CHARGE syndrome: A review


  • Conflict of interest: The authors declare no conflict of interest.


CHARGE syndrome is a complex genetic syndrome, owing to the wide range of tissues/systems affected by mutations in the CHD7 gene. In this review, we discuss the diagnosis, clinical features and management of CHARGE syndrome.

Key Points

  1. CHARGE syndrome remains a clinical diagnosis. Genetic confirmation can be made in the majority of patients by detection of heterozygous mutations in the CHD7 gene.
  2. Absent/hypoplastic semicircular canals are present in the majority of patients with CHARGE and are highly predictive of the presence of a CHD7 mutation.
  3. Early involvement of a cardiologist, ophthalmologist, endocrinologist, geneticist and ear, nose and throat surgeon is recommended.
  4. Complete thymic aplasia rarely occurs but leads to severe combined immune deficiency. Persistent lymphopenia in a patient with CHARGE must always be investigated. The prevalence of other immune defects in CHARGE remains unclear.

CHARGE syndrome is a rare genetic syndrome with an estimated Australian incidence of 1–2.8/10 000 births.[1] The term ‘CHARGE’ is an acronym that describes a constellation of clinical features including Coloboma, Heart defects, choanal Atresia, Retardation (of growth and/or development), Genitourinary malformation and Ear abnormalities. The association was described independently by Bryan Hall[2] and HM Hittner et al.,[3] but the acronym CHARGE was first suggested by Pagon et al.[4] The term ‘syndrome’ rather than ‘association’ is used since the discovery that the majority of patients have a single aetiology – mutations within the CHD7 gene.[5]

The broad range of systems affected means that management of CHARGE syndrome is a challenge. Multiple clinicians are usually involved, and children attend frequent, often fragmented outpatient visits. For this reason, we initiated a multidisciplinary ‘CHARGE clinic’ at the Children's Hospital at Westmead, where children are assessed at the same visit by a geneticist, endocrinologist, ear, nose and throat (ENT) surgeon, general paediatrician and immunologist. Referral to other subspecialists (e.g. cardiologist, ophthalmologist, allied health professionals) is initiated if warranted. This review is aimed at the general paediatrician and discusses the many facets of this disorder.

Diagnosis of CHARGE Syndrome

CHARGE syndrome remains a clinical diagnosis based on major and minor criteria as outlined by Blake et al.,[6] modified by Verloes[7] and summarised in Table 1. The diagnosis should be considered in any child who presents with one of the major criteria ‘C's of Coloboma, Choanal atresia or hypoplastic semicircular Canals. The notable phenotypic features of CHARGE syndrome are summarised in Table 2. Typical facial features are illustrated in Figure 1.

Figure 1.

Clinical features of CHARGE syndrome. (a) Ten-year-old female. Cleft lip/palate repair, mild left facial palsy, broad forehead. (b) Six-year-old male. Cleft lip/palate, square face with mild right facial palsy. (c) A 2.5-year-old male. Left-sided microphthalmia, with prosthesis in situ. Square face with broad forehead and broad nasal root. (d) ‘J’-shaped hockey stick palmar crease (yellow arrow). (e) Typical CHARGE ear with hypoplastic, overfolded helix and lobe, and the triangular concha. (f) Less typical appearing ear but has squared superior helix and crease on lobe.

Table 1. CHARGE syndrome diagnostic criteria, revised and updated
Blake criteria (1998)[6]Verloes criteria (2005)[7]
  1. CN, cranial nerve.
Definite (4 major or 3 major and 3 minor)Typical: 3 major or 2 major and 2 minor
Probable/possible CHARGE (1 or 2 major & several minor features)Partial: 2 major and 1 minor
Atypical: 2 major but no minor, or 1 major and 2 minor
Major criteriaMajor criteria
ColobomaColoboma (ocular)
Choanal atresia/stenosisChoanal atresia/stenosis

Characteristic ear anomalies

Cranial nerve dysfunction (especially CN VII and VIII)

Hypoplasia/aplasia of semicircular canals
Minor criteriaMinor criteria
Genital hypoplasiaRhombencephalic dysfunction (brainstem and cranial nerve anomalies)
Developmental delayHypothalamo-hypophyseal dysfunction
Cardiovascular malformationMalformation of the internal/external ear
Growth deficiencyMalformation of mediastinal organs (heart, oesophagus)
Orofacial cleftIntellectual disability
Tracheo-oesophageal fistula 
Distinctive facial features 
Table 2. Phenotypic features of CHARGE syndrome[8]
  1. AV, atrioventricular; CNS, central nervous system; IQ, intelligence quotient; NA, not applicable.
ColobomaIris, retina, choroid, disc or microphthalmia75–90%
Choanal atresia/stenosisUnilateral or bilateral, bony or membranous.65%
Cranial nerve anomalies

Facial nerve palsy, auditory, vestibular, vagal (swallowing problems)

CNS abnormalities can also involve arhinencephaly, holoprosencephaly spectrum, forebrain and hindbrain abnormalities.

Facial: 50–90%

CNS abnormalities 55–85%

Characteristic ear anomalies

Outer ear tends to be symmetrically misshapen, low set, anteverted, cup shaped, wide with reduced vertical height

Triangular concha is a common finding

Microtia, hypoplasia of the auditory canal and preauricular tags can also be seen

Middle: ossicular malformation

Cochlear: mondini defect

Temporal: absent/hypoplastic semicircular canals. Highly predictive of the presence of a CHD7 mutation[7, 9]

Outer ear 95–100%

Inner ear: 90%

Genital hypoplasia

Males: micropenis/cryptorchidism.

Females: hypoplastic labia

Delayed puberty

Developmental delayIQ < 70 is present in over 70%70%
Cardiovascular malformationUsually conotruncal, AV canal and aortic arch abnormalities50–85%
Growth deficiencyHypothalamo-hypophyseal dysfunction leading to short stature and pubertal delay. Often birth centiles are low-normal, around 10th centile.70–80%
Orofacial cleftCleft lip/palate15–20%
Distinctive facial featuresSquare face, prominent forehead, prominent nasal bridge and columella, flat midfaceNA
Additional features

Omphalocele/umbilical hernia

Bony scoliosis/hemivertebrae

Renal anomalies: dysgenesis, horseshoe/ectopic kidney

Hand and limb anomalies in 37%: polydactyly, J-shaped ‘hockey stick’ palmar flexion crease

Short neck, sloping shoulders, nipple anomalies

Immune deficiency


The main differential diagnoses include 22q11.2 deletion syndrome, oculo-auriculo-vertebral spectrum, VACTERL association, Kabuki syndrome and teratogen-related embryopathies (maternal diabetes, oral retinoic acid). None of these usually meet the full diagnostic criteria for CHARGE syndrome.

Genetics and Aetiology of CHARGE Syndrome

CHD7 (chromodomain helicase DNA-binding protein), located on 8q12, is currently the only gene known to be associated with CHARGE syndrome. 90–95% of patients fulfilling the formal diagnostic criteria will have a heterozygous mutation or deletion affecting CHD7,[10, 11] but rare translocations and chromosomal rearrangements disrupting CHD7 are also described.[12, 13] The pathogenic mechanism is assumed to be haploinsufficiency of the CHD7 gene. CHD7 regulates the transcription of a number of tissue-specific target genes, the effects being tissue and developmental stage dependent and many, but not all features, of CHARGE syndrome can be attributed to disruption of neural crest migration.[11]

CHARGE syndrome usually occurs as a new autosomal dominant condition, with no family history; 97% of CHD7 mutations are de novo.[14] Most mutations are nonsense and frameshift, although missense mutations have been reported, often with milder clinical consequences.[15] Reports of familial CHARGE syndrome (including parent–child and sibling pairs) document wide clinical variability despite family members carrying the same mutation.[10] A 2–3% recurrence risk is suggested for children of clinically unaffected parents, attributed to parental germline mosaicism.[16]

Clinical Features of CHARGE Syndrome

Coloboma and ophthalmic features

Coloboma and other ocular abnormalities are reported in the majority (75–90%) of patients.[17] Colobomas can involve the eyelid, iris, retina, choroid, optic disc or macula, and are usually bilateral. The typical coloboma is chorioretinal, and these can predispose to retinal detachment in addition to visual impairment.[18] Significant variation in visual acuity is noted depending on the site and nature of defect, ranging from absent light perception to near normal vision.[19] Anterior segment abnormalities can also occur, as well as microphthalmia, microcornea and cataracts. Other less frequent ophthalmic features include refractive errors, strabismus and ptosis.[19]

Cardiac malformations

Cardiac malformations are also detected in the majority (75–85%) of patients.[20] The original studies performed before CHD7 found that conotruncal heart defects (aortic arch interruption, tetralogy of Fallot, double outlet right ventricle and arch vessel anomalies) and atrioventricular septal defects (AVSD) were common.[21] Studies since discovery of CHD7 have shown a much broader phenotype, with every type of cardiac defect (except heterotaxy and cardiomyopathy) documented, but conotruncal and AVSDs are still over-represented.[22]

Choanal atresia and other upper airway abnormalities

At birth, breathing may be obstructed because of choanal atresia (reported in 65% of patients; Fig. 2) and approximately one third of babies with bilateral choanal atresia will be found to have CHARGE syndrome.[23] Airway obstruction below the choanae is present in 70% of patients, of which half have multiple levels of obstruction: laryngomalacia is reported in 40% of patients, tracheomalacia in 20% and subglottic stenosis in 10%.[24] Because of aspiration and neurological deficits, supraglottoplasty, excising redundant mucosa and releasing tight folds around the laryngeal inlet are contraindicated.

Figure 2.

(a) CT scan – nasal mucous held in nostrils by choanal atresia plates and thick and medialised lateral wall of posterior nasal airway (arrow). (b) CT scan – c, abnormal cochlea; s, absent lateral semicircular canals and o, dysmorphic ossicles. CT, computed tomography.

In 15–20%, cleft lip and palate rather than choanal atresia is present and in another 15–20%, tracheo-oesophageal fistula (TOF) is reported.[24] Half of those with choanal atresia or TOF will demonstrate polyhydramnios,[25] so antenatal suspicion must arise, particularly if conotruncal cardiac defects are also detected.

Growth and developmental retardation

Children with CHARGE syndrome usually have a normal birthweight and length, but the majority experiences poor growth during late infancy.[26] Pinto et al. assessed growth hormone secretion in 25 children with CHARGE syndrome.[27] Ninety per cent had normal growth hormone production on provocation testing. The three children with low peak hormone values were significantly shorter (height ≤2.5 standard deviation score). It would be reasonable to reserve growth hormone provocative testing for children with a height <3rd centile. There are no published data on recombinant human growth hormone therapy in children with CHARGE syndrome and short stature.

Cognitive ability is often impaired in children with CHARGE syndrome. Using the Adaptive Behaviour Evaluation Scale (ABES) to assess cognitive ability, one study found 50% of subjects had scores >70 (reference mean 100, standard deviation 15). Those who walked earlier had fewer medical problems, better hearing and vision, and higher ABES scores.[28]

Communication and language ability are also often affected. Hartshorne[29] reported that only half of 123 CHARGE children studied over the age of 4 years used verbal or sign language in complete sentences. The remaining had significant impairments, with 16% making reactions or noises or behaviours that were difficult to interpret; 14% using two to five word phrases and sentences in speech, signs and picture symbols; 12% using single words, signs, symbols or object symbols to represent basic needs; and 10% using behaviours such as gestures, sounds and body movements.

Genitourinary problems

Genital hypoplasia is a well-described and a common feature of children with CHARGE syndrome.[27, 30, 31] Although most cases are easily recognised in boys (micropenis/cryptorchidism), it has also been reported in females with reduced clitoral size.[15] Genital hypoplasia is thought to be secondary to hypogonadotropic hypogonadism,[30] which during adolescence may result in pubertal delay or arrest in pubertal development. As such, annual assessment of pubertal development is recommended from 11 years of age. If there is pubertal delay, supplementation of oestrogen or testosterone is offered. Other potential causes of pubertal delay/arrest such as hypothyroidism or hyperprolactinaemia should also be excluded. Renal anomalies such as renal dysgenesis and duplex kidneys have been reported.[8]

Ear and hearing problems

The characteristic outer ear abnormalities may aid the diagnosis of CHARGE syndrome and are described in Figure 1 and Table 2. The most common inner ear abnormality is absence of the lateral semicircular canals, but dysplasia of both the vestibular (all semicircular canals) and the cochlear parts (such as a ‘Mondini’ malformation) can occur (Fig. 2), resulting in variable degrees of sensorineural hearing loss.[32] Vestibular hypoactivity and thus poor balance later causes a delay in walking, often not achieved until the fourth year of life and with a wide-based gait.[33]

Conductive and/or sensorineural hearing loss can occur in CHARGE syndrome. A conductive hearing loss may be due to ‘glue ear’ from Eustachian tube dysfunction but if it persists even after grommet insertion, then an ossicular abnormality such as a dysplastic or even absent ossicle is likely.[34]

Cranial nerve dysfunction

Feeding and swallowing difficulties are present in almost all babies. Almost 90% need tube feeding at some time.[35] These problems arise from cranial nerve dysfunction (rather than from craniofacial abnormality) as reflected in weak sucking and chewing, swallowing difficulty, gastro-oesophageal reflux and particularly chronic aspiration.[36] While neurologic function in CHARGE syndrome can improve over time, the early presence of gastro-oesophageal reflux and aspiration foreshadows prolonged feeding problems.[35]

An absent sense of smell is present in almost all children with CHARGE syndrome[37] and will make a substantial contribution to reduced taste. This anosmia is due to the absence or hypoplasia of the olfactory bulbs, evident on magnetic resonance imaging (MRI) scans. This association has been described relatively recently and, thus far, invariably found.[38]

Behavioural phenotype and sleep-related issues

Several studies have evaluated the behavioural phenotype of children with CHARGE. Autistic-like social withdrawal, goal-directed persistent behaviour and repetitive motor mannerisms are often reported,[39, 40] although this behaviour phenotype is probably adaptive to their visual and auditory disabilities[41] and partially related to problems with arousal and self-regulation.[42]

Sleep in these children is typically disturbed, compounding parental stress and anxiety. Common sleep issues reported include problems with initiating/maintaining sleep, breathing, arousal, transition, somnolence and hyperhidrosis.[43] Obstructive sleep apnoea was found to affect 65% of children with CHARGE syndrome in one study, but was amenable to standard therapies (positive airway pressure, tonsillectomy and/or adenoidectomy and tracheostomy).[44]

Other potential endocrine problems

Asakura et al. reported one of nine children with CHARGE syndrome had hypothyroidism, although it was not possible to ascertain if this was due to hypothalamic-pituitary dysfunction.[31] Routine biochemical assessment of thyroid function would appear unnecessary but reserved for those with clinical features of hypothyroidism. Secondary hypoadrenalism has been reported in one patient with CHARGE syndrome[45] but was not observed in larger cohorts of subjects.[31, 46] There is insufficient evidence to recommend routine assessment of adrenal function.

Infections and immune deficiency

Immune deficiency has been reported in CHARGE syndrome. This is not unexpected, given CHARGE syndrome bears remarkable phenotypic similarity to 22q11.2 deletion syndrome. Both disorders are characterised by maldevelopment of the pharyngeal arch structures including the thymus, a structure vital for T-cell maturation.[47]

Whereas the frequency and type of immune defects in 22q11.2 deletion have been well studied, the opposite is true for CHARGE syndrome. ‘Evidence’ that immune defects occur in CHARGE syndrome are relatively recent and come from case reports and small case series. To date, there have been 31 published cases of CHARGE patients with immune defects, although in many of these reports, immune evaluation was incomplete.[48-50] Out of these 31 cases, ∼60% had severe combined immunodeficiency (SCID), some of whom have died, 20% had isolated T-cell lymphopenia and 20% had antibody deficiencies. Although reports of SCID in CHARGE likely represent a reporting bias of severe cases, it highlights that like 22q11.2 deletion, complete thymic aplasia can occur. In addition, an atypical SCID (Omenn-like) phenotype with the combination of dermatitis, alopecia, eosinophilia and high immunoglobulin E level despite normal lymphocyte count has been described.[50] The presence of these features or persistent lymphopenia in an infant with CHARGE must never be ignored.

Many children with CHARGE syndrome present with recurrent suppurative ear and chest infections.[51, 52] These infections may be partially explained by altered Eustachian tube anatomy and bulbar dysfunction with aspiration, but are also typical features seen in patients with antibody defects. In the largest retrospective case series of only nine patients, four had lymphopenia, one had hypogammaglobulinemia and one had specific antibody deficiency (SAD) (the inability to make adequate antibody responses to polysaccharide antigens).[49] SAD is particularly common in 22q11.2 deletion, but its prevalence in CHARGE syndrome has never been examined. Prospective studies are required to better delineate the prevalence of immune defects in CHARGE syndrome.

Investigation and Management Considerations

Genetic diagnosis

We recommend children with suspected CHARGE syndrome be referred to a clinical geneticist for discussion of the diagnosis, genetic background and genetic testing options. Sanger sequencing of the CHD7 gene will detect CHARGE-causing mutations (point mutations, small insertions or deletions within exons) in 90–95% of cases that fulfil diagnostic criteria. Whole gene deletions make up 2% of the mutations reported to date and can be detected by standard chromosome microarray platforms (CMA).[11] Exonic deletions are not detectable by standard Sanger sequencing, and most are too small to be detected by CMA but can be demonstrated by a CHD7-targeted ‘exon-dosage’ technique called multiplex ligation-dependent probe amplification (MLPA).

Paediatricians should perform CMA to check for whole deletions of the CHD7 gene and other chromosomal imbalances with clinical overlap with CHARGE, such as 22q11.2 deletion. If CMA is negative, CHD7 sequencing +/− targeted MLPA can then be arranged. CHD7 sequencing and MLPA are expensive and currently are only available through a limited number of overseas commercial laboratories.

ENT and feeding assessment

Audiometry and auditory brainstem response should be performed to document the nature (conductive vs. sensorineural) and severity of hearing loss. Cochlear implant may be indicated in those with sensorineural hearing loss; however, surgery is more difficult because of abnormal facial nerve location and the absence of partitions within the cochlea.[53]

Temporal bone imaging by computed tomography (CT) or MRI is an important part of the routine assessment because absent or hypoplastic semicircular canals are common in CHARGE (>90%), rare in other syndromes and highly predictive of the presence of a CHD7 mutation.[7, 9, 26]

Gastrostomy or jejunostomy feeding tubes may be initially required to overcome feeding problems.

Ophthalmology assessment

Visual assessment by a paediatric ophthalmologist is required to document the presence and nature of colobomas and the severity of visual loss. Problems with photophobia are common and can be relieved by tinted spectacles. Artificial tears may be required in the presence of facial palsy to prevent corneal ulceration.

Developmental and behavioural management

Early and appropriate developmental intervention is crucial. Sign language training in parallel with expressive language development is important. Redirection of inappropriate behaviours may help.[54] The overall aim is to help children adapt to their disabilities and maximise function.

Cardiac assessment

A cardiologist should be involved and an echocardiogram should be done in all children with CHARGE syndrome.

Endocrine and genitourinary assessment

Genital hypoplasia and/or pubertal delay due to hypogonadotropic hypogonadism are the most common endocrine condition in patients with CHARGE. Short stature is also common but usually not due to a hormonal insufficiency. Repeated assessment of thyroid and adrenal function is unnecessary. Specific investigations and managements are highlighted in Table 3. Renal ultrasound is recommended in all children to exclude renal anomalies.

Table 3. Summary of recognised endocrine issues in children with CHARGE syndrome
Hormonal associationPhysical signInvestigationsManagement
  1. FSH, follicle-stimulating hormone; fT4, free thyroxine; IGF1, insulin-like growth factor 1; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.
Hypogonadotropic hypogonadismMicropenisLH, FSH, testosteroneMay require surgery and/or testosterone therapy
CryptorchidismLH, FSH, testosteroneSurgery
Pubertal delay or pubertal arrestLH, FSH, oestradiol/testosterone, pelvic ultrasound, bone age X-ray. Assess for other causes (see above).Oestrogen or testosterone replacement therapy
Growth hormone deficiency (note: short stature in CHARGE syndrome usually is not due to an endocrine disorder)Poor growth with height <3rd centileScreening tests including: IGF1, TSH, fT4, coeliac screen, electrolytes, renal function, calcium metabolism, bone age X-ray. May require growth hormone stimulation testing.As indicated from results of investigation.

Immunological assessment

All infants with CHARGE syndrome should have a full blood count. SCID must be considered in any infant with persistent lymphopenia or eosinophilia with features of atypical SCID (described above). SCID is an immunological emergency and lethal without immune reconstitution.

Paediatricians should not assume recurrent suppurative chest or ear infections in children with CHARGE are due to anatomical issues alone. Antibody defects should be excluded in such children, and we would recommend performing immunoglobulins, full blood count, T- and B-cell subsets and evaluation of functional responses to protein and polysaccharide vaccines.

Management of identified immune deficiency depends on the type of defect. Unlike other forms of SCID, SCID in CHARGE and 22q11.2 deletion is better corrected by thymic transplantation.[55] For antibody defects (e.g. hypogammaglobulinemia and specific antibody defects), prophylactic antibiotic (such as co-trimoxazole) and/or monthly intravenous immunoglobulin infusions may be recommended.


Given the number of potential systems affected in CHARGE syndrome, we believe that a multidisciplinary clinic model is beneficial in the management of these children. Such a clinic would not only facilitate a holistic care model for these children but would also provide avenues for future research to improve their management. The general paediatrician plays an integral role in diagnosis, initiating appropriate investigations, management of the many potential health issues, collaborating with the various specialists and supporting the family. The CHARGE Syndrome Association of Australasia remains an invaluable resource of information and support for families.

Multiple Choice Questions

  • 1.Chromosome microarray will NOT detect which one of the following?
    1. Deletions involving CHD7 on 8q12.1
    2. Sequencing mutations within the CHD7 gene
    3. 22q11.2 microdeletion syndrome
    4. Unbalanced chromosomal translocations
    5. Duplications of the CHD7 gene

Answer: b. Chromosome microarray will detect submicroscopic imbalances (deletions and duplications of DNA, chromosomal translocation) but not individual base pair sequence mutations (e.g. frameshift, missense, nonsense mutations).

  • 2.In CHARGE patients with chronic suppurative infections, which is the most appropriate initial investigation?
    1. NK cell function
    2. CH50
    3. Lymphocyte proliferative assay
    4. Immunoglobulins
    5. Neutrophil function tests

Answer: d. Immunoglobulins. The most common infectious manifestation in CHARGE syndrome is recurrent sinopulmonary infections, which can suggest a defect in the humoral immune system (i.e. a defect in antibody production). While serum immunoglobulins will not pick up more subtle immune deficiencies such as specific antibody deficiency, it is a good initial screen. There is no report of NK cell, complement or neutrophil defect in CHARGE syndrome, excluding a, b and e. Lymphocyte proliferative assay is a second-line investigation looking for severe combined immune deficiency, which although can occur rarely in CHARGE syndrome, is often obvious clinically and should be initially investigated with full blood count and T- and B-cell subsets.

  • 3.A baby is born with bilateral choanal atresia. A CT is ordered to assess the nostrils to plan surgery on day 2. The differential diagnosis includes CHARGE syndrome. This CT scan request should also ask for views of:
    1. Subglottis
    2. Petrous temporal bones
    3. Olfactory cleft
    4. Brain stem

Answer: b. Petrous temporal bone views will demonstrate cochleovestibular malformations; absence or hypoplasia of lateral semicircular canals occurs in >90% CHARGE patients and the diagnosis is virtually clinched on day 1.