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CHARGE Syndrome

CHARGE syndrome

Definition

CHARGE syndrome, also known as CHARGE association, is a group of major and minor malformations that have been observed to occur together more frequently than expected by chance. The name of the syndrome is an acronym for some of its features, and each letter stands for the following conditions:

  • C—Coloboma and/or cranial nerves
  • H—Heart defects
  • A—Atresia choanae,
  • R—Retarded growth and development
  • G—Genital anomalies
  • E—Ear anomalies

While these features have classically been used for identification of affected individuals, many other malformations and medical problems have been observed to occur with this syndrome.

Description

CHARGE syndrome was first described in 1979 as an association of multiple congenital anomalies, all of which included choanal atresia, meaning the blocking of the choanae, the passages from the back of the nose to the throat which allow breathing through the nose. Soon after, several other papers were published describing similar patients who all had both choanal atresia and coloboma , that is a cleft or failure to close off the eyeball. It was in 1981 that the CHARGE acronym was proposed to describe the features of the condition. Due to the large number of patients described since 1979, many physicians now regard CHARGE association as a recognizable syndrome. However, the cause for the condition remains unclear. It is believed that perhaps a new dominant change in a gene is the cause for many cases. There have been a few familial cases but most cases are sporadic. Crucial development of the choanoa, heart, ear, and other organs occurs 35-45 days after conception and any disruption in development during this time is believed to lead to many of the features of the syndrome.

Infants with CHARGE syndrome generally have difficulty with feeding and most of those affected have mental retardation. About half die during the first year of life from respiratory insufficiency, central nervous system (CNS) malformations, and bilateral choanal atresia.

Genetic profile

Most cases of CHARGE syndrome are sporadic, meaning that they occur in a random or isolated way. However, reports of parent-to-child transmission of the condition indicate an autosomal dominant type of inheritance . There have also been cases in which a parent with one or two features of CHARGE had a child with enough features to fit the diagnosis. These families may demonstrate variable expressivity of a dominant gene. In addition, there have been a few cases of siblings affected, suggesting the possible presence of a mixture of cell types (germ line mosaicism) in a parent for a dominant mutation. Therefore, the recurrence risk for healthy parents of an affected child would be low, but not negligible.

Twin studies are often used to determine if the occurrence of a condition has a strong genetic component. One such study compared a pair of monozygotic twins, meaning identical twins resulting from a single zygote (fertilized egg that leads to the birth of two individuals), who were both affected with CHARGE syndrome and a pair of dizygotic twins, meaning twins that result from fertilization of two different eggs, of whom only one had the syndrome. Since monozygotic twins are roughly 100% genetically identical, this supports the idea that there is a strong genetic factor involved in CHARGE syndrome. Other interesting observations include slightly increased paternal age in sporadic cases. The mean paternal age in one study was 34 years as opposed to 30 years in a control group. Increased paternal age has been known to be associated with the increased occurrence of new dominant mutations in offspring.

Several patients with various chromosome defects have been diagnosed with CHARGE syndrome, again pointing to genetic factors as a cause. These cases of chromosomal abnormalities point to particular genes that should be further studied. In addition, some patients with CHARGE syndrome also have features of another condition called Di George sequence, which involves an immune deficiency, characteristic heart abnormalities and distinct craniofacial features. Many patients with Di George sequence have a missing chromosome 22q11. Therefore, newly diagnosed cases of CHARGE syndrome should have chromosome studies as well as molecular testing.

Demographics

The incidence of CHARGE syndrome is approximately one in 10,000. However, this is probably an underestimate of the true number of people affected. The incidence is likely to increase as the diagnostic features of the condition are refined and milder cases are diagnosed. CHARGE syndrome affects males more seriously than females, resulting in a higher number of females who survive. The cause of this is unclear. The syndrome has not been reported more often in any particular race or geographic area.

Signs and symptoms

CHARGE syndrome is believed to be caused by a disruption of fetal growth during the first three months of pregnancy and affecting many different organ systems undergoing development at that time.

Choanal atresia

Choanal atresia, the narrowing passages from the back of the nose to the throat, may occur on one or both sides (bilateral) of the nose. This condition usually leads to breathing difficulties shortly after birth. Bilateral choanal atresia may result in early death and surgery is often required to open up the nasal passages. Choanal atresia is also often accompanied by hearing loss. Since bilateral choanal atresia is rare, CHARGE syndrome should be considered in all babies with this finding. Fifty to sixty percent of children diagnosed with CHARGE syndrome have choanal atresia.

Heart abnormalities

Seventy-five to eighty-five percent of children with CHARGE syndrome have heart abnormalities. Many are minor defects, but many require treatment or surgery. Some of the heart problems seen in CHARGE Syndrome are very serious (e.g., Tetralogy of Fallot) and life threatening. Every child with a diagnosis of CHARGE syndrome should have an echocardiogram, a test that uses sound waves to produce pictures of the heart.

Coloboma and eye abnormalities

A coloboma is a cleft or failure to close off the eyeball properly. This can result in a keyhole shaped pupil or abnormalities in the retina of the eye or its optic nerve. The condition is visible during an ophthalmology exam. Colobomas may or may not cause visual changes. About 80% of children with CHARGE syndrome have colobomas and the effect on vision varies from mild to severe. Other eye abnormalities include microphthalmia (small eye slits) or anophthalmia (no eyes). Consistent eye examinations are recommended for children diagnosed with the syndrome.

Ear abnormalities and deafness

At least 90% of patients with CHARGE syndrome have either external ear anomalies or hearing loss. The most common external ear anomalies include low-set ears, asymmetric ears, or small or absent ear lobes. The degree of hearing loss varies from mild to severe. It is important for all patients to have regular hearing exams over time so that changes in sound perception can be detected. Hearing aids are used as soon as hearing loss is detected. Some patients require corrective surgery of the outer ear, so that a hearing aid can be worn. Children with CHARGE syndrome often develop ear infections and this can affect hearing over time as well.

Cranial nerve defects

Defects related to the formation of the cranial nerves during fetal development are common in patients with CHARGE syndrome. The defects include anosmia (inability to smell), facial palsy, hearing loss, and swallowing difficulty. Facial palsy is the inability to sense or control movement of part of the face. This usually occurs on one side of the face, which, in affected individuals, results in a characteristic asymmetric and expressionless look. Swallowing problems can also occur along with several different defects in the formation of the throat.

Facial features

The facial features of CHARGE syndrome are considered minor diagnostic signs because they are not as obvious as the facial features of other genetic syndromes. However, many patients have facial asymmetry, a small and underdeveloped jaw, a broad forehead, square face, arched eyebrows, and external ear malformations.

Growth and developmental delays

Most babies with CHARGE syndrome have normal length and weight at birth. Difficulty with feeding and the presence of other malformations often leads to weight loss, so that these babies usually weigh less for their age. Teenagers are also often shorter than average due to a delay in the onset of puberty. In a small number of patients, growth delay is due to a lack of growth hormone.

There are serious delays in motor development of children with CHARGE syndrome as well. Many children have low muscle tone and difficulty with balance that leads to delays in walking. Physical therapy is often helpful. Most children with CHARGE syndrome are classified as mentally retarded. However, successful treatment of other features of the condition can improve learning potential. Therefore, assessments made before other medical problems are addressed are often more pessimistic than later exams.

Urogenital abnormalities

Most obvious in males, underdevelopment of the genitals occurs in at least half of the male patients diagnosed with CHARGE syndrome and in some females as well. Abnormalities of genitalia in males include an underdeveloped penis (micropenis or microphallus) and testicles that fail to descend to the scrotum (cryptorchidism). In females, there may be overgrowth or underdevelopment of the labia or clitoris. Information concerning the fertility of patients is not available. About 25% of children have renal abnormalities that may lead to repeated infections. A renal ultrasound is indicated in children with the syndrome.

Central nervous system anomalies

In one series of tested patients, CNS anomalies were noted in 83% of the patients who underwent imaging tests that produce pictures of the brain such as MRI, CT scan, and ultrasound, or after autopsy. The CNS anomalies included diminution of the size of the brain (cerebral atrophy), asymmetry, and midline defects such as partial development (e.g., agenesis of the corpus callosum). In addition, brain stem dysfunction has also been observed after birth, a disorder that can cause respiratory and swallowing problems. These findings were associated with a poor prognosis.

Associated anomalies

Many other features have been reported in patients with CHARGE syndrome. Some of these include a cleft lip and/or palate, dental anomalies, absence of the thymus and parathyroid glands that leads to immunodeficiency (the inability of the body to produce a normal immune response), seizures, abnormally low levels of calcium (hypocalcaemia) or sugar (hypoglycemia) in the body, obstruction of the anal opening (imperforate anus), groin hernias, curvature of the spine (scoliosis ), skeletal anomalies, body temperature regulation problems and umbilical hernias.

Diagnosis

Since there is currently no genetic test available for CHARGE syndrome, the diagnosis is based on clinical features. There is disagreement about the conditions required for diagnosis. Some suggest that one major malformation plus four of the other features suggested by the CHARGE acronym are sufficient. Others suggest that four major characteristics or three major characteristics plus three minor characteristics are sufficient for diagnosis.

The Charge Syndrome Foundation defines a specific set of birth defects and most common features to diagnose CHARGE syndrome. These major features include: choanal atresia, coloboma, cranial nerve abnormalities and conditions, such as swallowing problems (due to cranial nerve IX/X defects), facial palsy (due to cranial nerve VII defects), hearing loss (due to cranial nerve VIII defects), heart defects, and retardation of growth and development.

Other minor features have also been reported that are either less common or less specific to CHARGE syndrome. These include genital abnormalities, cleft lip and/or palate, tracheoesophageal fistula and facial distortions.

Diagnosis of CHARGE syndrome before birth has not yet been reported. The condition may be suspected when a prenatal ultrasound reveals fetal growth restriction, CNS malformations, heart defects, and urinary tract malformations. In one series, 37.5% of patients diagnosed with CHARGE were noted to have an abnormal feature noted on ultrasound.

There are several other conditions that include signs similar to CHARGE syndrome. These include VACTERL association (for vertebral, anal, cardiac, tracheoesophageal, renal and limb abnormalities, velocardiofacial (VCF) syndrome (deletion 22q11 syndrome ), and prenatal retinoic acid exposure (Accutane embryopathy ).

Treatment and management

Treatment for CHARGE syndrome is specific to the features present in each child. Choanal atresia can be treated with dilatations of the choanoa or nasal passages. Heart defects may require surgery. Children with CHARGE syndrome should get ophthalmology and hearing screens every six months. Plastic surgery is sometimes needed for corrections of ear malformations or facial asymmetry. Medications are needed when seizures are present and growth hormone is sometimes taken for growth delay or underdeveloped genitalia.

A developmental evaluation and a plan for special education are required. Patients with CHARGE syndrome who have both hearing and vision difficulty should receive care from childhood educators experienced in dual sensory impairment. Once these children establish a system of mobility and communication, the degree of developmental retardation may improve. Lengthy hospital stays for children with CHARGE syndrome may limit the ability of specialists to work with the child in the early months. Once major hospitalizations are completed, development may improve as the result of regular care by the appropriate child specialists. Other learning problems have been noted and should also be addressed if present. These include attention deficit disorder, autism , and obsessive-compulsive disorder. Parents are often in the position of coordinating the many components of special education for their children. The national and international support groups for CHARGE syndrome are able to provide information and assistance in this area.

Prognosis

It has been noted in several studies that about half of patients diagnosed with CHARGE syndrome die from complications of the condition. One study suggests that 40% of those die after birth. Factors that appear to influence survival include the presence of CNS malformations, bilateral choanal atresia, TE fistula, and male gender. Heart abnormalities and brain stem dysfunctions were not found to be related to poor prognosis. Significant hospitalizations are needed for most children with CHARGE syndrome.

Resources

BOOKS

Jones, Kenneth Lyons. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia: W.B. Saunders Company, 1997.

McKusick, Victor. Mendelian Inheritance in Man: A Catalog of Human Genes and Genetic Disorders. 12th ed. Baltimore: The Johns Hopkins University Press, 1998.

PERIODICALS

Blake, K., et. al. "CHARGE Association: An Update and Review for the Primary Pediatrician." Clinical Pediatrics (1998): 159-173.

Tellier, A. L., et al. "CHARGE Syndrome: Report of 47 Cases and Review." American Journal of Medical Genetics (1998): 402-409.

ORGANIZATIONS

CHARGE Family Support Group. 82 Gwendolen Ave., London, E13 ORD. UK 020-8552-6961. <http://www.widerworld.co.uk/charge>.

CHARGE Syndrome Foundation. 2004 Parkade Blvd., Columbia, MO 65202-3121. (800) 442-7604. <http://www.chargesyndrome.org>.

Sonja Rene Eubanks, MS, CGC

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