Zellweger syndrome

Prader-Willi syndrome is an infrequent, but distinctive, genetic disorder that is expressed as cognitive and adaptive deficits, sexual immaturity, poor gross motor skills, emotional lability, sleep difficulties, and behavioral disturbances (Alexander, VanDyke, & Hanson, 1995; Akefeldt, Gillberg, & Larsson, 1991). This constellation was first described by Down (1887) and at a later date by Prader, Labhart, and Willi (1956). The most striking and easily identified behavioral manifestations of the chromosomal disorder are an intense preoccupation with food and marked abnormalities in satiety (Dykens, Leckman, & Cassidy, 1996; Zellweger, 1984). Serious behavioral difficulties, such as aggression, may often be related to food seeking.

In addition, persons with Prader-Willi syndrome typically also display severe behavioral difficulties not related to food seeking that include: irritability, lethargy, impulsiveness, obsessive behavior, temper tantrums, stubbornness, argumentativeness, and self-injurious behavior (Clarke, Boer, Chung, Sturmey, & Webb, 1996; Dykens et al., 1996; Greenswag, 1987). There is some evidence of a higher incidence of acute reoccurring psychotic symptoms not entirely accounted for by intellectual disability (Beardsmore, Dorman, Cooper, & Webb, 1998; Clarke, 1998). Despite severe behavioral outbursts, persons with a diagnosis of Prader-Willi syndrome are often described as generally good natured (Greenswag).

Individuals with the diagnosis of Prader-Willi syndrome present a challenge to vocational rehabilitation programs. Dykens et al. (1997) note that the supervision necessary to assist individuals with Prader-Willi syndrome in maintaining a quality lifestyle and preventing a premature death may be in conflict with the philosophical and ethical standards that promote consumer independence, choice making, and personal responsibility. To be vocationally successful, and to avoid the life threatening complications associated with morbid obesity, persons with the diagnosis of Prader-Willi benefit from vocational services that recognize the strong genetic component of behaviors characteristic of the syndrome (Saporito, 1995). These behavioral characteristics may limit the consumer's vocational choices. Many of these behaviors that have an organic basis are not easily modified by typical environmental supports or therapeutic interventions.

Understanding the genotype-phenotype relationship of the syndrome is critical in recognizing that emotional and behavioral disturbances, especially those that center on food, are not driven by cognitive processes, but rather are a behavioral manifestation of a chromosomal disorder (Alexander et al., 1995). These behaviors are extremely difficult to change through behavioral, cognitive, or other interventions that focus on self-awareness and self-control (Whitman & Greenswag, 1995). A clear understanding of this syndrome can help vocational counselors design more effective strategies for vocational guidance and placement of persons with the diagnosis of Prader-Willi syndrome.

The purpose of this paper is to review the incidence and diagnostic criteria of Prader-Willi syndrome. The functional features of the syndrome are presented and illustrated by several composite case examples that feature typical expressions of the syndrome and functional difficulties that arise from those expressions. Finally, vocational strategies are reviewed. This discussion focuses on strategies to assist rehabilitation counselors in the vocational assessment and counseling of persons with Prader-Willi syndrome.

Etiology and Diagnostic Criteria

Prader-Willi syndrome is a chromosomal disorder that results from the deletion or inactivation of information that codes for the organization of sub cellular organelles called nucleoli (Cassidy, 1995). Males and females appear to be equally affected (Alexander et al., 1995). In 60 to 70% of clinically typical individuals, the syndrome is caused by the deletion of the father's contribution to chromosome 15q (Butler, 1990). In a smaller number of cases, the syndrome is the result of uniparental disomy in which the maternal contribution to chromosome 15q is replicated, replacing the paternal contribution (Knoll, Nicholls, Magenis, & Graham, 1989). In less than 1% of cases, the disorder is the result of micro deletions, translocations, or imprinting mutations (Dimitropoulos et al., 2000). The chromosomal disorder results in insufficient function of the hypothalamus, which plays a major role in the regulation of homeostatic functions including hunger, thirst, sleep-wake cycles, and temperature, as well as the release of hormones that affect the pituitary gland that, in turn, control the release of other hormones that stimulate growth, sexuality, and thyroid function (Cassidy, 1995).

The development of persons with Prader-Willi syndrome is unique because there are two distinct phases (Alexander et al., 1995; Gunay-Aygun, Schwartz, Heeger, O'Riordan, & Cassidy, 2001). Infants and young children to age two or three typically display low birth weight, hypotonia, lethargy, poor reflexes, and skeletal abnormalities of the cranium (Zellweger, 1984). These children may be misdiagnosed as failure to thrive due to poor eating (Alexander et al.). However, due to the chromosomal disorder, the hypothglamus and pituitary fail to regulate satiety, and the child begins to exhibit an insatiable appetite that is characterized by constant feelings of hunger. Adolescence and young adulthood are marked by insatiable appetite as well as behavioral and emotional difficulties unrelated to food seeking (Cassidy, 1984). Without environmental management, persons with this syndrome die prematurely from complications of gross obesity (Zellweger, 1981).

Estimations of the incidence of Prader-Willi syndrome in the population vary (Alexander et al., 1995; Whittington et al., 2001). There have been only three estimates based on epidemiological data. Akefeldt et al. (1991) conducted a survey of health professionals and health services in a rural county in Sweden and estimated the prevalence of Prader-Willi syndrome among persons age zero to 25 years at 1:8,500. Whittington et al. conducted a study of the syndrome in eight counties in the United Kingdom and found a birth incidence rate of 1:20,000, a prevalence rate of 1:28,000 among persons age zero to 27 years, and a whole population prevalence rate of 1:45,000. A survey of health care and service providers in the state of North Dakota conducted by Burd, Vesely, Martsolf, and Kerbeshian (1990) yielded a prevalence rate of 1:16,062 in the population age nine to 30 years. The range in prevalence estimates may reflect sampling errors, differences in the inclusion criteria, high mortality rates between the ages of 25 and 30, or actual variations in the prevalence rates (Whittington et al.). Prader-Willi syndrome is not considered to be rare among the younger age cohorts utilizing educational and work entry services (Alexander et al.). However, the syndrome is less often found among older cohorts due to early morbidity often caused by complications of morbid obesity (Whittington et al.).

The diagnostic process for the identification of Prader-Willi syndrome includes genetic testing for the chromosomal abnormality. A physician may request genetic testing for an individual who exhibits characteristics congruent with the major, minor, and supportive diagnostic criteria for Prader-Willi syndrome. This criterion was established in 1993 by a group of national and international experts (Holm et al., 1993). Five or more of the major clinical criteria must be present, including: (a) infantile hypotonia that gradually improves, (b) feeding problems in infancy, (c) excessive and rapid weight gain after one year but before six years, (d) atypical facial features, including narrow face, almond shaped eyes, and small mouth, (e) hypogonadism with delayed maturation, (f) mild to moderate mental retardation, (g) hyperphagia, food foraging, and an obsession with food, and (h) chromosomal abnormality. (Alexander et al., 1995; Gunay-Aygun et al., 2001). Approximately 17% of the persons who have the genetic diagnosis do not meet the clinical criterion, which suggests that the clinical criterion may be too exclusive (Gunay-Aygun et al.).

Case Examples

The impact of phenotypical behaviors associated with Prader-Willi syndrome on vocational outcome can be illustrated through case examples. The following two composite descriptions highlight typical vocational challenges resulting from the functional features of Prader-Willi syndrome. Both cases illustrate that the maladaptive features of the syndrome, while not eliminated, may be reduced in severity and intensity with a team approach to intervention.

Case 1

"A" is a 26 year old woman with a diagnosis of Prader-Willi syndrome, whose productivity at work has been decreasing for the last several months. When confronted by her supervisor, she became verbally and at times physically aggressive. A behavioral intervention implemented to increase productivity was unsuccessful. Subsequently, she was facing disciplinary action for her behavior.

"A" lives with her mother. She receives no medications, is a non-smoker, and has had no known hospitalizations or surgeries. Her last cognitive evaluation, which was in her final year of high school, indicated a verbal Intellectual Quotient score of 69 and a nonverbal score of 60. Although she followed a carefully supervised diet, she had experienced a significant weight gain in the past 12 months, and she had become increasingly obese.

Generally, she is quiet and cooperative, although somewhat lethargic and sleepy. Snoring is a problem at night. An overnight sleep study demonstrated several dozen episodes of obstructive sleep apnea each night.

The clinical team recommended a trial of nasal positive airway pressure during sleep. Because her obesity contributed to the apnea, the team also made nutritional recommendations designed to result in weight loss, including locking the cupboards and the refrigerator and promptly removing the garbage.

Following intervention provided by a community health care assistance program contracted by her case manager, employers reported that although there was not a significant improvement in productivity, there was a significant decrease in work refusal and irritability on the job. As a result of the intervention, her employment was not as likely to be terminated and employers were better able to recognize that many of her work characteristics are expressions of her disability rather than expressions of dissatisfaction with her work environment. Medical staff noted that dietary management remained difficult, thus weight gain continued, compromising the goal to improve productivity.

Case 2

"B" is a 20 year old man with a diagnosis of Prader-Willi syndrome and moderate cardiac impairment secondary to morbid obesity. He was referred for vocational services because he plans to graduate from high school in six months. His current transitional work experience is cleaning trays in the high school cafeteria with 1:1 supervision. His vocational goal is to work in a fast food restaurant. He has difficulty with anger management, which has resulted in several school suspensions and the creation of a highly structured school day. His parents believe his behavior will improve once he obtains full time paid employment.

The vocational counselor recommended a comprehensive vocational, medical, nutritional, and psychological evaluation prior to the development of a rehabilitation plan. Results of the vocational and psychological evaluations indicated that "B" has the entry-level skills and abilities to consider employment in the restaurant industry. However, both the medical and nutritional reports noted that "B" has gained 15 pounds since starting his current work activity, which began two months ago. A nutritional plan was recommended for school and home, which included an increase in supervision and a behavior modification plan to reduce covert eating. In the month following implementation, there was negligible weight gain. There was also a marked increase in arguing and threats of physical aggression resulting in several suspensions. The school principal now recommends early graduation at the end of the fall semester.

The consumer and his family have proposed an intensively supervised trial placement in a restaurant. The rehabilitation counselor providing transition services notes that a weight gain could lead to further cardiac impairment, further disability secondary to morbid obesity, and premature death. Supervision is

unlikely to be effective in limiting food seeking because an insatiable appetite is an expression of the genotype. The consumer's work history suggests that supervision to prevent food foraging will result in an increase in arguing, aggression, and subsequent termination of employment. Employment with clear task boundaries that prevent access to edible items may be more appropriate. Highly structured job trials and career counseling are recommended to help "B" develop alternative vocational goals.

Vocational Strategies

Little has been written regarding the career development and vocational placement needs of persons with Prader-Willi syndrome. As illustrated in the case examples, autonomy and food control issues are often key factors in considering the choice of vocational activities. However, these issues are symptomatic of the larger considerations of choice and the limits placed on choice for individuals with a genetic condition that results in self-destructive behavior (Dykens et al., 1997). Choice making within a management plan that recognizes the functional expressions of the genotype and how these expressions impact independence and choices can result in consumer driven career development and vocational placement strategies (Saporito, 1995). A team approach, as illustrated in the case examples, will likely increase the opportunities for individuals to be successful in developing a satisfying career (Holm, 1995).

Service plans and intervention strategies may focus on behavior problems (i.e., food stealing, stubbornness) secondary to the disability, which are used to establish service eligibility (i.e., a diagnosis of mental retardation) (Holm, 1995). As noted in the case examples, it is important to differentiate: (a) behaviors that are expressions of the genotype, (b) behaviors that are secondary to the medical complications of obesity, and (c) behaviors that are learned, maladaptive responses (Whitman & Greenswag, 1995). Overt expressions of the genotype (preoccupation with food, emotional lability, perseverative speech and behavior, severe behavioral disturbances, daytime sleepiness) and physiological expressions of the genotype (low metabolic rate, hypotonia, insatiability, sleep difficulties) are resistant to change and may be more difficult to manage than food seeking (Dykens et al., 1996). Such behaviors have a significant impact on career choices and intervention options.

Interdisciplinary assessment and intervention strategies are highly recommended (Hagerman, 1999; Holm, 1995; Krueger & Kanary, 1995; Martin et al., 1998). Maximizing choices and independence can only occur when accurate information regarding medical, nutrition, leisure, residential, case management, and vocational progress is available. Accurate information is particularly important in vocational planning when choices must be made about career options (i.e., placement in an area with access to food) or when choices must be made about treatment components (i.e., the use of food as a reward).

Assessment

Vocational rehabilitation counselors must recognize the unique behavioral expressions of the genotype associated with Prader-Willi syndrome in order to provide effective assessment and intervention. If unfamiliar with the genotype, helping professionals may form unrealistic expectations and develop ineffective strategies (Greenswag, 1987). Despite the characteristics common to Prader-Willi syndrome, the achievements, aptitudes, and interests of this population are diverse, and individualized assessment is important (Waters, Clarke, & Corbett, 1990).

Environmental management is a key factor in improving the accuracy of assessment (Whitman & Greenswag, 1995). Based on clinical experiences, the authors suggest that the assessment process allow the consumer as many choices as possible within a structured routine. Consumer cooperation appears to improve when there is a single primary staff member responsible for instruction, redirection, or intervention. Further, many consumers with Prader-Willi syndrome appear to have a greater sense of control when provided with a written schedule. The consumer's primary counselor should describe the time, place, duration, and activities that will occur during breaks in the schedule. In addition, the consumer and the counselor should clearly identify a location away from the evaluation or treatment area where the consumer can vent frustrations. Counselors should liberally provide positive praise and reinforcement. To encourage the consumer's participation, feedback about the consumer's performance, especially feedback that may be perceived as negative, should be restricted until the task is complete.

The authors have found that adaptation of standardized instruments and techniques may be required to meet the unique needs of consumers with Prader-Willi syndrome. For example, consumers who engage in persistent behavior (i.e., continuing to explain prior answers, attempting to redo prior activities) following task or topic completion may benefit from prolonged breaks between activities. Such breaks may help the consumer improve his or her performance on subsequent activities. Activities that emphasize psychomotor speed or productivity may not be appropriate because of the characteristic hypotonia, diminished arousal levels, and the sleep difficulties most persons with Prader-Willi syndrome exhibit (Levine & Wharton, 1995).

Career Planning

A sequential career development strategy that includes early identification of career goals, adapted career readiness activities, transition planning and activities in adolescence, and support for career development activities throughout adulthood improves vocational opportunities and quality of life. Difficulties arise in vocational assessment and placement when individuals and their support network are neither ready nor able to accept the functional limitations associated with the syndrome (Dykens et al., ! 997). Saporito (1995) noted, "Thoughtful intervention by a vocational counselor is essential to successful programming, because persons with PWS and their families continually struggle to accept the presence of the syndrome and its effect on goal planning and attainment" (p. 252). In the authors' experiences, unrealistic expectations, such as the expectation that behaviors associated with the expression of the genotype will diminish with the transition from school to the world of work, may need to be addressed with the consumer and his or her support network in order to develop a career strategy that results in vocational success.

Persons with Prader-Willi syndrome are most likely to be successful when their vocational aspirations can be realized within a predictable schedule that maximizes choice within routine and structure (Whitman & Greenswag, 1995). Consumers with Prader-Willi syndrome who are successful in their careers are able to incorporate the following management strategies into the work environment: (a) supervised access to all potentially edible items, (b) the opportunity for praise emphasizing pride in work, (c) clearly defined "off-limits" areas, (d) a single supervisor with a procedure for addressing problems, (e) written work schedules and expectations, (f) limits on questioning to reduce arguments, and (g) a designated place to vent frustrations (Saparito, 1995).

Many persons with Prader-Willi syndrome have relatively good fine motor skills and are precise and persistent (Saporito, 1995). A characteristic of the syndrome is the unusual ability to complete jigsaw puzzles (Alexander et al., 1995). Sedentary, repetitive tasks that utilize fine motor abilities are work activities that may be congruent with the abilities of many persons with Prader-Willi syndrome. Such work activities may be the basis of a career in assembly work, office work, assistant in a laboratory, or other activities that involve precision and repetition (Saporito).

Intervention

Current behavioral and pharmacological therapies do not appear to significantly impact the behavioral expressions of Prader-Willi syndrome (Akefeldt & Gillberg, 1999). Behavioral techniques may help the consumer with Prader-Willi syndrome reduce non-food related, obsessive behaviors (Dykens et al., 1996). Akefeld and Gillberg as well as Rose and Walker (2000) reported that behavioral interventions can reduce the rate of challenging behaviors, thus reducing the number of confrontations with others. However, the generalization of behavioral treatment appears to be particularly difficult for persons with Prader-Willi syndrome (Hurley & Sovner, 1984).

Outpatient and inpatient behavior modification programs have demonstrated limited short-term effectiveness in reducing food-stealing behavior (i.e., Banzett, Marshall, Bowen, and Glynn, 1991; Maglieri, DeLeon, Rodriguez-Catter, & Sevin, 2000; Page, Stanley, Richman, Deal, & Iwata, 1983). Likewise, behavior modification in combination with outpatient nutrition management programs has shown little success in promoting weight management. (Stadler, 1995). Overall, behavioral approaches have had little success in reducing food foraging unless such strategies are combined with supervision and inaccessible food sources (Dykens et al., 1996).

Anecdotal reports suggest that psychopharmacological treatments may be beneficial in modifying some phenotype related behaviors (Martin et al., 1998; Stein, Keating, Zar, & Hollander, 1994). For example, Yaryura-Tobias, Grunes, Bayles, and Neziroglu (1998) reported that serotonin reuptake blockers and phenothiazines were effective in reducing self-injurious behavior but were ineffective in controlling appetite. The effectiveness of fluoxetine in reducing compulsive eating and other obsessive behaviors has been inconsistent. Hagerman (1999) cited several anecdotal reports of the effectiveness of fluoxetine in reducing compulsive eating and other behaviors such as skin picking. Conversely, Kohn, Weizman, and Apter (2001) reported an aggravation in food related symptoms in an adolescent with Prader-Willi syndrome treated with fluvoxamine and fluoxetine. The biological mechanisms underlying the obsessive characteristics associated with the syndrome and the potential effect of psychopharmalogical interventions in reducing hyperphagia are areas of current interest to researchers (Dimitropoulos et al., 2000). However, controlled studies are needed to establish the efficacy of medication treatment (Hagerman, 1999). Although growth hormone replacement therapy for children and adolescents with Prader-Willi syndrome does not prevent the behavioral expression of the disorder, there is evidence that such therapy does diminish the predictable behavioral deterioration that is characteristic of the adolescent period (Whitman, Myers, Carrel, & Allen, 2002).

Behavioral and pharmacological interventions to improve sleep may improve behavior (Helbing-Zwanenburg, Kamphuisen, & Mourtazaev, 1993). Excessive daytime sleepiness, rapid eye movement sleep disturbance, and shortage of slow wave sleep patterns associated with the syndrome may contribute to irritability and antisocial behavior (Clarke et al., 1996). As illustrated in the case example, continuous positive airway pressure (CPAP) treatment may improve sleep, reduce daytime somnolence, and improve mental acuity (Doshi & Udwadia, 2001). Stress also contributes to behavioral difficulties and poor responses to various interventions (Bartolucci & Younger, 1994; Hodapp, Dykens, & Massino, 1997). Dykens et al. (1996) reported that a significant positive relationship exists between the level of family stress and non-food related behaviors such as hoarding, insistence on routine, and temper tantrums. The stress created by demands for productivity, compliance, and skill acquisition in work settings may exacerbate compulsive and other phenotypical behaviors, even though such demands may be consistent with the individual's cognitive and motor capacities (Saporito, 1995).

Vocational interventions should focus on a comprehensive integrated program of behavior management rather than on behavioral or cognitive change strategies (Whitman & Greenswag, 1995). Supervision is the most widely used approach to managing food seeking and related behavioral difficulties (Dykens et al., 1997; Whitman & Greenswag). Career goals that are predicated on the successful implementation of an intervention to significantly modify temperament, food seeking behavior, activity level, sleep patterns, or behavioral outbursts are likely to frustrate both the consumer and the service providers.

Work activities that are not closely supervised are usually not a feasible employment goal for persons diagnosed with Prader-Willi syndrome because they require continuous supervision in vocational settings in order to maintain their weight (Carpenter, 1994; Whitman & Greenswag, 1995). While exceptions have been reported (e.g., Goldman, 1988), overtly and covertly obtained food coupled with significantly slowed metabolic rate leads to morbid obesity and early death for many persons with Prader-Willi syndrome (Alexander et al., 1995; Banzett et al., 1991; Dykens & Cassidy, 1999). In addition, supervision is required as some persons with Prader-Willi syndrome, although they show understanding about the purpose of food, eat inedible and contaminated items, placing them at risk for illness or poisoning (Dykens, 2000). Other common physical characteristics of persons with Prader-Willi, such as delicate skin and decreased sensitivity to pain, necessitate that vocational choices and supervision decrease the individual's exposure to chemical or hot liquid burns and to harsh environments (Saparito, 1995).

Social skills training is an important component of early intervention for persons with Prader-Willi syndrome (Levin, Wharton, & Fragala, 1993). Behavioral outbursts, persistent focus on food, and stubbornness may limit the opportunities for persons with Prader-Willi Syndrome to form positive relationships with peers and co-workers (Downey & Knutson, 1995). Workplace relationships may be further compromised by dysfluent speech, another common characteristic of the syndrome (Defloor, VanBorsel, & Curfs, 2000). Thus vocational social skill training may need to be incorporated into career development plans in order to increase the individual's vocational choices that may otherwise be limited due to the inability to get along with co-workers.

Conclusion

Although Prader-Willi syndrome is an infrequent diagnosis, and many vocational rehabilitation counselors will never serve a consumer with this diagnosis, most members of this population are eligible for and use vocational rehabilitation services (Saporito, 1995). More than 80% of adults with Prader-Willi syndrome receive vocational services, most often through sheltered workshops (Saporito). Greenswag (1987) surveyed 232 persons with Prader-Willi syndrome and reported that 45.7% of the adults were employed in sheltered settings, 35.3 % were unemployed, 3.9% were competitively employed, 2.6% were doing voluntary work activity, and 2.2% worked at home. In the United Kingdom, most adults with Prader-Willi syndrome attend training centers (Waters et al., 1990).

In order to effectively serve these consumers, rehabilitation counselors must differentiate the behaviors that are expressions of the genetic disorder from behaviors that are learned maladaptive responses. One of the most significant expressions of the phenotype is insatiable appetite. Unrestricted access to food for persons diagnosed with Prader-Willi syndrome can quickly lead to significant harm due to overeating (Aguilar, 1990). Persons with Prader-Willi syndrome, when permitted to have unrestricted access to food in experimental conditions, eat continuously (Holland, Treasure, Coskeran, & Dalleo, 1995). Harm can occur at work through the overt consumption of food that may occur through sharing food with co-workers and food purchases during work breaks, as well as through the covert consumption of food obtained through the theft of food from co-workers and employers, consumption of uncooked or contaminated food items, and foraging through garbage. Rehabilitation counselors need to carefully assess potential work environments to identify and remove all sources of potentially edible items.

Behavioral and pharmacological interventions may be effective in reducing the severity of compulsive behaviors. However, there appears to be considerable variation between individuals in their responsiveness to these interventions (Hagerman, 1999). Thus, environmental management remains a key factor in vocational success for most persons with Prader-Willi syndrome. Consumer choice can be maximized within a management plan when vocational exploration, training, and work experiences encourage exploration of activities other than those related to food. Career development activities that focus on abilities rather than on interest may help consumers expand their choices of work environments in which the potential for confrontations regarding food are reduced. Realistic expectations, environmental management, and an interdisciplinary team approach to evaluation and treatment can assist persons with Prader-Willi syndrome in achieving career success.

The environmental management required by persons with Prader-Willi syndrome may conflict with the right to self-determination and interfere with the rights of other consumers (Dyken et al., 1997). Restricting access to edible items in the work environment effects all employees, including those who have the right to have access to their own purchases. Environmental management strategies that limit access to food may create ethical and legal concerns that are difficult to resolve. Rehabilitation professionals can contribute to the resolution of these concerns through their knowledge of workplace environments and their knowledge of the needs of persons diagnosed with Prader-Willi syndrome.

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John S. Wadsworth, PhD, The Graduate Programs in Rehabilitation, The University of Iowa, N376 Lindquist Center, Iowa City, IA 52242-1529. Email: john-s-wadsworth@uiowa.edu

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