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CHARGE Syndrome

CHARGE syndrome is a rare genetic condition with autosomal dominant inheritance Autosomal dominant inheritance Autosomal Recessive and Autosomal Dominant Inheritance in which almost all body systems are affected. The acronym CHARGE stands for the constellation of clinical features seen with this condition: Coloboma, Heart defects, Atresia choanae, Growth retardation, Genital abnormalities, and E ar AR Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation abnormalities. Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies confirms the diagnosis. Treatment is symptomatic with management of the airway Airway ABCDE Assessment, heart defects, and feeding ability as the priorities in early life. There is no definitive curative therapy.

Last updated: 4 Apr, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Epidemiology and Genetics

Epidemiology

  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 1 in 12,000–15,000 newborns
  • Mortality Mortality All deaths reported in a given population. Measures of Health Status is highest during neonatal period.

Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics

  • Most commonly due to loss of function Loss of Function Inflammation mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in CHD7 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics 
    • Produces the CHD7 protein, involved in chromatin remodeling Chromatin remodeling Epigenetic Regulation
    • Chromatin remodeling Chromatin remodeling Epigenetic Regulation controls the gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics expression. 
    • The defective CHD7 protein breaks down prematurely. 
    • Results in a disrupted chromatin remodeling Chromatin remodeling Epigenetic Regulation and poor gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics expression 
    • Neural crest Neural crest The two longitudinal ridges along the primitive streak appearing near the end of gastrulation during development of nervous system (neurulation). The ridges are formed by folding of neural plate. Between the ridges is a neural groove which deepens as the fold become elevated. When the folds meet at midline, the groove becomes a closed tube, the neural tube. Hirschsprung Disease differentiation into various structures throughout the body is impaired.
  • Inheritance pattern: autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance 
  • May be familial, but more often results from de novo ( idiopathic Idiopathic Dermatomyositis) mutations
  • Advanced paternal age possibly a risk factor

Related videos

Clinical Presentation

Characteristic symptoms

CHARGE is an acronym to describe the clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor of this syndrome: 

  • C for Coloboma Coloboma Congenital anomaly in which some of the structures of the eye are absent due to incomplete fusion of the fetal intraocular fissure during gestation. Esophageal Atresia and Tracheoesophageal Fistula (a hole in the choroid Choroid The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. Eye: Anatomy, retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy, iris Iris The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers – the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. Eye: Anatomy, and/or optic disc Optic disc The portion of the optic nerve seen in the fundus with the ophthalmoscope. It is formed by the meeting of all the retinal ganglion cell axons as they enter the optic nerve. Eye: Anatomy)
    • Unilateral or bilateral
    • Impairment of vision Vision Ophthalmic Exam depending on the location and size 
    • May also present with microphthalmia
  • H for Heart defects (60%–70% of cases) 
    • Coarctation of the aorta Aorta The main trunk of the systemic arteries. Mediastinum and Great Vessels: Anatomy
    • Aortic valve Aortic valve The valve between the left ventricle and the ascending aorta which prevents backflow into the left ventricle. Heart: Anatomy stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS)
    • Tetralogy of Fallot Tetralogy of Fallot Tetralogy of Fallot is the most common cyanotic congenital heart disease. The disease is the confluence of 4 pathologic cardiac features: overriding aorta, ventricular septal defect, right ventricular outflow obstruction, and right ventricular hypertrophy. Tetralogy of Fallot
    • Patent ductus arteriosus Patent ductus arteriosus The ductus arteriosus (DA) allows blood to bypass pulmonary circulation. After birth, the DA remains open for up to 72 hours and then constricts and involutes, becoming the ligamentum arteriosum. Failure of this process to occur results in patent ductus arteriosus (PDA), a condition that causes up to 10% of congenital heart defects. Patent Ductus Arteriosus (PDA)
  • A for Atresia Atresia Hypoplastic Left Heart Syndrome (HLHS) of the choanae (choanal atresia Atresia Hypoplastic Left Heart Syndrome (HLHS))
  • R for growth Retardation Growth Retardation Failure of a fetus to attain expected growth. Fetal Alcohol Spectrum Disorder (60%–70% of cases)
    • Noticeable in the first 6 months of life
    • May be noted in utero
    • Short stature
    • Due to growth hormone (GH) deficiency and a gonadotropin deficiency
  • G for Genital abnormalities 
  • E for Ear abnormalities (100% of cases)
    • Hypoplastic semicircular canals Semicircular canals Three long canals (anterior, posterior, and lateral) of the bony labyrinth. They are set at right angles to each other and are situated posterosuperior to the vestibule of the bony labyrinth (vestibular labyrinth). The semicircular canals have five openings into the vestibule with one shared by the anterior and the posterior canals. Within the canals are the semicircular ducts. Auditory and Vestibular Pathways: Anatomy are pathognomonic.
    • External ear is small, low-set, and square-shaped with protruding helices.
    • Developmental defects of the middle and inner ear Inner ear The essential part of the hearing organ consists of two labyrinthine compartments: the bony labyrinthine and the membranous labyrinth. Ear: Anatomy hearing impairment Hearing impairment Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss 

Associated conditions

  • Additional facial dysmorphic features: square face, facial nerve Facial nerve The 7th cranial nerve. The facial nerve has two parts, the larger motor root which may be called the facial nerve proper, and the smaller intermediate or sensory root. Together they provide efferent innervation to the muscles of facial expression and to the lacrimal and salivary glands, and convey afferent information for taste from the anterior two-thirds of the tongue and for touch from the external ear. The 12 Cranial Nerves: Overview and Functions palsy Palsy paralysis of an area of the body, thus incapable of voluntary movement Cranial Nerve Palsies, malar flattening, micrognathia Micrognathia Abnormally small jaw. Pierre Robin Sequence, orofacial clefting
  • Skeletal anomalies such as scoliosis Scoliosis Scoliosis is a structural alteration of the vertebral column characterized by a lateral spinal curvature of greater than 10 degrees in the coronal plane. Scoliosis can be classified as idiopathic (in most cases) or secondary to underlying conditions. Scoliosis, polydactyly Polydactyly A congenital anomaly of the hand or foot, marked by the presence of supernumerary digits. Physical Examination of the Newborn, oligodactyly, or clubfoot Clubfoot Clubfoot, also called talipes equinovarus, is a complex condition with a plantar flexed foot (equinus), adductus of the forefoot, and an inversion deformity of the heel (varus). Foot Deformities
  • Tracheoesophageal fistula Fistula Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. Anal Fistula
  • Feeding and swallowing Swallowing The act of taking solids and liquids into the gastrointestinal tract through the mouth and throat. Gastrointestinal Motility difficulties/under-nutrition
  • Neurological anomalies 
  • Intellectual disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment and developmental delay
  • Renal anomalies

Diagnosis

Diagnostic criteria

The diagnosis of CHARGE syndrome can be established if 2 major criteria plus any number of minor criteria are present.

  • 4 major criteria (4 Cs):
    1. Coloboma Coloboma Congenital anomaly in which some of the structures of the eye are absent due to incomplete fusion of the fetal intraocular fissure during gestation. Esophageal Atresia and Tracheoesophageal Fistula
    2. Choanal atresia Atresia Hypoplastic Left Heart Syndrome (HLHS) or cleft palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Palate: Anatomy
    3. Characteristic external, middle, or inner ear Inner ear The essential part of the hearing organ consists of two labyrinthine compartments: the bony labyrinthine and the membranous labyrinth. Ear: Anatomy anomalies including hypoplastic semicircular canals Semicircular canals Three long canals (anterior, posterior, and lateral) of the bony labyrinth. They are set at right angles to each other and are situated posterosuperior to the vestibule of the bony labyrinth (vestibular labyrinth). The semicircular canals have five openings into the vestibule with one shared by the anterior and the posterior canals. Within the canals are the semicircular ducts. Auditory and Vestibular Pathways: Anatomy
    4. CHD7 variant (pathogenic)
  • 7 minor criteria:
    1. Cranial nerve dysfunction including hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss
    2. Dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming “stuck.” Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia/feeding difficulties
    3. Structural brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification anomalies
    4. Developmental delay/intellectual disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment/autism
    5. Hypothalamo-hypophyseal dysfunction (including hormonal deficiencies) and genital anomalies
    6. Heart or esophageal malformations
    7. Renal/skeletal/limb anomalies

Laboratory tests

  • Complete blood count (CBC)
  • Renal function tests
  • Hormonal analysis (↓ growth hormone, ↓ gonadotrophins)
  • Immunological studies

Imaging studies

  • Ultrasonography (US): 
    • Cranial US: done during neonatal period to exclude major brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification malformations
    • Abdominal US: to exclude renal abnormalities
  • Echocardiography Echocardiography Ultrasonic recording of the size, motion, and composition of the heart and surrounding tissues. The standard approach is transthoracic. Tricuspid Valve Atresia (TVA): valvular abnormalities and structural heart defects
  • Barium swallow Barium Swallow Imaging of the Intestines: esophageal dysmotility Esophageal Dysmotility Scleroderma
  • Chest radiographs: to detect cardiopulmonary abnormalities
  • Computed tomography (CT) and magnetic resonance imaging (MRI):  forebrain forebrain The anterior of the three primitive cerebral vesicles of the embryonic brain arising from the neural tube. It subdivides to form diencephalon and telencephalon. Development of the Nervous System and Face anomalies, cerebral atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation, midbrain Midbrain The middle of the three primitive cerebral vesicles of the embryonic brain. Without further subdivision, midbrain develops into a short, constricted portion connecting the pons and the diencephalon. Midbrain contains two major parts, the dorsal tectum mesencephali and the ventral tegmentum mesencephali, housing components of auditory, visual, and other sensorimotor systems. Brain Stem: Anatomy defects
Severe basal ganglia epvs

Magnetic resonance imaging showing cerebral atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation from mild (A) to moderate (B) to severe (C) stages

Image: “EPVS” by Department of Neurology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China. License: CC BY 4.0

Other tests

  • Electroencephalogram ( EEG EEG Seizures)
  • Electrocardiogram Electrocardiogram An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Electrocardiogram (ECG) ( ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Electrocardiogram (ECG))
  • Audiometry Audiometry The testing of the acuity of the sense of hearing to determine the thresholds of the loWest intensity levels at which an individual can hear a set of tones. The frequencies between 125 and 8000 hz are used to test air conduction thresholds and the frequencies between 250 and 4000 hz are used to test bone conduction thresholds. Ménière Disease
  • Ophthalmologic exam
  • Psychological and educational assessments

Management and Prognosis

Management

Various supportive and corrective treatment options are available. Treatment is tailored to the symptoms and anomalies present. 

  • Medical treatment:
    • Oxygen supplementation for cyanotic heart disease
    • Nasogastric feeding for swallowing Swallowing The act of taking solids and liquids into the gastrointestinal tract through the mouth and throat. Gastrointestinal Motility difficulties
    • Artificial tears for facial palsy Palsy paralysis of an area of the body, thus incapable of voluntary movement Cranial Nerve Palsies to avoid scarring Scarring Inflammation of a cornea Cornea The transparent anterior portion of the fibrous coat of the eye consisting of five layers: stratified squamous corneal epithelium; bowman membrane; corneal stroma; descemet membrane; and mesenchymal corneal endothelium. It serves as the first refracting medium of the eye. Eye: Anatomy
    • Hearing aids AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS/cochlear implants
    • Durable medical equipment such as braces or wheelchairs to help with mobility Mobility Examination of the Breast
    • Androgen therapy given in some cases for penile growth
    • Physical therapy Physical Therapy Becker Muscular Dystrophy to help with mobility Mobility Examination of the Breast
    • Speech therapy Speech Therapy Treatment for individuals with speech defects and disorders that involves counseling and use of various exercises and AIDS to help the development of new speech habits. Myotonic Dystrophies as needed
  • Surgical treatment:
    • Tracheostomy Tracheostomy Surgical formation of an opening into the trachea through the neck, or the opening so created. Laryngomalacia and Tracheomalacia ( tube placement Tube placement Surgical procedure involving the creation of an opening (stoma) into the chest cavity for drainage; used in the treatment of pleural effusion; pneumothorax; hemothorax; and empyema. Thoracic Surgery into the trachea Trachea The trachea is a tubular structure that forms part of the lower respiratory tract. The trachea is continuous superiorly with the larynx and inferiorly becomes the bronchial tree within the lungs. The trachea consists of a support frame of semicircular, or C-shaped, rings made out of hyaline cartilage and reinforced by collagenous connective tissue. Trachea: Anatomy to stabilize air passage)
    • Gastrostomy ( tube placement Tube placement Surgical procedure involving the creation of an opening (stoma) into the chest cavity for drainage; used in the treatment of pleural effusion; pneumothorax; hemothorax; and empyema. Thoracic Surgery into the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach: Anatomy for feeding)
    • Myringotomy ( tube placement Tube placement Surgical procedure involving the creation of an opening (stoma) into the chest cavity for drainage; used in the treatment of pleural effusion; pneumothorax; hemothorax; and empyema. Thoracic Surgery into the tympanic membrane Tympanic membrane An oval semitransparent membrane separating the external ear canal from the tympanic cavity. It contains three layers: the skin of the external ear canal; the core of radially and circularly arranged collagen fibers; and the mucosa of the middle ear. Ear: Anatomy for otitis media)

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

Differential Diagnosis

  • VACTERL association VACTERL Association VACTERL association is a rare disorder that affects multiple body systems in fetal development. There is no clear genetic cause or inheritance pattern for the development of this disorder. The acronym VACTERL stands for its characteristic anomalies: Vertebral abnormalities, Anal atresia, Cardiac defects, Tracheoesophageal abnormalities, Renal anomalies, and Limb abnormalities. VACTERL Association: a disorder that affects multiple body systems in fetal development. VACTERL is the acronym for the constellation of clinical features seen with this condition: Vertebral defects, Anal atresia Atresia Hypoplastic Left Heart Syndrome (HLHS), Cardiac defects, Tracheoesophageal fistula Fistula Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. Anal Fistula, Renal anomalies, and Limb abnormalities. The disorder appears to occur sporadically with no clear inheritance pattern. Cognition is not affected. The disorder is a diagnosis of exclusion in the setting of the presence of at least 3 of the above clinical features. Treatment is conservative and surgical based on symptoms and abnormalities. 
  • Kallmann syndrome Kallmann syndrome Kallmann syndrome (KS), also called olfacto-genital syndrome, is a genetic condition that causes hypogonadotropic hypogonadism due to decreased secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus. The lack of sex hormones results in impaired pubertal development. Kallmann Syndrome: a genetic condition that causes hypogonadotropic hypogonadism Hypogonadotropic Hypogonadism Hypogonadism and impaired sense of smell Smell The sense of smell, or olfaction, begins in a small area on the roof of the nasal cavity, which is covered in specialized mucosa. From there, the olfactory nerve transmits the sensory perception of smell via the olfactory pathway. This pathway is composed of the olfactory cells and bulb, the tractus and striae olfactoriae, and the primary olfactory cortex and amygdala. Olfaction: Anatomy. Mutations in the same gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics (CHD7) implicated in CHARGE syndrome have been seen in those with Kallmann syndrome Kallmann syndrome Kallmann syndrome (KS), also called olfacto-genital syndrome, is a genetic condition that causes hypogonadotropic hypogonadism due to decreased secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus. The lack of sex hormones results in impaired pubertal development. Kallmann Syndrome. Given the overlap, individuals with suspected Kallmann syndrome Kallmann syndrome Kallmann syndrome (KS), also called olfacto-genital syndrome, is a genetic condition that causes hypogonadotropic hypogonadism due to decreased secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus. The lack of sex hormones results in impaired pubertal development. Kallmann Syndrome may have similar features to that of CHARGE syndrome, albeit much milder, and should undergo additional screening Screening Preoperative Care. Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies with gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics sequencing helps with diagnosis and differentiation.

References

  1. Van Ravenswaaij-Arts, C. & Martin, Donna M.(2017). New insights and advances in CHARGE syndrome: Diagnosis, etiologies, treatments, and research discoveries. Am J Med Genet C Semin Med Genet. 175(4): 397–406. Published online 2017 Nov 24. doi: 10.1002/ajmg.c.31592
  2. CHARGE Syndrome. Online Mendelian Inheritance in Man (OMIM). Retrieved December 2, 2020. URL:https://www.omim.org/entry/214800#creationDate
  3. Jongmans, M.C., et al.  (2006). CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. J Med Genet. 43(4): 306–314.Published online 2005 Oct 14. doi: 10.1136/jmg.2005.036061
  4. Dijk, D. R., Bocca, G., & van Ravenswaaij-Arts, C. M. (2019). Growth in CHARGE syndrome: optimizing care with a multidisciplinary approach. J Multidiscip Healthc.12: 607–620. Published online 2019 Aug 1. doi: 10.2147/JMDH.S175713
  5. Jongmans M.C., van Ravenswaaij-Arts C.M., Pitteloud N., et al. (2009). CHD7 mutations in patients initially diagnosed with Kallmann syndrome–the clinical overlap with CHARGE syndrome. Clinical Genetics. 75(1):65-71. DOI: 10.1111/j.1399-0004.2008.01107.x.
  6. Blake, K. M., Prasad, C. (2015). Orphanet: CHARGE syndrome.  Retrieved December 9, 2020, from https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=138

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