Prenatal Sonographic Features of CHARGE Syndrome

Abstract

CHARGE syndrome is a rare autosomal dominant disorder, associated with coloboma (C), heart defects (H), choanal atresia (A), retardation of growth and/or central nervous system (R), genitourinary anomalies (G) and ear abnormalities (E). Prenatal diagnosis of the syndrome is very rare but may be suspected when a combination of such abnormalities is identified. We describe a prenatally suspected case of CHARGE syndrome due to unique findings of cardiac defects (DORV) in combination with minor clues, including a structurally malformed ear with persistent non-response to an acoustic stimulation (which has never been prenatally described elsewhere), renal malrotation and growth restriction. Postnatal diagnosis was made based on confirmation of the prenatal findings and additional specific findings of bilateral coloboma, choanal atresia and ear canal stenosis. Finally, molecular genetic testing by whole exome sequencing of the neonate and her parents revealed a novel de novo heterozygous frameshift c.3506_3509dup variant in the CHD7 gene, confirming the clinical diagnosis of CHARGE syndrome. In conclusion, we describe unique prenatal features of CHARGE syndrome. Educationally, this is one of the rare examples of CHARGE syndrome, comprising all of the six specific anomalies as originally described; it is also supported by the identification of a specific genetic mutation. The identified genetic variant has never been previously reported, thereby expanding the mutational spectrum of CHD7. Finally, this case can inspire prenatal sonographers to increase awareness of subtle or minor abnormalities as genetic sonomarkers.

Morphological and sensorimotor phenotypes in a zebrafish CHARGE syndrome model are domain-dependent

“…In C. elegans , loss of chd7 via RNA interference causes undetached cuticle, gonad migration defects, and stunted length (Jofré et al, 2022). Although we did not find significant differences in length and size in our zebrafish chd7 mutants, mouse models have been reported to have delayed growth (Bosman et al, 2005), a symptom sometimes seen in CHARGE patients pre- and postnatally (Antoniou et al, 2019; Kim et al, 2022; Traisrisilp et al, 2021). In Drosophila , mutations in kismet , the orthologue of chd7 , cause movement deficits, eye defects, and wing abnormalities, as well as improper axon pruning, mislocalized neurons, and decreased glutamate receptor localization (Ghosh et al, 2014; Melicharek et al, 2010).…”

Morphological and sensorimotor phenotypes in a zebrafish CHARGE syndrome model are domain‐dependent

“…elegans , loss of chd7 via RNA interference causes undetached cuticle, gonad migration defects, and stunted length 56 . Although we did not find significant differences in length and size in our zebrafish chd7 mutants, mouse models have been reported to have delayed growth, 26 a symptom sometimes seen in CHARGE patients pre‐ and postnatally 57–59 . In Drosophila , mutations in kismet , the orthologue of chd7 , cause movement deficits, eye defects, and wing abnormalities, as well as improper axon pruning, mislocalized neurons, and decreased glutamate receptor localization 60,61 .…”

“… 56 Although we did not find significant differences in length and size in our zebrafish chd7 mutants, mouse models have been reported to have delayed growth, 26 a symptom sometimes seen in CHARGE patients pre‐ and postnatally. 57 , 58 , 59 In Drosophila , mutations in kismet , the orthologue of chd7 , cause movement deficits, eye defects, and wing abnormalities, as well as improper axon pruning, mislocalized neurons, and decreased glutamate receptor localization. 60 , 61 These defects in neural architecture in kis −/− may provide insight into potential mechanisms driving the deficits we see in our zebrafish model.…”

Increased nuchal translucency with normal karyotype and genomic microarray analysis: A multicenter observational study

“…Sotos syndrome is characterized by hypotonia and may manifest prenatally with increased NT; heart and kidney defects, macrocephaly, polyhydramnios, and central nervous system abnormalities such as ventriculomegaly and corpus callosum abnormalities have been described in affected fetuses 20 ; however, these anomalies are not present in all cases. Fetuses with CHARGE syndrome show prenatal ultrasound abnormalities in 30%-40% of cases and these are mainly unspecific findings (polyhydramnios, mild ventriculomegaly, cardiac anomalies), 21,22 as our case (single umbilical artery, aberrant right subclavian artery, and mild ventriculomegaly in the third trimester with normal magnetic resonance imaging).…”