CHARGE syndrome includes the following features:
Coloboma
This feature may be unilateral or bilateral and may affect only the iris or extend to involve the retina, or only the retina. Vision may be normal or impaired. The eye abnormalities range from iris coloboma without visual impairment to microphthalmos and anophthalmos. Retinal coloboma is more prevalent than iris coloboma and can affect the optic nerve. Eye malformations have been reported in as many as 80% of patients with CHARGE syndrome, with retinal involvement being the most common [11]. External inspection is not sufficient and testing for functional vision is important but challenging especially in CHARGE individuals with extensive bilateral chorioretinal coloboma involving the optic nerve [12].
Heart defect
Congenital heart defects occur in 75–80% of patients with CHARGE syndrome. The most common major heart defect is tetralogy of Fallot (33%). Other frequent anomalies are patent ductus arteriosus, double outlet right ventricle with atrioventricular canal, ventricular septal defect and atrial septal defect with or without cleft mitral valve. Vascular rings and more complex heart defects need to be anticipated [13-16].
Atresia choanae
Choanal atresia is a narrowing or a blockage of the passages between the nasal cavity and the naso-pharynx. It represents a primary feature with a high index of suspicion for CHARGE syndrome and it should focus attention on other organ systems such as the eye and heart. Choanal atresia may be membranous or bony; bilateral or unilateral. Bilateral posterior choanal atresia (BPCA) was shown to be associated with increased neonatal mortality, especially if associated with major cardiac malformations +\- tracheoesophageal atresia [13]. However, the Canadian epidemiological study data suggests that an individual from this population with a more severe clinical presentation of CHARGE features generally survive [9]. Polyhydramnios in pregnancy is seen commonly in individuals with bilateral posterior choanal atresia, and may also be present without BPCA, probably due to an insufficient swallowing mechanism. Chronic middle ear infections and deafness can be associated complications of choanal atresia [17].
Retardation of growth and development
Growth and developmental retardation become more obvious as the child matures. At birth, children with CHARGE syndrome usually have normal weights and lengths [18]. When growth deceleration is due to cardiac and respiratory problems, there may be catch up growth, and normal height can be obtained [19]. However, the influence of feeding problems on growth in infancy should not be underestimated. Early and continued intervention for feeding difficulties is vitally important [20]; occasionally there is growth hormone deficiency. The majority of school-aged children with CHARGE syndrome are below the third percentile for physical growth norms [18]; feeding with solids and lumpy foods, and risk of aspiration may still exist.
Mental retardation is variable with intelligence quotients (IQ) ranging from near-normal to profound retardation. Behavioral issues and an autism-like spectrum disorder are now being recognized as features of the syndrome [21,22].
The adult patient population is at risk of obesity (personal communication and observation by Dr. Kim Blake). Growth in height can occur in adults with CHARGE syndrome well into their 20's [19].
Genitourinary problems
Under-development of the external genitalia is a common finding in males but it is more difficult to recognize in females. Microphallus, penile agenesis, hypospadias, chordee, cryptorchidism, bifid scrotum, atresia of uterus, cervix and vagina, hypoplastic labia and clitoris are reported genital anomalies in this syndrome. Reported renal anomalies include solitary kidney, hydronephrosis, renal hypoplasia, duplex kidneys and vesicoureteral reflux. Hypogonadotrophic hypogonadism has been reported and is associated with delays in puberty or pubertal arrest [23,24].
Ear, olfactory and other cranial nerve anomalies
Ear abnormalities include a classical finding of unusually shaped ears [6]. Lack of cartilage to the outer ear with deficient 7th nerve innervation to intrinsic ear muscles produces a prominent lop- or cup-shaped ear with a hypoplastic lobule (Figure 1). Hearing loss, conductive and/or nerve deafness, ranges from mild to severe. Ear anomalies were reported in 80–100% of cases in different series [5,7,15,25]. Facial nerve palsies were noted to be a reliable predictor of sensorineural hearing loss. The characteristic abnormalities demonstrated by temporal bone computerized tomography (CT) or magnetic resonance imaging (MRI) scan include hypoplastic incus, decreased numbers of turns to the cochlea (Mondini defect), and, in particular, absent semicircular canals. These distinctive radiological findings are classical for CHARGE syndrome and can aid diagnosis in a suspected case [26]. For this reason, a neonatal CT scan to look at the choanae and temporal bones can be extremely useful.
The major diagnostic criteria for CHARGE syndrome [5] include cranial nerve (CN) anomalies, which are usually asymmetric. Cranial nerve dysfunctions include: CN I (anosmia). Absence or anomalies of the olfactory bulb are highly indicative of CHARGE syndrome [27] CN VII (facial palsy); CN IX/X/XI (swallowing problems, gastroesophal reflux, and velopharyngeal aspiration); and CN VIII (sensorineural hearing loss) [14,28]. CN V and CN II may also be involved [29].
Behavioral phenotype
There are many challenging behaviors that are expressed in individuals with CHARGE syndrome. Multiple studies [21] from four different countries, using a variety of test instruments, came up with similar themes and similar behavioral patterns in children with CHARGE syndrome [21,22,30-34]. Children with CHARGE syndrome have relatively low adaptive behavior skills and motor impairments being particularly significant, with symptoms of autistic spectrum disorder (ASD). The behavior they display is often very adaptive to their environment and to their own disabilities. These behaviors may be partially related to problems with arousal and self-regulation. Taken together, the articles in this series reveal the emergence of behavioral phenotypes that are perhaps specific to CHARGE syndrome [21]. Data are emerging about the unique behavioral phenotype of CHARGE syndrome compared to other genetic syndromes such as Down syndrome, Prader-Willi syndrome and Williams syndrome [30] and the Autism spectrum.
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