Issues and Challenges in XYY Syndrome ERIN TORRES MSN, CRNP-PMH DEVELOPMENTAL NEUROGENOMICS UNIT, NIMH NATIONAL INSTITUTES OF HEALTH BETHESDA, MD, USA Objectives ▶ Discuss the profile of mental health issues present in a large clinical research sample of individuals with XYY syndrome ▶ Discuss the wide range of presentations seen in youth with XYY syndrome ▶ Discuss the priorities for future research on the profile of developmental and mental issues in individuals with XYY syndrome Sex Chromosome Aneuploidy ▶ Typically there are 22 pairs of chromosomes plus one pair of sex chromosomes (X,Y) ▶ 47, XYY-males have an extra Y chromosome ▶ Mosaic vs non-mosaic Sex Chromosome Aneuploidy ▶ Typically there are 22 pairs of chromosomes plus one pair of sex chromosomes (X,Y) ▶ 47, XYY-males have an extra Y chromosome ▶ Mosaic vs non-mosaic Sex Chromosome Aneuploidy ▶ Typically there are 22 pairs of chromosomes plus one pair of sex chromosomes (X,Y) ▶ 47, XYY-males have an extra Y chromosome ▶ Mosaic vs non-mosaic XYY • Occurs in about 1 out of 1,000 newborn males • Believed that many men with XYY are undiagnosed • Increased amount of fetuses are being diagnosed due to increased amount of prenatal testing First Reports … ▶ 1959 47, XYY first identified ▶ Early studies falsely associated XYY with violent crime ▶ 1965 Patricia Jacobs conducted a research study examining XYY males in institutional settings ▶ State Hospital in Scotland-high number of men with XYY ▶ Careful studies of XYY began in 1976 with Witkin et al Key Findings Since … ▶ Birth cohorts (low ascertainment bias, but few individuals + measures)1 VIQ PIQ Motor and language delay/difficulties ”temper tantrums” ▶ Self-referred (ascertainment bias, but more individuals and measures) Raised rates of .. Motor and language difficulties ADHD and “externalizing disorders” (e.g. oppositional defiant disorder) Difficulties in social interaction and Autism Spectrum Disorder diagnoses GOOD REVIEWS: 1. Leggett et al, Dev Med Child Neurol, 2010 | 2. Hong et al, Lancert Neurology, 2014 Key Findings Since … ▶ Birth cohorts (low ascertainment bias, but few individuals + measures)1 VIQ PIQ Motor and language delay/difficulties ”temper tantrums” ▶ Non birth cohorts (ascertainment bias, but more individuals and measures) Raised rates of .. Motor and language difficulties ADHD and “externalizing disorders” (e.g. oppositional defiant disorder) Difficulties in social interaction and Autism Spectrum Disorder diagnoses GOOD REVIEWS: 1. Leggett et al, Dev Med Child Neurol, 2010 | 2. Hong et al, Lancert Neurology, 2014 X And Y Chromosome Variation Development Study At NIH Families From North America and Europe Participants seen so far Demographics: Our Research Program Talking About Differences: We all have strengths and weaknesses Milestones and Cognitive Development IQ Prenatal Post’ Milestones and Cognitive Development IQ Prenatal Postnatal Diagnosis Timing K-SADS Schedule for Affective ▶ Assessment completed with Disorders and Schizophrenia parent/guardian and child for School Aged Children ▶ Current Diagnoses ▶ Past Diagnoses Neurodevelopment And Mental Health DIAGNOSIS Previous [N (% of 65)] KSADS [N (% of 65)] 20 (31%) 9 (14%) Autism Spectrum Disorder 4 (6%) 10 (15%) Tic Disorder 35 (54%) 43 (66%) Attention Deficit Hyperactivity Disorder 6 (9%) 4 (6%) Oppositional Defiant Disorder 9 (14%) 11 (17%) Mood Disorder 11 (17%) 6 (9%) Anxiety Disorder 1 (1%) 2 (3%) Obsessive Compulsive Spectrum Disorder Neurodevelopment And Mental Health DIAGNOSIS KSADS Prenatal Diagnosis [n (% of 24) Postnatal Diagnosis [n (% of 41) Autism Spectrum Disorder 1 (4%) 8 (19%) Tic Disorder 1 (4%) 9 (22%) 17 (71%) 26 (63%) Attention Deficit Hyperactivity Disorder Oppositional Defiant Disorder - 4 (10%) Mood Disorder 5 (21%) 6 (15%) Anxiety Disorder 1 (4%) 5 (12%) - 2 (5%) Obsessive Compulsive Spectrum Disorder Neurodevelopment And Mental Health DIAGNOSIS KSADS DIAGNOSES FULL ONLY [n (% of 65) FULL or PARTIAL [n (% of 65) Autism Spectrum Disorder 9 (14%) N/A Tic Disorder 10 (15%) 14 (22%) 43 (66%) 50 (77%) Attention Deficit Hyperactivity Disorder 4 (6%) 10 (15%) Oppositional Defiant Disorder Mood Disorder 11 (17%) 20 (31%) Anxiety Disorder 6 (9%) 19 (30%) 2 (3%) 4 (6%) Obsessive Compulsive Spectrum Disorder Autism Spectrum Disorder (ASD) ▶ Persistent deficits in social communication and social interaction across multiple contexts ▶ Restricted repetitive patterns of behavior, interests or activities ▶ Symptoms must have been present during early developmental period ▶ Symptoms cause clinically significant impairment in social, occupational or other important areas of functioning ASD in XYY ▶ Social Communication deficits ▶ Difficulty socializing with peers ▶ Repetitive behaviors ▶ Difficulty with change ▶ Preoccupation with a certain object or subject Attention Deficit Hyperactivity Disorder (ADHD) ▶ A persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development ▶ 1 Inattention must have 6 or more symptoms present for at least 6 months ▶ 2 Hyperactivity and impulsivity must have 6 or more symptoms present for at least 6 months ▶ Several symptoms present before 12 ▶ Symptoms present in 2 or more settings ▶ Clearly interfere with functioning ADHD in XYY Inattentive Hyperactive/Impulsive Combined • Difficult to engage • Unable to sit through a meal • Having symptoms from both categories that cause an • Loses focus • Doing before thinking impairment in functioning • Unable to follow multiple step • Fidgety or restless instructions Tic Disorders Motor Tic Vocal Tic Tourette’s • Uncontrollable muscle • Uncontrolled noises • Both motor and vocal tics movements • clearing throat • frequent eye blinking • sniffing • raising eyebrows • grunting • scrunching up nose • animal sounds • shrugging shoulders Tics in XYY ▶ Motor tic ▶ Mouth movements ▶ Vocal tic ▶ Sniffing Behavioral Difficulties ▶ Oppositional behaviors ▶ Irritable Mood ▶ Tantrums Recommendations ▶ Individualized Education Plan ▶ Speech therapy ▶ Social Skills groups Next Steps- ▶ UNDERSTAND VARIABLITY IQ Prenatal Postnatal Diagnosis Timing Next Steps- ▶ UNDERSTAND VARIABLITY ▶ FROM CATEGORIES TO DIMENSIONS Next Steps- ▶ UNDERSTAND VARIABLITY ▶ FROM CATEGORIES TO DIMENSIONS ▶ FROM BRAIN TO BEHAVIOR Cortical thickness XYY<XY XYY>XY Next Steps- ▶ UNDERSTAND VARIABLITY ▶ FROM CATEGORIES TO DIMENSIONS ▶ FROM BRAIN TO BEHAVIOR ▶ FROM GENES TO BRAIN TO BEHAVIOR Next Steps- ▶ UNDERSTAND VARIABLITY ▶ FROM CATEGORIES TO DIMENSIONS ▶ FROM BRAIN TO BEHAVIOR XY, XYY, XXY, XXYY, ▶ FROM GENES TO BRAIN TO BEHAVIOR XXXY, XXXXY, … ▶ EXTENDING THIS SYSTEMATIC APPROACH TO ALL X-/Y-CHROMOSOME VARIATIONS XX, XXX, XXXX, … Developmental Neurogenomics Unit Armin Raznahan, MD, PhD Erin Torres, CRNP-PMH Francois Lalonde, PhD Catherine Mankiw, AB Ari Fish, BS David Lee Jonathan Blumenthal, MA Liv Clausen, PhD Jakob Seidlitz, BS Anastasia Xenophontos, BS Kirk Reardon, AB Thank you!!! References ▶ Bardsley, M. Z., Kowal, K., Levy, C., Gosek, A., Ayari, N., Tartaglia, N., . Ross, J. L. (2013). 47,XYY Syndrome: Clinical Phenotype and Timing of Ascertainment. The Journal of Pediatrics, 163(4), 1085-1094. doi:10.1016/j.jpeds.2013.05.037 ▶ Benn, P., Cuckle, H., & Pergament, E. (2013). Non-invasive prenatal testing for aneuploidy: current status and future prospects. Ultrasound in Obstetrics & Gynecology, 42(1), 15-33. doi:10.1002/uog.12513 ▶ Cover, Virginia Isaacs, MSW. Living with Klinefelter Syndrome (47,XXY) Trisomy X (47,XXX) and 47, XYY. New York: Virginia Isaacs Cover, 2012. ▶ Lalatta, Faustina, Emanuela Folliero, Ugo Cavallari, Marina Di Segni, Barbara Gentilin, Roberto Fogliani, Donatella Quagliarini, Paola Vizziello, Federico Monti, and Luigi Gargantini. "Early Manifestations in a Cohort of Children Prenatally Diagnosed with 47,XYY. Role of Multidisciplinary Counseling for Parental Guidance and Prevention of Aggressive Behavior." Ital J Pediatr Italian Journal of Pediatrics 38.1 (2012): 52. Web. ▶ Leggett, V., Jacobs, P., Nation, K., Scerif, G., & Bishop, D. V. (2010). Neurocognitive outcomes of individuals with a sex chromosome trisomy: XXX, XYY, or XXY: a systematic review*. Developmental Medicine & Child Neurology, 52(2), 119-129. doi:10.1111/j.1469-8749.2009.03545.x ▶ Re, L., & Birkhoff, J. M. (2015). The 47,XYY syndrome, 50 years of certainties and doubts: A systematic review. Aggression and Violent Behavior, 22, 9-17. doi:10.1016/j.avb.2015.02.003 ▶ Ross, J. L., N. Tartaglia, D. E. Merry, M. Dalva, and A. R. Zinn. "Behavioral Phenotypes in Males with XYY and Possible Role of Increased NLGN4Y Expression in Autism Features." Genes, Brain and Behavior 14.2 (2015): 137-44. ▶ Stochholm, K., A. Bojesen, A. S. Jensen, S. Juul, and C. H. Gravholt. "Criminality in Men with Klinefelter's Syndrome and XYY Syndrome: A Cohort Study." BMJ Open 2.1 (2012) ▶ Witkin, H., Mednick, S., Schulsinger, F., Bakkestrom, E., Christiansen, K., Goodenough, D., . Stocking, M. (1976). Criminality in XYY and XXY men. Science,193(4253), 547-555. doi:10.1126/science.959813.