title: Hypospadias and increased risk for neurodevelopmental disorders.
abstract: BACKGROUND
  Hypospadias (aberrant opening of the urethra on the underside of the penis) occurs in 1 per 300 newborn boys. It has been previously unknown whether this common malformation is associated with increased psychiatric morbidity later in life. Studies of individuals with hypospadias also provide an opportunity to examine whether difference in androgen signaling is related to neurodevelopmental disorders. To elucidate the mechanisms behind a possible association, we also studied psychiatric outcomes among brothers of the hypospadias patients.
  
  
  METHODS
  Registry study within a national cohort of all 9,262 males with hypospadias and their 4,936 healthy brothers born in Sweden between 1973 and 2009. Patients with hypospadias and their brothers were matched with controls by year of birth and county. The following outcomes were evaluated (1) any psychiatric (2) psychotic, (3) mood, (4) anxiety, (5) eating, and (6) personality disorders, (7) substance misuse, (8) attention-deficit hyperactivity disorder (ADHD), (9) autism spectrum disorders (ASD), (10) intellectual disability, and (11) other behavioral/emotional disorders with onset in childhood.
  
  
  RESULTS
  Patients with hypospadias were more likely to be diagnosed with intellectual disability (OR 3.2; 95% CI 2.8-3.8), ASD (1.4; 1.2-1.7), ADHD (1.5; 1.3-1.9), and behavioral/emotional disorders (1.4; 1.2-1.6) compared with the controls. Brothers of patients with hypospadias had an increased risk of ASD (1.6; 1.3-2.1) and other behavioral/emotional disorders with onset in childhood (1.2; 0.9-1.5) in comparison to siblings of healthy individuals. A slightly higher, although not statistically significant, risk was found for intellectual disability (1.3; 1.0-1.9). No relation between other psychiatric diagnosis and hypospadias was found.
  
  
  CONCLUSIONS
  This is the first study to identify an increased risk for neurodevelopmental disorders in patients with hypospadias, as well as an increased risk for ASD in their brothers, suggesting a common familial (genetic and/or environmental) liability.
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Child Psychiatry, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Butwicka
authors.forename: Paul
authors.initials: P
authors.lastname: Lichtenstein
authors.forename: Mikael
authors.initials: M
authors.lastname: Landén
authors.forename: Anna S
authors.initials: AS
authors.lastname: Nordenvall
authors.forename: Anna
authors.initials: A
authors.lastname: Nordenström
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordenskjöld
authors.forename: Louise
authors.initials: L
authors.lastname: Frisén
mesh_terms: D000293:Adolescent; D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000453:epidemiology*; D002648:Child; D002653:Child Behavior Disorders / Q000453:epidemiology*; D002659:Child Development Disorders, Pervasive / Q000453:epidemiology* / Q000235:genetics; D002675:Child, Preschool; D015897:Comorbidity; D006801:Humans; D007021:Hypospadias / Q000453:epidemiology* / Q000235:genetics; D008607:Intellectual Disability / Q000453:epidemiology*; D008297:Male; D012042:Registries; D012306:Risk; D035781:Siblings; D013548:Sweden / Q000453:epidemiology; D055815:Young Adult
keywords: ADHD; Hormones; ICD; autism spectrum disorder; intellectual disability