Developmental, Medical, Personal, and Social History
Family Psychiatric History
Physical Examination
Mental Status Examination
Investigations and Consultations
Consultations
Initial Formulation
Working Diagnoses and Initial Treatment Plan
Clinical Course
Eight-Month Follow-Up
Discussion
William’s syndrome is a neurodevelopmental disorder caused by a hemizygous deletion of approximately 1.6 megabases containing approximately 28 genes on chromosome 7q11.23, resulting in a gene defect associated with elastin (ELN) that is pathognomonic of the syndrome. The diagnosis is made via a fluorescent in-site hybridization probe demonstrating the absent region. These microdeletions are due to spontaneous failure of meiosis, so that William’s syndrome is not ordinarily an inherited condition (1) .
Clinical characteristics include an “elfin” or “pixie-like” appearance of the ears and face. Microcephaly is often seen. Other physical manifestations include a stellate blue iris (thought to be due to the role of elastin in functional localization of pigment), curly hair, undeveloped dentition, brachydactyly, and clinodactyly. The elastin gene defect accounts for the hallmark cardiovascular impairment, supravalvar aortic stenosis, which ultimately results in left ventricular hypertrophy and global cardiopulmonary disease. Calcium dysregulation, hypercalcemia, gastrointestinal problems, orthopedic impairments, hypotonia, and a life expectation of approximately 40 years are common (1) .
Neurological problems include hyperreflexia, strabismus, nystagmus, hyperacusis with hypersensitivity to sound, sensori-neural hearing loss, and coordination difficulties (1, 4) . Neuropsychiatrically, William’s syndrome is often associated with mild to moderate mental retardation or learning difficulties, with impairments of long-term visual and verbal memory, although short-term memory remains intact. Typically, patients demonstrate a severe visuo-spatial construction deficit. As with our patient, individuals with William’s syndrome are characteristically absorbed with music, and many are highly musical (1, 4) . Interpersonally, individuals with William’s syndrome are ordinarily socially fearless, engaging eagerly in social interactions with both acquaintances and strangers (1, 2) .
Psychiatrically, a variety of anxiety disturbances are often seen related to nonsocial objects. The most prevalent psychiatric disorders are attention deficit hyperactivity disorder and simple phobias (1, 5, 6) . Although patients with William’s syndrome are notably constitutionally thin when they are young, their weights typically approach normal ranges for peers in adulthood (1, 2) . To our knowledge, eating disorders per se have not previously been described in adolescent or adult individuals with William’s syndrome. Table 1 summarizes the presumed relationships among brain structural anomalies and neurocognitive functional deficits seen in William’s syndrome.
Research into the molecular genetics and the pathophysiology of William’s syndrome is proceeding rapidly, through clinical studies and through the use of animal knockout models. Although the ELN haploinsufficiency that characterizes William’s syndrome leads to its identification as a result of cardiovascular abnormalities, ELN mutations do not affect cognitive function and elastin is not strongly expressed in the brain. The three candidate genes currently believed to contribute most strongly to the neurobehavioral abnormalities are LIM domain kinase 1 (LIMK1), CLIP-115 (Cyln2), and general transcription factor IIi (GTF2I). LIMK1, a regulator of cofilin phosphorylation and actin dynamics, has been robustly connected to the visuospatial deficit by linkage studies. Cyln2 encodes a cytoplasmic linker protein implicated in the local regulation of microtubule dynamics, especially in response to positional cues. Knockout mice lacking this gene develop coordination impairment and decreased contextual, but not cue-conditioned, fear responses. GTP2I is a ubiquitously expressed transcription factor linking signal transduction to transcription. Based on kindred analyses, a hemideletion of the GTF2I gene appears necessary for the mental retardation seen in individuals with William’s syndrome (1) .
Clinically, the life-course of patients with William’s syndrome is known to be foreshortened, with patients ordinarily living to their 40s. As with any developmentally, intellectually, and neuropsychologically challenged individuals, the difficulties to be faced by these patients, their families, and clinicians are considerable. For any given individual, the challenges include establishing appropriate social, educational, and vocational expectations, determining what can be done to maximize the individual’s capacity for autonomy and quality of life, and fostering successful and enduring relationships with caregivers (5, 6) .
Unanswered questions abound regarding the nature and quality of attachments of individuals with William’s syndrome and their abilities to emotionally self-nourish and self-regulate. Parents of these patients are frequently preoccupied with how to best care for and protect their children, who seem open, friendly, and lacking in social fear. National support groups have been established through which families offer each other the benefits of their experiences (see http://www.wsf.org/family/support/orgs.htm). Undoubtedly, such mutual aid provides one of the most helpful resources available to patients and families. Many questions remain regarding the psychological and pharmacological management of patients with William’s syndrome who happen to develop co-morbid psychiatric disorders, including, most commonly, anxiety spectrum pathology. In the absence of a substantial database, clinicians are left to judiciously approach the problems they encounter with compassionate combinations of education, individual and family psychotherapies, and the medications known to be effective for treating such disorders in non-William’s syndrome individuals (1, 2, 5) .
Weight and Eating Behavior Considerations
William’s syndrome patients tend to be very thin when young, but growth chart data on these patients show that their body mass indices on average tend to approach the 50th percentile in adulthood, and some even become obese (1) .
The patient had a very slight-built body habitus to begin with. Given the fact that he never previously weighed more than 78 lb (body mass index=13.0 kg/m 3 ) in his life, how could we assess the presence of an eating disorder, and what diagnosis did this merit? Eating disorders manifest disturbed eating-associated psychological and behavioral processes often accompanied by physical impairments due to poor nutritional practices and related maladaptive routines. If we can presume that patients with William’s syndrome ordinarily eat appropriately in accord with their genetically determined nutritional needs and approximate set-point ranges, the fact that many are slim does not by itself indicate the presence of an eating disorder (7) .
But, clearly, it is more complicated than that. Why Mr. T would settle specifically on undereating as a primary interpersonal strategy around which to play out a need to exert control in relation to his parents is unclear. Certainly, his tilt in that direction may have simply resulted from an iterative snowballing of physiological vulnerabilities, the anxiety-inducing impact of his curtailed eating on his parents, and, in turn, the impact of their reflected efforts to take control of his eating on his diminished sense of autonomy. These interpersonal iterations, in which Mr. T’s parents showed increasingly anxious concerns, may have offered him some unfortunate combination of attention and gratification. However, if Mr. T truly felt painfully hungry as a result of his reduced caloric intake, he would probably not have maintained a battle around eating. Of note, neither his parents nor the staff perceived that he was experiencing or fighting off hunger pangs, consistent with the observation that after prolonged food restriction patients with eating disorders often experience little hunger.
Mr. T demonstrated the considerable challenges facing clinicians who attempt to unearth the psychological underpinnings of disordered eating in individuals who function in this intellectual range. Patients with such limited intellects are unable to adequately describe their inner experiences or conjecture about their origins or meanings. Furthermore, the patient never communicated that he was personally suffering much subjective distress as a result of his eating disorder, although we suspect that this lack of distress owed more to his eating disorder than to his intellectual limitations. Did the patient harbor a distorted self-image with regard to his shape and weight? There’s little evidence to support this idea since he repeatedly emphasized that he thought he was “too skinny” at his low weight, suggesting that he retained at least an intellectual appreciation for the unhealthiness of his status. Was he “fat phobic”? Again, at least according to his declarations, there’s no evidence to support this hypothesis.
Mr. T’s feeling of being “backed up” suggests a somatic sensation of bodily tension, perhaps a visceral somatization, in association with ingestion, something seen when one attempts to overfeed or force feed individuals experiencing true anorexia (the symptom). A gastrointestinal workup showed that he did have functionally delayed gastric emptying. Gastroparesis is often associated with satiety and nausea (1) . While malnutrition itself has been associated with delayed gastric emptying, a finding frequently found in conjunction with bloating and gastrointestinal distress during refeeding, the mechanisms by which this occurs are not well understood. Substantial deficiencies exist in current knowledge relating to the pathophysiology of gastroparesis (1, 8, 9), although in the restrictive type of anorexia nervosa, delayed gastric transit has been associated with atrophy of the smooth muscles of the gastrointestinal tract (2) . Numerous other hormone and neurotransmitter agents, including CRF, CCK, NPY, agouti, glucagons, and gastric-related peptides, nitrous oxide, and a variety of cytokines, among others, affect appetite, satiety, and transit in the gut (1, 2) . Furthermore, we know that appetite loss occurs in patients with major depression and anxiety syndromes, again resulting from poorly understood mechanisms. Cytokines such as tumor necrosis factor have been implicated in the pathophysiology of the “psychogenic” anorexia occurring in depression (1, 2) . How the patient’s other neuropsychological limitations might create vulnerabilities for the eating disorder-related thoughts and behaviors is unclear, but we might speculate that unstudied processes involving early satiety might be present, so that food restriction might not have been as subjectively painful for Mr. T as for others. On balance, it is conceivable that as yet poorly understood physiological processes, perhaps provoked by Mr. T’s increased distress about intercurrent life events and family processes ultimately evoked the sensation of “backing up” and turned off his appetite, making it easier for him to subsequently construe his weight loss in terms of interpersonal conflict. Although some children, adolescents, elderly demented individuals, and otherwise powerless political prisoners may initiate food refusal or “hunger strikes” as a manifestation of willfulness and passive-aggressive attempts to achieve some degree of control over overpowering situations, most individuals find other means to deal with their conflicts (10, 11) .
General management strategies for treating patients with eating disorders apply to the patient’s case as well (2) . These strategies, described in the American Psychiatric Association’s Practice Guideline for the Treatment of Patients With Eating Disorders, emphasize the importance of attending to physical, behavioral, psychological, and interpersonal, particularly family, issues, none to the exclusion of the others. Clinicians are obliged to assess the relative urgency and priorities of the patient’s problems in these domains for the immediate and long term. In turn, clinicians must decide on the urgency and on priorities for initiating suitable interventions addressing each of these problem areas. The first priority is the patient’s physical safety, specifically, assuring sufficient nutritional intake to prevent malnutrition and physiological collapse. When it became clear that usual behavioral and supportive interventions were insufficient and that even adding overnight supplemental feedings shown elsewhere to assist in the treatment of pediatric anorexia nervosa patients (1) was not adequate, the more definitive option of a percutaneous gastrostomy tube seemed necessary. How accessible Mr. T might be over the long run to various psychotherapeutic strategies, including educational, cognitive, behavioral, and interpersonal approaches, remains to be seen. We continue to support the idea of the patient moving to a group home environment, where he would have the necessary support system to manage his individual needs while exploring a more independent and autonomous existence. We also acknowledge the difficulty of this process for both Mr. T and his parents. Following the patient over the ensuing months and years will be informative regarding the resolution of his eating attitudes and behaviors, his interactions with his parents, and his ability to achieve a reasonable quality of life.
Footnotes
Received May 24, 2008; revision received Sept. 20, 2008; accepted Sept. 29, 2008 (doi: 10.1176/appi.ajp.2008.08050773). From the Department of Psychiatry, University of New Mexico School of Medicine. Address correspondence and reprint request to Dr. Young, Department of Psychiatry MSC09/5030, University of New Mexico School of Medicine, 1 University of New Mexico, Albuquerque, N. Mex.; [email protected] (e-mail).
Dr. Apfeldorf discloses the following industrial supports: research support from Pfizer/EISAI; speakers bureau honoraria from Pfizer/Eisai, Eli Lilly, AstraZeneca, and Forrest; and advisory board payments from Forrest. The remaining authors report no competing interests.
References
1.
Meyer-Lindenberg A, Mervis CB, Berman KF: Neural mechanisms in William’s syndrome: a unique window to genetic influences on cognition and behaviour. Nat Rev Neurosci 2006; 7:380–393
American Psychiatric Association Practice Guideline for the Treatment of Patients With Eating Disorders, 3rd Revision, Part A. Am J Psychiatry 2006; 163, pp 1–54
O’Reilly MF, Lancioni GE: Treatment food refusal in a child with Willam’s syndrome using the parent as therapist in the home setting. J Intellect Disabili Res 2001; 45(Part I); 41–46
Farran E: Evidence for unusual spatial location coding in William’s syndrome: and explanation for the local bias in visuo-spatial construction tasks? Brain Cogn 2005; 59:159–172
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