CHARGE syndrome

Qu'est-ce que CHARGE syndrome?

CHARGE syndrome is a genetic disorder that usually presents with a variety of birth defects.

The disorder is rare and not always easy to diagnose as symptoms may vary widely between individuals. Clinical criteria was established in 2005, the absence of a specific gene, responsible for the syndrome, for many years complicated the diagnosis.

CHARGE syndrome is characterized by symptoms that affect the central nervous system, as well as the eyes, nose, and ears.

Syndrome Synonyms:
Charge Association--coloboma, Heart Anomaly, Choanal Atresia, Retardation, Genital And Ear Anomalies Hall-hittner Syndrome; Hhs Pagon's syndrome

Quelles sont les causes du changement de gène CHARGE syndrome?

Le syndrome est causé par des mutations du gène CHD7. Elle est généralement causée par une nouvelle mutation. Un deuxième gène, SEMA3E, est à l'étude en tant que cause du syndrome. Il est hérité selon un modèle autosomique dominant.

Dans le cas de l'hérédité autosomique dominante, un seul parent est porteur de la mutation génique, et ils ont 50% de chances de la transmettre à chacun de leurs enfants. Les les syndromes hérités d'une transmission autosomique dominante sont causés par une seule copie de la mutation génique.

Quels sont les principaux symptômes de CHARGE syndrome?

The main symptoms of the syndrome, and from which the syndrome derives its name, are:

Coloboma: a slit in the iris or retina that may lead to vision loss
Cranial nerve abnormalities: issues with the connection between the nose and throat
Choanal Atresia: a blockage in the back of an individual’s nose that can make breathing difficult.
Heart defects
Genital abnormalities

Physical features of the syndrome include asymmetrical facial palsy, short and wide ears with little or no earlobe, small thumbs and fingers, and upper body hypotonia.

Other symptoms may include a cleft palate, issues with balance, kidney health concerns and intellectual disability. As well as, rhombencephalic abnormalities, hypothalamo-hypophyseal dysfunction, external/middle ear malformations, mediastinal visceral malformations, and mental retardation.

Possible clinical traits/features:
Dental malocclusion, Deep palmar crease, Delayed puberty, Malar flattening, Delayed eruption of teeth, Brachydactyly, Clinodactyly of the 5th finger, Broad columella, Chorioretinal coloboma, Anophthalmia, Cleft upper lip, Retinal detachment, Epicanthus, Split hand, Esophageal atresia, Cupped ear, Dandy-Walker malformation, Cryptorchidism, Dysphagia, Duodenal atresia, Downslanted palpebral fissures, Double outlet right ventricle, Facial palsy, Facial asymmetry, Feeding difficulties in infancy, External ear malformation, Posterior choanal atresia, Overfolded helix, Hand polydactyly, Nystagmus, Obsessive-compulsive behavior, Optic atrophy, Renal hypoplasia, Omphalocele, Preaxial hand polydactyly, Autosomal dominant inheritance, Parathyroid hypoplasia, Preauricular skin tag, Otitis media, Patent ductus arteriosus, Sinusitis, Retinal coloboma, Retinopathy, Renal agenesis, Webbed neck, Vesicoureteral reflux, Aplasia/Hypoplasia of the earlobes, Aplasia/Hypoplasia of the corpus callosum, Aplasia/Hypoplasia of the cer

Comment quelqu'un se fait-il tester pour CHARGE syndrome?

Les premiers tests de CHARGE syndrome peut commencer par un dépistage par analyse faciale, en passant par le FDNA Telehealth plateforme de télégénétique, qui permet d'identifier les marqueurs clés de la syndrome et souligner la nécessité de tests supplémentaires. Une consultation avec un conseiller génétique puis un généticien suivra. 

Sur la base de cette consultation clinique avec un généticien, les différentes options pour les tests génétiques seront partagées et le consentement sera recherché pour des tests supplémentaires.

Informations médicales sur CHARGE syndrome

CHARGE syndrome is a complex genetic disorder caused by heterozygous pathogenic CHD7 variants (most often private, truncating), which are usually de novo but can be inherited in an autosomal dominant fashion. Features typically include multiple congenital anomalies (coloboma, choanal atresia, facial clefts and/or defects of ears, cranial nerves, heart, esophagus, kidneys and genitalia) and sensory deficits (hearing, vision, balance, smell). CHARGE syndrome should be considered in any individual with coloboma, choanal atresia, semicircular canal anomalies, or cranial nerve anomalies along with other congenital anomalies. Congenital anomalies and sensory deficits contribute to delayed motor and language development despite many individuals having normal intelligence.

CHARGE syndrome consists of multiple congenital anomalies and sensory deficits. The syndrome is phenotypically complex and highly variable among individuals. The clinical diagnostic criteria have undergone a number of revisions since the original description by Pagon, Zonana, and Yong (1981) without a clear consensus (Blake et al., 1998; Verloes, 2005; Hale et al., 2016). The features most helpful in distinguishing CHARGE from other syndromes are coloboma, choanal atresia, semicircular canal anomalies, cranial nerve anomalies and the characteristic dysmorphic features, particularly the external ears (PMID: 29088501).

The most ubiquitous feature is hypoplastic semicircular canals, which are present in 95%. This results in problems with balance and processing of visual and auditory information. The vast majority of individuals will have at least some hearing loss and some vision loss (90-95% and 80-90%, respectively) and therefore are considered deafblind. The combination of multiple sensory deficits (hearing, vision, balance, smell) dramatically interferes with the development of motor skills and communication. Individuals who are medically complex in infancy do not necessarily have poor long-term developmental outcomes.

Eye: Unilateral or bilateral coloboma of the iris, retina-choroid, and/or disc; microphthalmia
Ear: dysmorphic external ear, sensorineural and conductive hearing loss, ossicular malformations, Mondini defect of the cochlea, absent or hypoplastic semicircular canals, absent or hypoplastic auditory and vestibular nerves
Nose: Unilateral or bilateral choanal atresia (bony or membranous) or stenosis. Prominent nasal columella
Nervous system: Cranial nerve dysfunction resulting in hyposmia or anosmia, unilateral or bilateral facial palsy, sensorineural hearing impairment, and/or swallowing problems, developmental delay. Possibly abnormal pain sensation. Unusual reactions to anesthesia. Clivus abnormality (PMID: 29622552)
Reproductive system: Cryptorchidism, genital hypoplasia, genital malformations, delayed or absent puberty (correlated with anosmia)
Cardiac: simple or complex congenital heart defects, especially conotruncal abnormalities; aortic abnormalities including vascular ring
Bones and joints: joint hypermobility; limb abnormalities including polydactyly, syndactyly, split hand, abnormalities of radius or femur, extra or missing ribs; vertebral abnormalities including hemivertebrae, missing or fused vertebrae
Endocrine: hypogonadotropic hypogonadism, small size, short stature, growth hormone deficiency, delayed or absent puberty, hypothyroidism
Gastrointestinal: dysphagia, poor feeding, reflux, tracheoesophageal fistula, esophageal atresia, constipation, malrotation of the intestines
Renal: small, absent or horseshoe kidney; cystic kidney; vesicoureteral reflux; hydronephrosis
Immunity: immunodeficiency (sometimes appearing in late childhood), thymic hypoplasia/aplasia
Infections: increased infections, often due to poor immune system; chronic otitis media
Respiratory: tracheoesophageal fistula, laryngotracheomalacia, sleep apnea (obstructive and/or central)
Head/neck: cleft lip, cleft palate, submucous cleft palate, velopharyngeal insufficiency, short neck, torticollis
Psychology: deafblind behaviors, behavior issues, obsessive compulsive disorder, autistic-like behaviors, poor social interactions (in part due to sensory deficits). Behavior issues often appear in childhood or adolescence
Development: motor delay due to physical and vestibular issues, language delay due to sensory deficits, intellectual disability
Other: hockey stick palmar crease

MODE(S) OF INHERITANCE: Autosomal dominant, usually unique, truncating variants often de novo (PMID 18074359)
PENETRANCE: Penetrance appears to be complete with widely varying expression
PREVALENCE: 1/15,000 to 1/10,000 (PMID 15637722, 22461308)
LIFE EXPECTANCY: Mortality is high in the first few years due to the severity of birth defects (particularly complex heart defects), often in combination with airway and feeding issues. Feeding difficulties are usually due to cranial nerve abnormalities and improve gradually. Multiple complex surgeries, along with breathing problems or difficulty with anesthesia reported in CHARGE syndrome (Blake et al., 2009), increase the risks associated with procedures. After the first two or three years, there remains increased mortality (and certainly increased morbidity and medical fragility), with parents reporting frequent illnesses, infections and hospitalizations (Bergman et al., 2010). In childhood, adolescence and adulthood, increased mortality is likely related to a combination of residual heart defects, infections, aspiration or choking, respiratory issues including obstructive and central apnea, and possibly seizures. A number of families have reported serious (and in some cases, lethal) intestinal issues such as volvulus and intussusception. Several individuals have been diagnosed with severe immune deficiencies, including severe combined immunodeficiency due to absent thymus. Wong et al., (2015) found decreased T cells in half of patients, presumed to be due to insufficient thymic output. Despite these complications, the lifespan for many individuals can be normal. Individuals in their 60s who are in good health have been observed.
AGE OF ONSET: In utero
PRENATAL PRESENTATION: Abnormalities detectable by mid-trimester ultrasound include orofacial clefting, malformed external ears, and defects of the heart, kidneys, limbs (PMID 27061523), gastrointestinal tract, and genitalia (in males). Other features that may not be apparent until the third trimester include brain anomalies (arhinencephaly, cerebellar hypoplasia [PMID 11509849], dysplastic choroid plexus [PMID 11509849], abnormal development of olfactory sulci [PMID 26255985]), ventriculomegaly (PMID 11509849), microphthalmia and polyhydramnios. Typically, a specific diagnosis of CHARGE syndrome is not made based on ultrasound abnormalities, but may be suspected when the common trisomies and microdeletion syndromes have been ruled out. Ultrasound anomalies have been reported in about half (46.6 percent) of affected pregnancies (PMID 29178447)

ASSOCIATED GENE(S): CHD7, possibly SEMA3E (PMID:15235037) and possibly FAM172A (PMID: 29311329)
RECURRENT MUTATION(S): No major hotspots (PMID 22461308)
TYPE OF MUTATION(S): CHD7 mutations are heterozygous. 78% of pathogenic variants are null/loss-of-function alleles. 13% are splice site variants that can result in a null allele (due to a frameshift) or a hypomorphic allele (due to exon skipping). 9% are missense variants (PMID 29171162). Deletions (intragenic or whole gene) can be seen. The frequency of exon deletions is about 2-6% (PMID 18472328). Mutations are equally distributed along the coding region . Pathogenic missense mutations are mainly present in the middle of the gene (PMID 22539353). Most mutations are unique (PMID 22461308, 21378379). The detection rate of a CHD7 pathogenic variant in patients with clinical CHARGE syndrome ranges from 67% to 90% in the literature (PMID 22461308, 16155193, 20186815).
GENOTYPE/PHENOTYPE CORRELATION: Overall, there is wide variability in clinical presentation among affected individuals and even between affected relatives within a family. Genotype does not predict phenotype (PMID 16155193). Familial mutations are more likely to be missense than truncating (PMID 22461308). Missense mutations tend to be associated with a milder phenotype, with some individuals with missense mutations being less likely to fulfill the clinical criteria. Individuals with a missense variant are less likely to have choanal atresia and congenital heart defects than those with a truncating variant (PMID 22539353).

Abnormality of head or neck: craniosynostosis, choanal atresia/choanal stenosis in 49% (PMID 29171162), oral cleft* in 40% (PMID 29171162), square face*, broad forehead*, prominent forehead, prominent nasal bridge/wide nasal bridge, low hanging columella*, midface retrusion*, torticollis, facial asymmetry*, short neck, broad neck, cleft palate, microcephaly, abnormal facial shape
Abnormality of the skeletal system: scoliosis, abnormality of the vertebral column, abnormality of limbs (PMID: 17937444), finger syndactyly, toe syndactyly, split hand, hip dysplasia, talipes equinovarus, oligodactyly (PMID: 17937444), absent tibia (PMID: 17937444), bifid femur (PMID: 17937444), polydactyly
Abnormality of integument: abnormality of the palmar creases
Abnormality of the ear: external ear malformation in 95% (PMID: 29171162), short ear, absent earlobe, abnormality of the helix, prominent antihelix, abnormality of the outer ear, abnormality of cartilage of external ear, protruding ear, lop ear/cupped ear, asymmetry of the ears, hearing impairment in 90-95% (PMID: 29088501), sensorineural hearing impairment, conductive hearing impairment, abnormality of the middle ear ossicles, abnormality of the round window, incomplete partition of the cochlea type II, hypoplasia of the semicircular canal/aplasia of semicircular canal in 94% (PMID: 29171162), abnormality of the temporal bone, recurrent otitis media
Abnormality of the digestive system: dysphagia/gastroesophageal reflux in >75% (PMID: 29171162), esophageal atresia/tracheoesophageal fistula in 20%, aspiration, constipation
Abnormality of the nervous system: facial palsy* in 58% (PMID: 29171162), abnormal cranial nerve morphology in 94% (PMID: 29171162), aplasia of the vestibular nerve, anosmia in 80% (PMID: 29171162), hyposmia, abnormality of the cerebellar vermis, ventriculomegaly, hypoplasia of the frontal lobes, ectopic posterior pituitary, anterior pituitary hypoplasia, hypoplasia of the olfactory bulb, abnormal hypothalamus morphology (PMID: 29168326), seizures
Abnormality of prenatal development or birth: see Prenatal Presentation section
Abnormality of the genitourinary system: abnormality of the kidney in 30-40%, renal agenesis, horseshoe kidney, multicystic kidney dysplasia, abnormality of the genital system, cryptorchidism, external genital hypoplasia in 68% of males (PMID: 29171162), micropenis, labial hypoplasia, aplasia of the uterus
Abnormality of the musculature: generalized hypotonia, muscular hypotonia of the trunk, abnormality of the pectoral muscles
Growth abnormality: short stature, growth delay in 55% (PMID: 29171162)
Abnormality of the endocrine system: growth hormone deficiency (PMID:29152903), hypogonadotropic hypogonadism, aplasia/hypoplasia of the thymus (PMID: 29152903)
Abnormality of the respiratory system: tracheoesophageal fistula, abnormality of the trachea, laryngomalacia
Abnormality of the cardiovascular system: abnormality of cardiovascular system morphology, abnormal heart morphology in 78% (PMID: 29171162), tetralogy of Fallot, conotruncal defect
Constitutional system: behavioral abnormality, intellectual disability in 60-80% (PMID: 29171162)
Abnormality of the eye: coloboma in 80% (PMID: 29171162), iris coloboma, retinal coloboma, optic nerve coloboma, microphthalmia, myopia, visual impairment in 80-90% (PMID: 29088501)
Abnormality of the immune system: immunodeficiency, aplasia of the thymus (PMID: 26563674)
Abnormality of connective tissue: joint hypermobility

The CHARGE acronym was coined by Pagon, Zonana and Graham (1982). Specific clinical diagnostic criteria were initially proposed by Blake et al., (1998) and revised by Verloes (2005) after the recognition of CHD7 (chromodomain helicase DNA binding protein) as the CHARGE gene was reported in 2004 by Vissers et al.

Authors who propose slightly varying diagnostic criteria include Verloes (2005), who added semicircular canal hypoplasia; Blake and Prasad (2006); Sanlaville and Verloes (2007); and Hale et al., (2015). Bergman et al., (2011) proposed guidelines for a genetic diagnosis of CHARGE syndrome by CHD7 analysis.

The décembre 2017* Part C issue of the American Journal of Medical Genetics is devoted to CHARGE syndrome. Articles succinctly summarize the clinical and molecular features, diagnostic criteria and management.

Trider et al., (2017) developed a CHARGE Health Checklist, which covers recommended medical investigation and surveillance throughout the lifespan (PMID: 28160409). This checklist was validated and other CHARGE management guidelines added by de Geus et al., (PMID: 29168326). Hefner and Fassi (2017) recommend that every infant or child with one of the major characteristics of CHARGE syndrome (coloboma, choanal atresia, semicircular canal or cranial nerve abnormalities) should have a complete evaluation of all possible CHARGE syndrome features, for purposes of diagnosis and for medical management (PMID: 29088501). The evaluations include dilated eye exam, echocardiogram, renal ultrasound, and MRI of the brain, choanae and inner ears (temporal bone).

Medical management involves investigation of all potential issues, then monitoring of multiple organ systems by a multidisciplinary healthcare team, often beginning at birth. Ideally, care is coordinated by a primary care physician, medical genetics team or complex care clinic. Every child has a unique combination of medical, physical, and psychological issues and requires a unique management protocol. See de Geus (PMID 29168326) for comprehensive management and treatment guidelines.
Language and development guidelines were collected in a book on CHARGE
(Hartshorne, Hefner, Davenport, & Thelin, 2011). Additional resources for management are available at the CHARGE syndrome Foundation website (
Early attention to the sensory deficits and establishment of communication systems is essential to positive outcomes.

None at present. For a review of preclinical research discoveries that may eventually be translated into clinical trials, see PMID 29171162

CHARGE syndrome Foundation
The CSF website includes links to many additional CHARGE support groups and resources around the world at: -> Read more about Support Groups

(1) St. Luke’s Health System, Boise, ID; (2) Saint Louis University, St. Louis, MO.

décembre 16, 2018

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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