Summary:
Very little information has been published about adolescents and older individuals with Coloboma, Heart defects, Atresia choanae, Retarded growth and development, Genital hypoplasia, Ear anomalies and deafness (CHARGE) syndrome. This paper describes the results of a study that identifies the unique issues faced by adolescents and adults with CHARGE. Descriptive information was gathered from parents of patients with CHARGE, and/or the patients themselves, about their developmental, medical, educational, and social history. The resulting body of information provides important insights into the prognosis and special needs of individuals with CHARGE, as well as further research questions. Clin Pediatr. 2005;44:151-159
Introduction
CHARGE syndrome is a congenital disorder that affects multiple organ systems. Hall1 and Hittner et al2 first described the association of malformations in 1979. In 1981 Pagon and colleagues3 coined the acronym CHARGE, representing Coloboma, Heart defects, Atresia choanae, Retarded growth and development, Genital hypoplasia, Ear anomalies and deafness. The etiology of CHARGE has challenged geneticists; however, a mutation in a new member of the chromodomain gene family (CHD7) have been identified in CHARGE individuals and offers a genetic cause for CHARGE syndrome.4 Blake et al5 refined the diagnostic criteria for CHARGE syndrome to include major, minor, and occasional findings (Table 1).
Until now very little information has been published about adolescents and older individuals with CHARGE syndrome.6-8 This is for 2 reasons. First, since CHARGE syndrome is a relatively recent diagnosis, many adolescents and adults with the syndrome were not diagnosed as infants. second, the many complicated medical problems encountered by infants born with CHARGE syndrome meant that, until recently, survival beyond early childhood was uncommon. This is changing with improving medical technology, and many infants with CHARGE syndrome are surviving into their teens and beyond.
The appearance of an older cohort in the CHARGE syndrome population raises many questions, particularly as these patients often present with issues that are not represented in the syndrome criteria. For example, little is known about puberty and the utility of hormone replacement therapy (HRT) in CHARGE syndrome. It has also been difficult to predict the level of independence that adults with CHARGE syndrome achieve. As more patients are diagnosed and survive into their teens, specific medical, psychological, behavioral, and educational concerns arise that should be anticipated and addressed.
Table 1
MEDICAL CHARACTERISTICS OF CHARGE SYNDROME, ESTIMATED POPULATION FREQUENCIES, AND SAMPLE FREQUENCIES (n = 30)
This paper describes the results of a study of the unique issues faced by adolescents and adults with CHARGE syndrome. Descriptive preliminary information was gathered from parents of patients with CHARGE syndrome, and/or the patients themselves, about their developmental, medical, educational, and social history. The resulting body of information provides important insights into the prognosis and special needs of CHARGE syndrome individuals, as well as further research questions.
Methods and Materials
Participants were identified by using address lists of the CHARGE Syndrome Foundation, Inc., and United Kingdom CHARGE family support group. Additional participants were recruited at 2 biannual International CHARGE Syndrome Foundation Conferences (1999 and 2001). Inclusion criteria included the following: (1) having a diagnosis of CHARGE syndrome and (2) being age 13 years or older. One or both parents and/or the individual with CHARGE were asked to take part in a structured interview lasting approximately 45 minutes. (The interview questionnaire can be requested from the corresponding author [KDB]). If consent was forthcoming, the interview was conducted in person or over the phone, by either the primary investigator or a research assistant. The data were entered into a Microsoft Excel spreadsheet and analyzed by use of descriptive statistics.
Results
Thirty participants were identified. Sixteen were female (53%), and 14 were male (47%). Participants ranged in age from 13 to 30 years. The mean age was 17.6 (M = 4.24). Females had a mean age of 17 (M = 3.65), and males had a mean age of 18.4 (M = 4.86). The average age at diagnosis was 5.39 years (M = 6.87), though this information was missing for 2 of the females. Age at diagnosis ranged from 1 week to 21 years.
Interviewees were asked about the presence of specific CHARGErelated abnormalities. The following were reported in order of decreasing frequency: developmental delay, ear abnormalities, coloboma, cranial nerve dysfunction, cardiovascular malformations, genital hypoplasia, growth deficiency, choanal atresia, orofacial cleft, renal anomalies, tracheoesophageal fistula, spinal anomalies, abdominal defects, hand anomalies, and thymic/parathyroid hypoplasia. All frequencies for the sample were equal to or above expected population frequencies reported by Blake et al5 (Table 1). Spinal anomalies, orofacial clefts, and hand anomalies were reported more frequently in this sample than by Blake et ai.5 In addition, as is reportedly typical in this population, walking was delayed for most participants. The mean age at walking (n = 30) was 4.1 years (SD = 3.3).
Participants reported the following specialties as being frequently involved in their care: Ophthalmology, ENT, Endocrinology, Cardiology, Psychiatry, Orthopedics, Neurology, with Orthodontics, Chiropractics, Urology, and Nephrology, less frequent (Table 2).
Information on the development of secondary sex characteristics was gathered for both males and females. Males (n = 14) showed late development of puberty, both with and without HRT. Only 2 males developed secondary sex characteristics when not receiving HRT. Three male individuals had not yet shown signs of pubertal development at the average age of 13.3 years. The average age of pubertal development for males receiving HRT was 15.1 years (n = 8). One individual who had received HRT had not yet reached pubertal milestones at the age of 17. Females (n = 16) showed somewhat late development of puberty but were not as dependent on the use of HRT as males were. The average age of pubertal development for girls not receiving HRT was 13.3 years (n = 8), whereas the average age of pubertal development for girls receiving HRT was 14.3 (n = 3). Five girls who did not receive HRT had not yet reached pubertal milestones at the average age of 13.8. Data on stature were analyzed for the 12 participants who were 19 years or older. Males (n = 5) ranged from 155 to 182 cm (mean = 167.5), and females (n = 6) [missing data from 1 participant] ranged from 50 to 170 cm (mean = 161 cm).
Table 2
REPORTED FOLLOW-UP WITH MEDICAL SPECIALISTS (n = 30)
Figure 1. A 14-year-old male with CHARGE syndrome. Facial features show the flattened cup/lop ear shape. Left-sided facial palsy. Broad forehead and tip of nose. Rounded shoulders, short neck.
Numerous new medical issues were identified by participants. These included scoliosis, sleep apnea, abdominal colic (described as pain in the center of the abdomen that was gripping and coming and going intermittently), retinal detachment, cataracts, migraines, seizures/epilepsy, urinary tract infections, and hypoglycemia (Table 3).
Psychiatric and behavioral diagnoses were also common, as outlined in Tables 4 and 5. Twenty-two participants (73%) reported having sought help from a psychologist.’and 18 of 29 (62%) took prescription medications for specific behavioral problems. These medications included stimulants, antidepressants, sympatholytics, and mood stabilizers. One participant did not provide information about psychotropic medications.
Several questions were asked regarding daily independent living skills. These included questions ranging from personal care (dressing, washing, toileting self) to independent mobility in the community (getting to/from work or school independently) to home care and finances (cleaning, cooking, shopping, finances). Ten of the 30 study participants (33%) had not yet reached a level of independence in any of the areas assessed. These 10 participants ranged in age from 13 to 18 years. Results are summarized in Table 6. Almost two thirds of participants had achieved near or full independence in dressing and toileting. The mean age for toilet training (n = 24) was 5.5 years (SD = 3.1). Ten participants were not yet trained. Of these 10, 2 had persistent nighttime wetting only. Sixty-five percent had achieved near or full independence in washing themselves. Higher order daily living skills showed a different result. Forty-five percent had achieved near or full independence in getting to and from work or school. Thirty percent achieved this in cleaning, and 20% achieved it in shopping. Near or full independence in cooking was not achieved by any of the participants. One participant had achieved full independence in taking care of finances.
Table 3
NEW MEDICAL ISSUES (n = 30)
Table 4
MENTAL HEALTH DIAGNOSES RECEIVED (n = 30)
Table 5
REPORTED BEHAVIORAL CONCERNS (n = 30)
Table 6
DEGREE OF INDEPENDENCE (n = 30)
Discuss\ion
Age at Diagnosis
Participants in this study were diagnosed, on average, at over 5 years of age. This is late, considering that CHARGE syndrome is a congenital condition with a number of characteristic features. The delay in diagnosis is likely due to a lack of awareness of CHARGE syndrome among both health care professionals and the population in general. A population study performed by the Canadian Paediatric Surveillance Program suggests that this is changing, as there has been a trend toward earlier diagnosis in recent years.9
Early diagnosis is important in caring for patients with CHARGE, for it enables families and health care professionals to anticipate and address health care and developmental issues more effectively. Early information enables caregivers to prepare for and perhaps even prevent some medical problems. For example, if CHARGE syndrome is suspected in infancy, the infants can be expected to have some hearing and/or vision problems before they would otherwise be clinically detected. Early ascertainment and correction of hearing and vision problems can have a significant impact on developmental prognosis. Careful coordination of medical and early intervention services is clearly indicated to support the growth and development of these individuals.10
Frequencies of CHARGE Syndrome Anomalies
The frequencies of CHARGE syndrome anomalies reported by participants were equal to or above expected population frequencies reported by Blake et aP (Table 1). Spinal anomalies showed the largest increase in comparison. This follows logic, as many spinal anomalies will not manifest until children are older. Additionally, the present sample of older children and adults is likely to have more identified and more accurate diagnoses for many anomalies than the more age-diverse sample described by Blake et al5 because of the luxury of time.
Orofacial clefts were found 3 times as often in this study group than in previous reports. One hypothesis is that this could be a survival phenomenon. Those who have cleft palate may have survived the neonatal period because the clefting acted as an airway. It has been postulated that in the criteria for CHARGE syndrome the cleft palate may be a substitute for bilateral postnasal choanal atresia (personal communication).
Number of Professionals
Participants in this study engaged a great number of professionals in their care. This is similar to the findings of Hartshorne11 and Blake and Brown12 in the early 1990s. Parents of children with CHARGE syndrome in the study by Hartshorne contacted an average of 17 professional types on a regular basis in caring for their children. Families of individuals with CHARGE syndrome become responsible for keeping track of all of the information given them. Because of this, primary care physicians should attempt to support these efforts by taking the following steps: ( 1 ) provide some level of case coordination for these individuals and their families, (2) engage in case collaboration with attending specialists, (3) facilitate the scheduling of multiple appointments together in order to ease the logistical difficulties many families face, and (4) enhance parents’ understanding of issues by interpreting results and (sometimes conflicting) recommendations made by specialists in order to provide the best medical management for the whole individual.13
Puberty
There appears to be a range in pubertal development and a pattern unique to each gender. Males demonstrated significant delays in puberty, even with HRT. Females did not seem to depend on HRT, but puberty was still somewhat delayed. Hypogonadism has been postulated in CHARGE syndrome.14 The current data show a difference between the male and female participants. It is likely that end-organ unresponsiveness also plays a role in the lack of secondary sexual characteristics in the male. Pubertal delay and the problems that ensue, i.e., osteoporosis, are often overlooked in the management of CHARGE syndrome.? Adolescents with CHARGE syndrome should be followed up closely by endocrine specialists in order to determine problems with growth and puberty, as well as risks for other conditions such as osteoporosis and hypoglycemia. The attainment of normal adult height is supported by the literature.7,15 It is also important to monitor for obesity in later adult life, for this has been shown to be prevalent in those individuals who have reached midlife7 (personal observations by Dr. Blake).
New Issues Identified
This study identified a number of issues that are either being newly recognized as part of the spectrum of CHARGE syndrome characteristics or surfacing as unique to CHARGE in adolescence and adulthood. Anticipating these issues is of great importance, so that appropriate screening and follow-up care can be arranged. The following examples illustrate this point.
Scoliosis was present in 19 of the 30 study participants (63%). Scoliosis typically progresses during periods of accelerated growth. Therefore, children with CHARGE should be monitored closely by orthopedics and physical therapists during these times.
Thirteen (43%) of the study participants experienced sleep apnea. Because children with CHARGE often have tracheal anomalies and low muscle tone, a sleep study/screening and followup with an ENT specialist may be warranted. If others sleep disturbances are present, physicians should provide families with information about sleep hygiene before attempting pharmacologie intervention.
Abdominal colic, defined as “pain in the center of the abdomen, which is gripping and comes and goes intermittently,” was reported by 40% of the individuals surveyed. Individuals with CHARGE syndrome have significant problems with oral feeding, often needing gastrostomy or jejenostomy feeding.12,16 Gastroesophageal (GER) reflux is common and often requires reflux medicine and/or surgery. Ruling out GER is important; however, older individuals with CHARGE may present with gallstones (personal communication from 3 families and a recent case history7).
Parents of children with CHARGE syndrome have reported relief of pain by abdominal massage around the colon location, venting gastrostomy tubes, and avoiding foods likely to cause extra gas.16
One third of participants reported retinal detachment or cataracts. Retinal detachment is more common in individuals with chorioretinal (posterior) colobomata, and can be exacerbated by trauma from head banging or eye poking, behaviors observed frequently in individuals with CHARGE syndrome. Consequently, regular and ongoing ophthalmologic follow-up care is recommended in order to provide treatment at the earliest stages.17
Migraine headaches were reported by more than one fourth of participants. Additionally, 17% reported seizures. Other neurologic problems may be present for those displaying behavioral difficulties. Neurologic assessment, including an EEG, is recommended for individuals presenting with a recent onset of behavior difficulties. In addition, individuals with CHARGE syndrome and their families should be provided with education on seizure management.
Urinary tract infections had been experienced by 17% of participants. For individuals with CHARGE who are experiencing difficulty with communicating, identifying the source of an infection may be difficult. Consequently, it is important to keep in mind that a urinary tract infection may be a viable cause of pain.
Behavior
Behavioral concerns and psychiatric diagnoses were common in participants. Almost one fourth of participants had seen a psychologist. Sixty-two percent took medication for problems with behavior or mood. The most common problems treated were socializing problems, obsessivecompulsive disorder, anxiety disorder, tics/ Tourette syndrome, and autism/pervasive developmental delay. Hartshorne and Cypher18 also found obsessivecompulsive disorder, Tourette syndrome, and autism/pervasive developmental delay, along with attention deficit hyperactivity disorder, to be the most common diagnoses reported by parents of children with CHARGE syndrome in their sample. Reported behavioral concerns for the current sample included aggressiveness/outbursts, self-abuse, sleep problems, and tactile defensiveness. Note that many of these behaviors may be a result of neurologic difficulties.19,20 In addition, sensory impairments, balance and equilibrium difficulties, unrecognized pain, and communication barriers can lead an individual to engage in behaviors such as self-abuse and abuse of others. Further, common, regular life demands placed on an individual with a condition as complex as CHARGE syndrome can result in the individual’s engaging in behaviors aimed at reducing anxiety (repetitive motion, compulsions, social withdrawal). Consider the following example:
A 14-year-old young man (Figure 1) with CHARGE syndrome is lying on the floor of his home, curled in a fetal position. He is wringing his hands and blowing “raspberries” into them, repeatedly, at the rate of 1 time per second. He appears to be very tense and somewhat distressed. He has engaged in this behavior on and off for 2 hours. Attempts to stop the behavior verbally have no effect. Attempts to physically redirect the individual result in short cessations of the behavior. When the adult is no longer in view, the behavior continues.
A psychologist or psychiatrist unfamiliar with CHARGE syndrome may observe this individual and conclude that this young man meets the criteria for any of the following diagnoses: obsessive- compulsive disorder, tic disorder, anxiety disorder, autism, or others.
A psychologist or psychiatrist familiar with CHARGE syndrome will conduct a thorough Functional Behavior Assessment (FBA, now required of educational systems in certain circumstances by federal law in the United States) to determine any existing causes or functions of the behavior. Interventions are then based on these causes or fun\ctions. Upon carefully constructed interview and consultation with this young man’s family and school personnel, the psychologist found that (1) the youth is deaf; (2) he is legally blind; (3) he is not, at the time of the behavior, wearing his glasses or cochlear implant speech processor; (4) the youth is currently being treated for otitis media; (5) he is currently taking a broad-spectrum antibiotic, which frequently causes abdominal cramping; (6) he has some skin breakdown around his gastrostomy area; and (7) the youth is bored, with no one and nothing to engage him at the time of the observation.
After careful consideration, the professional will assist the family and caregivers to plan interventions that will (1) reduce the child’s pain, (2) reduce the child’s anxiety (this is done chiefly by giving the child a highly predictable environment), and (3) reduce the child’s boredom by stimulating his available senses.
After a thorough FBA is carried out, remaining behavioral symptomatology should be assessed. If no function or cause can be determined for the behavior, the professional, the individual, and the family should then determine whether the remaining symptoms warrant an exploration of pharmacologie interventions, taking the individual’s full medical history into account.
Independence
Participants in this sample had more independence in self-care skills than they did in higher order, complex tasks of daily living. One interpretation could be that the participants simply lack the ability to learn these skills. However, it could also be argued that these participants have lacked exposure to learning situations designed to teach these higher order skills, it is well known that individuals with both vision and hearing impairments have great difficulty learning things incidentally. Tasks must be broken down into steps and taught in controlled and organized ways in order for learning to take place. For those individuals still living at home (at least 80% of this sample), it is likely that parents and caregivers, lacking the time, energy, and expertise to teach these skills to their dependent youth, take primary responsibility for household chores such as shopping, cleaning, cooking, and managing finances. In contrast, a youth’s independence in self-care (i.e., toileting, dressing, washing) is important to caregivers, as a person’s independence at these tasks eases the burden of care for the caregiver. Thus, these self-care skills are more likely to be taught within the home setting. In-home training, in the form of occupational or educational therapy, can help to bridge this gap for these individuals. Skills should be task analyzed (broken down into simple steps) and taught within natural environments to facilitate learning and generalization.
Limitations
Caution should be observed in interpreting the results of this study, because of its limitations. The survey used was not pilot tested before use. Pilot testing may have ensured better understanding and reliability, which are necessary elements in a new instrument. Additionally, questions posed within this survey were based on parent report alone. Ideally, medical, educational, and psychological records would have been used to increase the validity of information. However, this is difficult to achieve in practice.
The participant pool for this study was obtained through the CHARGE Syndrome Foundation and other parent support groups. This is not likely to be a completely representative sample of the overall population of individuals with CHARGE syndrome. There are many individuals with CHARGE who have very few disabilities or difficulties, and these individuals may not maintain membership or request support from these groups. Therefore, this sample is not likely to fully represent that segment of the population, e.g., those who are more able and less medically involved.
Questions about independent living skills covered lower level skills and high-level skills but did not cover the middle range of independent living skills. Therefore, it was not possible to deHne the entire scope of ability in this sample.
Directions for Future Research
This line of research should be continued with this sample and others to confirm these findings and to determine if there are additional common adolescent and adult issues in CHARGE syndrome. As the population ages, these factors will become increasingly important for early diagnosis and treatment of individuals with CHARGE syndrome. In addition, the effectiveness of various medical, educational, and pharmacologie interventions on health, development, and behavior in CHARGE syndrome should be evaluated.
Conclusions
There is much still to know about individuals with CHARGE syndrome. This paper describes an attempt to identify commonly occurring issues for adolescents and adults. Several new medical issues were identified including scoliosis, delayed puberty, seizures, and ophthalmologic complications. The population of individuals with CHARGE syndrome is highly variable across all areas of development. We cannot describe a typical person with CHARGE syndrome. Therefore, those encountering a child with CHARGE syndrome are urged to gather as much information as possible about the range of medical, educational, and psychological outcomes possible, and to educate fami lies and caregivers about this range before their children move into adolescence. The CHARGE Syndrome Foundation publishes a manual on CHARGE syndrome for fami lies and professionals.8 This is a valuable comprehensive resource written by experts in the field of CHARGE syndrome. It contains medical and developmental information written for physicians, service providers, and families, to aid in management and understanding of the multiple medical and educational facets of CHARGE syndrome.
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11. Hartshorne TS. Dealing with professionals: experience and some suggestions. First International CiHARGK Syndrome Conference for Families and Professionals, St. Louis, MO, 1993.
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14. August PA, Rosebaum KN, Friendly D. Hypopituahag and CiHARGF associauon.JPediatr. 1983;103:424-425.
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16. Marche DM, Dobbelslcyn C, Rash id M, Blake KD. Oral sensory experiences and feeding development in children with GHARGE syndrome: a report of live cases. Presented at the 28th Annual Conference of the Canadian Association of Speech Language Pathologists and Audiologists, May 2003.
17. Russell-Eggill IM, Blake KD, Taylor DSl, Wyse RKH. The eye in the GHARGK association. UrJ Ophthalmol. 1990:74:421-420.
18. Hartshorne TS, Cypher AD. Challenging behavior in CHARGE syndrome. Ment Health Aspects Dev Dixabil. (in press 2004).
M). Lavvand GMD. Prasad C, Graham JM Jr, Blake KD. The cranial nerve anomalies in CHARGE association/syndrome. I’nedialr CMId 1 ImUh, 2003;8 (Suppl B):26B:3H.
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Kim D. Blake, MD1
Nancy Salem-Hartshorne, PhD2
Marie Abi Daoud, BSc3
Janneke Gradstein3
1 Department of Pediatrics, IWK Health Centre, Dalhousie University, NS, Canada; department of Psychology, Central Michigan University, Mount Pleasant, Michigan, USA; and 3Dalhousie Medical School, Halifax, NS, Canada.
Reprint requests and correspondence to: Kirn Blake, MD, Associate Professor of Paediatrics, Dalhousie University, 5850/5980 University Avenue, PO Box 3070, Halifax, NS B3J 3G9, Canada.
2005 Westminster Publications, Inc., 708 Glen Cove Avenue, Glen Head, NY 11545, U.S.A.
Copyright Westminster Publications, Inc. Mar 2005
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