Neurodevelopmental disorders in children with neurofibromatosis type 1

Abstract

Over the past several decades, neurofibromatosis type 1 (NF1) has become increasingly recognized as a neurodevelopmental disorder conferring increased risk for several important neurodevelopmental problems. In this review, we summarize the specific neurodevelopmental problems encountered in the context of NF1. These include impairments in general cognitive function, deficits in specific cognitive domains such as executive function and visuospatial processing and risk for specific learning disorders, impairments in attention and social skills and the overlap with attention-deficit-hyperactivity disorder and autism spectrum disorder, and the risk of developing other psychiatric conditions including anxiety and depression. Early recognition of these developmental impairments is important for the effective treatment of children with NF1, and further characterization is essential to improve our understanding of how mutations in the NF1 gene create the diversity of clinical neuropsychiatric symptomatology observed in this at-risk population.

Nf1deletion results in depletion of theLhx6transcription factor and a specific loss of parvalbumin+ cortical interneurons

“…Neurofibromin contains a centrally located GTPase activating protein (GAP) domain, which inhibits RAS GTPase activity (Klose et al, 1998), but also contains many other regions for unique protein-protein interactions that could underlie different cellular functions (Ratner and Miller, 2015). NF-1 is one of many RAS-opathies (Rauen et al, 2010), and is often diagnosed by the appearance of skin discoloration (café-au-lait spots) and benign tumors, however, there are also cognitive changes, including a high incidence of autism spectrum disorder (ASD) and learning disabilities (Garg et al, 2013;Morris et al, 2016;Vogel et al, 2017). While the link between RAS-opathies and ASD has been documented (Vithayathil et al, 2018), the cellular and molecular mechanisms underlying how these cognitive changes arise are poorly understood.…”

Adaptive functioning in children with neurofibromatosis type 1: relationship to cognition, behavior, and magnetic resonance imaging

“…Approximately 80% of children with NF1 display difficulties with learning and/or behavior . However, neuropsychological profiles vary considerably between individuals with deficits observed in multiple domains, including intellectual ability, executive functioning, externalizing behaviors, and adaptive behavior …”

“…3 However, neuropsychological profiles vary considerably between individuals with deficits observed in multiple domains, including intellectual ability, executive functioning, externalizing behaviors, and adaptive behavior. 4,5 Adaptive functioning is a multifaceted construct that encompasses an individual's effectiveness in achieving ageappropriate maturity, judgment and reasoning, social sensibility, and personal independence. Adaptability affects all areas of early childhood development and has been closely linked to long-term functional outcomes for many neurodevelopmental disorders, such as intellectual disability 6 (wherein deficits in adaptive behavior are, by definition, criteria for diagnosis), autism spectrum disorder, 7 and attention-deficit/hyperactivity disorder (ADHD).…”

Bladder Dysfunction in Children with Neurofibromatosis Type I: Report of Four Cases and Review of the Literature

“…However, when NF1 has been previously diagnosed (because of cutaneous lesions in most cases), associated urinary involvement should be suspected. Although it is described in the literature [14], none of our patients developed neurodevelopmental impairment.…”