Social difficulties in Turner syndrome
David Skuse MD
Institute of Child Health, University College London
Great Ormond Street Hospital for Children
2
The ‘little actress’
Members of the Turner syndrome support society (UK)
Learning social skills by observation
•
Many - perhaps most TS girls, do not spontaneously ‘absorb’ social skills
•
They acquire social skills by observing others (e.g. an older sister or a
school friend)
•
Hence
– Social skills are acquired later than usual - often not until school
age
– They often have a stilted or non-spontaneous quality - but this can
be very subtle
– Social interactions are easier in dyadic (two people) rather than in
group situations
Genetics and Turner
syndrome
• Why does having just one complete Xchromosome lead to difficulties with
social adjustment?
• Are those difficulties due to small
stature, lack of confidence, looking
‘different’, hormonal problems, or what?
Social difficulties and Turner
syndrome
• Most social difficulties in TS have a genetic basis
• They are due to the loss of an X-chromosome
• This loss leads to unusual development of the ‘social
brain’
• If the ‘social brain’ is not working properly, people
with TS will find it difficult to build and sustain social
relationships, within and outside the family
Human chromosomes
typical 46,XX
Human chromosomes
Turner syndrome (45,X)
Comparative sizes of X and Y chromosome
X-chromosome
• Normally present
in two copies in
females
• Normally present
in one copy in
males
X-chromosome
Known Protein-coding Genes:
820
Ensembl: August 2014
Many X-linked genes are expressed exceptionally
strongly in brain
All genes that are NOT on
X-chromosome
Brain
All genes that ARE on
X-chromosome
Other tissues
Nguyen and Disteche, 2005, 2006
Y Chromosome Statistics
Known Protein-coding Genes:
What is it good for?
64
What is the influence of the Y-chromosome on the ‘male brain’ ?
• Impact upon cognitive function - lacking…
• Impact upon male-typical rough-housing – convincing
So if males can manage with just one X-chromosome
…why do females with Turner syndrome have problems?
X-linked genes in Turner syndrome
• Typical human females have much more DNA
more than males (because they have 2 Xchromosomes)
• How did our evolution cope with this imbalance?
• It led to the inactivation of most genes on the X
chromosome
• This means that even typical females have only
one active X-chromosome – just like people with
Turner syndrome!
Random X-inactivation
A mechanism only found in 46,XX females
In all female body cells (excluding germ cells)
there is random inactivation of one Xchromosome, and most of its associated
genes are silenced.
Demonstration of X-inactivation
At a VERY early stage of
development (when we are about
32 cells in size), one of the two X
chromosomes in adjacent cells
undergoes inactivation at random
:
•blue implies paternal X is
inactivated
•red implies maternal X
inactivated
46,XX Females are ‘epigenetic mosaics’
Daughter cells retain the same pattern
of X-inactivation
•Females are mosaics of tissue blocks
in which either one of the two Xchromosomes is inactivated.
•Silencing mechanism is removed
during formation of germ cells – it is
not passed on to next generation
Sexual dimorphism – inactivated
X-linked genes
Females are mosaics
of two cell populations
with respect to X-linked
gene expression
IN 45,X TURNER SYNDROME THERE IS NO
X-INACTIVATION
In about 80% of cases all the X
chromosomes come from the
mother, and in about 20% all the
X-chromosomes come from the
father
So all daughter X chromosomes
come either from mother OR
from father
Mechanisms by which X-linked genes could influence
social behaviour
Purple – PAR
genes
In typical
females,
about 20% of
genes
escape Xinactivation
Blue – genes
that escape Xinactivation
Yellow – genes
subject to Xinactivation
White –
unknown
Carrel and
Willard, 2005
Turner syndrome
Genes that are
needed for
development of the
‘social brain’ are not
working normally in
females who are
45,X
Brain
At least 1 in 6 females with TS meets DSM-IV.TR
criteria for an Autism Spectrum Disorder
Reciprocal
social
interaction
skills
Communication,
non-verbal skills,
Repetitive,
stereotyped
behaviors,
inflexibility, sensory
sensitivities
25
Behaviours characteristic of
TS in childhood
• Finds it hard to follow commands unless they are carefully worded
• Usually can only remember one command at a time
• Does not respond when told to do something
• Does not realise when she offends people with her behaviour
• Does not understand how to behave in social situations outside the
home
More characteristic
behaviours…
• Does not pick up on other people’s body language
• Does not understand other people’s social cues
• Difficult to reason with when she is upset
• Very demanding of other people's time
• Her behaviour disrupts normal family life
And more…
• Does not notice effects of her behaviour on
other people
• Does not realize when others are angry or
upset
• Often appears to be unaware of other
people's feelings
Behavioural characteristics of girls with Turner syndrome
Parental ratings (% of total)
Difficult to reason with when upset
Does not follow command unless carefully worded
Does not respond when told to do something
Very demanding of people's time
56
51
45
45
Does not pick up on body language
Does not understand social cues
Behaviour disrupts normal family life
Does not notice effects of behaviour on others
35
31
31
33
Unaware of other people's feelings
Does not realize when others are angry/upset
Does not understand how to behave when out
Does not realize when offends people with behaviour
29
25
24
25
Feels disliked by other
children…
• Turner syndrome (maternal X
chromosome) 42%
• Turner syndrome (paternal X
chromosome) 25%
The nature of autistic traits
• ASD
– Deficits in reciprocal social
interaction skills
– Deficits in the onset of
language and use of
language for social
communication
– Unusual patterns of
stereotyped behavior,
sensory sensitivities, and
restricted interests
Autism spectrum disorders
Communication,
non-verbal skills,
social imagination
Reciprocal
social
interaction
skills
Repetitive,
stereotyped
behaviours,
inflexibility, sensory
sensitivities
32
DSM-5 criteria
Autism Spectrum Disorder
Social-emotional reciprocity
• abnormal social approach
• difficulties with normal back and forth conversation
• reduced sharing of interests
• reduced sharing of emotions
• lack of initiation of social interaction
DSM-5 criteria
Autism Spectrum Disorder
Nonverbal communicative behaviors used for social interaction
• poorly integrated- verbal and nonverbal communication
• abnormalities in eye contact and body-language
• lack of understanding and use of nonverbal communication
• diminished facial expression or gestures.
DSM-5 criteria
Autism Spectrum Disorder
Developing and maintaining relationships, appropriate to
developmental level (beyond those with caregivers)
• difficulties adjusting behavior to suit different social contexts
•
• difficulties in sharing imaginative play and in making friends
DSM-5 criteria
Autism Spectrum Disorder
Restricted, repetitive patterns of behavior, interests, or activities
Stereotyped or repetitive speech, motor movements, or use of objects
• simple motor stereotypies
• echolalia
• repetitive use of objects
• idiosyncratic phrases).
DSM-5 criteria
Autism Spectrum Disorder
Excessive adherence to routines, ritualized patterns of verbal
or nonverbal behavior, or excessive resistance to change
• motoric rituals
• insistence on same route
• insistence on same food
• repetitive questioning
• extreme distress at small changes.
DSM-5 criteria
Autism Spectrum Disorder
Highly restricted, fixated interests that are abnormal in intensity or
focus
• strong attachment to or preoccupation with unusual
objects
• excessively circumscribed or perseverative interests
DSM-5 criteria
Autism Spectrum Disorder
Hyper-or hypo-reactivity to sensory input
+ unusual interest in sensory aspects of environment
• apparent indifference to pain/heat/cold
• adverse response to specific sounds or textures
• excessive smelling or touching of objects
• fascination with lights or spinning objects
X-monosomy and social cognitive competence
Origins of adult adjustment in
TS have their roots in childhood
Despite normal verbal IQ many
girls with TS have serious
deficits in the use of language
for social communication
TS is associated with difficulty
responding fully reciprocally in
social interactions
These problems often become
more prominent in adolescence
Turner syndrome in Adulthood
Adult members of the TSSS - UK
X-monosomy and social cognitive competence
•
Many adults with TS find it hard to
become accepted in a working
environment with other adults
•
In the UK many seek jobs with children,
such as nursery nursing
•
There is no evidence that low self-esteem
linked to small stature or infertility is
salient factor in social adjustment
• TS is associated with primary
neurodevelopmental problem
in processing social cues
Appropriate management of Turner syndrome
•
Managing the difficulties in
perceiving and responding
appropriately to social cues is of
paramount importance in childhood
•
In adults, risk of social isolation,
depression and worsening social
anxiety
•
Clinicians must not assume
treatment of short stature/infertility
will solve social adjustment
problems in childhood or adulthood!