Individuals with neurofibromatosis type 1 (NF1) are prone to the evolution of neurodevelopmental symptomatology including motor delays, learning disabilities, autism, and attention deficits. Caused by heterozygous germline mutations in theNF1gene, this monogenic condition offers unique opportunities to study the genetic etiologies for neurodevelopmental disorders and the mechanisms that underlie their formation. Although numerous small animal models have been generated to elucidate the causes of these alterations, there is little consensus on how to align preclinical observations with clinical outcomes, harmonize findings across species, and consolidate these insights to chart a cohesive path forward. Capitalizing on expertise from clinicians; human, animal, and cellular model research scientists; and bioinformatics researchers, the first Cognition and Behavior in NF1 (CABIN) meeting was convened at the Banbury Center of Cold Spring Harbor Laboratory in October 2024. This Perspective summarizes the state of our understanding and a proposed plan for future investigation and exploration to improve the quality of life of those with NF1.

Objective: The current study tested (1) how ADHD symptoms and internalizing or externalizing problems covaried across ages 3–18 in children with neurofibromatosis type 1 (NF1), and (2) whether demographic and NF1-specific factors moderated the associations. Method: We analyzed integrated cross-sectional data of 685 observations from 455 children and adolescents with NF1 (M_age = 9.79 years, SD = 3.88; 43% female) across six institutions in the United States and Australia. ADHD symptoms (inattention and hyperactivity/impulsivity) and internalizing/externalizing problems were assessed via parent-report measures. Time-varying effect modeling was employed to examine the age-specific associations between ADHD symptoms and internalizing/externalizing problems. Moderation analyses tested effects of sex, parental education, and NF1 inheritance mode (familial vs. sporadic). Results: Inattention and hyperactivity/impulsivity symptoms were associated with greater internalizing and externalizing problems across ages 3–17. Inattention links were similar across ages, while the hyperactivity/impulsivity-externalizing link was stronger in early childhood than during adolescence. NF1 inheritance mode significantly moderated the inattention-externalizing link, with stronger associations observed among children with familial NF1. Other moderators were nonsignificant. Conclusions: ADHD symptoms are robustly linked to internalizing and externalizing problems from childhood to middle adolescence in children with NF1, with familial NF1 emerging as a potentially elevated risk factor. Future longitudinal and experimental research is needed to inform integrated intervention approaches, especially for those with familial NF1.

Purpose: This study investigates receptive and expressive language abilities in individuals with Smith-Lemli-Opitz syndrome (SLOS) and examines how these are associated with intellectual functioning, sex, autism spectrum disorder (ASD) diagnosis, and biochemical markers of cholesterol metabolism. Methods: Participants (ages 4–18) with mild to classic SLOS were enrolled from a double-blind, placebo-controlled simvastatin trial. Receptive and expressive language scores were assessed using the Peabody Picture Vocabulary Test, Third Edition (PPVT-3), the Expressive One-Word Picture Vocabulary Test, 2000 Edition (EOWPVT-2000), and the MacArthur Communicative Developmental Inventories (MCDI). Intellectual ability and adaptive functioning were measured using the Stanford-Binet Intelligence Scales, Fifth Edition (SB-5) and Vineland Adaptive Behavior Scales, Third Edition (VABS-3). The SLOS Severity Scale (SSS) quantified disease severity. Associations with plasma and CSF sterol biomarkers (cholesterol, 7-dehydrocholesterol [7-DHC], 8-dehydrocholesterol [8-DHC]) were examined using nonparametric statistics with correction for multiple comparisons. Results: Twenty-one participants (mean age 7.85 years) had complete data; 71.4% had a diagnosis of ASD. Receptive and expressive language scores correlated with IQ and adaptive functioning. Receptive vocabulary scores were significantly negatively associated with disease severity, plasma 7-DHC and 8-DHC, and CSF 7-DHC. Expressive vocabulary scores also declined with increasing disease severity, but associations with sterol biomarkers were not significant. ASD was linked to higher rates of non-scorable assessments, though did not fully explain floor effects. No sex differences were found. Conclusions: Language impairment in SLOS reflects contributions from disease severity, disrupted cholesterol metabolism, and ASD. Receptive language showed stronger biomarker associations, while expressive impairments were more pervasive. Integrating clinical, biochemical, and caregiver-report tools is critical for comprehensive assessment of individuals with SLOS.