Spectrum of CHARGE Syndrome in Fetuses With CHD7 Mutations
Spectrum of CHARGE Syndrome in Fetuses With CHD7 Mutations
Background CHARGE syndrome is a rare, usually sporadic disorder of multiple congenital anomalies ascribed to a CHD7 gene mutation in 60% of cases. Although the syndrome is well characterised in children, only one series of 10 fetuses with CHARGE syndrome has been reported to date. Therefore, we performed a detailed clinicopathological survey in our series of fetuses with CHD7 mutations, now extended to 40 cases. CHARGE syndrome is increasingly diagnosed antenatally, but remains challenging in many instances.
Method Here we report a retrospective study of 40 cases of CHARGE syndrome with a CHD7 mutation, including 10 previously reported fetuses, in which fetal or neonatal clinical, radiological and histopathological examinations were performed.
Results Conversely to postnatal studies, the proportion of males is high in our series (male to female ratio 2.6:1) suggesting a greater severity in males. Features almost constant in fetuses were external ear anomalies, arhinencephaly and semicircular canal agenesis, while intrauterine growth retardation was never observed. Finally, except for one, all other mutations identified in our antenatal series were truncating, suggesting a possible phenotype–genotype correlation.
Conclusions Clinical analysis allowed us to refine the clinical description of CHARGE syndrome in fetuses, describe some novel features and set up diagnostic criteria in order to help the diagnosis of CHARGE syndrome after termination of pregnancies following the detection of severe malformations.
CHARGE syndrome (OMIM 214800) was described in 1979 when it was recognised independently by Hall and Hittner et al as the association of coloboma, choanal atresia and congenital heart defects in several patients. The acronym was coined by Pagon et al in 1981 and summarises some of the main features, including ocular coloboma (C), heart disease (H), choanal atresia (A), retarded growth and/or development (R), genitourinary defects and/or hypogonadism (G) and ear anomalies and/or deafness (E). Other diagnostic criteria were proposed later based on major/minor anomalies. However, all features have variable expression, and each of them is inconstant and non-specific. For some of them, such as ocular coloboma or choanal atresia, diagnosis by prenatal ultrasound is generally not affordable. Moreover, fetal presentation of the syndrome probably represents the more severe end of the spectrum. The incidence of CHARGE syndrome ranges from 1/8500 to 1/12 000 live births. Vissers et al first described mutations in the CHD7 gene as the major cause of CHARGE syndrome. CHD7 belongs to an evolutionarily conserved family of proteins thought to be involved in chromatin organisation and gene expression, and to play an important role during embryonic development. Since then, 802 patients with CHARGE syndrome and a CHD7 mutation have been reported, but prenatal descriptions remain scarce. In the first report of a series of 10 prenatally detected cases, we noted a high frequency of anomalies of the external ears, agenesis/hypoplasia of the semicircular canals (SCC) and arhinencephaly. It is important to define other frequent signs in fetuses, because cardinal signs, such as growth retardation, developmental delay, deafness or genital anomalies are absent or undetectable before birth.
In the present study, we expanded our series of 10 CHARGE syndrome cases to 40 cases bearing a mutation in the coding or intronic (splice site) sequence of the CHD7 gene. Twenty additional fetal cases were also tested and no mutation/deletion was found. Except for one case, all fetuses underwent x-ray examination and detailed autopsy, including neuropathological examination. This permitted us to expand the phenotypical spectrum and to refine the antenatal presentation of CHARGE syndrome. Diagnostic criteria previously defined by Verloes in postnatal cases are not suitable for antenatal cases. Therefore, from this series of 40 mutated fetuses and 20 fetal cases without CHD7 mutation, we defined features more specific for fetal presentation of CHARGE syndrome.
Abstract and Introduction
Abstract
Background CHARGE syndrome is a rare, usually sporadic disorder of multiple congenital anomalies ascribed to a CHD7 gene mutation in 60% of cases. Although the syndrome is well characterised in children, only one series of 10 fetuses with CHARGE syndrome has been reported to date. Therefore, we performed a detailed clinicopathological survey in our series of fetuses with CHD7 mutations, now extended to 40 cases. CHARGE syndrome is increasingly diagnosed antenatally, but remains challenging in many instances.
Method Here we report a retrospective study of 40 cases of CHARGE syndrome with a CHD7 mutation, including 10 previously reported fetuses, in which fetal or neonatal clinical, radiological and histopathological examinations were performed.
Results Conversely to postnatal studies, the proportion of males is high in our series (male to female ratio 2.6:1) suggesting a greater severity in males. Features almost constant in fetuses were external ear anomalies, arhinencephaly and semicircular canal agenesis, while intrauterine growth retardation was never observed. Finally, except for one, all other mutations identified in our antenatal series were truncating, suggesting a possible phenotype–genotype correlation.
Conclusions Clinical analysis allowed us to refine the clinical description of CHARGE syndrome in fetuses, describe some novel features and set up diagnostic criteria in order to help the diagnosis of CHARGE syndrome after termination of pregnancies following the detection of severe malformations.
Introduction
CHARGE syndrome (OMIM 214800) was described in 1979 when it was recognised independently by Hall and Hittner et al as the association of coloboma, choanal atresia and congenital heart defects in several patients. The acronym was coined by Pagon et al in 1981 and summarises some of the main features, including ocular coloboma (C), heart disease (H), choanal atresia (A), retarded growth and/or development (R), genitourinary defects and/or hypogonadism (G) and ear anomalies and/or deafness (E). Other diagnostic criteria were proposed later based on major/minor anomalies. However, all features have variable expression, and each of them is inconstant and non-specific. For some of them, such as ocular coloboma or choanal atresia, diagnosis by prenatal ultrasound is generally not affordable. Moreover, fetal presentation of the syndrome probably represents the more severe end of the spectrum. The incidence of CHARGE syndrome ranges from 1/8500 to 1/12 000 live births. Vissers et al first described mutations in the CHD7 gene as the major cause of CHARGE syndrome. CHD7 belongs to an evolutionarily conserved family of proteins thought to be involved in chromatin organisation and gene expression, and to play an important role during embryonic development. Since then, 802 patients with CHARGE syndrome and a CHD7 mutation have been reported, but prenatal descriptions remain scarce. In the first report of a series of 10 prenatally detected cases, we noted a high frequency of anomalies of the external ears, agenesis/hypoplasia of the semicircular canals (SCC) and arhinencephaly. It is important to define other frequent signs in fetuses, because cardinal signs, such as growth retardation, developmental delay, deafness or genital anomalies are absent or undetectable before birth.
In the present study, we expanded our series of 10 CHARGE syndrome cases to 40 cases bearing a mutation in the coding or intronic (splice site) sequence of the CHD7 gene. Twenty additional fetal cases were also tested and no mutation/deletion was found. Except for one case, all fetuses underwent x-ray examination and detailed autopsy, including neuropathological examination. This permitted us to expand the phenotypical spectrum and to refine the antenatal presentation of CHARGE syndrome. Diagnostic criteria previously defined by Verloes in postnatal cases are not suitable for antenatal cases. Therefore, from this series of 40 mutated fetuses and 20 fetal cases without CHD7 mutation, we defined features more specific for fetal presentation of CHARGE syndrome.
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