CHARGE syndrome

Was ist CHARGE syndrome?

CHARGE syndromeist eine genetische Störung, die normalerweise mit einer Vielzahl von Geburtsfehlern auftritt.

Die Störung ist selten und nicht immer leicht zu diagnostizieren, da symptome kann zwischen einzelnen Personen stark variieren. Klinische Kriterien wurden in 2005 festgelegt, das Fehlen eines spezifischen Gens, das für die verantwortlich ist syndrom, erschwerte jahrelang die Diagnose.

CHARGE syndrome ist charakterisiert durch symptome die das zentrale Nervensystem sowie Augen, Nase und Ohren betreffen.

Syndrom Synonyme:
Ladungsassoziation - Kolobom, Herzanomalie, Choanalatresie, Retardierung, Genital- und Ohranomalien Hall-hittner Syndrom; Hhs Pagons syndrom

Was Genveränderung verursacht CHARGE syndrome?

Das Syndromes wird durch Mutationen im CHD7-Gen verursacht. Es wird normalerweise durch eine neue Mutation verursacht. Ein zweites Gen, SEMA3E, wird als Ursache des Syndroms untersucht. Es wird in einem autosomal dominanten Muster vererbt.

Im Fall einer autosomal dominanten Vererbung ist nur ein Elternteil der Träger der Genmutation, und sie haben eine 50% ige Chance, sie an jedes ihrer Kinder weiterzugeben. Syndromes, die in einer autosomal dominanten Vererbung vererbt werden, werden durch nur eine Kopie der Genmutation verursacht.

Was sind die wichtigsten symptome von CHARGE syndrome?

Das Wichtigste symptome des syndrom, und von denen die syndrom leitet seinen Namen ab, sind:

Kolobom: ein Schlitz in der Iris oder Netzhaut, der zu Sehverlust führen kann
Hirnnervenanomalien: Probleme mit der Verbindung zwischen Nase und Rachen
Choanalatresie: eine Blockade im Nasenrücken einer Person, die das Atmen erschweren kann.
Herzfehler
Genitale Anomalien

Physikalische Merkmale des syndrom umfassen asymmetrische Fazialisparese, kurze und breite Ohren mit wenig oder keinem Ohrläppchen, kleine Daumen und Finger und Oberkörperhypotonie.

Andere symptome kann eine Gaumenspalte, Gleichgewichtsstörungen, Nierengesundheitsprobleme und geistige Behinderung umfassen. Sowie rhombenzephale Anomalien, hypothalamo-hypophysäre Dysfunktion, Außen-/Mittelohrfehlbildungen, mediastinale viszerale Fehlbildungen und geistige Behinderung.

Mögliche klinische Merkmale/Merkmale:
Zahnfehlstellung, tiefe palmare Falte, verzögerte Pubertät, Abflachung der Malare, verzögerter Zahndurchbruch, Brachydaktylie, Klinodaktylie des 5. Fingers, breite Columella, chorioretinales Kolobom, Anophthalmie, Oberlippenspalte, Netzhautablösung, Epikanthus, gespaltene Hand, Ösophagus Atresie, Schalenohr, Dandy-Walker-Fehlbildung, Kryptorchismus, Dysphagie, Duodenalatresie, Downslanted Lidspalten, Doppelauslass rechter Ventrikel, Gesichtslähmung, Gesichtsasymmetrie, Ernährungsschwierigkeiten im Säuglingsalter, Außenohrfehlbildung, Posterior Choanalatresie, Übergefaltete Helix, Handgefaltete Helix , Nystagmus, Zwangsverhalten, Optikusatrophie, Nierenhypoplasie, Omphalozele, präaxiale Handpolydaktylie, autosomal-dominante Vererbung, Nebenschilddrüsenhypoplasie, präaurikuläre Hautmarkierung, Otitis media, offener Ductus arteriosus, Sinusitis, Netzhautkolobom, Nacken-Agenesis, Retinopathie, , Vesikoureteraler Reflux, Aplasie/Hypoplasie der Ohrläppchen, Aplasie/Hypoplasie des Corpus callosum, Apl Asien/Hypoplasie des Cer

Wie wird jemand getestet? CHARGE syndrome?

Die ersten Tests für CHARGE syndrome kann mit einem Gesichtsanalyse-Screening beginnen, durch die FDNA Telehealth Telegenetik-Plattform, die die Schlüsselmarker der syndrom und skizzieren Sie die Notwendigkeit weiterer Tests. Es folgt ein Beratungsgespräch mit einem genetischen Berater und dann einem Genetiker. 

Basierend auf dieser klinischen Konsultation mit einem Genetiker werden die verschiedenen Optionen für Gentests geteilt und die Zustimmung für weitere Tests eingeholt.

Medizinische Informationen zu CHARGE syndrome

SYNDROME OVERVIEW:
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.

CLINICAL DESCRIPTION (GENERAL):
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.

CLINICAL DESCRIPTION (BODY SYSTEMS):
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

SYNDROME CHARACTERISTICS:
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)

MOLECULAR GENETICS:
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).

KEY CLINICAL FEATURES/PHENOTYPES:
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

KEY PUBLICATIONS:
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 Dezember 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.

SURVEILLANCE:
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).

MANAGEMENT AND TREATMENT:
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 (www.chargesyndrome.org)
Early attention to the sensory deficits and establishment of communication systems is essential to positive outcomes.

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

PATIENT ORGANIZATIONS:
CHARGE syndrome Foundation
https://www.chargesyndrome.org/
The CSF website includes links to many additional CHARGE support groups and resources around the world at: https://www.chargesyndrome.org/for-families/resources/ -> Read more about Support Groups


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

DATE OF UPDATE:
Dezember 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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