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American Journal of Medical Genetics Part C (Semin. Med. Genet.) 142C:3 –7 (2006)
A R T I C L E
Etiologic Yield of Autistic Spectrum Disorders:
A Prospective Study
AGATINO BATTAGLIA* AND JOHN C. CAREY
Studies addressing etiologic yield in childhood developmental disabilities have mainly looked at individuals with
developmental delay/mental retardation. The few studies addressing the question of etiologic yield in patients
with pervasive developmental disorders (PDDs) had a major drawback, in that the enrolled subjects were
diagnosed as having the autistic spectrum disorders based only on history and clinical examination, and/or on
unspecified instruments. In addition, only some of these patients underwent a complete laboratory evaluation. To
investigate the etiologic yield of PDDs, we undertook a large prospective study on subjects selected according
to very strict criteria and diagnosed as having PDD based on the present ‘‘gold standard’’ (ADI-R and ADOS-G),
and a clinical diagnosis made by a child psychiatrist. Eighty-five (85) patients with PDD and their first degree
relatives participated in this study. These patients were selected from a sample of 236 subjects who had received a
clinical diagnosis of PDD at the Stella Maris Institute between March 2002 and 2005. Selection criteria for entering
the study were: (1) a diagnosis of PDD (with exclusion of the Rett syndrome) confirmed after the administration of
the ADI-R (autism diagnostic interview-revised) and the ADOS-G (autism diagnostic observation schedulegeneric). In addition, a clinical diagnosis was made by the child psychiatrist, on the basis of presence or absence of
DSM-IV symptoms of autism; (2) chronological age between 4 and 18 years; (3) IQ>30; (4) availability of both
biologic parents. Patients, 65/85 (76.5%), had autism, 18/85 (21.2%) had PDD-NOS, and the remaining 2/85
(2.3%) had Asperger syndrome. Ages varied between 4 years 2 months and 12 years 5 months (mean 7.6 years),
and there was a marked male preponderance (68/85). All subjects underwent various laboratory studies and
neuroimaging. With respect to possible etiologic determination, a detailed history and physical examination in this
group of patients with PDD was informative in 10.5% (9/85). HRB karyotype was diagnostic in one, and molecular
fragile X studies in one child. Brain MRI was informative in two children (2.3%) with relative macrocrania but no
neurological features; and EEG was helpful in one child, identifying a Landau–Kleffner disorder. Audiometry and
brainstem auditory evoked potentials (BAEPs) showed a bilateral sensorineural loss in another child. Metabolic
evaluation gave normal results in all subjects. The results suggest an evaluation paradigm with reference to
etiologic determination for individuals with PDDs that does not presently justify metabolic or neuroimaging on a
screening basis. Recurrence risk, treatment implications, and significant and long-lasting emotional relief for the
parents suggest that serious consideration be given to clinical genetic examination, genetic testing, EEG study
(during wakefulness and sleep), and audiometry, despite a relatively low yield. ß 2006 Wiley-Liss, Inc.
KEY WORDS: autism; autism spectrum disorders; pervasive developmental disorders; comprehensive assessment; diagnostic yield;
rational evaluation
INTRODUCTION
Dr. Agatino Battaglia is Adjunct Professor of Child Neuropsychiatry at the University of Pisa,
Italy; and Adjunct Professor of Pediatrics at the University of Utah Health Sciences Center, Division
of Medical Genetics, Department of Pediatrics, Salt Lake City, UT, USA. He is board certified in
Clinical Pediatrics and in Neurology. He is Head of the Center for the Study of Congenital
Malformation Syndromes, Director of Research in Neuropsychiatric Genetics, and Director of the
Clinical Neurophysiology Service at Stella Maris Clinical Research Institute for Child and
Adolescent Neuropsychiatry, Calambrone (Pisa), Italy. He has a strong research interest in clinical
dysmorphology, neuropsychiatric genetics, and clinical neurophysiology. For the years 2002–
2005 he was awarded a grant from the Italian Ministry of Health devoted to studying the genetics
and neurobiology of autism, and he currently is the on-site director of the multicenter research
project ‘‘Using European and International Populations to identify Autism Susceptibility Loci’’
funded by the European Union through contract no. 512158.
Dr. John C. Carey is a Medical Geneticist, Professor of Pediatrics at the University of Utah
Health Sciences Center, formerly Chief Division of Medical Genetics, Department of Pediatrics,
Salt Lake City, UT, USA. He is the Editor-in-Chief of the American Journal of Medical Genetics,
and Vice-Chair Department of Pediatrics.
Grant sponsor: Italian Ministry of Health; Grant number: 181 of October 19, 2001.
*Correspondence to: Agatino Battaglia, MD, Stella Maris Clinical Research Institute for Child
and Adolescent Neuropsychiatry, via dei Giacinti 2, 56018 Calambrone (Pisa), Italy.
E-mail: [email protected]
DOI 10.1002/ajmg.c.30076
ß 2006 Wiley-Liss, Inc.
Determining the underlying etiology
for a child’s developmental disability is of
the utmost importance for several reasons. Establishing a diagnosis and etiology may help in predicting the prognosis
with relative certainty; establishing an
accurate recurrence risk; organizing
appropriate laboratory testing; establishing a health maintenance plan; initiating
adequate treatment, when feasible; and,
in many instances, may be crucial for
the therapeutic alliance [Battaglia et al.,
1999; Battaglia and Carey, 2003], and
provides significant and long-lasting
4
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMIN. MED. GENET.): DOI 10.1002/ajmg.c
emotional relief for the parents [Lenhard
et al., 2005].
Establishing a diagnosis and
etiology may help in predicting
the prognosis with relative
certainty; establishing an
accurate recurrence risk;
organizing appropriate
laboratory testing; establishing
a health maintenance plan;
initiating adequate treatment,
when feasible; and, in many
instances, may be crucial for the
therapeutic alliance, and
provides significant and
long-lasting emotional relief
for the parents.
Autistic spectrum disorders or pervasive developmental disorders (PDDs)
are one of the nosologic categories
of childhood developmental disability.
PDDs are characterized by severe
and pervasive impairment in reciprocal
social interaction and communication
skills, as well as repetitive and stereotyped behavior and interests, with onset
before age 3. PDDs comprise, autistic
disorder, Rett disorder, childhood
disintegrative disorder, Asperger disorder and pervasive developmental
disorder not otherwise specified (PDDNOS) [American Psychiatric Association, 1995]. Autistic disorder or autism is
the prototypical pervasive developmental disorder, and affects at least 5 in
10,000 individuals [Fombonne, 1999].
A number of etiologies have been described in association with autistic spectrum disorders [Gillberg and Coleman,
2000], and, as a consequence, autism
has been claimed to be a behavioral
syndrome, which is the final common
pathway triggered by a number of different medical disorders. On the other
hand, the evidence for a complex gene-
tic predisposition to most cases of PDDs
has prompted many investigations to
identify susceptibility loci. The lack
of robust pointers to the nature or
location of susceptibility genes has led
most researchers to perform genomewide scans for linkage in affected relative
pair samples [Weeks and Lathrup, 1995].
Recently, six potential genomic susceptibility regions for PDDs have been
identified on 7q, 2q, 16p, 17q, 6q, and
3q [IMGSAC, 1998, 2001; Philippe
et al., 1999; Auranen et al., 2002].
Nevertheless, the size of the susceptibility regions and resource limitations
have impeded identification of the putative susceptibility alleles. As a result of
these different viewpoints, the clinician
does not yet have a clear idea of how
extensive medical investigations in the
autistic children should be. Of note,
between 65% and 85% of individuals
with autism spectrum disorders also
show mental retardation [Mauk, 1993;
Chudley et al., 1998; Gillberg, 1998;
Sponheim and Skjeldal, 1998]. Chromosomal rearrangements are known to
be one of the most common causes of
cognitive impairment, accounting for
4–34.1% of subjects with MR [Xu
and Chen, 2003]. Our prospective study
presents the results of extensive medical
investigations of 85 patients with PDD.
SUBJECTS AND METHODS
The Institutional Review Board
of the Stella Maris Clinical Research
Institute for Child and Adolescent
Neurology and Psychiatry approved
this project, and informed consent was
obtained from each participant. Eightyfive (85) patients with PDD and their
first degree relatives participated in this
study. These patients were selected from
a sample of 236 subjects who had received a clinical diagnosis of PDD at the
Stella Maris Institute between March
2002 and 2005. Eighty-one (81) out of
the 236 patients were excluded from the
study enrollment due to failure to attend
diagnostic investigations requested by
the evaluating physician or due to sociofamilial problems. Selection criteria for
entering the study were: (1) a diagnosis
of PDD (with exclusion of the Rett
ARTICLE
syndrome) confirmed after the administration of the ADI-R (autism diagnostic interview-revised) [Lord et al., 1994]
and the ADOS-G (autism diagnostic
observation schedule-generic) [Lord
et al., 2002]. Both instruments assess
the symptoms of PDD, including autism,
as defined in DSM-IV [American Psychiatric Association, 1995]. In addition,
a clinical diagnosis was made by the child
psychiatrist evaluating the child, on the
basis of presence or absence of DSM-IV
symptoms of autism; (2) chronological
age between 4 and 18 years; (3) IQ>30;
(4) availability of both biologic parents.
Consequently, 43 of the patients
were excluded from the study because
the previous clinical diagnosis of PDD
was not confirmed after performing
ADI-R and ADOS-G; while the
remaining 27 were excluded from the
study due to an IQ <30.
Pregnancy, medical, and developmental histories together with a three to
four generation pedigree were obtained
on each patient. Physical and neurological examinations were performed.
Particular attention was paid to growth
parameters, to any dysmorphic trait or
minor anomaly especially involving the
face, limbs and skin; and to abnormal
muscle tone or reflexes, to the presence
of involuntary movements, or coordination abnormalities. Blood was collected
on all subjects to perform high resolution banding (HRB), molecular fragile
X studies, and subtelomeric FISH
analysis [Battaglia and Bonaglia, this
issue]. Due to funding restraint, CGHmicroarray was performed only in the
14 subjects with apparent idiopathic
PDD-NOS, in order to exclude a possible microduplication 15q11-13 [Cook
et al., 1997; Schroer et al., 1998; Gurrieri
et al., 1999]. Parental bloods were banked
to determine if any detected anomalies
were de novo or inherited. Electroencephalograms (EEGs), brain magnetic
resonance imaging (MRI) (to exclude
the presence of any brain abnormality),
a thorough metabolic evaluation, and
audiologic evaluation (including brain
stem auditory-evoked potentials when
needed) were carried out virtually on all
patients.
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMIN. MED. GENET.): DOI 10.1002/ajmg.c
RESULTS
During the 3 years of study enrollment
85 patients met the inclusion criteria and
completed the evaluating physician’s
requested laboratory investigations.
Sixty-five (76.5%) patients had autism,
18 (21.2%) had PDD-NOS, and the
remaining 2 (2.3%) had Asperger syndrome. As expected, there was a marked
male preponderance (68/85) in this
group as a whole. The ages of the
enrolled subjects varied between 4 years
2 months and 12 years 5 months (mean
7.6 years). The initial age of parental concern regarding their child’s developmental progress ranged between
18 months and 3 years.
Most of these 85 patients had been
referred to our Institute by the child
psychiatrist working in the area health
authority of the child’s residence;
whereas the remaining had been referred
by the family pediatrician. With respect
to possible etiologic determination, a
detailed history and physical examination in this group of patients with
PDD was informative in 10.5% (9/85).
With respect to possible
etiologic determination, a
detailed history and physical
examination in this group
of patients with PDD was
informative in 10.5% (9/85).
lines, one male aneuploid with trisomy
8, the other male euploid: 47,XY,þ
8(40%)/46,XY(60%). All the three provisional clinical diagnoses (Sotos, Angelman, inv dup(15) syndromes) were
confirmed by the respective molecular
cytogenetics analyses. Molecular fragile
X studies were informative in one further
child, aged 5 years and thought to
be nonsyndromic, showing a CGG full
mutation. Brain MRI was informative in
two children (2.3%) with relative macrocrania but no neurological features,
showing a focal band heterotopia at the
level of the right lateral ventricle (1), and
partial agenesis of the corpus callosum
with right cerebellar hemisphere hypoplasia (1). Etiologic yield of waking and
sleep video-EEG-polygraphy was very
low, identifying only a Landau–Kleffner
picture in one child (1.1%). A single
child was identified as having a congenital bilateral sensori-neural deafness, on
audiometry and brainstem auditoryevoked potentials (BAEPs) (Table I).
CGH-microarray did not show any
15q11-q13 microduplication in the
PDD-NOS subjects studied. Metabolic
evaluation gave normal results in all
subjects. Physical/neurological examination, and all laboratory investigations
were normal in the other 71 patients.
None ever had seizures.
DISCUSSION
Studies addressing etiologic yield
in childhood developmental disabilities
have mainly looked at individuals with
developmental delay/mental retardation
[Opitz et al., 1978; McLaren and Bryson,
1987; Bodensteiner and Schaefer, 1995;
Majnemer and Shevell, 1995; Battaglia
et al., 1999; Hunter, 2000; Battaglia and
Carey, 2003; Shevell et al., 2003; Moog,
2005; van Karnebeek et al., 2005]. The
overall variations in reported yields largely
depends on the application of and
advances in testing modalities, especially
in molecular cytogenetics and neuroimaging. As of now, only very few studies have
addressed the question of etiologic yield in
patients with PDDs [Chudley et al., 1998;
Skjeldal et al., 1998; Shevell et al., 2001;
Steiner et al., 2003]. However, all of them
have a major limitation, as the enrolled
subjects were diagnosed as having classic
infantile autism, PDD-NOS, or Asperger
syndrome based only on history and
clinical examination, and/or on unspecified ‘‘well-established instruments.’’
As of now, only very few studies
have addressed the question
of etiologic yield in patients
with PDDs. However, all of
them have a major limitation,
as the enrolled subjects were
TABLE I. Diagnostic Yield of PDDs (n ¼ 85)
Distinctive historical features included
an acute Epstein–Barr virus encephalitis
at age 18 months in one child. Distinctive
physical features were evident in eight
children, leading to a provisional clinical
diagnosis of Sotos syndrome (1), Angelman syndrome (1), inv dup(15) syndrome
(1), and to the recognition of a pattern of
human malformation in five. Four of
these five children were classified as
having a ‘‘provisionally unique syndrome,’’ after HRB karyotype, DNA
fragile-X, and subtelomeric FISH analysis had given normal results. HRB was
diagnostic in one of the five subjects,
showing a mosaicism with two cellular
5
Etiologic categories
Environmental/acquired
Encephalitis
Recognizable syndromes
Sotos
Angelman
Idic(15)
Diagnosed by HRB/molecular-cytogenetics
Trisomy 8 mos.
Fra(X) syndrome
Pathogenetic categories
Provisionally unique syndrome
Abnormal brain MRI
Landau–Kleffner
Deafness
1
1
1
1
1
1
4
2
1
1
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMIN. MED. GENET.): DOI 10.1002/ajmg.c
diagnosed as having classic
infantile autism, PDD-NOS,
or Asperger syndrome based
only on history and clinical
examination, and/or on
unspecified ‘‘well-established
instruments.’’
In addition, only part of the study
sample underwent a complete laboratory
evaluation. Therefore, to reexamine the
etiologic yield of PDD, we undertook
this larger prospective study on subjects
selected according to very strict criteria
and diagnosed as having PDD based on
the present ‘‘gold standard’’ (ADI-R
and ADOS-G), in addition to a clinical
diagnosis made by the child psychiatrist,
on the basis of the presence or absence of
DSM-IV symptoms of autism. In our
cohort of children with PDD a causal/
pathogenetic diagnosis was reached in
16.5%. This is in agreement with the
results of previous studies of PDD
children, showing a range of 10%-30%
with another associated or etiologically
relevant condition [Rutter et al., 1994;
Gillberg and Coleman, 2000]. On
In our cohort of children with
PDD a causal/pathogenetic
diagnosis was reached in
16.5%. This is in agreement
with the results of previous
studies of PDD children,
showing a range of 10%-30%
with another associated or
etiologically relevant condition.
physical examination, eight children
(9.4%) were felt to have a genetic
syndrome. The pathognomonic clinical
and neurophysiologic features led to a
likely diagnosis of Sotos, Angelman and
inv dup(15) syndromes in three of them,
and molecular cytogenetic testing confirmed the clinical diagnosis in all.
Sporadic children with Sotos syndrome
have previously been described as having
autism [Morrow et al., 1990; Zappella,
1990], whereas a strong association
between isodicentric chromosome 15
and autistic features has been reported in
several subjects [Rineer et al., 1998;
Borgatti et al., 2001], and about 40% of
AS patients have been shown to meet
criteria for autism on ADOS-G and
ADI-R [Peters et al., 2004]. One
cytogenetic abnormality was discovered
in 1/8 children, who was found to have
trisomy 8 mosaicism. A ‘‘provisionally
unique syndrome’’ was the possible
diagnosis in the remaining 4/8 patients,
in whom, however, we are planning to
pursue CGH-microarray. Of note, a
CGG full mutation was found in one
nonsyndromic child. Depending on the
age of the patients, between 15% and
28% of individuals with fragile-X syndrome have significant social deficits
fulfilling DSM-III-R or DSM-IV criteria for autism [Reiss and Freund, 1992;
Baumgardner et al., 1995; Cohen, 1995;
Turk and Graham, 1997; Hagerman,
2002]. The occurrence of a CGG full
mutation in individuals thought to be
nonsyndromic prior to puberty, is well
known [Curry et al., 1997; Battaglia
et al., 1999].
Based on these results, an evaluation
paradigm for individuals with PDD with
reference to etiologic determination can
be suggested. A detailed history and
physical examination by a geneticist with
special interest in these disorders remains
essential. The relevance of making a
genetic diagnosis in children with PDD,
mainly in relation to the familial and
recurrence risk implications, is quite
obvious, and mandates state-of-the-art
cytogenetic and molecular cytogenetic
investigations [Rutter et al., 1997; Gillberg and Coleman, 2000]. Serious consideration should also be given to routine
EEG-polygraphic recordings both during wakefulness and sleep [Beaumanoir,
1992; Tuchman and Rapin, 1997], since
a condition such as the Landau–Kleffner
syndrome that may mimick an autistic
disorder, can be pharmacologically treated. Full audiometric evaluation to rule
ARTICLE
out a treatable hearing impairment that
may masquerade as autistic disorder is
also a necessary component of the assessment of the child with PDD. Brain MRI
seems to be useful in showing brain
abnormalities even in the absence of
neurological features. However, seeing
its low yield (2/85), it is hard to
recommend it in a routine assessment of
PDD children. The same should apply to
the metabolic evaluation, which should
only be carried out in the presence of
specific indications. This is consistent
with the recent recommendations of a
consensus conference sponsored by the
American College of Medical Genetics,
and with the practice parameters published by the American Academy of
Neurology and the Child Neurology
Society on the evaluation of the child
with developmental delay/mental retardation [Curry et al., 1997; Shevell et al.,
2003].
Bearing in mind the complexity of
the PDDs, and the consequent multiple
needs both for the individual and his/
her family, we stress the importance of
evaluating children with PDDs in a
multidisciplinary clinic that brings together professionals with various expertise
sharing the goal of the best possible
patient and family care.
ACKNOWLEDGMENTS
We thank Arthur R. Brothman, Ph.D.,
FACMG, Professor of Pediatrics and
Director of Cytogenetics at the University of Utah Health Sciences Center,
for performing CGH-microarray. This
study was supported by funds from the
Italian Ministry of Health through contract no. 181 of October 19. 2001.
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