Social difficulties in Turner syndrome David Skuse MD Institute of Child Health, University College London Great Ormond Street Hospital for Children

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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 X- chromosome 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 Nguyen and Disteche, 2005, 2006 Brain Other tissues All genes that are NOT on X-chromosome All genes that ARE on X-chromosome

Y Chromosome Statistics Known Protein-coding Genes: 64 What is it good for?

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 X- chromosomes) 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 X- chromosome, 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 inactivatedblue implies paternal X is inactivated red implies maternal X inactivatedred 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 X- chromosomes is inactivated.Females are mosaics of tissue blocks in which either one of the two X- chromosomes is inactivated. Silencing mechanism is removed during formation of germ cells – it is not passed on to next generationSilencing 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 In typical females, about 20% of genes escape X- inactivation Purple – PAR genes Blue – genes that escape X- inactivation Yellow – genes subject to X- inactivation 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 25 Reciprocal social interaction skills Communication, non-verbal skills, Repetitive, stereotyped behaviors, inflexibility, sensory sensitivities

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)

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 32 Reciprocal social interaction skills Communication, non-verbal skills, social imagination Repetitive, stereotyped behaviours, inflexibility, sensory sensitivities

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.

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 DSM-5 criteria Autism Spectrum Disorder

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!