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40 years!
Last updated:
September 05, 2018
Years published: 1988, 1988, 1990, 1996, 1997, 1998, 2000, 2002, 2007, 2008, 2012, 2015, 2018
NORD gratefully acknowledges John M. Graham, JR., M.D., Sc.D., Pediatric Consultant in Clinical Genetics and Dysmorphology, Department of Pediatrics, Cedars-Sinai Medical Center and Harbor-UCLA Medical Center for assistance in the preparation of this report.
CHARGE syndrome is a rare disorder that arises during early fetal development and affects multiple organ systems. The CHARGE acronym comes from the first letter of some of the more common features seen in these children: (C) = coloboma (usually retinochoroidal) and cranial nerve defects (80-90%) (H) = heart defects in 75-85%, especially tetralogy of Fallot (A) = atresia of the choanae (blocked nasal breathing passages) (50-60%) (R) = retardation of growth (70-80%) and development (G) = genital underdevelopment due to hypogonadotropic hypogonadism (E) = ear abnormalities and sensorineural hearing loss (>90%). Diagnosis is based on a specific set of features (see below). In addition to the CHARGE features above, most children with CHARGE syndrome have other features, including characteristic facial features: asymmetric facial nerve palsy, cleft lip or palate, esophageal atresia (blind-ending food pipe) or tracheoesophageal fistula (connection between the wind pipe and the food pipe). The symptoms of CHARGE syndrome vary greatly from one child to another. The cause of CHARGE is usually a new mutation (change) in the CHD7 gene, or rarely, genomic alterations in the region of chromosome 8q12.2 where the CHD7 gene is located. Among 119 French children with CHARGE syndrome, CHD7 mutations were found in 83% of typical CHARGE syndrome individuals, and 58% of atypical cases. The following cardinal symptoms were found among CHD7+ cases: coloboma 73%; heart defects 63%; choanal atresia 43%; IUGR 24%; genital abnormalities 56%; semicircular canal agenesis/hypoplasia 99%; deafness 97%; external ear anomalies 86%; internal ear anomalies (SCC defects excluded) 65%; anosmia 83%; olfactory bulb agenesis 76%; cranial nerve defects 74%; intellectual disability 62%; CNS defects 51%; kidney 31%; esophageal anomalies 24%; and cleft lip and/or palate 20%. Postnatal growth failure and swallowing problems are very frequent associated with cranial nerve dysfunctions. Three-dimensional reconstructions of MRI scans showed temporal bone abnormalities in over 85%.
CHARGE syndrome affects multiple organ systems, resulting in multiple problems apparent at birth. Other characteristics of CHARGE syndrome may not become apparent until later in life. The diagnosis of CHARGE syndrome should be made by a medical geneticist based on the presence of at least one major criterion and several minor and/or occasional criteria of CHARGE syndrome (see below).
Major Diagnostic Criteria (The 4 C’s):
Features seen commonly in CHARGE, rarely in other conditions: Coloboma, Cranial nerve abnormalities, Choanal atresia, typical CHARGE Ear.
Coloboma
A coloboma is a cleft or failure to close of the eyeball during fetal development. This can result in a keyhole-shaped pupil (iris coloboma) and/or abnormalities in the retina, macula or optic nerve. Very small eyes (microphthalmia) or missing eyes (anophthalmia) can be severe forms of coloboma. Colobomas of the retina or optic nerve may result in significant vision loss, including blind spots, problems with depth perception or legal blindness. Colobomas occur most frequently in the retina and are present in at least 70-90% of patients with CHARGE syndrome. Examination of 38 eyes in 19 patients with CHARGE syndrome and confirmed CHD7 mutations revealed colobomata affected the posterior segment of 35 eyes in 18 patients. Both retinochoroidal and optic disk colobomata were observed bilaterally in 15 patients and unilaterally in 3 patients. The coloboma involved the macula totally or partially in 21 eyes of 13 patients. Bilateral large retinochoroidal colobomata are the typical ophthalmic feature of CHARGE syndrome in patients with confirmed CHD7 mutations; however, even eyes with large colobomata can form maculas. Many children with colobomas (even just an iris coloboma) may be sensitive to bright light (photophobia). Surgery cannot correct ocular colobomas. Near-sightedness or far-sightedness can be helped with glasses. Sunglasses and a hat with a protective bill can help the photophobia.
Cranial nerve abnormalities
Sensorineural (nerve) hearing loss in CHARGE is due to abnormalities in cranial nerve VIII. Cranial CT scan often reveals a hypoplastic cochlea (81%) with absent semicircular canals in most cases. Hearing loss and difficulty with balance are the most common features associated with cochlear hypoplasia and absent semicircular canals. CHARGE syndrome is associated with characteristic external ears that tend to protrude and lack lobes. The hearing loss can range from a mild hearing loss to profound deafness. Hearing loss can be very difficult to measure in young children. Many children with CHARGE receive cochlear implants to aid their sensorineural hearing loss. Most also have balance problems (vestibular abnormalities) associated with absent semicircular canals, which is a key finding in making the diagnosis of CHARGE syndrome.
Most children with CHARGE have swallowing problems (cranial nerves IX/X). These swallowing problems include the inability to coordinate suck and swallow, leading to gagging and aspiration of food into the lungs (which can cause pneumonia). Many children require feeding via a gastrostomy tube (tube directly into the stomach through the abdominal wall) until they are able to swallow safely.
Many children with CHARGE have asymmetric facial palsy resulting in paralysis of one side of the face (cranial nerve VII). This results in a lack of facial expression, which is important when a child is working with teachers or therapists.
Most children with CHARGE have an absent or reduced sense of smell (cranial nerve I), which complicates learning to eat normally. Most patients with CHARGE syndrome have absent or abnormal olfactory bulbs in MRI, leading to a diminished sense of smell. Smell-testing can predict the presence of hypogonadotropic hypogonadism. The combination of defective olfaction (anosmia or hyposmia) with hypogonadotropic hypogonadism (termed Kallman syndrome) results in small external genitalia. This is very common in CHARGE syndrome and warrants consultation with an endocrinologist.
Choanal atresia
Choanae are the passages from the back of the nose to the throat that make it possible to breathe through the nose. In about half of all children with CHARGE, these passages may be blocked (atresia) or narrowed (stenosis). Among 12 patients with bilateral choanal atresia, 10 had related malformations, 3 of which had CHARGE syndrome. Surgery can often correct these defects. Patients with unilateral atresia can usually be corrected with 1 surgical procedure at a later age (median 6 years, range 6 months to 18 years), while patients with the bilateral form need a median of 2.85 interventions at an early age (median 25 days, range 6 days-6 years). If both sides are affected, immediate measures must be taken to allow the newborn to breathe properly and prevent respiratory failure.
CHARGE ear
Most children with CHARGE have unusual external ears. The “typical CHARGE ear” is short and wide with little or no earlobe. The helix (outer fold) may end abruptly in mid-ear. The center of the ear (concha) is often very triangular in shape. The ears are often floppy and may stick out due to weak cartilage. The two ears often look different from each other. There are also typical findings in the middle ear in CHARGE, including malformed bones of the middle ear (93%) and incomplete cochlea (Mondini defect), which is diagnosed with an MRI scan. In many cases, the external ear can be unique enough to suspect the diagnosis of CHARGE before examining other features, and a temporal bone CT scan to look for absent semicircular canals and evaluate the choanae for atresia or stenosis should prompt mutation analysis of CHD7 to confirm the diagnosis.
Minor Diagnostic Criteria:
Features less specific to CHARGE syndrome and/or not consistent enough to be considered major: heart defects, genital abnormalities, kidney abnormalities, cleft lip or palate, TE fistula or esophageal atresia, poor growth, hypotonia, typical CHARGE face, and typical CHARGE hand.
Heart defects
About 75-80% of children with CHARGE syndrome have congenital heart defects. Although all types of heart defects have been seen in children with CHARGE syndrome, the most common are tetralogy of Fallot (33%), VSD (ventricular septal defect), AV (atriventricular) canal defect, and aortic arch anomalies. The heart defects can range from an innocent murmur to life-threatening heart defects involving the outflow tracts of the heart. Most require medication and/or surgery. Severe heart defects are a major cause of death in children with CHARGE. The heart defects in CHARGE are similar to those seen in Deletion 22q11.2 syndrome.
Genital abnormalities
Most boys with CHARGE syndrome have a small penis, often with undescended testes (cryptorchidism). The urethral opening may not be at the end of the penis (hypospadias). Girls may have small labia. Among 46 boys with hypogonadotropic hypogonadism, 14 (30.4%) had Kallmann syndrome, 4 (8.7%) had CHARGE syndrome and 28 (60.9%) had hypogonadotropic hypogonadism without an olfaction deficit or olfactory bulb hypoplasia. Most children with CHARGE require hormone therapy to achieve puberty due to hypogonadotropic hypogonadism, and a pediatric endocrinologist should evaluate their pituitary gonadal axis.
Kidney abnormalities
About 40% of children with CHARGE syndrome have kidney abnormalities. These can include hydronephrosis (extra fluid in the kidneys) or reflux (backflow into the kidneys); horseshoe kidney; small or absent kidney; or multicystic dysplastic kidneys. All children with CHARGE should have a kidney ultrasound.
Cleft lip and/or cleft palate
About 25% of children with CHARGE have a cleft lip or cleft palate. The cleft lip can be one-sided or two-sided and may or not include the palate. A positive family history of any individual with an apparently isolated unilateral major CHARGE anomaly, or someone with a few of the minor features, should precipitate testing the affected child and both parents for CHD7. Some have cleft palate without cleft lip. Submucous cleft palate (just the muscle, not the bone in the roof of the mouth) may be hard to diagnose.
Tracheoesophageal Fistula/Esophageal atresia
About 15-20% of children with CHARGE are born with an esophageal atresia (EA), where the food pipe is not connected to the stomach or with tracheoesophageal fistula (TEF), where there is a connection between the windpipe (trachea) and the food pipe (esophagus). Both of these conditions require surgery. In addition, the trachea may be weak or floppy due to weak cartilage. This can complicate surgery to treat these conditions.
Poor growth
Although birth weight is usually normal, many children with CHARGE are small after birth. Sometimes this is due to nutrition problems, heart problems or multiple illnesses. Some children with CHARGE have growth hormone insufficiency, which can be evaluated with a growth hormone stimulation test.
Hypotonia of the trunk
Most children with CHARGE syndrome have upper body hypotonia (weakness). They are weak, especially in the trunk, and may have sloping shoulders. This weakness, especially combined with balance problems and/or vision problems, will delay walking. The average age of walking is about 3 or 4 years in children with CHARGE syndrome, and this results from the combination of hypotonia and diminished balance due to their underdeveloped semicircular canals.
Typical CHARGE face
Children with CHARGE syndrome often look similar to one another. The typical child has a square face, with broad prominent forehead, arched eyebrows, large eyes, occasional droopy eyelids, a prominent nasal bridge with square root, small nostrils, prominent nasal columella, flat midface, small mouth, occasional small chin, which improves with age. The face is often very asymmetric.
Typical CHARGE hand
Many children with CHARGE have a small thumb, broad palm with “hockey-stick” palmar crease, and short fingers.
Other Common Findings
These features may be important for management, but not very helpful in making the diagnosis. Brain abnormalities, including small head (microcephaly), enlarged cerebral ventricles or other abnormalities identified by brain imaging such as MRI or CT scan are occasionally seen. Apnea and seizures are rarely seen in children with CHARGE. Weak cartilage (as seen in the ears) can also affect the trachea (windpipe) making it weak. Sometimes the baby has a very weak cry due to laryngomalacia (weak vocal cords). A few children with CHARGE syndrome have missing or extra nipples. Some have a relatively wide neck, with occasional cervical vertebral abnormalities. Rarely, children with CHARGE have an umbilical hernia, omphalocele or limb abnormalities, such as abnormal thumbs or extra fingers.
A few children with CHARGE have DiGeorge sequence, consisting of a complex heart defect, immune deficiency, and abnormalities of the thyroid and parathyroid glands. Because these features are also seen in VCF, children with possible CHARGE and no mutation in CHD7 should have array comparative genomic hybridization testing done. Some children with CHARGE appear to have a poor immune response even, and the presence of hypocalcemia should prompt an immunologic evaluation. Most children with CHARGE syndrome and immunodeficiency have T-cell deficiency.
Many children with CHARGE develop scoliosis, even as relatively young children. This may be due in part to their weak upper body, but a skeletal survey should be carried out to exclude skeletal anomalies, particularly those of the cervical spine.
Developmental Features as Signs of CHARGE Syndrome
Most young children with CHARGE are developmentally delayed. Often, this is primarily due to sensory deficits (vision and/or hearing loss) and frequent illnesses and hospitalizations as infants and young children. Although developmentally delayed, many children with CHARGE will show significant catch up in later childhood, manifesting normal intellectual abilities, and ending up as independent adults. It is not possible to predict eventual development for any one child, and early intervention with a deaf-blind specialist is essential to remediate their sensory deficits and prevent behavioral problems. Regardless of the extent of inner ear anomalies and intellectual faculties, cochlear implantation with careful treatment planning can be a highly effective option for hearing rehabilitation in children with sensorineural hearing loss and CHARGE syndrome.
As children with CHARGE grow older, challenging behaviors can emerge. Some children display autistic-like behaviors such as hand waving or head banging. Often, these are attempts at communication by a child who has not yet developed language or other communication skills due to hearing and vision problems. These behaviors occur less often when a communication system (speech, signs, or a combination of both) is established. Older individuals with CHARGE may show signs of obsessive-compulsive disorder. Many children with CHARGE begin communication using sign language or some form of gestures and communication boards. Those with cochlear implants or hearing aids that bring hearing into the normal range will usually switch over to oral speech at some point. Learning signs first does not keep children from speaking later.
The cause of CHARGE is usually a new mutation (change) in the CHD7 gene, or rarely, genomic alterations in the region of chromosome 8 (8q12.2) where the CHD7 gene is located. CHD7 function is required for the development of the retina and cranial motor neurons. Over 90 % of typical CHARGE patients have mutations in the CHD7 gene, while 65 %-70 % of all typical and suspected cases combined are demonstrate CHD7 mutations. The mutations are equally distributed along the coding region of CHD7 and most are nonsense or frameshift mutations. Pathogenic missense mutations are mainly present in the middle of the CHD7 gene, whereas benign variants are mainly clustered in the 5′ and 3′ regions. CHD7 missense mutations are, in general, associated with a milder phenotype than truncating mutations. Intragenic or promotor sequence complex genomic rearrangements can be missed by current sequencing without duplication/deletion or MLPA analysis. Most cases of CHARGE syndrome occur sporadically, often in association with older paternal age. In 12 out of 13 families, the mutation affected the paternal allele (92.3%), with a mean paternal age at birth of 32.92 years. In rare cases, CHARGE has run in families, either two affected children or a parent and child affected, either because of parental mosaicism for a CHD7 mutation, which results in a parent being mildly affected or not affected at all.
There are no known teratogens (exposures during pregnancy) that have been associated with CHARGE syndrome. Retinoic acid or isotretonin (a medicine taken for severe acne) can cause similar malformations when taken during the first trimester of pregnancy.
CHARGE syndrome is a rare disorder, affecting 0.1-1.2/10,000 live births. It affects males and females in equal numbers and has been seen in all races and on every continent. There are far more cases of CHARGE than those described in the medical literature. Many cases are misdiagnosed or undiagnosed, especially in children with fewer problems. Although many features of CHARGE are apparent at birth, some features will not become apparent for weeks, months, or perhaps years later. The recurrence risk of CHARGE for parents with one affected child is low, around 2-3 percent. The recurrence risk for an adult with CHARGE to have an affected child may be as high as 50 percent.
A medical geneticist or other specialist familiar with CHARGE syndrome should do a complete physical exam and order tests to look for the major and minor features of CHARGE listed above. Other similar disorders such as 22q11.2 deletion syndrome, Mowat-Wilson syndrome, Kabuki syndrome, Kallman syndrome, and EFTUD2 haploinsufficiency (multiple congenital anomalies/intellectual disability syndrome characterized by the association of mandibulofacial dysostosis with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, esophageal atresia, congenital heart defects, and radial ray defects) need to be ruled out as well. Among 28 Mowat-Wilson syndrome patients with molecular confirmation of a ZEB2 mutation, 2 patients had clinical features of CHARGE syndrome (choanal atresia, coloboma, cardiac defects, genitourinary anomaly, and severe intellectual disability). Cases of Kabuki syndrome have presented with atypical features, consisting of bilateral microphthalmia, coloboma, anal atresia and panhypopituitarism, showing considerable phenotypic overlap with CHARGE syndrome. Mutations in the KMT2D gene, which encodes a H3K4 histone methyltransferase, are the major cause of Kabuki syndrome. Another patient, who was initially diagnosed with CHARGE syndrome (choanal hypoplasia, heart defect, anal atresia, vision problems and conductive hearing impairment), but sequencing and MLPA analysis of all coding exons of CHD7 revealed no pathogenic mutation, while sequence analysis of the KMT2D gene identified the heterozygous de novo nonsense mutation confirming a diagnosis of Kabuki syndrome. CHD7 and KMT2D function in the same chromatin modification machinery, providing a probable explanation for the phenotypic overlap between Kabuki and CHARGE syndromes.
Molecular Genetic testing is available for mutations in the CHD7 gene associated with the condition, and if this is negative, a SNP chromosomal microarray should be done, because in a few cases, there has been a submicroscopic genomic alteration of chromosome 8q12.2. If both these tests are negative, whole genome exome sequencing should be done, since other genetic disorders share some clinical features with CHARGE syndrome, and de novo mutations in ZEB2, KMT2D and EFTUD2 have been detected in children previously diagnosed as having CHARGE syndrome.
Treatment
Although these children have many problems, they can survive and become healthy, happy citizens. Many of the structural abnormalities (choanal atresia, heart defects, cleft lip, etc.) can be surgically corrected. Others, such as feeding problems and speech and language deficits may require years of therapy and other interventions. Infants diagnosed with CHARGE syndrome will need to be followed by a number of medical and developmental specialists, depending on their individual needs. Some of the medical specialists who often follow children with CHARGE syndrome include genetics, cardiology, audiology and ENT, ophthalmology, urology, and endocrinology.
More than 50% of children with CHARGE syndrome experience sleep disturbances, and obstructive sleep apnea appears to be prevalent in children with CHARGE syndrome. All conventional treatments for obstructive sleep apnea reduce symptoms. Botulinum toxin A (Botox) has been used to reduce excess salivary secretions in a ventilator-dependant infant with CHARGE syndrome who would have required a tracheotomy. Venous anomalies of the temporal bone were present in 10 of 18 (56%) patients with CHARGE syndrome. The pattern of venous abnormality suggests that there is a failure of the sigmoid sinus/jugular bulb to fully develop, resulting in persistence of emissary veins. Recognition of these abnormal venous structures during otologic surgery is critical to avoiding potentially catastrophic bleeding.
Analysis of CHD7 in 12 patients with semicircular canal dysplasia and variable clinical features of CHARGE syndrome revealed 6 CHD7 mutations, 5 of which occurred in patients who fulfilled diagnostic criteria for typical CHARGE syndrome, and three of which were previously undiagnosed. Among 7 children with CHARGE and congenital profound hearing loss, all had hypoplastic or absent auditory nerves, affecting their outcomes with cochlear implants. Of 30 ears evaluated with CT, 28 (93%) had major abnormalities of the inner ear including hypoplasia or aplasia of the semicircular canals and abnormalities of the cochlea and vestibule. CT imaging revealed cochlear aperture narrowing or occlusion in 16 ears, one of which had normal hearing. Among 8 patients with profound sensorineural hearing loss who underwent magnetic resonance imaging 13 of 14 ears were noted to have absent or deficient cochlear nerves. Because of the implications of cochlear nerve deficiency in therapeutic decision-making regarding cochlear implantation, MRI evaluation of the eighth nerve should be considered in CHARGE patients with profound sensorineural hearing loss. In patients with markedly abnormal middle ear anatomy, CT image guided surgery was helpful. These children were offered a bilingual early intervention approach, using sign language and verbal language, to ensure best language outcomes. Children with CHARGE syndrome and progressive profound hearing loss did well with cochlear implants and continued to use verbal language. Numerous patients have undergone cochlear implantation, with most patients demonstrating favorable outcomes. Larger diameter of the cochleovestibular nerve on imaging and absence of severe intellectual disability were factors related to better outcomes after cochlear implantation, rather than the type of CHD7 mutations. Auditory brainstem implantation may be a viable option in patients with CHARGE syndrome who have failed to benefit from cochlear implantation.
A novel mouse model of CHD7 dysfunction, termed Looper, harbors a nonsense mutation within the Chd7 gene. Looper mice exhibit growth retardation, facial asymmetry, vestibular defects, eye anomalies, hyperactivity, ossicle malformation, hearing loss and vestibular dysfunction. Chd7 also regulates genes involved in neural crest cell guidance, demonstrating a significant role in the pathogenesis of CHARGE syndrome. Mice with heterozygous Chd7 mutations exhibit semicircular canal dysgenesis and abnormal inner ear neurogenesis. Chd7 is highly expressed in mature inner and outer hair cells, spiral ganglion neurons, vestibular sensory epithelia and middle ear ossicles.
Among 202 patients with CHD7 mutations and CHARGE syndrome, a wide range of heart defects in 74% this cohort of patients. Conotruncal defects and atrioventricular septal defects were over-represented in patients with CHD7 mutations compared with patients with non-syndromic heart defects. However, CHD7 mutations are not a major cause of atrioventricular septal and conotruncal heart defects. Work with mouse models demonstrate that CHD7 plays an important role in the cardiogenic mesoderm during cardiovascular development.
Among 25 patients with CHARGE syndrome, 76% of subjects had some type of endocrine disorder: short stature (72%), hypogonadotropic hypogonadism (60%), hypothyroidism (16%), and combined hypopituitarism (8%). A mutation in CHD7 was found in 80% of these subjects. Analysis of growth in 19 children with CHARGE syndrome, revealed a significant loss of median body length, at around 4 weeks of age from -0.5 to -2.3 standard deviations (SDS). At 1 year, the median length was -2.6 SDS and it remained low until 5 years of age when the lowest value was found to be -2.8 SDS. There was a significant increase in median body mass index (BMI) from -1.15 SDS at 1 year to -0.15 SDS at 5 years. Children with CHARGE syndrome displayed almost normal length and weight data at birth, with just one of the 19 infants having below average length for gestational age. Among 16 children with CHARGE syndrome, short stature, and decreased levels of serum growth hormone (GH), conventional doses of GH had a positive effect on short-term growth velocity without any safety issues or adverse effect on BMI. At the start of GH therapy, height was -3.6 SDS and after 2.7 years of GH therapy, height increased to -2.2 SDS in these patients with CHARGE syndrome. Hormonal management also helps treat symptoms of hypogonadism. Among 209 Kallman syndrome patients who had not been diagnosed with CHARGE syndrome, mutations in CHD7 were found in 24 patients (11.5%). Among 783 patients with isolated gonadotropin-releasing hormone deficiency lacking full CHARGE features, CHD7 variants were found in 5.2% of this cohort (73% missense and 27% splice variants), of which 75% were deleterious. Chd7 mutant mouse embryos have CHD7 dosage-dependent reductions in expression levels of Fgfr1, Bmp4 and Otx2 in the olfactory placode suggesting that that CHD7 plays a critical role in the development and maintenance of gonadotropin-releasing hormone neurons for regulating puberty and reproduction.
Others involved in the treatment of children with CHARGE include deaf/blind specialists, occupational therapy, physical therapy and speech therapy. Appropriate therapies and educational interventions must take into account any hearing and vision loss, which is present. The intelligence of children with CHARGE is often underestimated due to the combined hearing and vision problems. A deaf/blind specialist (not just a vision specialist and a hearing specialist) is critical for any child with someone with both vision loss and some hearing loss.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. A team approach is essential for these complex children.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder (e.g., visual handicaps, heart disease, short stature, etc.)
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INTERNET
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. CHARGE Syndrome; Entry No: 214800. Last Edited August 31, 2016. Available at: http://omim.org/entry/214800 Accessed July 21, 2018.
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