Discussion

CHARGE syndrome is a rare, autosomal-dominant genetic disorder that affects multiple areas of the body.¹ The name “CHARGE” is an acronym for several common features of the disorder, including coloboma, heart defects, atresia of the choanae (also known as choanal atresia), growth retardation, genital abnormalities, and ear abnormalities. In approximately 60%-65% of cases, the syndrome is caused by heterozygous loss‐of‐function mutations in the CHD7 gene, a chromatin remodeler gene essential for normal development.^{2, 3}

The prevalence of CHARGE syndrome is approximately 1 in 10,000 births, and it is not typically inherited, with most cases being sporadic.⁴ Individuals with CHARGE syndrome may also have distinctive facial features, cognitive function ranging from normal intelligence to major learning disabilities, and various other health problems affecting the kidneys, immune system, spine, and limbs. CHARGE was originally based on the clinical presentation of 4-6 cardinal signs. It has since been updated by Blake et al, who focused on brainstem and cranial nerve anomalies, and Verloes, who focused on the 3C triad (coloboma, choanal atresia, abnormal semicircular canals), which is highly predictive of a CHD7 mutation.^{4, 5} CMA is initially performed for infants with multiple anomalies.⁶ However, if CMA is nondiagnostic, then CHD7 genetic testing is recommended in potentially affected individuals.

The CHD7 gene plays a crucial role in brain development, and heterozygous mutations in this gene have been characterized by brain structural anomalies and associated with various neurological conditions like CHARGE syndrome.⁷ An ATP-dependent chromatin remodeler, CHD7 is essential for the development of migratory, multipotent neural crest cells by controlling gene expression. Studies have shown that CHD7 is indispensable for mammalian brain development and controls a core neuronal differentiation program during cerebellar development.⁸ One study utilizing MRI and high-angular resolution diffusion MRI tractography demonstrated statistically significant reduction in volume of the bilateral putamen, brainstem, bilateral cerebellum, bilateral globus pallidus, and left subthalamic nucleus in patients with CHARGE syndrome compared with their gender- and age-matched controls.⁹

Thymic aplasia and hypoplasia are observed in patients with CHD7 mutations.¹⁰ In mouse embryos, Randall et al reported that approximately 11% of mice with the heterozygous CHD7 mutation had either thymic hypoplasia or an ectopic thymus, which was correlated with downregulation of the FOXN1 gene.¹⁰

As part of his stroke workup, our patient was found to have a patent foramen ovale with shunting that puts him at risk of thromboembolic events, especially given the multifocal nature of the stroke. This could have been precipitated by diarrhea- and/or vomiting-induced dehydration. The patient has been referred to the cardiology service for device closure.

There is no known increased stroke risk in CHARGE syndrome. The patient’s stroke could have been precipitated by diarrhea and/or vomiting induced dehydration, which was not specific to the patient’s diagnosis of CHARGE.