Williams Syndrome: Pediatric, Neurologic,
and Cognitive Development
Ximena Carrasco, MD*, Silvia Castillo, MD†, Teresa Aravena, MD†, Paula Rothhammer, Ps‡,
and Francisco Aboitiz, PhD‡
This study examines the developmental history of 32
Introduction
Williams syndrome patients, positive to the fluores-
cence in situ hybridization (FISH) test. The informa-
Williams syndrome is a genetic disease caused by the
tion is intended to provide help for early diagnosis and
hemizygous deletion of a segment in chromosome
appropriate stimulation of these patients. In the sample
7q11.23, which includes about 25 genes. This defect is not
reported here, only about half of the patients referred
observed in standard karyotypes and requires a clinically
with presumptive diagnosis were in fact FISH , indi-
directed, molecular genetic analysis for its detection [1-6].
cating that facial dysmorphism may not be the most
Williams syndrome includes several phenotypic features
reliable sign for diagnosis. Initial pediatric signs are
which affect most organic systems and include congenital
developmental delay and nocturnal irritability. In con-
heart disease, mental retardation, and a characteristic
sultation, facial dysmorphies and heart murmur are
facies [7-11]. Despite this, diagnosis of Williams syn-
detected. There is also low birth weight, failure to
drome can be delayed for years, especially in those cases
thrive, unsuccessful breastfeeding, and gastroesopha-
in which the most common cardiopathy, supravalvular
geal reflux. All these symptoms are strongly suggestive
aortic stenosis, is not present [12]. Williams syndrome
of Williams syndrome. Subsequent steps consist of
patients also manifest a peculiar cognitive profile which
cardiologic studies. Our results indicate that the triad
has been often described as consisting of outstanding
of symptoms consisting of infantile hypercalcemia,
social, verbal, and musical skills combined with poor
dysmorphic facies, and supravalvular aortic stenosis,
performance in visuoconstructive tests [13-20]. For these
which until recently was considered fundamental for
reasons, in the last decade Williams syndrome has been
Williams syndrome diagnosis, is not usually present
the subject of intense investigations in the study of
and does not lead to an early diagnosis. Cognitively,
gene– cognition correlations. Although research in this
these children are characterized by hypersociability,
line has been of the highest interest, there is a noticeable
hyperacusia, deficient visuoconstructive abilities, at-
contrast between the specialized molecular-cognitive-be-
tentional deficit and hyperactivity, and in some cases,
havioral knowledge of these patients and the situation of
spontaneous musical interests. There are no special
their parents who have to deal with them daily, or the
verbal skills. The results of this study indicate that the
knowledge that many health professionals have about this
concept of Williams syndrome patients as language-
syndrome. In this context, this report describes the most
and musically-gifted is not fully accurate.
outstanding clinical characteristics observed in our expe-
rience of 32 cases including infants, children, and adoles-
cent patients. This information was acquired after a
scheduled interview with parents and physical and neuro-
Carrasco X, Castillo S, Aravena T, Rothhammer P,
logic examinations of the patients; also included were data
Aboitiz F. Williams Syndrome: Pediatric, neurologic, and
on developmental milestones. This data will be useful for
cognitive development. Pediatr Neurol 2005;32:166-172.
an earlier diagnosis and therapeutical intervention, for a
more documented and effective familial support, and also
From *Instituto de Ciencias Biomédicas, Facultad de Medicina,
Communications should be addressed to:
Universidad de Chile & Servicio de Neurología, Hospital de niños
Dr. Aboitiz; Depto. Psiquiatría; Facultad de Medicina; Pontificia
Luis Calvo Mackenna, Santiago, Chile; †Sección Genética, Hospital
Universidad Católica de Chile; Marcoleta N°. 387 2° piso; Casilla
Clínico Universidad de Chile; and ‡Departamento de Psiquiatría,
114-D Santiago 1, Chile.
Pontificia Universidad Católica de Chile, Santiago, Chile.

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Figure 1. Complaint at first appointment of 32 Williams syndrome patients.
for a wider knowledge of the natural history of this
Results
disease.
Motive of First Appointment and
Presumptive Diagnosis
Patients and Methods
The first signs and symptoms were usually evident in
Patients
infants and were the motive for clinical consultation, but
did not always lead to early diagnosis of Williams syn-
Between June 2000 and May 2002, 101 children with presumptive
drome (Fig 1). The focus in this study was on early
diagnosis of Williams syndrome were directed by diverse health
detected signs whose proportion may not reflect the
specialists to the Genetics Unit of Hospital Clínico Universidad de
incidence observed at later ages; for example, at first
Chile. These patients were subjected to a fluorescence in situ
hybridization (FISH) test with a Vysis probe complementary to the
appointment facial dysmorphism appears with a lower
chromosome band 7q11.23, which includes the genes for elastin
incidence than in the school age population. Congenital
(ELN) and other neighboring genes (RFC2, WSCR1, FZD3, STX1A,
heart disease (84.3% of the cases) was usually established
and LIMK1). This test is a standard diagnostic method and does not
after detection of a heart murmur in the routine pediatric
allow one to distinguish between different types of mutations leading
examination. Detection of Williams syndrome tended to
to Williams syndrome. Williams syndrome diagnosis with the dele-
tion was confirmed in 49 subjects. From this sample, we report here
be earlier when supravalvular aortic stenosis was con-
the results of 32 cases in which a complete clinical assessment was
firmed. In patients with supravalvular aortic stenosis, age
performed. At the time of FISH confirmation, 6.25% of the patients
at diagnosis of Williams syndrome was 1.45
0.28 years,
were between 1 and 23 months of age; 37.5% were between 2 years
whereas in patients without supravalvular aortic stenosis
to 5 years and 6 months; 40.6% between 6 years and 13 years and 11
(even though having other heart diseases) it was 4.94
months; and 15.6% were between 14 years and 15 years and 11
months. The subjects were 56.25% male and 43.75% female.
1.69 years (P
0.0275). Developmental delay was the
second cause of early consultation (71.9%), which could
be global (18/23 cases), purely motor delay (4/23 cases),
Methods
or isolated language delay (1/23 patient). Dysmorphic
facies were detected early in 62.5% of the cases. However,
FISH
patients and their relatives were notified about the research and
this characteristic was usually not obvious to the parents
consented to participate in it. Patients were physically examined by a
and was detected by health professionals (18/20 cases),
geneticist and a neuropediatrician; their parents were interviewed, ac-
and in 3/20 cases was observed at birth as nonspecific
cording to a preestablished schedule, concerning the perinatal period,
reason of the first clinical appointment, morbidity, development, out-
alterations that did not lead to a diagnosis of Williams
standing behavioral characteristics, and familial background.
syndrome.
Carrasco et al: Williams Syndrome Clinical History
167

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Irritability (59.4% of the patients) was described as
polymalformations were observed (heart murmur, facial
sleep disturbances, frequent and uncontrolled crying and
and genitourinary malformations, among others). The
was interpreted as a sleeping disorder or cramps. In one
duration of breastfeeding was exceptionally low, with an
case irritability was correlated with transient hyperam-
average of 4.92
2.78 months and mode of 2 months, and
monemia. On the other hand, hyperpassivity, i.e., exces-
this was always due to deficient suction. Breastfeeding
sively quiet behavior and minimal or no crying, was
lasted more than 7 months only in five cases.
observed in 40.6% of the cases. In three of these cases,
there was diurnal hyperpassivity and nocturnal irritability.
Failure to thrive was another cause of early consultation
Morbidity
(43.7%), as well as gastroesophageal reflux and vomiting
(31.2%). In 25% of the cases, the study leading to
Tables 1 and 2 present the most important instances of
Williams syndrome diagnosis was initiated after repeated
morbidity. These findings agree with evidence reported
episodes of bronchial obstructive syndrome. In other
elsewhere [7-9,11]. The most common congenital heart
cases, patients presented with abnormal cranial features
disease was supravalvular aortic stenosis, which in only
(21.9%, including one case of congenital microcephaly
five cases (29.4%) required surgery. Dental pathologies
and two of plagiocephaly, one of which required cranio-
included multiple cavities, microdontia, multiple diaste-
plasty), inguinal hernia (15.6%), undescended testes
mas, and occlusion defects. Skeletal pathology consisted
(12.5%), and strabismus (9.4%). In isolated cases (3.1%),
of radiocubital sinostosis, clubfoot, congenital hip dyspla-
first time medical attention was motivated by hyperactiv-
sia, and vertebral column anomalies (the latter appeared
ity, non-delivery associated peripheral facial palsy, poste-
more often during adolescence). One of the adolescent
rior cleft palate, precocious dentition, congenital hip dys-
patients underwent surgery for kyphoscoliosis, with good
plasia, clubfoot, episodes of cyanosis (attributed later to
results. Respiratory pathology was due to obstructive
heart disease), and hemangioma.
bronchial syndrome and repeated bronchopneumonia.
In our sample, a trend to decrease the age of the
Gastrointestinal morbidity consisted mainly of gastro-
presumptive clinical diagnosis of Williams syndrome was
esophageal reflux in infants and preschool children, which
observed, which in most cases resulted from multidisci-
tended to disappear in later age, and chronic constipation,
plinary discussion and occurred after a series of consulta-
which persists in adolescence. In one case chylous diar-
tions with different specialists. On average, the two infants
rhea was observed. Genitourinary pathology included
were diagnosed at 2.4 months whereas the five adolescents
cryptorchidism, single testicle, enuresis, repeated urinary
were diagnosed at 9.2
7.05 years of age.
infections, one case of renal agenesis, and one case of
duplicated pyelocalicial system. Strabismus and refractive
Perinatal History
errors were the elements of ocular pathology, plus a case
of congenital palpebral ptosis. Hernias were inguinal and
The main data obtained from interviews with parents
bilateral in most cases. Craniofacial defects included
were validated by registered information. Parents were
plagiocephaly, brachiocephaly, microcephaly, and one
relatively young; average maternal age was 27.2
5.8
case of posterior palatal cleft. Endocrine defects were
years; paternal age was 29.6
4.6. Gestation was nearly
precocious puberty and one case of hypothyroidism. There
normal (38.6
3.2 weeks). Birth weight was low (2.77
were also cases of tonsil hypertrophy.
0.5 kg); height at birth was low (47.2
2.6 cm); Apgar
score was close to optimal (mode at first and fifth minutes
was 9). Pregnancy pathologies were intrauterine dwarfism
Table 1.
Observed morbidity in 32 Williams syndrome patients
(12.5%), urinary infection (12,5 %), miscarriage symp-
toms (9.4%), gestational diabetes (9.4%), gravid hy-
Morbidity
%*
peremesis (6.3%), placenta previa (6.3%), and toxemia of
pregnancy (6.3%). Exposure to substances was low (anti-
Cardiovascular
85 (80)
biotics 4 cases, domperidone 3 cases, tobacco 1 case,
Mental retardation
87 (75)
Dental
75 (95)
hormonal contraceptives 1 case). Delivery was vaginal in
Neurologic
62 (70)
17 cases (one of them with forceps). Fifteen cesarean
Respiratory
59
sections were programmed by delayed intrauterine growth
Gastrointestinal
59 (70)
Skeletal
41 (20-50)
and signs of premature delivery. Neonatal jaundice was
Ocular
38
considered idiopathic in 25% of the cases; in three cases it
Hernias
38 (40-50)
occurred in the context of neonatal hepatitis. Neonatal
Craniofacial
35
hospitalizations were for phototherapy, for weight in-
Genitourinary
28 (5-50)
Endocrine
8 (5-30)
crease, and to treat cyanotic episodes (related to cardiop-
athy which was detected later). In no case was mechanical
* In parenthesis, data from the American Academy of Pediatrics,
ventilation required. A diagnosis of Williams syndrome
Committee on Genetics: Health care supervision for children with
was never considered in this context, even if in some cases
Williams syndrome (2001).
168

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Table 2.
Cardiovascular pathology found in Williams syndrome
achieve than in normal children (Fig 2). Noteworthy,
patients
cumulative frequency graphs indicate that achievement in
the production of at least five meaningful words was also
Defect
Frequency
much slower than observed for normative data.
Supravalvular aortic stenosis
17
Pulmonary stenosis
7
Functional murmur*
4
Ventricular septal defect
4
Cognitive Aspects According to Clinical History
Coarctation of the aorta
2
Systemic hypertension
1
The following are some behavioral and cognitive fea-
Pulmonary hypertension
1
tures of children and adolescent Williams syndrome pa-
Ductus
1
Combined valvulopathy†
9
tients which are of concern to parents and health special-
ists, and are of relevance when considering a presumptive
Abbreviations:
Williams syndrome diagnosis.
CoAo
Coarctation of the aorta
PS
Pulmonary stenosis
Language was reported as outstanding in only 31% of
SVAS
Supravalvular aortic stenosis
the cases, including two patients who, according to their
VSD
Ventricular septal defect
parents, speak much but in an unintelligible jargon. How-
* Functional murmur refers to a transient condition without clear
ever, in all cases there is a global delay of language
etiology, at least for parents (it cannot be excluded that some of
these are SVAS
or PS ).
development, with patients producing the first words at
† SVAS
PS (4 cases), SVAS
VSD (2 cases), SVAS
CoAo (1
around 3 years and being semantically, morphosyntacti-
case), and PS
VSD (2 cases).
cally, and phonologically deficient until adolescence. In
summary, in schoolchildren and adolescent (but not
Psychomotor Development
younger) Williams syndrome patients, there is a relatively
preserved language in relation to general intelligence, but
In most aspects psychomotor development was delayed
in no case is there outstanding linguistic ability. Never-
when compared with normal data [21]. Achievement
theless, an outstanding communicative intention and high
curves have a lower slope, and the 100% takes longer to
emotional content are obvious in all of them, except for the
A
B
Head support
Sitting without support
)
)
% 100
100
(
%
80
SW patients
80
e
ncy
60
Normal subjects
r
e
q
u
ency (
60
r
equ
i
ve f 40
i
ve f 40
u
l
at
20
u
l
at
m
20
m
m
u
m
Cu
0
C
0
2
4
6
8
10
12
6
9
12
15
18
21
24
Age (months)
Age (months)
C
D
Walking without support
More than 5 meaningful words
)
)
% 100
% 100
80
80
e
ncy (
e
ncy (
60
60
r
equ
r
equ
40
40
u
l
a
t
i
ve f
u
l
a
t
i
ve f
20
20
m
m
u
m
u
m
C
0
C
0
12
18
24
30
36
42
48
1
2
3
4
5
6
Age (months)
Age (years)
Figure 2. (A-C) Achievement of gross motor developmental milestones in 28 children with Williams syndrome. (D) Age to achieve more than five
meaningful words in 17 children with Williams syndrome.
Carrasco et al: Williams Syndrome Clinical History
169

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three cases with autistic features, all of whom were
Table 3.
Neurologic signs found in our Williams syndrome
included in our sample.
sample
Sociability is the most noticeable behavioral character-
Defect
Frequency
istic of these patients, and is spontaneously referred to in
87.5% of the cases, including one of the two infants of the
Sensorimotor incoordination
13 (40.6%)
sample. In preschool stages there is absolute lack of fear of
Hypotonia
15 (46.9%)
strangers and no separation anxiety; there is a higher
Joint laxity
18 (56.25%)
Hyperactive tendon reflexes
20 (62.5%)
tendency to relate with adults than with children of the
Clumsiness of gait
20 (62.5%)
same age. They maintain strong eye contact, often use the
Microcephaly
6 (18.75%)
words “please” and “thank you”, are highly affectionate in
their interactions, and are sensitive to the feelings of
others.
fication (computed axial tomography) were also detected;
Musical interests were reported spontaneously by par-
both patients were female adolescents without any corre-
ents in 81.3% of the cases (including patients with autistic
lated symptoms.
features), and were evident in school ages. Parents high-
light musical memory and recognition. Patients can be
Discussion
selective regarding the kinds of music they like. Although
in some cases an ability to play musical instruments was
In 2 years, we have collected a sample of 32 children
reported, in our sample there was no case of systematic
and adolescents with Williams syndrome, which com-
musical training. In 84.4% of the cases, parents reported
prises the first large-scale study of this syndrome in Chile.
hyperacusis, which produced great discomfort and was
Only about half of the patients who were referred to us
selective to certain types of sound. In five cases, parents
with a presumptive Williams syndrome diagnosis were
reported an affinity for metallic sounds made with tools
confirmed as FISH . The high proportion of FISH– cases
(such as a hammer or a saw).
may have been due to the fact that a presumptive diagnosis
Deficient visuoconstructive abilities were reported
was made by specialists who were not fully acquainted
spontaneously in 37.5% of the cases, but after direct
with Williams syndrome. In fact, according to our clinical
questioning the proportion increased. Patients were unable
evaluation, only three of the FISH– patients had a pheno-
to copy drawings and manifested a dislike for the use of
type suggestive of Williams syndrome. Samples of these
pencils, painting materials, and puzzles. They also had
three patients were sent to another laboratory for further
great difficulty with reading and writing. Face perception
analyses. Another possible explanation for this is that
was reported to be good; they recognize people they have
facial dysmorphism is usually considered an important
seen only for a few minutes or a long time ago.
sign, although it can be equivocal. In a previous study
Attentional deficit and hyperactivity is a salient charac-
[22], we observed that the most reliable morphologic
teristic, reported by parents and confirmed by health
features were periorbital fullness, long and smooth phil-
specialists according to Diagnostic and Statistical Manual
trum, and congenital heart disease (especially supravalvu-
of Mental Disorders, Fourth Edition criteria in 62.5% of
lar aortic stenosis), while the less reliable features were
the cases. This feature is common in preschool and early
anteverted nostrils, large mouth, and long and slender
school age (66%), and declines in adolescence (20%). It is
neck. Despite our significant experience with Williams
usually treated with stimulants, with good response. In
syndrome patients, in some cases it is still difficult to make
70% of the preschool children there was pathologic
an accurate diagnosis based exclusively on facial dysmor-
oppositionism, associated with pathologic hyperactivity
phism (Fig 3). Nonetheless, in the last years we have
(exceeding the normal hyperactive behavior of this age).
detected that presumptive Williams syndrome diagnosis is
Signs of anxiety were reported in 59.4% of the cases, and
made at a progressively earlier age. This fact, together
simple phobias in 50%. Most phobias were related to
with the availability of molecular diagnosis, is especially
intense sounds. Obsessive behavior was observed in
relevant when considering strategies of early stimulation.
46.9% of the cases.
Our morbidity and perinatal findings are close to those
reported elsewhere. However, clinically we observed a
Neuropsychiatric Evaluation
higher incidence of mental retardation than in other studies
(87% vs 75%, respectively). This difference becomes even
Besides retarded psychomotor development, subnormal
higher when performing a formal intelligence quotient
intelligence ranged from borderline to moderate (in 100%
evaluation. In the present sample, 13 randomly selected
of the cases); hyperactive behavior was observed in 68.8%
patients were assessed psychometrically with the Wech-
(more common among preschool [67%] and schoolchil-
sler intelligence scales. There was one borderline case,
dren [76.9%]), and there were three cases with autistic
eight cases with mild mental retardation, and four cases
features. There were several other neurologic signs, sum-
with moderate retardation (adding up to a 92% incidence
marized in Table 3. Single cases of Chiari I malformation
of mental retardation). More extended studies are needed
(magnetic resonance imaging) and bilateral pallidal calci-
to verify this apparent discrepancy. Patients tended to
170

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Figure 3. Faces of Williams syndrome, FISH
patients. Note that there is some phenotypic heterogeneity, which makes clinical diagnosis difficult on
the basis of facial features. In these patients, many of the facial features that have been usually described in Williams syndrome are present: anteverted
nares, smooth and long philtrum, fullness of periorbital region, full cheeks, open mouth appearance. However, despite the presence of these aspects,
global appearance is not always suggestive of the typical elfin face described for Williams syndrome.
perform better in the verbal than in the nonverbal part, but
drome, have been demonstrated to improve neurologic
there were only two cases in which verbal scores exceeded
outcome [23,24]. Only three of our patients were able to
the manual scores by more than 15 points. Although the
read and write (two of them at 6 years and the other at 9
dysharmony between the verbal and nonverbal scores is
years of age; there was no relation between this skill and
considered an indication of organic brain damage, in these
intelligence quotient). All three cases belong to middle-
patients it may be related to the impairment in visuocon-
class families in which one of the parents underwent
structive tasks. Considering that the Wechsler scale is
higher education.
sensitive to cultural factors, one possibility is that the
Cognitively, the main features of Williams syndrome
discrepancy in the incidence of mental retardation between
patients are high sociability, hyperacusis, musical interests
our findings and those in the literature may be due to
(but not always), deficient visuoconstructive abilities, and
insufficient stimulation of our patients. In fact, many of
attention deficit/hyperactivity. In our sample, abilities
the patients in this study belong to low-income families
commonly cited in the literature such as music and
and were diagnosed at a relatively late age. If this is
language were not especially prominent. Moreover, lan-
correct, this situation would stress the importance of
guage development was somehow delayed in these chil-
making a presumptive diagnosis as soon as possible, in
dren, which contrasts with the good linguistic level that is
order to intervene with appropriate stimulation from an
achieved later. In our sample, the use of unintelligible
early age.
jargon in the preschool stage was a common sign. Thus,
Psychomotor development in Williams syndrome is
we consider that the concept of language- and musically-
scarcely documented in the literature. There is significant
gifted children is not the best descriptor of their abilities.
motor and linguistic developmental delay, which appar-
As mentioned, these children are extremely sociable, and
ently exceeds the delay observed in a group of patients
their eloquent speech may be more related to their com-
with Down syndrome that we are studying in parallel
municative intentions rather than to their language skills.
(preliminary data not shown). However, it is possible that
There is a significant psychomotor delay in the achieve-
these children with Down syndrome have been more
ment of motor milestones; furthermore, hypotony is observed
properly stimulated from early infancy, which could ex-
especially in infants and preschool children. There is also
plain the above differences. Contrary to many Down
deficient sucking which made breastfeeding especially diffi-
syndrome patients in our environment, who are diagnosed
cult and brief in most of our subjects, in agreement with
at birth, the patients in this study have not participated in
previous reports [9,11,25]. Interestingly, in one case imaging
early stimulation programs, which at least in Down syn-
studies revealed bilateral calcification in the globus pallidus,
Carrasco et al: Williams Syndrome Clinical History
171

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without clinical correlate. This case may merit further studies
inversion polymorphism in families with Williams-Beuren syndrome.
on calcium metabolism in these patients.
Nat Genet 2001;29:321-5.
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This research was supported by FONDECYT project 1010816 and by the
liams: Estudio clínico, citogenético, neurofisiológico y neuroanatómico.
Millennium Nucleus for Integrative Neuroscience. We would like to
Rev Méd Chil 2002;130:631-7.
thank Dr. Fernando Novoa, MD for reviewing the manuscript; Javier
[23]
Ludlow JR, Allen LM. The effect of early intervention and
López, electronic engineer; and Conrado Bosman, MD for help in the
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Document Outline

• Williams Syndrome: Pediatric, Neurologic, and Cognitive Development
  • Introduction
  • Patients and Methods
    • Patients
    • Methods
  • Results
    • Motive of First Appointment and Presumptive Diagnosis
    • Perinatal History
    • Morbidity
    • Psychomotor Development
    • Cognitive Aspects According to Clinical History
    • Neuropsychiatric Evaluation
  • Discussion
  • Acknowledgment
  • References

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