Issues and Challenges in XYY Syndrome · issues and challenges in xyy syndrome erin torres msn,...

Issues and Challenges in XYY Syndrome

ERIN TORRES MSN, CRNP-PMHDEVELOPMENTAL NEUROGENOMICS UNIT, NIMHNATIONAL INSTITUTES OF HEALTHBETHESDA, 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

▶ Self-referred (ascertainment bias, but more individuals and measures)

VIQ PIQ Motor and language delay/difficulties”temper tantrums”

GOOD REVIEWS: 1. Leggett et al, Dev Med Child Neurol, 2010 | 2. Hong et al, Lancert Neurology, 2014

Raised rates of ..Motor and language difficultiesADHD and “externalizing disorders” (e.g. oppositional defiant disorder)Difficulties in social interaction and Autism Spectrum Disorder diagnoses

Key Findings Since …

▶ Birth cohorts (low ascertainment bias, but few individuals + measures)1

▶ Non birth cohorts (ascertainment bias, but more individuals and measures)

VIQ PIQ Motor and language delay/difficulties”temper tantrums”

GOOD REVIEWS: 1. Leggett et al, Dev Med Child Neurol, 2010 | 2. Hong et al, Lancert Neurology, 2014

Raised rates of ..Motor and language difficultiesADHD and “externalizing disorders” (e.g. oppositional defiant disorder)Difficulties in social interaction and Autism Spectrum Disorder diagnoses

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 PostnatalDiagnosis Timing

K-SADS

Schedule for Affective Disorders and Schizophrenia for School Aged Children

▶ Assessment completed with parent/guardian and child

▶ Current Diagnoses▶ Past Diagnoses

Neurodevelopment And Mental Health

DIAGNOSIS Previous [N (% of 65)] KSADS [N (% of 65)]

Autism Spectrum Disorder 20 (31%) 9 (14%)

Tic Disorder 4 (6%) 10 (15%)

Attention Deficit Hyperactivity Disorder

35 (54%) 43 (66%)

Oppositional Defiant Disorder 6 (9%) 4 (6%)

Mood Disorder 9 (14%) 11 (17%)

Anxiety Disorder 11 (17%) 6 (9%)

Obsessive Compulsive Spectrum Disorder1 (1%) 2 (3%)

Neurodevelopment And Mental Health

DIAGNOSIS KSADSPrenatal Diagnosis [n (% of 24) Postnatal Diagnosis [n (% of 41)

Autism Spectrum Disorder 1 (4%) 8 (19%)

Tic Disorder 1 (4%) 9 (22%)

Attention Deficit Hyperactivity Disorder

17 (71%) 26 (63%)

Oppositional Defiant Disorder - 4 (10%)

Mood Disorder 5 (21%) 6 (15%)

Anxiety Disorder 1 (4%) 5 (12%)

Obsessive Compulsive Spectrum Disorder- 2 (5%)

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%)

Attention Deficit Hyperactivity Disorder43 (66%) 50 (77%)

Oppositional Defiant Disorder4 (6%) 10 (15%)

Mood Disorder 11 (17%) 20 (31%)

Anxiety Disorder 6 (9%) 19 (30%)

Obsessive Compulsive Spectrum Disorder2 (3%) 4 (6%)

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• Difficult to engage

• Loses focus

• Unable to follow multiple step instructions

Hyperactive/Impulsive • Unable to sit through a meal

• Doing before thinking

• Fidgety or restless

Combined • Having symptoms from both

categories that cause an impairment in functioning

Tic Disorders

Motor Tic• Uncontrollable muscle

movements• frequent eye blinking

• raising eyebrows

• scrunching up nose

• shrugging shoulders

Vocal Tic• Uncontrolled noises

• clearing throat

• sniffing

• grunting

• animal sounds

Tourette’s • Both motor and vocal tics

Tics in XYY

▶ Motor tic▶ Mouth movements

▶ Vocal tic▶ Sniffing

▶ Oppositional behaviors▶ Irritable Mood▶ Tantrums

Behavioral Difficulties

Recommendations

▶ Individualized Education Plan▶ Speech therapy▶ Social Skills groups

Next Steps-

▶ UNDERSTAND VARIABLITY

IQ

Prenatal PostnatalDiagnosis Timing

Next Steps-

▶ UNDERSTAND VARIABLITY▶ FROM CATEGORIES TO DIMENSIONS

Next Steps-

▶ UNDERSTAND VARIABLITY▶ FROM CATEGORIES TO DIMENSIONS▶ FROM BRAIN TO BEHAVIOR

XYY>XYXYY<XYCortical thickness

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▶ FROM GENES TO BRAIN TO BEHAVIOR▶ EXTENDING THIS SYSTEMATIC

APPROACH TO ALL X-/Y-CHROMOSOME VARIATIONS

XY, XYY, XXY, XXYY, XXXY, XXXXY, …

XX, XXX, XXXX, …

Developmental Neurogenomics UnitArmin 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