CHARGE syndrome

¿Que es CHARGE syndrome?

CHARGE syndromees un trastorno genético que generalmente se presenta con una variedad de defectos de nacimiento.

El trastorno es poco común y no siempre es fácil de diagnosticar como síntomas puede variar ampliamente entre individuos. Los criterios clínicos se establecieron en 2005, la ausencia de un gen específico, responsable de la síndrome, durante muchos años complicó el diagnóstico.

CHARGE syndrome Es caracterizado por síntomas que afectan el sistema nervioso central, así como los ojos, la nariz y los oídos.

Síndrome Sinónimos:
Asociación de carga: coloboma, anomalía cardíaca, atresia coanal, retraso, anomalías genitales y del oído Hall-hittner Síndrome; Hhs Pagon's síndrome

¿Qué causa el cambio genético? CHARGE syndrome?

El síndrome es causado por mutaciones en el gen CHD7. Por lo general, es causada por una nueva mutación. Un segundo gen, SEMA3E, está bajo investigación como causa del síndrome. Se hereda con un patrón autosómico dominante.

En el caso de la herencia autosómica dominante, solo uno de los padres es el portador de la mutación genética y tiene un 50% de posibilidades de transmitirla a cada uno de sus hijos. Los síndromes heredados en una herencia autosómica dominante son causados por una sola copia de la mutación genética.

¿Cuales son los principales síntomas de CHARGE syndrome?

El principal síntomas de El síndrome, y de la cual el síndrome deriva su nombre, son:

Coloboma: una hendidura en el iris o la retina que puede provocar la pérdida de la visión.
Anomalías de los nervios craneales: problemas con la conexión entre la nariz y la garganta
Atresia de coanas: un bloqueo en la parte posterior de la nariz de una persona que puede dificultar la respiración.
Defectos cardiacos
Anomalías genitales

Características físicas del síndrome incluyen parálisis facial asimétrica, orejas cortas y anchas con poco o ningún lóbulo de la oreja, pulgares y dedos pequeños e hipotonía de la parte superior del cuerpo.

Otro síntomas puede incluir paladar hendido, problemas de equilibrio, problemas de salud renal y discapacidad intelectual. Además, anomalías rombencefálicas, disfunción hipotálamo-hipofisaria, malformaciones del oído externo / medio, malformaciones viscerales mediastínicas y retraso mental.

Posibles rasgos / características clínicas:
Maloclusión dental, Pliegue palmar profundo, Pubertad tardía, Aplanamiento del malar, Erupción tardía de los dientes, Braquidactilia, Clinodactilia del 5 dedo, Columela ancha, Coloboma coriorretiniano, Anoftalmia, Labio superior hendido, Desprendimiento de retina, Epicanto, Mano partida, Esofágica atresia, oreja ahuecada, malformación de Dandy-Walker, criptorquidia, disfagia, atresia duodenal, fisuras palpebrales inclinadas hacia abajo, ventrículo derecho de doble salida, parálisis facial, asimetría facial, dificultades de alimentación en la infancia, malformación del oído externo, atresia coanal posterior, hélice sobreplegada, polidactilia de la mano , Nistagmo, Comportamiento obsesivo-compulsivo, Atrofia óptica, Hipoplasia renal, Onfalocele, Polidactilia de la mano prexial, Herencia autosómica dominante, Hipoplasia paratiroidea, Mancha cutánea preauricular, Otitis media, Conducto arterioso persistente, Sinusitis, Coloboma retiniano, Retinopatía, Agenesia renal , Reflujo vesicoureteral, Aplasia / Hipoplasia de los lóbulos de las orejas, Aplasia / Hipoplasia del cuerpo calloso, Apl asia / Hipoplasia del cer

¿Cómo se hace la prueba a alguien? CHARGE syndrome?

La prueba inicial para CHARGE syndrome puede comenzar con la detección del análisis facial, a través de la plataforma FDNA Telehealth de telegenética, que puede identificar los marcadores clave del síndrome y describa la necesidad de realizar más pruebas. Seguirá una consulta con un asesor genético y luego con un genetista. 

Sobre la base de esta consulta clínica con un genetista, se compartirán las diferentes opciones para las pruebas genéticas y se buscará el consentimiento para realizar más pruebas.

Información médica sobre 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 diciembre 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:
diciembre 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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