fs). We assessed changes of the TB and the degree of neural preservation, which may influence the potential benefit of cochlear implantation. The TB was analyzed using synchrotron radiation-based micro computed tomography, and by light microscopy. The vestibular partition consisted of a rudimentary vestibule with agenesis of the SCCs. The cochlea was hypoplastic with poor or deficient interscaling and shortened (Mondini dysplasia). The organ of Corti had near normal structure and innervation. Modiolus and Rosenthal's canal were hypoplastic with perikarya displaced along the axon bundles into the internal acoustic meatus, which may be explained by the arrest or limited migration and translocation of the cell nuclei into the cochlear tube during development.
