Neurodevelopmental Phenotype in Pitt-Hopkins Syndrome

Background: Pitt-Hopkins syndrome (PTHS) is characterized by intellectual disability, distinctive facial characteristics, breathing abnormalities, epilepsy and repetitive behaviors. It is caused by deletions/mutations in Transcription Factor 4 (TCF4) on chromosome 18 (18q21). Previous publications have primarily focused on genetic/somatic aspects.

Objectives: To study whether autism spectrum disorder (ASD) is part of PTHS neurodevelopmental phenotype.

Methods: Subjects with molecularly confirmed TCF4mutations were recruited through the Dutch PTHS Family Association (N=10). Participation of 4 girls and 6 boys was determined by proximity to researchcenter, and availability within the study timeframe; median age was 10 years (range 3-24). All participants completed individual psychiatric and neuropsychological assessments,  including  Bayley Scales of Infant Development (BSID-II), Vineland Adaptive Behaviour Scales – Survey Form (VABS), and Developmental Behavior Checklist-Primary Carer (DBC-P) for  ≤18 years and Adults (DBC-A) for those >18 years. 8 subjects completed the Autism Diagnostic Interview-revised (ADI-R).

Results: Clinical psychiatric assessments (n=10). Most participants showed amiable demeanor, but had difficulties engaging socially. 9 had no speech or only single words. All participants made repetitive hand/finger movements, 9 repetitively fiddled with toys and showed a fascination with a (part of a) specific object. 6 participants repetitively played with the same toy or same activity (music, video). 6 participants had breathing abnormalities. Self injury was seen in 5, aggression in 4 participants. Parents of 5 participants noted difficulties with changes in daily routine. BSID-II (n=10). All participants had severe intellectual disability. Chronological ages ranged from 32 to 289 months; the range of age equivalent scores for the mental scale was 3.5 to 15 months, and for the motor scale 4 to 19 months. VABS (n=10). No participant, except the eldest, performed beyond a developmental age of 20 months. Adaptive functioning on the domains of daily living skills and communication appeared better than functioning on the socialization domain. Progress in adaptive functioning with age was limited. DBC (n=10). Two participants scored above the clinical cut-off for problem behaviors for age group (with elevated scores on Self-Absorbed, and Communication Disturbance/Disruptive Behaviour scales). All participants had high scores on self-absorption. Five of 7 subjects <18 years scored above threshold on DBC Autism Screening Algorithm. ADI-R (n=8). Highest scores for all participants were found on the social interactions and play domains. All subjects scored ≥ cut-off scores on social and communication domains. Two participants did not score above cut-off for behavioral domain.

Conclusions: In this first study of neurodevelopment and behavior in PTHS all subjects shared a phenotype of (very) profound intellectual disability, severe impairments in social interaction, communication/language, and highly frequent, intense stereotyped behaviors. Psychiatric assessments additionally showed repetitive play, fascinations, and insistence on sameness. The quality and intensity of social, communication and behavioral difficulties in our sample are beyond what would be expected even for the very low cognitive level found and therefore cannot be readily explained by it. We conclude that the PTHS phenotype includes ASD in varying degrees of severity.