Behavioural Sciences Unit, Institute of Child Health
Mothercare Clinical Genetics Unit, Institute of Child Health, London, UK
Correspondence: Dr Jane Gilmour, Behavioural Sciences Unit, Institute of Child Health, London WCIN IEH, UK
Declaration of interest J.G. was funded by a Wellcome Trust Prize Studentship.
See editorial, pp.
9394, this issue.
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ABSTRACT |
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Aims To compare the behavioural and stress profiles of HSS with those of Prader-Willi syndrome (PWS), and to test the hypothesis that the genetic locus that predisposes to HSS co-inherits with the PWS locus at 15q11-13.
Method Twenty-five children with HSS, mean age 9.1 (s.d. 3.8) years, 28% female, were compared with 30 children with PWS, mean age 8.8 (s.d. 2.8) years, 33% female.
Results The clinical profiles were largely similar across the conditions, but no evidence was found in HSS of co-inheritance of the PWS critical region.
Conclusions Hyperphagic short stature is one of the very few behavioural diseases associated with a pathognomonic physiological abnormality. Investigations of the suggested genetic dysregulation, which is so sensitive to environmental influences, may well be of importance in a broader context.
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INTRODUCTION |
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Hyperphagic short stature and PraderWilli syndrome
compared
Many signs of HSS are remarkably similar to PraderWilli syndrome
(PWS), although to date no study has directly compared the conditions.
Children with HSS show hyperphagia, including gorging, pica, food hoarding
(Bowden & Hopwood, 1982;
Mouridsen & Nielsen, 1990)
and polydipsia (Skuse et al,
1996). Hyperphagia is also a cardinal symptom of PWS
(Cassidy, 1992). Sleep cycle
disruption is described in both HSS
(Gilmour & Skuse, 1999) and PWS (Helbing-Zwanenburg et
al, 1993). Short stature is a common feature of PWS
(Cassidy, 1992), although there
is debate about whether individuals have primary growth hormone deficiency
(e.g. Angulo et al,
1992; Ritzen et al,
1992). Growth hormone insufficiency is invariable in HSS
(Skuse et al, 1996), but it is exquisitely responsive to environmental circumstances. We
hypothesise that the dysregulation of appetite, growth and sleep
characteristic of HSS might constitute an inherited predisposition to
hypothalamic dysfunction, as has been described in PWS
(Cassidy, 1992).
The developmental histories of each condition closely correspond. Infants with PWS have poor muscle tone, feeding problems and delayed motor milestones (Butler, 1990; Cassidy, 1992). Failure to thrive and feeding problems commonly occur in HSS (Bowden & Hopwood, 1982), together with delayed motor milestones (Hopwood & Becker, 1979; Ferholt et al, 1985) and hypotonia (Gilmour & Skuse, 1999). The onset of hyperphagia is delayed until early childhood in PWS (Holm Et al, 1993). In HSS, hyperphagia is not evident until children are at least 3 years old. Both conditions are associated with global learning disability (Bowden & Hopwood, 1982; Money et al, 1983; Ferholt et al, 1985; Butler, 1990; Skuse et al, 1996), although the degree of learning disability is less marked in HSS than in PWS. Greater degrees of learning disability may be associated with increased risk of behavioural problems in children with PWS (Dykens et al, 1992), although this is not a consistent finding (e.g. Dykens & Cassidy, 1995).
Skin-picking is characteristic of the PWS phenotype (Greenswag, 1987). Children with HSS also show self-injury, including skinpicking (Money et al, 1985). Oppositional behaviour (Blizzard & Bulatovic, 1992), deliberate enuresis and encopresis (e.g. Money et al, 1985; Blizzard & Bulatovic, 1992; Skuse et al, 1996) and depression (Ferholt et al, 1985) are associated with HSS. Many children with PWS show marked internalising and externalising disorders (Dykens et al, 1992; Dykens & Cassidy, 1995; van Lieshout et al, 1998a). These may be provoked by food restriction (Butler, 1990), although this is unlikely to be the only causative mechanism. The disturbance is more severe in individuals with a chromosomal deletion compared with those with uniparental disomy, though the quality is the same (Dykens et al, 1999).
Differentiating features
While there are striking parallels between the two conditions, some
features differentiate them. Children with PWS are characteristically obese
and lethargic (Butler, 1990;
Cassidy, 1992), while those
with HSS have a body mass index (BMI) in the normal range
(Bowden & Hopwood, 1982; Mouridsen & Nielsen, 1990;
Skuse et al, 1996) and are usually overactive (Skuse et
al, 1996). Their overactivity may account for the lack of
weight gain despite their hyperphagia, but the possibility of a hypermetabolic
disorder has not yet been investigated. Symptoms of psychosis
(Clarke, 1998) and
obsessive-compulsive features (e.g. Dykens
et al, 1996) have been described in individuals with PWS.
Such symptomatology has not been described in the HSS population, but nor has
it been investigated directly. Clinical features of the two conditions are
compared and contrasted in Table
1.
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While a high incidence of familial aggregation is common in HSS (Bowden & Hopwood, 1982; Money et al, 1983; Skuse et al, 1996), it is rare in PWS, with most cases being sporadic genetic anomalies (Cassidy, 1992). Prader-Willi syndrome is a congenital condition with an established anomaly at chromosome 15q11-13 (see Nicolls et al, 1999). This is commonly due to a deletion at the critical region (Ledbetter et al, 1981) or uniparental disomy in which the affected individual has two maternally derived copies of the critical region on chromosome 15 and no paternally derived copy (Nicolls et al, 1999). This observation and rare imprintor mutations associated with PWS indicate that it is an imprinted condition (Nicolls et al, 1999). Imprinting means that a gene is silent or expressed in children depending on whether it is inherited from the mother or father. A mutation in a normally imprinted gene means that the gender of the transmitting parent determines whether the child manifests the disorder or not. The phenotype will not be expressed if the mutated allele is silenced.
Intrafamilial stress
In the case of HSS, we propose that a gene-environment interaction is
necessary for the key clinical features to become apparent. Children who meet
diagnostic criteria for HSS invariably live in conditions of stress. The
nature of that stress is often intra-familial abuse
(Bowden & Hopwood, 1982;
Skuse et al, 1996),
but not necessarily so. For example, one child in our series lived in
extremely poor housing conditions and was not the subject of parental abuse;
another developed symptoms during a civil war. However, abuse of a child by a
parent is a potent form of stress, and so is especially likely to precipitate
the clinical features. Removing the child from the stressful environment
coincides with the rapid recovery of growth hormone levels from insufficient
to high normal levels (Skuse et
al, 1996); hyperphagia and associated sleep disruption also
resolve within a matter of days (Skuse
et al, 1996). Over a substantial period of time separated
from the stressor, catch-up growth occurs (e.g. Powell et al,
1967a,b).
In contrast, the non-specific emotional and behavioural disturbances
(Gilmour & Skuse, 1999) associated with living in psychosocial adversity, which are common to affected
and unaffected children, do not show such a rapid response to environmental
change. Re-introduction to the original environment is associated with a
return of the key clinical features and a limitation or cessation of linear
growth (Taitz & King,
1988).
While stress does not provoke the PWS symptoms, high levels of intrafamilial stress are reported in association with the disorder. Families of a child with PWS describe more negative family and child characteristics and greater pessimism about the future than comparison families who have a child with learning disability (Hodapp et al, 1997). They regard themselves as angry, controlling, inconsistent and subject to marital conflict (van Lieshout et al, 1998b). The PWS behavioural phenotype is reported to be particularly demanding on a family's coping resources (Hodapp et al, 1997; van Lieshout et al, 1998b). In other words, it is generally accepted that managing the PWS child induces intrafamilial stress. No previous study has considered that managing children with a genetic predisposition to HSS may induce stress in their families too.
Aims
We aimed to assess, using standardised measures, the degree of similarity
between the clinical features of HSS and PWS. We also wished to test the
hypothesis that the major locus predisposing to HSS co-inherits with the PWS
locus at chromosome 15q11-13 or that there is an abnormal pattern of
methylation at this locus.
We predicted that equivalently high levels of intrafamilial stress and arousal would be identified in the families of PWS and HSS probands, using a measure of expressed emotion (EE; Vaughn & Leff, 1976). In general, parents rated as high EE report higher levels of family conflict and mental health problems (Hibbs et al, 1993) and their children show higher levels of physiological arousal (Hibbs et al, 1992). Children living in conditions of persistent stress show attenuated hypothalamic-pituitary-adrenal (HPA) axis reactivity following an acutely stressful stimulus (Kaufman et al, 1997). This characteristic pattern is due to a physiological adaptation to their chronically stressful environment (e.g. Kirschbaum & Hellhammer, 1989). We also predicted that HSS, and possibly also PWS, subjects would show a blunted HPA response to an exogenous stressful stimulus.
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METHOD |
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Recruitment
Children with HSS were recruited largely from specialist growth clinics
(n=24). We also advertised in women's magazines, asking for families
with a hyperphagic child to contact us. One additional case of HSS was
identified this way. Fifty per cent of the PWS sample (n=15) were
recruited through the parent support group, the Prader-Willi Association (UK).
Seventeen per cent (n=5) were recruited from the advertisements.
Paediatricians and psychiatrists referred others. Owing to the methods of
recruitment that we were required to employ, we are unable to report the true
refusal rate.
Measures
Direct assessment
Anthropometric measures were obtained using standard clinic equipment by
trained personnel. We used the Castlemead Growth Programme
(Boyce & Cole, 1993) to
convert heights and weights into standard deviation scores, corrected for age.
A standard deviation score of -1.88 corresponds approximately to the third
centile in height. The short form of the Wechsler Intelligence Scale for
Children (3rd UK edition) (WISC-III-UK) and the Wechsler Pre-school and
Primary Scale of Intelligence (revised) (WPPSI-R) were used to assess
cognitive ability (Wechsler,
1990,
1992). Using four sub-scales,
full-scale, performance and verbal IQ scores were pro-rated.
Parent and teacher report
The Hyperphagic Short Stature Diagnostic Interview (HSSDI) was designed
specifically for the study of HSS children. No existing published measure was
suitable. The interview is semi-structured, requiring parents to provide
specific examples of their child's behaviour. Ratings (0-3) were justified on
the basis of reported behaviour, rather than parental opinion or
generalisations. The behaviours described were rated against specified
behavioural anchors. This method is more consistent than asking parents to
make their own judgements about the relative severity or abnormality of
behaviour. Frequency, severity and the context in which behaviour occurred
were noted. Previous studies have confirmed the predictive validity of this
instrument for HSS (Skuse et al,
1996).
Teachers also completed the HSS Teacher Questionnaire (Skuse et al, 1996). Copies of this questionnaire and the HSSDI are available from the author upon request. Parents and teachers completed the Child Behaviour Checklist (CBCL) and the Teacher's Report Form (TRF) respectively (Achenbach, 1991a,b).
Molecular genetics
Two investigative methods were used: a methylation status test and sibling
pair linkage analyses. The critical region of PWS is imprinted, which means
that the parental origin of a critical region plays a crucial role in normal
development. Normally only the paternal allele is expressed at 15q11-13, while
those with PWS have only the maternal allele or maternal disomy (two maternal
alleles) at this region, and therefore no paternal allele. The methylation
test is sensitive to allelic expression. A normal methylation pattern in the
current investigation indicates that PWS is highly improbable.
Sibling-pair linkage analysis is a more stringent test of the PWS co-inheritance theory as it can, for example, exclude rare point mutations. For details of the probes used, see Buiting et al (1994). Sibling-pair linkage analysis is based on the premise that loci close to one another on the chromosome will stay together during meiosis, but that loci further apart have a higher probability of recombining. If the PWS locus is not associated with HSS then affected siblings would share the DNA marker alleles according to standard Mendelian ratios. In other words, there would be evidence of allelic discordance between affected siblings across the PWS region. The markers that we used in the current study are tightly linked to the critical region. Four CA repeat markers covering different parts of the critical PWS region were used: IR4, D15S210, GABRB3 and MS14. Protocols are available from the author upon request.
Intrafamilial stress measure
The Camberwell Family Interview (Vaughn
& Leff, 1976) provided ratings of expressed emotion on the
following scales: Critical comments, Positive remarks, Emotional
overinvolvement (EOI), Hostility, and Warmth. Caregivers who score over 3 on
EOI or are rated 1 and above on hostility, or make six or more critical
comments, are rated high EE. The ratings of EE reported in this
study were completed by a trained rater, unaware of case status, but aware of
the child's IQ and age. In the rating of EOI a correction was made for
children with moderate to severe learning disabilities (an IQ less than 50),
who were judged to require protection beyond that expected in normal children
of equivalent age.
Physiological stress reactivity
Each child's HPA reactivity was measured by inducing elevated levels of
cortisol through a brief period of intensive exercise. Cortisol levels were
measured serially using salivary cortisol assays, which provide an accurate
measure of plasma free cortisol (Vining
et al, 1983). Physical stress such as exercise increases
salivary cortisol levels in normal children
(Kirschbaum & Hellhammer,
1989). We used the Harvard Step Test
(Kirkendal et al,
1987) and children took 60 steps per minute, which increased their
heart rate to about 150 beats per minute, a level that is normally associated
with a significant increase in salivary cortisol levels (R. Lane, personal
communication, 1996). The full protocol is available from the author upon
request. In children who were subject to chronically high levels of day-to-day
stress, we expected to see an attenuation of the exercise-induced cortisol
response.
Comparison group (salivary cortisol only)
Twenty unselected children from a mainstream primary school, aged 8-9 years
(of whom 12 were boys), provided normative salivary cortisol samples. Parents
were informed by letter of our study. The exercise was carried out in the
early afternoon, with all children participating simultaneously.
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RESULTS |
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Child characteristics
In the HSS group IQ scores ranged from 50 to 118; the range was 40 to 91 in
the PWS group. Because 40 is the lowest IQ score attainable on the WISC (41 on
the WPPSI-R) it may be that a floor effect has biased the estimate of mean IQ
in the PWS sample; in this sample 23% of children (n=7) scored at the
floor of the test. Lower IQ scores are associated with greater emotional and
behavioural disturbance in general (e.g.
Goodman et al, 1995). Accordingly, we considered using IQ as a covariate in all the following
analyses, but did not do so on the grounds that our aim was to report and
compare absolute levels of behavioural disturbance in the two samples.
The HSS children were significantly shorter than the PWS children, but the PWS group had a significantly higher BMI (Table 2). Six of the children in the PWS group had been treated with growth hormone. There was no significant difference in height or in BMI between those who had been so treated and those who had not.
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Parent and teacher reports
Standardised population (T) scores (mean 50, s.d. 10) on the Child
Behaviour Checklist and the Teacher Report Form (Achenbach,
1991a,b)
are reported in Table 3.
Standardised T scores of 65-69 fall into the borderline clinical
range, while scores of 70 and above can be regarded as clinically significant
(Achenbach,
1991a,b).
On the basis of teacher reports both groups show broadly similar group
profiles. Parents of PWS children reported more thought problems and social
problems than the HSS caregivers, who reported significantly more
anxious/depressed symptomatology. The total-problems scores were similar in
both groups.
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Hyperphagia
Thirteen variables relating to appetite disturbance, from the HSSDI and the
Teacher Questionnaire (school data were unavailable for one child in the PWS
group), were entered into a principal components analysis (PCA) with varimax
rotation. The data were generated from a larger data-set, including the
children from this study and a consecutive series (n=25) of children
living in psychosocial adversity. Three factors were identified.
General hyperphagia explained 33.2% of the variance,
school-specific hyperphagia explained a further 15.7%, and
pica/polydipsia explained 9.7%
(Table 4). Scores were compiled
for the three variables derived from this analysis by summing together the
untransformed values for all relevant questions.
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Full-scale IQ did not correlate significantly with hyperphagia at school,
general hyperphagia or pica/polydipsia in either group. There were no
significant differences between the groups, with set at 0.05, on any
of the factor summary scores for acute hyperphagia, general hyperphagia or
pica/polydipsia. Figure 1 shows
that the quality of the appetite disturbance was similar in both groups.
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Parents' reports of their management techniques for hyperphagia were considered in mutually exclusive categories. There are no significant group differences. Three (12%) of the HSS caregivers reported that they did not try to prevent their child from taking food at all, despite an excessive appetite, and three (10%) of the PWS group did not use preventive measures. Six (32%) of the HSS caregivers used verbal warnings not to take food, compared with 11 (37%) in the PWS group. Nine (36%) of the HSS families used locks on food cupboards, compared with 13 (43%) in the PWS group. Excluding the child from the kitchen or other areas of the house was reported in four (16%) of the HSS cases compared with two (7%) of the PWS cases. There was a trend in the PWS group for more behaviour problems (measured as a sum of parent- and teacher-reported total-problems scores) to be associated with more restrictive techniques of denying children's access to food. Mean behaviour problem scores in the PWS group were 126 (s.d. 15) for children whose parents used verbal warnings, 136 (s.d. 14) for those who used locks on food cupboards, and 140 (s.d. 6) for children who were excluded altogether from certain areas of the house. In the HSS group equivalent scores were 121 (s.d. 22), 123 (s.d. 28) and 131 (s.d. 9) respectively for each management tactic.
Sleep
In the HSSDI, parents were asked to describe their children's sleep
patterns. Sixty-three per cent of the PWS group and 44% of the HSS group had
frequent and persistent sleep disturbance, including night roaming, to a
degree that was developmentally inappropriate: a non-significant group
difference.
Molecular genetic studies
Fourteen children in the HSS group were tested with the methylation status
test (Dittrich et al,
1992; Buiting et al,
1994). All showed a normal methylation pattern at 15q11-13, which
indicates that all children with HSS had one paternally derived allele and one
maternally derived allele at the critical region of chromosome 15. For the
sibling pair linkage analysis, two family pedigrees were tested using four
marker probes (Mutirangura et al,
1993) across the PWS region. In family studies these closely
linked markers can be used to establish the array of alleles (haplotype) for
individual chromosomes. The pattern of haplotype inheritance is shown in
Fig. 2. In family C, DNA was
available from both biological parents and all three affected full siblings,
but was not available from a further unaffected half-sibling. While the index
case (JC) and his affected sister (CC) have inherited the same two haplotypes,
GC, who is also affected, has no haplotype in common. This is evidence against
a locus for HSS being located in the PWS region, regardless of the Mendelian
pattern of inheritance of HSS.
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In family M, maternal but not paternal DNA was available (family M are part of a retrospective series, not the current sample). Samples of DNA were gathered from two affected and three unaffected full siblings (Fig. 3). The paternal haplotypes have been inferred on the basis of his children's allele pattern. The children LM and LaM were both affected, and although they almost certainly inherited the same maternal and paternal alleles at D15S210, MS14 and possibly at GABRB3, so did an unaffected sibling (LiM). These data from family M are also evidence against a locus for HSS being located in the PWS region.
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Intrafamilial stress
Each sub-scale of the Camberwell Family Interview
(Vaughn & Leff, 1976) was
analysed separately in order to develop a more detailed profile for each index
child. Critical comments were classified according to whether they were
food-related or not (Table 5).
Examples of food-related comments include: Nine times out of ten he
can't be bloody hungry. Why he needs it or why he wants it is a complete
mystery to me. The total number of food-related comments was
significantly related to the degree of hyperphagia in the PWS group
(r=0.4, P<0.05). Although the trend was similar in HSS,
it was not significant. In the PWS group caregivers made proportionately more
food-related critical comments relative to all critical comments (52%) than
the HSS group caregivers (32%), but this difference did not reach
significance. Twelve (50%) of the HSS caregivers were rated as high EE
compared with seven (23%) in the PWS group (2=4.2 (1),
P<0.05).
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Hostility was rated on a scale of 0 to 3. Vostanis & Nicholls
(1992) found none of the
parents in a non-referred group scored above 0. One (3%) of the PWS caregivers
expressed hostility (a score of 1 to 3), compared with five (21%) of the HSS
group caregivers (2=2.4 (2), not significant). There were no
significant group differences in EOI, positive remarks or food-related
critical comments.
Child's physiological reactivity
We aimed to discover the patterns of HPA reaction and recovery following an
acute stressor (an exercise step test) using salivary cortisol assays.
Obesity, a common feature of PWS, is associated with elevated cortisol levels
in plasma and saliva. Therefore we recruited, in addition to our case samples,
a normal comparison group. The test was administered in early afternoon in all
cases. There was no significant relationship with baseline cortisol level and
BMI in either the HSS or PWS samples. These results are consistent with
previous reports of baseline cortisol levels in the normal range for children
with PWS (Tu et al,
1992). Mean pulse rates at baseline were 95.9 beats per minute
(s.d. 15.7) and 92.9 beats/min (s.d. 15.1) for the HSS and PWS groups
respectively. Heart rates were 161.3 beats/min (s.d. 21.3) in the HSS group
and 161.1 beats/min (s.d. 17.9) in the PWS group after the step exercise. A
repeated measures analysis of variance (ANOVA) showed a significant increase
in pulse rate pre- and post-exercise for the whole sample (F (45,
1)=463, P<0.001), but no group x pulse rate change
interaction (F (45, 1)=0.05, not significant). Pulse rate data were
not available for the community comparison children.
Table 6 shows the cortisol
levels for the groups pre-test and at 10, 20, 30 and 60 minutes after the
exercise stress. Peak response is predicted approximately 30 minutes after the
exercise stress (Kirschbaum &
Hellhammer, 1989). There was wide variation within the groups,
with significantly greater variability among PWS than HSS children, especially
at 10 minutes (F=5.5, P<0.01), 20 minutes
(F=5.9, P<0.05) and 30 minutes (F=11.1,
P<0.01) after exercise. Such variability reduces the power to
detect significant mean differences between groups
(Kiess et al, 1995).
No group differences were detected overall, nor for any specific sample, and
there were no group x time of assay effects, using polynomial contrasts
on the assay.
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DISCUSSION |
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Sample size and bias
The specificity and sensitivity of both molecular genetic techniques
provide strong evidence of the exclusion of the HSS locus from the PWS region.
The sample sizes for the psychological assessments were small, limiting the
power to detect group differences. Accordingly, comparisons of means between
PWS and HSS samples were liable to be associated with type II errors. On the
other hand, statistically significant differences would have been associated
with large effect sizes (Cohen,
1992), equivalent to identifying phenomena of clinical
significance.
Both samples were largely recruited through medical services. It is likely that the children included had more severe clinical problems than one would observe in an epidemiological survey. Given that our aim was to compare the conditions, it is appropriate that both groups were recruited through similar routes, so any bias will apply equally to both conditions. It does not make the comparison invalid.
Future genetic investigations
Molecular genetic analyses were conducted to test for co-inheritance of the
PWS locus in HSS sibling pairs. Neither methylation patterns nor sibling pair
linkage analysis indicates that HSS subjects have an anomaly at the PWS
critical region. If children with HSS do indeed have a genetic predisposition
to the condition, alternative candidate genes need to be evaluated, including
those involved in appetite and growth regulation. A chromosomal anomaly may be
associated with HSS, but cytogenetic studies have not yet been conducted.
Physiological reactivity
The salivary cortisol results were difficult to interpret. Neither the HSS
nor the PWS group profiles differed significantly from the community
comparison group. Lack of mean group differences could be attributable in part
to the wide within-group variability, which was especially marked in children
with PWS. The level of stress experienced during the exercise
may not have increased cortisol levels to an adequate degree. Kirschbaum &
Hellhammer (1989) obtained a
peak response that was 250% greater than baseline salivary cortisol levels. We
induced increases of only 10%, 53% and 12% in the HSS, PWS and community
comparison groups respectively. A more challenging stressor, other than
exercise, might have produced significant results, but raises ethical
considerations.
Hyperphagia may precipitate stress
Given the broad similarities between HSS and PWS we might assume that
having a child with either condition would have a similar impact on the
family. A re-evaluation of the direction of effects that lead to
intra-familial stress in HSS has important clinical implications. It is often
assumed that HSS is entirely caused by psychosocial adversity. Children are
often subjected to care proceedings on the grounds that their symptoms usually
resolve in an alternative family, and catch-up growth ensues. However, our
experience over the past decade has shown that, in many instances, after a
honeymoon period, the child's unregulated behaviour recommences
in foster care, leading eventually to stress and rejection. Growth in stature
then reduces or ceases altogether. In support of our hypothesis that
hyperphagia induces similar reactions from families with HSS and PWS, there
were no group differences in the number of food-related critical comments. The
PWS group caregivers were all aware that hyperphagia is part of their child's
condition, information that was not available to families in the HSS group at
the time of the EE rating. The number of critical comments was related to the
degree of hyperphagia in both samples. As shown in
Fig. 4, the clinical features
of HSS, which are certainly exacerbated by stress, may also contribute to
intrafamilial stress.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication April 11, 2000. Revision received October 31, 2000. Accepted for publication October 31, 2000.
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