Neuropsychiatric phenotypes in children with Noonan syndrome

Abstract

Aim: We investigated neuropsychiatric outcomes in children with Noonan syndrome and addressed limitations in previous research with a focus on prepubertal children, comparison to typically developing children, comprehensive neuropsychiatric evaluation, and controlling for overall cognitive abilities.

Method: Forty-five children with Noonan syndrome (mean = 8 years 6 months, SD = 2 years 2 months; 29 females) and 40 typically developing children (mean = 8 years 9 months, SD = 2 years; 22 females) were evaluated with objective, parent-report, and psychiatric interview measures.

Results: Children with Noonan syndrome demonstrated elevated symptoms across attention-deficit/hyperactivity disorder (ADHD) (attention, hyperactivity, and inhibition), autism spectrum disorder (ASD) (maintaining social relationships, behavioral rigidity, and sensory sensitivity), and oppositional defiant disorder (ODD) (aggression) symptom clusters relative to typically developing children (all p < 0.05). Group differences in nearly all parent-report measures were significant after accounting for variations in intellectual functioning, suggesting that increased neurodevelopmental symptoms are not simply driven by overall intelligence. Twenty out of 42 children with Noonan syndrome met criteria for ADHD, eight out of 42 for ODD, and 11 out of 43 demonstrated clinically significant symptoms seen in children with ASD.

Interpretation: Children with Noonan syndrome are at increased risk for a range of ADHD, ASD, and ODD associated symptoms. A dimensional approach reveals significant ASD symptoms in Noonan syndrome that do not emerge when using the currently accepted categorical diagnostic approach.

What this paper adds: Neuropsychiatric disorders occur in more than half of children with Noonan syndrome. Children with Noonan syndrome demonstrate highly variable neurodevelopmental symptom profiles. Children with Noonan syndrome display variable impairments in attention, hyperactivity, and inhibition. Specific social concerns include behavioral rigidity, transitions, and difficulties maintaining social relationships. Children with Noonan syndrome display variably elevated levels of aggression and emotional dysregulation.

Figure 1:

Noonan syndrome can be considered a human model system for understanding the Ras-mitogen-activated protein kinase (MAPK) pathway’s role in neurodevelopmental disorders. (a) Visualization of key components within the Ras-MAPK pathway. SOS1 and SHP-2 proteins are displayed in warm colors, reflecting their activation of RAS phosphorylation and Neurofibromin in a cold colors reflecting loss of inhibition—that also results in pathway activation. (b) Noonan syndrome is caused by autosomal dominant mutations of high penetrance in five main genes: PTPN11 (50% of cases), SOS1 (10–13% of cases), RAF1 (5% of cases), RIT1 (5% of cases), and KRAS (< 5% of cases). (c) Noonan syndrome is the most common syndrome associated with Ras-MAP K pathway pathogenic variants (RASopathy) and most children have intelligence in the normal range. (d) Noonan syndrome is strongly associated with increased risk for neurodevelopmental disorders and 6 out of 10 children present with a neuropsychiatric disorder in childhood.^,,

Figure 2:

Study assessments were organized around three neurodevelopmental symptom clusters—green: attention/executive function; yellow: social skills; purple: aggression. Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder BASC-2, Behavior Assessment System for Children, Second Edition; BRIEF, Behavior Rating Inventory of Executive Function; KSADS, Neurodevelopmental Module of the Kiddie Schedule for Affective Disorders and Schizophrenia—Present Version; NEPSY, Developmental NEuroPSYchological Assessment, Second Edition; SRS, Social Responsiveness Scales.

Figure 3:

Percentage of children with Noonan syndrome who met full and subthreshold criteria for attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and oppositional defiant disorder (ODD) based on results from structured psychiatric interview, the Kiddie Schedule for Affective Disorders and Schizophrenia—Present Version. ADHD subthreshold criteria are defined as four or more symptoms of attention/hyperactivity endorsed with accompanying clinical impairment. ASD subthreshold criteria are defined by meeting criteria for one full category (in the case of our children it was criteria for the restricted or repetitive behaviors domain [criterion B] that was met), or showing functional impairment in both A and B but not meeting full symptom counts for diagnosis (e.g. met 2 out of 3 criteria in A and 2 in B). ODD subthreshold criteria are defined by three or more symptoms with accompanying impairment in at least one setting.

Figure 4:

Boxplots and probability density estimates for Noonan syndrome (red) and typically developing (blue) groups. Visualizations were made using the R package ggplot2.^, Background is colored according to symptom clusters (consistent with Figure 2). (a) (green) attention/executive functioning; (b) (yellow) social skills; (c) (purple) aggression. Dashed horizontal line indicates a T value of 60 which corresponds to symptom levels in the ‘at risk’ (BASC), ‘mildly elevated’ (BRIEF), or ‘mild difficulty’ (SRS) range. Abbreviations: BASC, Behavior Assessment System for Children; BRIEF, Behavior Rating Inventory of Executive Function; NEPSY, Developmental NEuroPSYchological Assessment; SRS, Social Responsiveness Scales.