Download case report: association of waardenburg syndrome with

The British Journal of Developmental Disabilities
Vol. 53, Part 1, JANUARY 2007, No. 104, pp. 53-62
CASE REPORT: ASSOCIATION OF WAARDENBURG
SYNDROME WITH INTELLECTUAL DISABILITY,
AUTISTIC SPECTRUM DISORDER AND UNPROVOKED
AGGRESSIVE OUTBURSTS: A NEW BEHAVIOURAL
PHENOTYPE?
Reza Kiani, Satheesh Kumar Gangadharan and Helen Miller
Introduction
Waardenburg syndrome (WS) is the
most common inherited form of congenital
deafness with a prevalence of about 1
in 42000 (Dourmishev and Janninger,
2005). Approximately 2-5% of congenital
deafness is due to WS (Nayak and Isaacson,
2003). Deafness in this syndrome may be
associated with changes in the eyes, hair or
skin. The degree of hearing loss is almost
always non-progressive but varies from
mild to severe and may be unilateral or
bilateral (Toriello et al., 1995). Four types
of WS have been identified. The most
common types of WS, type 1 (WS1) and
2 (WS2), are associated with more severe
hearing impairment. The prevalence of
hearing impairment is higher in patients
with WS2 than in those with WS1.
Affected individuals may also have other
congenital defects such as cleft palate /lip.
The mortality rate, however, is similar to
general population (Schwartz et al., 2006).
In 1947, Dutch ophthalmologist, Petrus
Johannes Waardenburg described the
main features of WS as congenital sensory
neural hearing loss, dystopia canthorum
(lateral displacement of the inner corner of
the eyes), hairy and hypo pigmented body,
premature greying of hair with white
forelock, synophrys (bushy eyebrows
which join each other in the midline), blue
eyes and pigmentary differences in the iris
*Reza Kiani, MD, MRCPsych
Specialist Registrar/Honorary Lecturer in Psychiatry of Learning Disability, and Honorary
Specialist Registrar, National Deaf Services. Leicester Frith Hospital, Leicester, UK
Tel: 0116 225 5273 Fax: 0116 225 5272 email: [email protected]
Satheesh Kumar Gangadharan, MD, MRCPsych
Consultant in Psychiatry of Learning Disability, Leicester Frith Hospital, Leicester, UK
Tel: 0116 225 5273 Fax: 0116 225 5272 email: [email protected]
Helen Miller, MRCPsych
Consultant Psychiatrist, National Deaf Services, South West London and St Georges Mental
Health Services, London, UK
Tel: 020 8675 2100 Fax: 020 8675 2266 email: [email protected]
* For Correspondence
53
(heterochromia iridium), broad high nasal
root and hypoplasia of the nasal septum
(Waardenburg, 1951). This eventually
became WS type 1 (WS1).
Waardenburg syndrome type 2 (WS2)
was defined by Arias in 1971. Patients with
WS2 have all the features of WS1 except
dystopia canthorum.
Waardenburg syndrome type 3
(WS3), also known as Klein-Waardenburg
syndrome has a similar phenotype to
WS1 but with additional musculoskeletal
characteristics, including Sprengel shoulder (congenital upward displacement
of the shoulder blade), limb muscle
hypoplasia, contractures, aplasia of the ribs,
lack of differentiation of the small carpal
bones and bilateral cutaneous syndactyly
(webbing of the fingers) (Klein, 1983).
Waardenburg syndrome type 4
(WS4), or Waardenburg-Shah syndrome,
has features of WS2 combined with
Hirschsprung disease (a congenital lack
of the nerve supply of the intestinal wall,
which leads to chronic constipation,
vomiting and intestinal obstruction during
infancy) (Dourmishev and Janninger,
2005).
TABLE I shows the clinical features of
the different types of WS.
Modes of inheritance in WS
The reason for the physical manifestation of WS is the absence of melanocytes
in the inner ear (cochlea), skin, eyes and
hair. Melanocytes are required in the
vascular layer of the cochlea for hearing
(Steel et al., 1989).
While the first three types of WS have
autosomal dominant inheritance (a child
of one affected parent has a 50% risk of
developing WS), WS4 has an autosomal
recessive inheritance (a child of one
54
affected parent has a 25% risk of developing
WS). WS may also be the product of de novo
mutations (i.e. without having an affected
mother or father). Several mutations in the
PAX3 gene (located on chromosome band
2q35) have been noted in people with WS1
and WS2.
The gene PAX3 helps in the activation
of the MITF promoter (microphthalmiaassociated transcription factor). MITF has
a role in the activation of the tyrosinase
gene, which is involved in melanocyte
differentiation. A mutation in the PAX3
gene therefore results in abnormalities
of melanocyte differentiation (Watanabe
et al., 1998). Abnormalities in melanocyte
development in the skin, hair, eyes
and inner ear lead to the physical
manifestations.
In some cases of WS2, mutations occur
in the MITF gene itself (Jones, 1997).
Mutations in other genes such as SNAI2
(Frith et al., 2005) and SLUG (Cryns and
Van Camp, 2004) have also been reported.
Genes affected in WS4 are either the
Endothelin-3 (EDN3) or the EndothelinB receptor (EDNRB) genes (Edery et al.,
1996). While homozygous mutation of
these genes causes WS4, heterozygous
mutation results in Hirschsprung disease
alone (Schwartz et al., 2006). Mutation of
the SOX10 gene has also been reported
in individuals with WS4 (Pingault et al.,
1998). TABLE II presents a summary of
chromosomal and genetic abnormalities
in WS.
Association of WS with intellectual
disability
There is limited evidence for an
association between WS and intellectual
impairment. Some researchers have
reported that WS does not affect
intelligence (Smith et al., 1998). A study
evaluating the clinical features of 11
affected families (with a total of 52
individuals) found delayed milestones or
poor school performance necessitating
special schooling in 9 unrelated individuals
with WS1 or WS2 patients (de Saxe, 1984).
There is a case report of a 13-year-old boy
where features of WS are associated with
marked mental and motor retardation,
severe gait disturbance, dystonia, muscular
stiffness and peripheral neuropathy
(Kawabata et al., 1987). Another case report
describes a patient with WS3 who had
microcephaly, mental retardation and
severe skeletal abnormalities (Pasteris et
al., 1993).
Similarly, little is known about the
prevalence of mental health problems
or autistic spectrum disorder in people
with WS. There is only one report in
the literature about the association with
psychiatric disorders (Siedlecka and
Smolenska, 1997).
In this paper we describe two individuals with WS3 and profound bilateral
deafness. We then explore the possibility
of new behavioural phenotypes in this
condition since both individuals present
with moderate to severe intellectual
disability, autistic spectrum disorder (ASD)
and severe behavioural problems (TABLE
III).
Case Histories
Case One
The first case, X, is a 36 year old south
Asian male who has had profound hearing
loss since birth. He appears to have WS3
as he has all the characteristics of WS1
associated with repeated dislocation of the
TABLE I
Distinguishing features in different types of Waardenburg syndrome (WS)
WS1
WS2
WS3
WS4
+/-
+/-
+/-
+/-
Dystopia canthorum
+
-
+
_
Hirschsprung disease
-
-
-
+
Musculoskeletal abnormalities
-
-
+
-
Sensory neural hearing loss
TABLE II
Genetic and chromosomal abnormalities in Waardenburg Syndrome
Type of WS
Mode of inheritance
Chromosomes
(involved)
Genes
(involved)
WS1 & WS3
Autosomal dominant
2q35
PAX3 (Paired box gene 3)
WS2
Autosomal dominant
3p12.3 - 14.1
MITF (Microphthalmia-associated
transcription factor)
SNAI2
SLUG
1p21 - p13.3
WS4
Autosomal recessive
20q13.2 - q13.3
13q22
Endothelin-3 receptor (EDNR 3)
Endothelin-B receptor
(EDNRB)
55
TABLE III
Clinical characteristics of the reported patients with WS3
Case 1
+
+
+
+
+
+
+
+
Hypopigmentation
· Hypopigmentation of skin
· White forelock
· White body hair, eyebrows
+
+
+
+
+
+
Eyes
· Heterochromia iridium
· Brilliant blue eyes
+
+
Sensory neural hearing loss
· Unilateral/ bilateral
· Severity
bilateral
profound
bilateral
profound
Musculoskeletal problems
· Sprengel shoulder
· Cleft lip or palate
· Hirschsprung disease
· Muscle contractures
· Limb muscle hypoplasia
· Other abnormalities
+
-
+
-
Intellectual disability
moderate
severe
Medical problems
-
diabetes mellitus,
psoriasis
Autistic spectrum disorder
+
+
Severity of autistic traits
56
Case 2
Facial features
· Broad high nasal root
· Synophrys or medial flaring of the eyebrows
· Hypoplastic alae nasi
· Dystopia canthrum
moderate
severe
Unpredicted violent outbursts
+
+
Epilepsy
-
-
Affected family member
father and sisters
-
Medical conditions in the family
diabetes mellitus
hypothyroidism
psoriasis
keratoconus
epilepsy
-
shoulder. He also has moderate intellectual
disability and moderate autistic trait based
on the Childhood Autism Rating Scale
(CARS). Although there is a history of
developmental delay, detailed information
regarding his early development is not
available.
He is the second oldest child in a family
of six. His father and two siblings also have
features of WS1 but without any hearing
impairment or intellectual disability.
X has been profoundly deaf since
childhood. He cannot hear or produce
spoken language. Although he can
understand and use basic British Sign
Language and Makaton, his ability to sign is
very limited. His level of understanding of
sign language is higher than his expressive
skills. He is physically fit and manages
most daily living activities without
assistance. He can write a few words and
draw pictures to communicate.
He has a longstanding history of
severe aggressive behaviour. When he
began special school at the age of 5, he was
reported as having disturbed behaviour
such as smashing windows, pulling
hair and inappropriate urination. He
subsequently attended a residential school
for children with hearing impairments
until he completed schooling.
Although the majority of the incidents
were aggression against objects such
as smashing windows and destroying
furniture, there were also documented
episodes of very severe aggressive
behaviour toward people, including
stabbing a person with a kitchen knife,
hitting another with a garden fork and
pouring boiling water over a third person.
He generally had a tendency to target the
most vulnerable people such as the more
disabled or female residents. Although
X was prescribed various antipsychotic
drugs for his aggressive outbursts, there is
no indication of any clear benefit from any
medication.
He recently required hospitalisation
under Mental Health Act subsequent to
breakdown of his long-term placement
and a series of aggressive behaviour in
a temporary placement. He displayed
unprovoked violent episodes including
throwing a coffee table aimed at a resident,
pushing a female resident against the wall
and smashing a plate on another resident’s
head. In the hospital, with one-to-one
support, a consistent approach, firm
boundaries and a structured daily routine,
he settled over a few weeks. He enjoys
outdoor activities, watching television and
doing puzzles. However, he continues
to have occasional aggressive outbursts.
Although most of these incidents appear
to have been impulsive aggression without
any obvious precipitating factors, a few
incidents may have involved some premeditation. Often X’s facial expression is
misleading, for example when he appears
to be smiling and friendly just before an
attack.
X’s
hearing
impairment
made
assessment of any features of ASD
difficult. However, the presence of ASD
symptoms became clearer over time as his
stereotyped communication patterns, rigid
adherence to routine, ritualistic tidying and
preoccupation with dates and events were
recognised. He is very sensitive to changes
in the environment and prefers to have
his belongings arranged in order. He may
become preoccupied with certain events
that are important to him and repeatedly
signs to confirm that they will happen.
He has limited interest in other people’s
activities. His social communication
has always been difficult as he does not
maintain a good eye contact and lacks
concentration. Subsequent assessment by
the professionals from the National Deaf
57
Services confirmed the presence of autistic
traits. He was found to be using signs in a
stereotyped manner. He tends to copy signs
used by others (echolalia) and continually
repeats some signs (perseveration). When
writings, he always refer to himself by
name rather than using ‘’I’’.
Case two
Y is a 29-year-old white male with
WS3. He has profound bilateral deafness,
crystal blue irises, dystopia cantrum, early
greying of his hair and muscular dysplasia
of his limbs (his arms and legs are very thin
due to loss of muscle bulk). He has severe
intellectual disability and severe traits of
ASD based on CARS. He also suffers from
psoriasis and diabetes mellitus (DM). He is
long-sighted and has astigmatism.
There is no family history of WS
or associated psychiatric and medical
disorders.
Y was born in a normal delivery but
showed delay in his developmental
milestones. His hearing impairment was
picked up in his second year of life after his
family suspected that he was not reacting
to others in a usual way. After attending
a special needs school for a short period,
he joined a deaf signing school. Reports
from the school suggest that he was very
settled there, with no report of challenging
behaviour before he was 18.
After leaving school, he stayed briefly
in two residential homes, with his mother
and in foster care. Around this time he
developed challenging behaviour such
as aggression towards others, destroying
property and stealing food. After a twoyear stay in an assessment and treatment
unit, he was moved to a residential place
for deaf people. Although he settled down
there initially, his challenging behaviour
gradually began to re-emerge. He would
58
clean in a driven and repetitive manner
and, if he was interrupted, he would
become extremely upset and aggressive.
Sometimes incidents happened out of the
blue for no apparent reason. The violent
outbursts tended to be towards the female
staff and those who were significantly
smaller than him. There was no evidence
of depression.
Although initially the presence of
ritualistic and repetitive behaviours
suggested a diagnosed of obsessive
compulsive
disorder,
a
detailed
assessment by professionals from The
National Deaf Services revealed that his
ritualistic behaviours were part of autistic
spectrum disorder. It was noticed that the
challenging behaviours increased when
he was uncertain about a situation and
the boundaries were unclear. Y was also
noted to be extremely tidy. He kept his
personal belongings in a particular order.
Any change in his room or routine led to
him becoming distressed and aggressive.
When he became anxious, he started
cleaning his room. If he was interrupted,
he would become extremely agitated and
violent. According to his mother, he as a
child, preferred his own company and to
play alone. He preferred soft cuddly toys
and would not play with other toys.
Even now as an adult, he keeps a soft
toy in his pocket and carries it everywhere
he goes. From time to time, he needs to
touch it and smell it. When he is anxious
he moves the toy in front of his eyes in
a flicking movement. He does not make
good eye-to-eye contact. He also does not
respect others’ personal space and often
walks into other service users’ bedrooms
inappropriately.
He had been tried on different
psychotropic drugs in the past without
any clear benefit. These included
carbamazepine (used as mood stabiliser),
various selective serotonin reuptake
inhibitors
and
risperidone.
The
multidisciplinary team, therefore, decided
to concentrate more on the behavioural
management of his challenging behaviours.
The medication was gradually tapered
and stopped completely. Using picture
books and involving staff who were fluent
in British Sign Language improved Y’s
communication skills. It was also advised
not to challenge him during the times that
he was cleaning as it was thought that
this gave him a sense of control. This was
regarded as an important coping strategy
for him. Limit setting was, however, used
to minimise the impact of this behaviour
on other activities.
It was also noticed that Y used to sweat
during some of the episodes. Aggression
occurred on occasions when he wanted
food but could not have it. The role of
diabetes mellitus was also explored as
a possible contributing factor to some
of his unpredictable behaviours. In his
management plan, he was encouraged to
take regular snacks to avoid hypoglycaemic
episodes.
Y currently participates in various daily
activities including swimming, bowling,
working on the computer, doing puzzles
and going out for lunch. His diabetes has
been controlled by dietary restriction.
The psychological strategies aimed at
increasing his level of communication such
as Treatment and Education of Autistic
and related Communication Handicapped
Children (TEACCH) and modifying his
behaviour through firm boundaries,
structured daily routine and positive
response strategies have generally been
successful.
Discussion
WS has been associated with cognitive
delay and other neurological abnormalities
(de Saxe, 1984, Kawabata et al., 1987). Our
case report highlights the presence of
moderate to severe intellectual disability
(ID), autistic spectrum disorder (ASD)
and severe problem behaviours in two
individuals with profound bilateral
congenital deafness secondary to WS3. To
the best of our knowledge, this association
has not been reported elsewhere in
the literature. We believe that there is
a striking similarity in the presentation
of these two individuals raising the
possibility of a behavioural phenotype
(the presence of ASD and impulsive
aggression). ASD is described as a part of
the behavioural phenotype of tuberous
sclerosis, fragile-X syndrome, congenital
rubella and herpes simplex encephalitis
(Melville and Cameron, 2003). Impulse
control disorder has also been described
as being part of certain genetic syndromes
such as tuberous sclerosis (Sadock and
Sadock, 2003). Challenging behaviours
are, however, common in people with ID,
ASD or hearing impairment (Timehin and
Timehin, 2004).
In exploring the possible association
of a behavioural phenotype of a genetic
disorder with ID, the first issue to consider
is whether the observed behaviour is a
reflection of the severity of ID (O’Brien,
2006). Therefore, it is possible that in our
case reports, the apparent association
between WS3 and ASD has arisen by
chance, as people with ID have higher
prevalence of ASD than the general
population (Bhaumik et al., 1997). ASD
occurs in about 10% of people with mild
ID (IQ 50-69) (Gillberg, 1992), increasing
to 27% in those with an IQ of less than 50
(Deb and Prasad, 1994).
Equally, there is an association between
ASD and hearing impairment (HI), as
the rate of HI is higher in people with
ASD than general population and vice
versa. Rosenhall et al., (1999) reported a
59
prevalence rate of 3.5% for profound HI
in 199 children with a diagnosis of ASD
(quoted in Carvill, 2001). Furthermore,
there are similarities between behaviours
in children with a visual and HI and
in those with ASD. Children with a
profound hearing loss who have not had
access to a good language model (i.e. sign
language) may show delayed or impaired
social and emotional development (e.g.
theory of mind and understanding others’
verbal and non-verbal cues). Deaf children
may also have to impose clear structure,
predictable routines and restrictive
behavioural patterns to their daily living
activities to be able to make sense of the
world around them and to feel safe and in
control (Edwards, 2004).
Given the above confounding factors,
it is difficult to establish the presence of a
behaviour phenotype based on a report of
two individuals with striking similarities.
Diagnosis of ASD was crucial to the effective management of behaviour problems in
both the individuals. This report highlights
the need for further research to estimate
the prevalence of ASD in people with WS.
We believe that it is possible that ASD is
under-diagnosed in people with WS due
to their hearing impairment. Jure et al
(1991), reporting a prevalence of 4% ASD
in a sample of 1150 children with HI, found
that in substantial proportion of them, ASD
was diagnosed with an average four years
delay. Conversely, hearing impairment
had been overlooked for up to six years in
some of the children with ASD (quoted in
Carvill, 2001).
The above association is also of interest
from a genetic point of view. A number of
studies have ascertained associations of
ASD traits with terminal 2q deletion (with
the breakpoint within 2q37). Lukusa et al.
(2004) describe a 12-year-old female patient
with terminal 2q37.3 cryptic deletion and
ASD behaviour. There is also another
60
report of a child with a cryptic deletion of
2q35 including part of the PAX3 gene and
a balanced 2; 8 translocation. Although
not qualified for a diagnosis of WS, the
child had ASD and very mild dystopia
canthorum (one of the characteristic
features of WS1 and 2). They speculated
that a gene or genes responsible for ASD
may lie at 2q35 (PAX 3 gene) or at the sight
of the translocation (Borg et al., 2002).
Conclusion
In both individuals reported in this
paper, a diagnosis of ASD had been either
missed or not given enough consideration
until early adulthood. This had, over the
years, led to the breakdown of their care
packages due to the display of severe
challenging behaviours.
Although it is difficult to draw any
conclusions from these associations found
in just two individuals with WS3, we
believe that it is worthwhile reporting
these cases, both to ensure that additional
diagnoses of ID and ASD are not missed
in people with WS3 and, most importantly,
to inform and pave the way for early and
appropriate intervention. Whether WS in
our patients per se has been the cause of
ASD directly or has increased the chance
of ASD by causing ID and HI is not clear
and a matter of further investigation and
research.
Summary
There is little information available
on psychiatric aspects of Waardenburg
Syndrome. The present paper highlights
the possible association of Warrdenburg
Syndrome type 3 in two individuals with
profound bilateral congenital deafness,
intellectual disability, autistic spectrum
disorder and severe aggressive behaviour.
There is a striking resemblance in clinical
presentation in both individuals. The paper
gives an overview of the syndrome; focuses
on the presence of intellectual disability,
autistic spectrum disorder, aggressive
outbursts and their complex relationship
in the individuals; and explores the
possibility of a new behavioural phenotype
in Waardenburg syndrome type 3.
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