Journal of Pediatric Psychology, Vol. 26, No. 8, 2001, pp. 477-484
© 2001 Society of Pediatric Psychology
Emotional Outcome of Adolescents and Young Adults With Early and Continuously Treated Phenylketonuria
University of Minnesota
All correspondence should be sent to Jill E. Sullivan, Northwestern Memorial Hospital, Outpatient Treatment Center, 222 East Superior, 4th Floor, Chicago, Illinois 60611. E-mail: jzsulliv{at}nmh.org .
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Abstract |
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Objective: To assess the emotional functioning of adolescents and young adults with early and consistently treated phenylketonuria (PKU).
Methods: Twenty PKU-affected participants, ages 14-25, were compared with age-matched chronically ill (n = 17) and peer (n = 16) controls on a structured clinical interview, the Minnesota Multiphasic Personality Inventory, and the Tennessee Self-Concept Scale-2. Affected participants and nonparticipants were assessed using a multidomain assessment of functioning interview.
Results: There were no significant differences between groups for observable psychiatric disorders or emotional and functional symptoms. No significant differences were found in self-concept. Although there were no differences between groups for IQ or treatment variables, PKU-affected participants were more likely than nonparticipants to have sought help for psychological concerns.
Conclusions: Results suggest that early-treated PKU-affected adolescents and young adults do not show a higher risk for psychological disturbance than appropriate controls.
Key words: phenylketonuria; PKU; metabolic disorder; chronic illness; cystic fibrosis; juvenile onset diabetes; asthma; adolescents; young adults; emotional functioning; behavioral functioning.
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Introduction |
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Phenylketonuria (PKU), an autosomal recessive disorder with an incidence rate of 1:10-20,000, is caused by the absence or inactivity of phenylalanine hydroxylase, the enzyme that converts the amino acid phenylalanine to tyrosine. Management of PKU requires an individually tailored diet of foods low in phenylalanine and supplementation of the essential nutrients the body cannot produce. Routine screening of newborns and the widespread initiation of dietary treatment within the first 3 months of life have essentially eliminated the severe, irreversible cognitive deficits and psychiatric disturbance associated with untreated PKU.
In accordance with standard medical practices, PKU-affected individuals who
began receiving treatment before 1980 typically discontinued the diet between
ages 6 and 8. Many studies of early-treated, off-diet PKU-affected
individuals, including participants ages 6 to 35, converge upon
characteristics of attention deficit-hyperactivity disorder
(Chang & Fisch, 1976
;
Fisch, Sines, & Chang,
1981; Realmuto et al.,
1986; Schor, 1986;
Smith, Beasley, Wolff, & Ades,
1988; Waisbren & Zaff,
1994). Psychiatric disorders within the depression and anxiety
spectrums (Fisch et al., 1995;
Realmuto et al., 1986;
Waisbren & Levy, 1991) and
internalizing symptoms (Pietz et al.,
1997) have been documented and corroborated by studies using the
Minnesota Multiphasic Personality Inventory (MMPI)
(Fisch et al., 1981;
Waisbren & Zaff, 1994).
Low self-confidence, social maturity deficits, and poor interpersonal
relationships have been widely reported
(Chang & Fisch, 1976;
Fisch et al., 1981; Matthews,
Barabas, Cusak, & Ferrari, 1986; Smith
et al., 1988; Waisbren &
Zaff, 1994), indicating an overall association between the absence
of phenylalanine (phe) restriction and emotional dysfunction
(Smith et al., 1988).
Intellectual outcome depends on adequate phe control during the first 8 to
10 years of life. Because the effects of toxic elevations of phe after this
time are unknown, many treatment clinics now advise patients to maintain the
restricted diet throughout their lives. Preliminary research indicates that
patients treated early and strictly do not show a higher incidence of
psychological maladjustment than healthy controls before age 13
(Griffiths, Tarrini, & Robinson,
1997; Weglage, Rupp, &
Schmidt, 1994). However, research with older adolescents
corroborates indications of negative self-image, social withdrawal, low
frustration tolerance (Weglage et al.,
1992), distractibility, problems with peers, and a significantly
higher rate of moderately severe psychiatric symptoms compared to age-matched
controls (Burgard, Armbruster, Schmidt,
& Rupp, 1994).
If these formulations are correct and if, despite treatment, serum phe continues to affect cerebral functioning, then individuals with PKU would be expected to exhibit more emotional and behavioral disturbance than normal controls. In fact, only 5 of the 17 studies conducted to date included a normative comparison group. Therefore, research still needs to address whether the emotional adjustment of individuals with treated PKU differs significantly from that of peer controls.
It also is important to consider the psychosocial effects of chronic
illness on emotional development. Data regarding the relationship between
chronic illness and psychological adjustment have been equivocal (see review
by Wallander, Varni, Babani, Banis, &
Wilcox, 1988). Recent research has focused on chronic illness as a
psychosocial stressor rather than a pathognomonic diathesis for emotional and
behavioral difficulties. Chronic illnesses vary greatly in biochemical and
physical consequences but may produce similar psychosocial sequelae,
particularly diminished self-concept
(Seigel, Golden, Gough, Lashley, &
Sacker, 1990). By comparing PKU-affected participants to those
with other chronic illnesses, one can examine the issue of whether emotional
outcome is illness-specific. A single study to date has attempted this type of
analysis, finding a significant difference between PKU-affected and diabetic
patients on a measure of agoraphobia
(Waisbren & Levy,
1991).
This investigation was designed to examine the quality and pattern of
emotional adjustment in early and consistently treated adolescents and young
adults with PKU in comparison to age-matched peers and chronically ill
controls. This comparison group was included to further empirical exploration
of illness-specific emotional and functional sequelae. A third goal of this
research involved attention to methodological issues that have limited the
conclusions drawn from previous studies. According to the recommendations
outlined in Sullivan and Chang
(1999), this protocol included
a proband group that was homogeneous for the diagnosis of classical PKU, onset
and length of dietary treatment, and adequacy of phenylalanine control;
controlled for IQ; and used age-appropriate, standardized measures that assess
the clinical features suggested by previous research and allow comparisons
across studies.
In comparison to the other groups, probands were expected to show more observable psychiatric disorders and emotional or functional symptoms (i.e., significantly more psychiatric symptoms and clinical diagnoses, as well as clinically significant elevations on a measure of personality and current symptomatology). Both probands and chronically ill controls were expected to differ significantly from healthy peers with regard to self-concept.
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Method |
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Participants
The institutional review board of the University of Minnesota fully approved the protocol of this investigation. Master lists from the PKU Clinic at Fairview University Medical Center were reviewed to identify patients 14-25 years old with early-treated, classical PKU. Because psychiatric disorder is known to be more common in children and adolescents with intellectual disability (Einfeld & Tonge, 1996
), potential participants were selected on the basis of having
previously measured IQs within the normal range (i.e., 
80). These
inclusion criteria yielded 38 potential participants with current address
information. Two comparison groups were recruited, including a group of age-matched controls with other chronic illnesses. Each of the chronic illnesses represented in this study, including PKU, is genetically determined and not eminently terminal, demands daily compliance with dietary/medical therapies and frequent visits to specialty clinics, and may involve problems managing treatment. This chronically ill control group (n = 17) was composed of patients with cystic fibrosis (n = 6) and juvenile onset diabetes (n = 4) from the Pediatric Pulmonary and the Pediatric Endocrinology Clinics at Fairview University Medical Center and asthmatic patients (n = 7) from the Pulmonology Clinic at Children's Health Care in St. Paul, MN. Probands and chronically ill controls recruited same-sex, age-matched peer controls (n = 16) without histories of chronic illness. Because PKU is genetically determined, comparisons to family members provide a unique context for the examination of long-term outcomes. Sibling controls [n = 6] were recruited through the 21 participants with one or more unaffected full siblings between the ages of 14 and 25 years. Results for this group have not been included as they are considered to be highly tentative due to sample size.
All families initially were contacted by letters sent to their last known address. Letters for peer controls were enclosed. Patients who did not wish to be recruited were asked to contact investigators either by telephone or pre-stamped postcards. The remaining patients were contacted by telephone to further explain the purpose of the study and schedule visits. Recruitment was complicated by the fact that many families were currently living some distance from the study site (e.g., out of state or in Canada). Of the initial pool of 38 eligible probands, 52.6% participated. Nine probands did not attend their scheduled appointments, even when multiple visits were scheduled, and nine probands refused to participate. Of the 78 eligible chronically ill patients, 21.8% participated. Eleven patients failed to attend their scheduled visits and 50 potential participants refused to participate.
Demographic characteristics are presented in Table I. PKU probands and controls were nearly evenly distributed across gender, age, and educational levels. Groups also were similar with respect to marital, employment, and socioeconomic status (SES). Participants were predominantly Caucasian, single, and either full-time students or employed full-time. Participants reported personal income if financially independent; otherwise, parental income was used. Median annual parental income was $40,000-$50,000 for all groups. Median annual personal income was $20,000-$30,000 for all groups. Groups did not significantly differ demographically.
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Materials
The presence or absence of current and lifetime clinical diagnoses, as well
as the frequency and severity of cumulative psychiatric symptoms that
correspond to DSM-IV diagnostic criteria, were assessed using portions of an
age-appropriate, standardized diagnostic interview. "Subthreshold"
diagnoses (i.e., all established criteria were met, but clinically significant
impairment was not present in an important area of functioning) also were
considered. Participants 14-17 years old were administered the Diagnostic
Interview for Children and Adolescents-Revised-Adolescent Version for DSM-IV
(DICA-R-A; Reich, Leacock, & Shanfeld,
1995). Participants 18-25 years old were administered the
Structured Clinical Interview for Axis I DSM-IV Disorders-Nonpatient Version
(SCID-NP; First, Spitzer, Gibbon, &
Williams, 1994), as well as portions of the DICA-R-A to assess
past symptoms and diagnoses of disorders usually first diagnosed in
childhood.
Participants were administered all of the items from the standard scales of
the age-appropriate version of the MMPI-A
(Butcher et al., 1992) or
MMPI-2 (Butcher, Dahlstrom, Graham,
Tellegen, & Kaemmer, 1989), as a measure of personality and
current emotional and functional symptoms. Raw scores were converted to
T-scores (M = 50, SD = 10); T-scores 65 are considered
clinically significant. Each profile was scored by National Computer Systems
(NCS) in Minneapolis.
The Tennessee Self-Concept Scale-2 (TSCS:2) is an 82-item self-rating scale
designed to assess how one feels about himself or herself, which can be
administered to individuals aged 13-90 who can read at a third-grade level
(Fitts & Warren, 1996).
Sample items include "I am satisfied to be just what I am" and
"I get along well with other people." Raw scores were converted to
T-scores (M = 50, SD = 10); T-scores 
40 indicate
significant disturbances in self-concept. Each questionnaire was scored with
carbonized sheets.
Proband participants and nonparticipants who could be reached by telephone were administered a semistructured interview developed for this project. Probands were asked a total of 23 questions, providing a brief assessment of self-reported psychiatric treatment; lifetime episodes of perceived clinically significant impairment of social, occupational, and academic functioning; and psychosocial and environmental problems. Content was based on those areas delineated as DSM-IV Axis IV categories (e.g., problems with primary support group, educational problems, legal difficulties, and economic problems). Sample items included, "Have you ever been treated by a psychologist, psychiatrist, or other professional counselor?" and "Has there ever been a period of time when you were unable to work or go to school?" Participants were asked to report their age at and details surrounding these events. Items were rated dichotomously. Using a 3-point scale (i.e., more often, less often, or about as often), probands also were asked to rate frequency relative to peers of illness, of visits to the doctor, and of important activities missed due to illness, and to rate their perception of their overall health relative to peers using a 5-point scale (i.e., extremely poor to much better than).
Procedure
All individuals were assessed on an outpatient basis between January 1997
and May 1998 during one 4-hour session. Minors were accompanied by their
parents; written informed consent and/or assent was obtained at that time. All
tests were administered according to standard instructions. Although this
study primarily was designed to address emotional outcome in early-treated
PKU, each participant also completed a computerized neuropsychological
battery. Cognitive testing took place during either the first or second hour
of the assessment; these data will not be reported here
(Luciana, Sullivan, & Nelson, in
press).
Chart review of medical records of PKU probands was utilized to obtain IQ scores from each participant's most recent neuropsychological assessment and the most recently collected serum phe levels. As these data are collected routinely by the treating clinic, this investigation did not include direct assessment of current IQ. The average IQ obtained (M = 103.45, SD = 11.33) was not significantly different from that of the normal population (M = 100, SD = 15). Seventy percent (n = 14) of the PKU probands had serum phe measured within a year of this investigation; the correlation between the most recent levels and averages for the preceding five years was r =.75. Phenylalanine and treatment data are presented in Table I.
To assess for possible self-selection bias among probands, each PKU-affected patient who met inclusion criteria was re-contacted by phone once data collection was completed. Verbal consent or assent was obtained, following a review of standard consent issues. Demographic information and general adjustment data were provided, and chart reviews of IQ and treatment data were completed for 66.7% (n = 12) of those who declined to complete the full protocol.
Data were analyzed using SPSS for Windows, version 7.0. Chi-square analyses on nominal data and analyses of variance (ANOVAs) on continuous interval data were conducted to ascertain significant between-group differences. When group differences were found, post hoc comparisons using Tukey's LSD were conducted. To reduce the risk of Type I errors resulting from multiple comparisons, observed significance levels of p <.01 were considered to be significant; observed significance levels of p <.05 are discussed as trends.
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Results |
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Cumulative and Discrete Psychiatric Symptomatology
As shown in Table II, ANOVAs found no statistically significant differences between groups for the mean number of full psychiatric symptoms, subthreshold symptoms, full psychiatric diagnoses, subthreshold diagnoses, or the total number of combined diagnoses (i.e., full and subthreshold).
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The means and standard deviations obtained by each group on the MMPI-2/A
are presented in Table III. All
scores were within normal range. Statistically, groups were indistinguishable
and no specific trends were observed. The percentage of participants obtaining
clinically significant scores on at least one scale was similar for the PKU
(35%), chronically ill (41.2%), and peer (25%) groups, (
2 [2,
n = 53] =.977, p =.614). These results do not support the
hypothesis that probands would show more observable psychiatric disorders and
emotional or functional symptoms than chronically ill and peer controls.
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Though groups did not differ in cumulative and discrete psychiatric
symptomatology, significantly more of the chronically ill groups had sought
help for psychological concerns. Compared to none of the peer controls, 40% of
the PKU-affected participants and 50% of the chronically ill participants,
(2 [2, n = 53] = 10.689, p <.01),
reported that they had received services from a psychologist, psychiatrist, or
other professional counselor. These services included individual and family
treatment, as well as psychiatric evaluations that were not a component of
routine illness-related evaluations or participation in research projects.
Self-Concept
PKU-affected participants achieved a mean T-score of 47.9 ± 11.59
for total self-concept, which was not significantly different from that for
comparison groups. Mean scores are shown in
Table IV. The conflict score
for the chronically ill group was nearly significantly lower than the PKU
group (p <.05), indicating a defensive tendency for chronically
ill participants to define themselves in terms of negation rather than
assertion. No significant differences were found between groups on individual
self-concept scales, supplementary scales, the number of critical items
endorsed, or the number of scale scores falling in the clinically significant
range. Only 20% of the PKU group, 11.8% of the chronically ill group, and
18.75% of peers obtained total scores indicating clinically significant
deficits in self-concept, (2 [2, n = 53] =.493,
p =.782). These results do not support the hypothesis that
PKU-affected and other chronically ill participants would differ significantly
from healthy peers with regard to self-concept.
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Participant Representativeness
Possible self-selection bias among probands was assessed with data from 80%
(n = 16) of the PKU-affected participants and 66.7% (n = 12)
of the non-participants. The average IQ of nonparticipants (100.33 ±
8.44) did not significantly differ from that of participants, and there were
no differences between groups for average phe level, age at onset of dietary
treatment, duration of dietary treatment, or current treatment compliance.
Trend analyses revealed that, while all of the initial participants who were
available for follow-up were actively participating with the treating clinic,
25% of nonparticipants were not, (2 [1, n = 28] =
4.48, p <.05).
Participants and nonparticipants did not differ with regard to
self-reported incidents of impaired self-care, problems related to peer
groups, educational difficulties, occupational problems, financial
difficulties, or interactions with the legal system. Despite being
indistinguishable demographically and with regard to important treatment
variables, half of the participants reported having received individual or
family treatment, (2 [1, n = 28] = 8.40, p
<.01), compared to none of the nonparticipants. However, affected groups
did not report significantly different rates of social, academic, or
occupational impairment.
When asked to rate their overall health relative to peers, 96.4% of all affected participants rated their health as the same as or somewhat better than most of their peers. There were no differences in perceptions of health between participants and nonparticipants with regard to frequency of illnesses, visits to the doctor, or activities missed due to illness. The results obtained are not consistent with selection bias toward healthier or higher functioning probands.
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Discussion |
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This study was designed to include use of standardized measures, control groups that were matched for age and gender, and a sample of probands that was homogeneous for IQ, age, and length of dietary treatment, thus addressing methodological problems that have limited the validity of results from previous investigations. The results obtained indicate that early-treated PKU-affected adolescents and young adults, ages 14 to 25, were not at increased risk for diagnosable psychiatric disorders, clinically significant impairment on the MMPI-2/A, or deficits in self-concept. Neither did other chronically ill adolescents and young adults show greater deficits in self-concept compared to healthy controls. The only difference obtained between the PKU-affected and chronically ill groups indicated a defensive tendency for chronically ill participants to define themselves in terms of negation rather than assertion on the TSC:2, whereas PKU-affected participants typically presented a balanced self-description. Thus, the overall pattern and quality of observed emotional adjustment do not appear to be illness-specific.
These data do not disregard the conceptualization of chronic illness as a stressor; however, chronic conditions do not preclude healthy emotional adjustment. In fact, high percentages of both the PKU-affected and chronically ill groups were attending school or employed full-time, maintained a positive view of their appearance and health status, defined themselves as broadly competent, and viewed themselves in generally positive ways.
Despite these competencies, 40% of the PKU-affected participants and 50% of the chronically ill group reported that they had sought help for psychological concerns, though these data indicate that they apparently were not treated for symptomatology meeting full criteria for psychiatric diagnosis. Given that none of the PKU-affected non-participants reported receiving these services, the proband sample may have been composed of those patients who had a stronger interest in psychological issues or those who had been assisted by the treating clinic to a greater degree. The consistency between the results from structured interviews and the MMPI-2/A, which measured overall emotional and psychological functioning, and the semistructured interview that assessed psychosocial and health-related problems, suggests that the interview was a valid measurement tool for obtaining information that was not otherwise available from non-participants.
Although some is known about the nonparticipants from the PKU group, little is known about the chronically ill patients who declined to participate. These patients generally were unwilling to participate with a lengthy assessment battery when they received no direct benefits or perceived benefits for their own treatment, had no personal connection with research personnel, and regularly participate in treatment-related assessments. These factors indicate the need for collaborative studies across treatment clinics with standardized, longitudinal protocols.
Overall, these data are consistent with current research converging upon a profile of normal emotional adjustment in chronically ill groups. Negative results with regard to the incidence of significant psychological impairment in PKU probands seem to suggest that early and continuous dietary treatment has a protective effect. However, given that PKU is a chronic, developmental disorder, and the adequacy of phe control decreases throughout the life span, disturbances in emotional and behavioral functioning may develop as these adolescents and young adults continue to mature and negotiate developmental demands.
Collaborative strategies geared toward prevention and treatment across the life span should include ongoing contact with clinicians for neuropsychological testing, assessment of psychosocial functioning, anticipation of significant events (e.g., worsening of clinical status, transitions in education, and unexpected pregnancy), and to serve as a conduit to forms of intervention (e.g., individual counseling or family therapy). Follow-up studies of adult adjustment will be a priority for elucidating the impact of long-term phenylalanine control and illness-related stress on emotional, behavioral, and personality development.
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Acknowledgments |
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Jill E. Sullivan is now at Northwestern Memorial Hospital. These data served as the basis for this author's doctoral dissertation. This research was supported by a grant from the PKU Foundation at the University of Minnesota.
Received February 16, 2000; revision received August 23, 2000; revision received November 20, 2000; accepted December 21, 2000
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Burgard, P., Armbruster, M., Schmidt, E., & Rupp, A. (1994). Psychopathology of patients treated early for phenylketonuria: Results of the German collaborative study of phenylketonuria. Acta Paediatrica, 407(suppl.), 108-110.
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