Investigation of children with "developmental delay"

Abstract

A 7-year-old boy is referred to you with h concerns about developmental delay. On assessment, he is found to have moderate mental retardation (1Q of 50) but no remarkable physical findings. His parents are considering having another child, and they wonder what caused the retardation in their first child and whether it is likely to recur in future offspring.

Full text

EVIDENCE-BASED CASE REVIEWS
Investigation of children with “developmental delay”
.........................................................................................................
A 7-year-old boy is referred to you with concerns
about developmental delay. On assessment, he is
found to have moderate mental retardation (IQ of
50) but no remarkable physical findings. His
parents are considering having another child, and
they wonder what caused the retardation in their
first child and whether it is likely to recur in future
offspring.
.........................................................................................................
BACKGROUND
Developmental delay is a common problem in pediatrics,
with an estimated population prevalence as high as
10%.
1-4
The etiology includes various genetic and envi-
ronmental processes, with the most common causes being
Down syndrome and the fragile X chromosome. The pro-
portion of children with severe mental retardation found
to have an organic cause is reported as 55% to 57%.
5-7
No consensus exists on the choice of investigations for
developmental delay, with clinicians using a wide variety
of investigations.
8
The example we give in this article
is intended to illustrate the process used to evaluate
developmental delay in a variety of circumstances, recog-
nizing that the specifics will vary according to the clinical
situation.
This scenario raises many clinical questions. You wish
to use an evidence-based approach, so you frame your
questions to maximize the yield from searching and look
first for high-quality systematic reviews and evidence-
based practice guidelines to answer your questions. How-
ever, because most systematic reviews address issues of
therapy, no reviews or guidelines are found that address
your questions, which are mostly related to the probability
of particular causes of developmental delay. You go to
MEDLINE and EMBASE searches to try to answer these
questions (box 1).
You want to know the best estimate for the prevalence
of fragile X chromosome in the general population and the
best estimate for the prevalence of fragile X chromosome
among children with learning disabilities. From the 133
articles found in your search, 10 described population-
based studies of the prevalence of fragile X chromosome
that were performed since the cloning of the fragile X
mental retardation gene (FMR1) in 1991. Of the 10 stud-
ies, only 2 meet most of the criteria for high-quality preva-
lence studies (box 2).
You decide to start with the study of Murray et al
Summary points
In a 7-year-old child who has moderate intellectual
impairment:
• The likely prior probability of having fragile X
syndrome is between 1 in 40 and 1 in 250 (ie, to find 1
child with the fragile X chromosome, between 40 and
250 children would need to be tested)
• Currently available evidence shows that when a
scoring system based on physical and behavioral
features is used, a diagnosis of fragile X syndrome can
be confidently ruled out in those with low scores
• Decisions that are made about testing will depend on the
population from which the child comes and the values
that the tester and the parents put on having a diagnosis
versus the disadvantages of unnecessary testing
• The benefits of using this “clinical diagnostic test”
include preventing children from being subjected to an
unnecessary blood test, sparing parents the anxiety of
awaiting the results, and reducing the cost of
investigation
• The benefits of testing for the fragile X chromosome
include the resolution of diagnostic uncertainty, the
prevention of further investigations, and the
identification of female carriers
Hattie Young/Science Photo Library
Down syndrome is one of the more common causes of developmental delay
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Best Practice
Louise Hartley
Dubowitz
Neuromuscular Centre
Hammersmith Hospital
Campus
Du Cane Rd
London W12 0NN
UK
Alison Salt
Neurodisability Service
Institute of Child Health
Mecklenburgh Square
London WC1N 2AP
Jon Dorling
Jenny Lind Children’s
Department
Norfolk and Norwich
Hospital
Brunswick Rd
Norwich NR1 3SR
UK
Paul Gringras
Imperial College of
Science, Technology and
Medicine
London, UK
Correspondence to:
Dr Hartley
louisehartley70@
hotmail.com
Competing interests:
None declared
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Volume 176 January 2002 wjm 29www.ewjm.com

because it was limited to boys, used a population-based
sample, and tested only those aged 18 years or younger.
9
Neither the case definition for mental retardation nor the
distribution of IQs in the population is stated in the study,
and the low prevalence of fragile X chromosome suggests
that this is a relatively lower risk group (higher IQ) than
that used in other studies. Only 70% of children with
special educational needs were tested, and no information
is available about nonresponders. Because the prevalence
estimate of fragile X chromosome from this study would
be affected if children with the chromosome were less or
more likely to participate, you try varying the prevalence
in the nonparticipating group to half or double that of the
participating group. This gives a prevalence range for the
overall population of between 1 in 3,990 and 1 in 6,171,
which is reassuring because these numbers overlap with
estimates from other studies identified by your search (de
Vries et al,
10
1/6,045; and Turner et al,
11
1/5,000). Ap-
plying the same assumptions to the population of learning
disabled boys in this study gives a range of 1 in 162 to 1
in 250 (0.6%-0.4%).
In the study by de Vries et al, the learning-disabled
group was stratified into mild and moderate-to-severe
learning difficulty.
10
Unfortunately, the authors excluded
those who already had a diagnosis of fragile X; these cases
must be included for accurate prevalence figures. If the
prevalence of fragile X chromosome among the nonre-
sponders is similar to that among the responders, then
adding those known to have fragile X and new diagnoses
to the numerator gives an estimated prevalence of fragile X
chromosome for mild mental retardation of 1 in 50, with
1 in 40 for moderate to severe mental retardation. In your
7-year-old child who has moderate intellectual impair-
ment, you estimate the probability of his having the fragile
X syndrome as somewhere between 1 in 40 and 1 in 250.
You would, therefore, need to test between 40 and 250
children to find 1 child with the fragile X chromosome.
You next consider the usefulness of dysmorphic fea-
tures in ruling in or ruling out the diagnosis of fragile X
syndrome. A search nets 33 articles regarding dysmorphic
features in those with the fragile X chromosome. From the
abstracts, two articles were found that used a combination
of physical and behavioral features to select who, among a
group of mentally retarded children, has the highest prob-
ability of testing positive for the fragile X chromosome,
using molecular testing for the FMR1 gene.
10,12
The article by Giangreco et al refines previously de-
fined checklists of phenotypic characteristics associated
with the fragile X chromosome into a six-item checklist
with a scoring system, shown in table 1.
12
In this study, a score of 5 or more of a maximum of 12
was found to identify all children who had the fragile X
chromosome. Using the identification of these features as
a“diagnostic test”for fragile X chromosome, with mo-
Box 1
Focusing a literature search
•Baseline risk In a 7-year-old boy (population) with
mental retardation who does not have a diagnosis
responsive to specific interventions (exposure), what is
the risk of having the fragile X chromosome (outcome)?
Search: MEDLINE 1966 to present and EMBASE
(Winspirs); search terms fragile X (text or MeSH heading)
AND prevalence
•Baseline risk In a boy with mental retardation
(population) and no dysmorphic features (negative
test result), what is the risk of having the fragile X
chromosome (outcome)?
•Baseline risk In a boy with mental retardation
(population) with dysmorphic features (positive test
result), what is the risk of having the fragile X
chromosome (outcome)?
Search: MEDLINE (PubMed Clinical Queries); search
term fragile X—click on “diagnosis” and “specificity”
•Intervention/therapy In a boy with mental retardation
(population), does knowing the diagnosis of fragile X
chromosome (exposure) improve the parents’ ability
to plan and cope (outcome)?
Search: MEDLINE (PubMed); search terms parents
AND fragile X/diagnosis
Box 2
Criteria for appraising the quality of prevalence
studies
•Was the case definition clear?
•Was case ascertainment complete?
•Were details of nonresponders or those not tested clear?
•Was the group studied representative of your patient?
•Did prevalence estimates include confidence intervals
and take into account the possibility of different
disease rates in the nonresponders?
Table 1 Phenotypic characteristics associated with fragile X: checklist and scoring system*
Characteristics Score
01 2
Mental retardation IQ >85 IQ 70–85 IQ <70
.............................................................................................................................................
Family history None Maternal female
with psychiatric
disorder
Maternal history of
X-linked mental
retardation
.............................................................................................................................................
Elongated face Not present Somewhat Present
.............................................................................................................................................
Large or prominent ears Not present Somewhat Present
.............................................................................................................................................
Attention deficit
hyperactivity disorder Not present Hyperactivity Present
.............................................................................................................................................
Autistic-like behavior† Not present 1 behavior >1 behavior
*From Giangreco et al.12
†Tactile defensiveness, perseverative speech, hand flapping, poor eye contact.
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lecular testing as the gold standard, you use the guidelines
on assessing diagnostic and screening tests summarized in
box 3.
13
In this retrospective study, the molecular polymerase
chain reaction (PCR) technique was used in all patients,
but the authors do not state whether those applying the
diagnostic test were blind to the (PCR-defined) fragile X
status of the patients. If the assessors already knew the
“answer,”the potential for biased assessment is high. The
scoring system is clear; however, some of the physical fea-
tures, such as long face and large or prominent ears, are
subjective, and no objective measurements are given.
Some of the behavioral characteristics may also be open to
interpretation. The provision of genetic testing at the time
of the study may have been unique to this study or this
location; if so, this could have attracted a highly selected
group of children, and the results may not be generaliz-
able. Because the clinical features of fragile X syndrome are
well known to clinicians, and all children were referred for
testing, the children referred are likely to have had a high
prevalence of the chromosome. The data necessary for
calculating likelihood ratios (LRs) presented in the article
are shown in table 2.
In this study, a negative result (those with a score <5)
will effectively rule out a diagnosis of the fragile X chro-
mosome because it is a highly sensitive test. That is, chil-
dren with a low score on the clinical assessment are un-
likely to have the chromosome. However, the calculated
LR of a positive test in this study is 2.5. In general, LRs
between 2 and 5 generate only small changes in probabil-
ity. Indeed, if the pretest probability is 3.5%, then a posi-
tive test increases the probability of having the fragile X
chromosome to only 8.2%.
de Vries et al studied a prospectively collected sample
with examiners blind to the fragile X result
10
using a simi-
lar scoring system: the phenotypic criteria described by
Laing et al.
14
Scores were divided into three groups: low
risk, when dysmorphic features suggested another diagno-
sis; medium risk, in the absence of dysmorphic features;
and high risk, in the presence of fragile X chromosome
characteristics. This sample contained many adults in
whom the phenotype is more characteristic than in chil-
dren. Despite this, the outcome was impressive. None of
the low- or medium-scoring males had the fragile X chro-
mosome, with all those who had the chromosome scoring
in the high range. Of course, this did not mean that all of
the high scorers had the syndrome. The LR for a high
score was 10, and the LR for a low or medium score was
0. The high LR for a positive test confirms your suspicion
that the patients in their group showed more distinct fea-
tures. This indicates how test performance, including LRs,
can vary when a test is applied to different groups.
Although neither of these studies is ideal, both show
that children who do not have the fragile X chromosome
can be correctly identified clinically (decreasing the num-
ber of molecular tests that are done) and that having clini-
cally identified features increases the likelihood of a posi-
tive genetic test but does not confirm the diagnosis. If our
group were similar to that described by Murray et al, with
a prevalence of 0.4% (the lowest possible estimate of
prevalence), and the diagnostic test performed in the same
way as described by Giangreco et al, with an LR of 2.5, the
Box 3
Criteria for appraising studies of diagnostic tests
•Does the study include an independent, blind
comparison with an adequate reference standard?
•Did the sample include an appropriate spectrum of
patients to whom the test should be applied in
practice?
•Did the test result influence the decision to perform
the reference standard?
•What are the results, and what is the precision of the
results?
•Will the test help in caring for patients?
Table 2 Calculation of likelihood ratios
Test score
Positive fragile
X PCR test,
no. of patients
Negative fragile
X PCR test, no.
of patients Likelihood ratios
5 12 129 For positive test:
(12/12)/(129/323) = 2.5
.............................................................................................................................................
<5 0 194 For negative test:
(0/12)/(194/323) = 0
.............................................................................................................................................
Total 12 323
PCR = polymerase chain reaction
Table 3 Considerations for genetic diagnostic testing in developmentally delayed children*
Positive effects Negative effects
Treatment—such as thyroid replacement
therapy if hypothyroid Harm from testing—the pain of
venepuncture or the risk of general
anesthetic for some investigations
.............................................................................................................................................
Genetic counseling—such as discussion
of chromosome abnormality with
extended family
False-positive and false-negative results
.............................................................................................................................................
Explanation—for parents and family,
even if no treatment identified Financial costs
.............................................................................................................................................
Prognostic information
.............................................................................................................................................
Research—if an investigation may
increase understanding of the
mechanisms and/or genetics of the
developmental delay
*From Gringras.8
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posttest probability of having the fragile X chromosome
would have increased from 0.5% to 1.0%.
9,12
However,
the high sensitivity of the test suggests that instead of
testing 250 children before finding 1 child with the fragile
X chromosome, you could exclude 150 of those children
(60%) from testing with minimal risk of missing a case. de
Vries et al suggest that in a group with moderate or severe
mental retardation, a higher prevalence may be expected
(the highest estimate being 3.3%).
10
Excluding those with
a known diagnosis from the denominator gives an esti-
mated prevalence of about 4%, so the posttest probability
is, therefore, increased to 10%. Under these circum-
stances, for every 24 children at risk, 14 could be excluded
from testing, and 1 of the remaining 10 would have the
fragile X chromosome.
You wonder about the benefit to the parents of know-
ing their son’s diagnosis but are not able to find random-
ized trials or cohort studies directly relating to the diag-
nosis of fragile X chromosome. A table is found that
provides a framework with the different values associated
with making a diagnosis in children with developmental
delay (table 3).
.........................................................................................................
Resolution of the scenario
You are now able to estimate the probability of
the patient’s having the fragile X chromosome as
somewhere between 1 in 40 and 1 in 250 and
would, therefore, need to test between 40 and
250 children to find 1 child with the chromosome
abnormality. If this child has a score of less than
5 for the features described by Giancreco et al,
you feel confident in ruling out the chromosome
abnormality and not proceeding to molecular
testing.
12
Because there is no well-established treatment
option, the direct benefit to the patient of making
a diagnosis is marginal. However, the use of this
clinical diagnostic test avoids subjecting some
children to an unnecessary blood test and spares
some parents the anxiety of awaiting the results,
as well as the unnecessary expenditure. In
addition, the resolution of diagnostic uncertainty
can provide much relief and stop further
investigations for a cause of developmental
delay. As more information on the prognosis of
this condition becomes available, parents and
patients may benefit from this knowledge. Also,
for the parents and relatives, the identification of
female carriers may allow an informed choice
regarding at-risk pregnancies.
.........................................................................................................
CONCLUSION
Within the limitations of current evidence, some infor-
mation is now available on the range of the possible preva-
lence of the fragile X chromosome in different groups, and
some understanding of how specific features of the fragile
X syndrome may influence your decision making. The
decisions that are made depend on the group from which
the child comes and the values that the tester and the
parents put on having a diagnosis versus the disadvantages
of unnecessary testing. In this article, we provide a model
for thinking through the issues involved in the investiga-
Fragile X syndrome: the benefits of testing include diagnostic certainty. (Courtesy of the Fragile X
Society, www.fraxa.org)
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tion of developmental delay and a way of incorporating
evidence into this process. We have chosen a common
example to illustrate the process, that of fragile X syn-
drome, the second most common cause of mental retar-
dation after Down syndrome. The prevalence of a par-
ticular disorder in different patient groups will influence
the outcome of any diagnostic investigations. This method
is generalizable to other causes of developmental delay.
This article was edited by Virginia A Moyer of the Department of
Pediatrics, University of Texas Medical Center at Houston. Articles in
this series are based on chapters from Moyer VA, Elliott EJ, Davis RL,
et al, eds. Evidence-Based Pediatrics and Child Health. London: BMJ
Books; 2000.
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