CHARGE Syndrome Clinical Presentation

The history in patients with CHARGE syndrome may include the following:^{[19, 7, 20, 17]}

• Prenatal presentation

  • Intrauterine growth retardation
  • Congenital heart defects
  • Orofacial clefting
  • Poor fetal movement
• Neonatal presentation

  • Small for gestational age
  • Dysmorphic features
  • Respiratory distress/cyanosis
  • Swallowing/feeding difficulty
  • Failed newborn hearing screen
  • Inability to pass nasogastric tube
• Infantile and childhood presentation

  • Failure to thrive
  • Developmental delay
  • Feeding difficulty
  • Poor growth

The typical defining features of CHARGE syndrome include coloboma, heart anomalies, choanal atresia, retardation of growth and development, and genital and ear anomalies. Other frequently occurring significant features include characteristic face and hand dysmorphology, hypotonia, urinary tract anomalies, orofacial clefting, deafness, dysphagia, and tracheoesophageal anomalies. Again, no single feature is universally present or sufficient for the diagnosis of CHARGE syndrome, and the degree of severity varies. Numerous guidelines have been published to aid in establishing a likely clinical diagnosis of CHARGE syndrome, requiring various combinations of these features.^{[3, 5, 6]}

• Coloboma of the eye (70-80%): This is usually bilateral and affects the posterior segment of the eye (ie, choroid, retina, optic disc). It rarely involves the iris. Microphthalmia and nystagmus are consistently associated with severe coloboma. Coloboma that does not involve the fovea does not affect vision. Retinal detachment is a frequent complication.^[21]
• Heart anomaly (60-70%): Septal defects (interventricular, interatrial) and conotruncal malformation (aortic valve stenosis, aortic coarctation, interrupted aortic arch) are the most frequent anomalies. Other anomalies include patent ductus arteriosus and tetralogy of Fallot. All variations of complex heart anomalies are reported.
• Choanal atresia/stenosis (30-60%): Choanal atresia is membranous or bony and bilateral in over 50% of cases, usually presenting in the newborn period with respiratory distress. Choanal atresia is a threat to life because infants cannot establish mouth breathing. A history of polyhydramnios in pregnancy is usually present. Of all features of CHARGE syndrome, choanal atresia (when bilateral) is the most easily ascertained. Its presence indicates poor prognosis for survival and necessitates multiple complex surgeries for correction. When associated with other anomalies (eg, cyanotic heart disease, tracheoesophageal fistula and/or atresia), most children with bilateral atresia do not survive beyond the first year of life. Unilateral atresia may present as persistent nasal discharge in early childhood.
• Growth retardation (failure to thrive - 80%): Intrauterine growth retardation and growth failure are observed in approximately 75% of patients. Growth failure is noticeable in the first 6 months of life. It is due to endocrine causes (eg, growth hormone deficiency, gonadotrophin deficiency). Feeding difficulty with poor caloric intake may also contribute to growth failure. No correlation between the severity of the growth defect and the severity of the component anomalies is observed.
• Mental retardation (70-75%)

  • Developmental delay is typically present and is often characterized as mild to moderate. More severe developmental delay is often associated with other significant birth defects and a greater degree of later mental retardation.
  • Patients with severe coloboma and inner ear problems are particularly affected.
  • Poor vision and hearing result in the absence of visual and auditory cues that are essential for early motor development, and abnormalities in the vestibular function affect the adoption of upright posture and, thus, lead to delay in motor development.
  • The need for multiple and prolonged hospitalizations and lack of active management of the sensory deficit can also contribute to developmental delay. These issues must be adequately addressed in a timely fashion, when present, to maximize developmental outcomes.
  • Mental retardation is not universal but is frequent.
  • One should be careful not to diagnose mental retardation until the full extent of sensory deficits are known and corrective measures have been implemented.
• Genital hypoplasia (male 70%, female 30%): Males have micropenis and are either cryptorchid or have complete absence of testis. Females have labial hypoplasia that is difficult to identify in the neonatal period. Hypogonadotrophic hypogonadism secondary to pituitary or hypothalamic causes is suggested as the cause, as evidenced by poor response to luteinizing hormone-releasing hormone (LHRH) and human chorionic gonadotropin (HCG) stimulation tests.
• Ear malformations (90-100%): External ear malformation was noted in 90-100% of patients. Ears may be small, simple, low set, and/or cup shaped; protruding helix may be unraveled. External ear malformations are more abnormal on the side of the facial palsy and may be related to denervation early in the developmental process of the ear. See the image below. Typical ear malformation
• Deafness/hearing Loss (60-90%): Usually bilateral and of mixed type. A unique, wedge-shaped audiogram has been described with a descending bone conduction curve intersecting at low frequencies with a flat curve for air conduction. Inner ear abnormalities include Mondini malformation or partial or complete semicircular canal hypoplasia/aplasia. Vestibular or cochlear defect leads to sensorineural deafness. Middle ear problems cause conductive hearing loss and are commonly due to ossicular malformations, stapedius tendon abnormality, or serous effusion. CT scan of the temporal bone demonstrates partial or complete semicircular canal hypoplasia.
• Other anomalies

  • Neurologic anomalies: Cranial nerve palsy (mainly facial nerve but also auditory), glossopharyngeal and vagus nerves, microcephaly, and neonatal brainstem dysfunction, which manifest in the form of feeding difficulty and swallowing difficulty, are observed.
  • Dysmorphic features: These features include a typically asymmetric square face, malar flattening, unilateral facial nerve paralysis, and micrognathia.
  • Hand dysmorphology: This includes brachydactyly and clinodactyly.
• Occasional anomalies (not consistently present)

  • Renal - Hydronephrosis, vesicoureteric reflux
  • Larynx - Laryngomalacia, laryngeal clefts
  • Esophageal - Atresia, tracheoesophageal fistula
  • Skeletal - Hemivertebrae, scoliosis, clinodactyly, syndactyly
  • Orofacial clefting - Found in approximately 30-50% of patients

CHARGE syndrome is an autosomal dominant condition with genotypic heterogeneity. Most cases (58-71% in unselected CHARGE referrals and as many as 90% of patients who meet criteria for typical CHARGE syndrome) are due to mutations of the CHD7 gene leading to haploinsufficiency.^{[1, 8, 19, 22]}

Microdeletions encompassing the entire CHD7 gene or affecting individual CHD7 gene exons occur in a minority of cases.^{[23, 24]} One case report detailed CHD7 duplication, which did not result in a CHARGE-like phenotype.^[25] Numerous case reports have described individuals clinically diagnosed with CHARGE syndrome who harbor various presumably pathologic cytogenetic abnormalities, including 22q11.2 deletions, 14q22-q24.3 inverted duplications, and 9p-, and single gene mutations (including SEMA3E gene mutation).^{[9, 10, 11, 12]}