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!