DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY INVITED REVIEW

Neurodevelopmental disorders in children with neurofibromatosis

type 1
ALECIA C VOGEL 1 | DAVID H GUTMANN 2 | STEPHANIE M MORRIS2
1 Departments of Psychiatry, Washington University School of Medicine, St. Louis, MO; 2 Department of Neurology, Washington University School of Medicine,
St. Louis, MO, USA.
Correspondence to Stephanie M Morris at Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
E-mail: morris.s@wustl.edu

Over the past several decades, neurofibromatosis type 1 (NF1) has become increasingly rec-
PUBLICATION DATA ognized as a neurodevelopmental disorder conferring increased risk for several important
Accepted for publication 18th May 2017. neurodevelopmental problems. In this review, we summarize the specific neurodevelopmen-
Published online 27th August 2017. tal problems encountered in the context of NF1. These include impairments in general cogni-
tive function, deficits in specific cognitive domains such as executive function and
ABBREVIATIONS visuospatial processing and risk for specific learning disorders, impairments in attention and
ASD Autism spectrum disorder social skills and the overlap with attention-deficit–hyperactivity disorder and autism spectrum
NF1 Neurofibromatosis type 1 disorder, and the risk of developing other psychiatric conditions including anxiety and
depression. Early recognition of these developmental impairments is important for the effec-
tive 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 neuropsychi-
atric symptomatology observed in this at-risk population.

Neurofibromatosis type 1 (NF1) is an autosomal dominant
condition caused by mutations in the NF1 gene on chromo-
some 17q11.2. NF1 is a common neurogenetic disorder,
affecting approximately 1 in 3000 people worldwide,1
exhibiting extreme clinical variability both within and
between families. Characterized by specific dermatological
findings, such as cafe-au-lait macules skinfold (intertrigi-
nous) freckling, and iris hamartomas (Lisch nodules), chil-
dren and adults are predisposed to the development of
multiple benign and malignant tumors.2 In addition to these
clinical findings, NF1 is becoming increasingly recognized
as a neurodevelopmental disorder conferring increased risk
for several specific neurodevelopmental problems, including
lowering of intellectual abilities, deficits in executive func-
tioning, impaired visuospatial processing, and motor delays.
Moreover, children with NF1 also harbor increased rates of
attention-deficit–hyperactivity disorder (ADHD), impair-
ments in specific academic domains of reading, spelling, and
mathematics, difficulties in social functioning with increased
rates of autism spectrum disorder (ASD), and elevated rates
of other psychiatric conditions (mood and anxiety disorders).
Since the underlying biological mechanism(s) of these neu-
rodevelopmental impairments remain incompletely under-
stood, this review will focus on the neurodevelopmental
problems encountered in the context of NF1.
NF1 AND IMPAIRMENTS IN INTELLECTUAL ABILITY
Intellectual disability (formerly mental retardation) is
defined in the Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition (DSM-5), as an IQ score of 70 or
below with associated impairments in adaptive function-
ing,3 and was the first reported cognitive impairment in
NF1. Initial estimates of intellectual disability were greatly
overestimated in early reports of cognitive function in
patients with NF1 owing to the inclusion of only the most
severe phenotypes;2 however, lowered school performance
and intellectual functioning were consistently reported,
suggesting a mildly affected subset of children not other-
wise meeting criteria for intellectual disability.4,5 In more
recent and larger studies using US National Institutes of
Health diagnostic criteria to diagnose NF1, estimates of
intellectual disability have varied (4% to 8%), but have
remained consistently above that of the general population
(3%).2,6 While the absolute rates of intellectual disability
are only modestly elevated, individuals with NF1 demon-
strate a reduction in expected IQ by approximately 1SD
relative to both the general population and unaffected sib-
lings, signifying a reduction in intellectual ability in the
presence of NF1 gene mutations, despite a shared genetic
background and environment.6 An exception to this 1SD
shift in cognitive ability is observed in individuals with the
17q11.2 1.4-megabase NF1 microdeletion syndrome. Over
half of these affected individuals have IQs less than 70,
constituting a diagnosis of intellectual disability, and nearly
all display characteristic facial dysmorphisms.7 Apart from
the well-established genotype–phenotype correlation asso-
ciated with 17q11.2 1.4-megabase microdeletions, NF1
clinical severity is not a reliable predictor of intellectual
ability, and impairment exists even when children with
intracranial lesions are excluded from these analyses.6

1112 DOI: 10.1111/dmcn.13526 © 2017 Mac Keith Press

However, children who require treatment for oncological
complications of NF1 remain at elevated risk for long-term
cognitive and behavioral sequelae typically associated with
cranial radiation and chemotherapy. The general reduction
in cognitive functioning observed among children with
NF1 has the potential to portend significant academic dif-
ficulties and result in school failure, thus requiring prompt
recognition through comprehensive neuropsychological
evaluations, and the early initiation of educational support
mechanisms.
SPECIFIC LEARNING DISORDERS AND DOMAIN-
SPECIFIC DEFICITS IN COGNITIVE PROCESSING
Nearly 20% of children with NF1 meet criteria for a
specific learning disorder, which is more than double that
observed in the typically developing pediatric population,6
although as many as 75% of children with NF1 will
require some type of school accommodation or remedial
teaching.8 Specific learning disorders connote substantially
lower performance in a particular subject, such as reading
(formerly dyslexia), mathematics (formerly dyscalculia), or
writing (formerly dysgraphia), that is not otherwise attri-
butable to lower general cognitive ability or comorbid
medical conditions, and continue despite targeted interven-
tion.3 In the DSM-5, there is no requirement for a specific
discrepancy between achievement testing in these areas
and IQ testing; however, most studies of children with
NF1 were performed using DSM-IV criteria, which
required a discrepancy between performance and IQ.
While early studies often used these more liberal criteria,
such as needing special instruction in certain subjects or
performance scores in specific subjects,2,4,5 children with
NF1 were disproportionately found to meet criteria for
specific learning disorders in reading, mathematics, and
writing/spelling,6 even when accounting for IQ.
In addition to specific learning disorders, children with
NF1 often have deficits in other specific cognitive
domains, including executive functioning and visuospatial
processing. Executive function includes aspects of both
organization and regulation, specifically with respect to
working memory, abstraction, initiation of mental rules or
task sets, cognitive flexibility, planning and problem solv-
ing, emotional regulation, and attentional control. When
directly tested, children with NF1 tend to show deficits in
more global measures of executive function, such as prob-
lem solving, planning, and task switching.4,9 Although
executive function has been previously demonstrated to be
tightly correlated to general intellectual ability,6 the
observed deficits may represent a core feature of NF1,
rather than a resultant effect of lower IQ.10 Similarly, there
is robust evidence to suggest that visuospatial processing is
specifically impaired in children with NF1, as evidenced by
deficits in the judgment of line orientation test.4 Subse-
quent studies investigating alternative spatial judgement
tasks, while controlling for motor speed and visual track-
ing, have continued to demonstrate widespread deficits in
visuospatial processing in children with NF1.6
What this paper adds
• Impairments in general cognition, executive function, and visuospatial pro-
cessing are common in children with neurofibromatosis type 1 (NF1).
• Children with NF1 are at high risk for specific learning disabilities involving
reading, writing, and math skills.
• Attention-deficit–hyperactivity disorder, autism spectrum disorder, and anxi-
ety are common in children with NF1.
• Early recognition of neurodevelopmental impairments in children with NF1 is
critical for initiation of early intervention therapies.
ATTENTION PROBLEMS AND OVERLAP WITH ADHD
For more than 30 years, researchers and clinicians have
reported significant attentional problems in children with
NF1.5 Over time, it has become increasingly recognized
that children with NF1 have specific deficits in attention,4
particularly in sustained attention.6 While the exact preva-
lence varies owing to differences in study methodology, as
many as 60% of children with NF1 meet diagnostic crite-
ria for ADHD.11 Unlike ADHD observed in the general
population, children with NF1 rarely meet criteria for
hyperactive/impulsive-type ADHD, and are more likely to
be diagnosed with either inattentive-type or combined-type
ADHD.11 The relative absence of the hyperactivity pheno-
type often delays clinical recognition of an impairment in
attention system function among children with NF1.
While ADHD is a highly heritable condition, the
genetic basis is not well understood.12 Research into the
underlying etiology of ADHD has largely focused on
dopaminergic and noradrenergic systems, particularly the
striatum12 given the efficacy of stimulant medication in
treating ADHD. While the neurobiology of the attentional
deficits in NF1 are also poorly understood, there is some
indication in animal studies that these problems reflect
changes in dopaminergic function,13,14 although given the
limited evidence of dopamine dysfunction in humans, the
relationship between dopamine and the ADHD phenotype
in NF1 remains unclear.11,15 Recently, research into the
neurobiology of ADHD has turned to understanding defi-
cits in terms of neural network systems, such as the
frontal–parietal attention system, thought to be related to
task-level attention, and the default mode network, which
may be related to both internal reflection and future pro-
jection,16 and potentially more similar to the deficits in
sustained attention seen in children with NF1. It is cur-
rently not known whether the neurobiological mechanisms
responsible for idiopathic ADHD translate to the atten-
tional deficits observed in NF1.15 However, despite a lim-
ited understanding of the potential etiology of ADHD in
NF1, it is of critical importance to recognize and treat
these symptoms as several studies have now demonstrated
the benefit of stimulant medications for the treatment of
ADHD in children with NF1.17,18
SOCIAL DEFICITS AND OVERLAP WITH ASD
Children with NF1 have long been recognized to exhibit
social perception problems, although the exact nature of
these deficits was not explored until recently. Previously, it
had been posited that the social difficulties experienced by
Review 1113
children with NF1 were related to the physical stigmata of
NF1.4 As the comorbidity with ADHD was better appreci-
ated, it was later hypothesized that impairments in atten-
tion were contributing to problems with social
interactions, as consistently observed in idiopathic
ADHD.19 There is now, however, increasingly strong evi-
dence that children with NF1 have a core deficit in social
functioning.
Several recent moderately sized studies,19,20 and one
large multisite study,21 have demonstrated an overall
decline in social functioning across multiple domains, as
well as a substantial increase in the incidence of clincial
ASD based on criterion standard diagnostic assessments:
approximately 25% to 40% of individuals with NF1,20,21
much higher than the 1% to 2% rate of ASD observed in
the general population.21 Moreover, using quantitative
measures of ASD symptom severity, the distribution of
quantitative ASD traits in NF1 is pathologically shifted
towards the more symptomatic end of the spectrum, with
nearly 40% of patients scoring within the impaired range.
In addition, 13% of children with NF1 score within the
most severe range, independent of general cognitive ability.
Symptoms in the two domains that characterize ASD
(social communication/interaction and restricted interests/
repetitive behaviors) are elevated in patients with NF1-
ASD, where these impairments moderately correlate with
ADHD symptom severity (Fig. 1). These findings indicate
a similar overall phenotype to idiopathic ASD.19–21 How-
ever, unlike idiopathic ASD, males and females appear to
be similarly affected, suggesting a lessening of the female
protective effect for ASD symptoms, similar to other syn-
dromic causes of ASD.21 The longitudinal trajectory of
ASD symptomatology in early childhood and the efficacy
of early intensive behavioral interventions in children with

Specific cognitive impairments

ADHD
IQ
Symptomatology

Genomic
ASD modifiers

NF1 gene mutation

Figure 1: The spectrum and severity of neuropsychiatric symptomatology reflects the contributions of individual variations in IQ, autism spectrum disor-
der (ASD), attention-deficit–hyperactivity disorder (ADHD), and specific cognitive impairments, coupled with genomic modifiers and the impact of the
germline neurofibromatosis type 1 (NF1) gene mutation. The dark grey colour denotes the schematic representation of the population distribution, while
the light grey colour denotes that for children with NF1.

1114 Developmental Medicine & Child Neurology 2017, 59: 1112–1116

NF1-ASD are currently unknown and require further
investigation.
MOOD AND ANXIETY DISORDERS IN NF1
Depression and anxiety have long been regarded as impor-
tant comorbid conditions in adults with NF1;22 however,
the impact of these common psychiatric disorders in child-
hood is incompletely understood. Studies exploring general
measures of quality of life have demonstrated a reduction
in quality of life among adults and children with NF1, and
recent larger studies have consistently revealed increased
rates of depression and anxiety in adults using standardized
measures.22,23 Studies investigating anxiety/depression
symptoms in children with NF1 have generally suggested
increased rates of both anxiety and depression, but have
relied on relatively small sample sizes and have used vary-
ing measurement tools.19,24,25 When investigating factors
that mediate well-being and quality of life in children, fam-
ily influences showed much stronger correlations than
measures such as disease severity.26
Interestingly, when compared with other chronic ill-
nesses, rates of depression reported in adults with NF1 are
similar to those found in individuals with multiple sclero-
sis, diabetes, and coronary artery disease, all of which pre-
dispose to intracranial pathology.23 This observation
suggests that the psychiatric manifestations in NF1 may be
related to underlying neuropathological changes, rather
than being a consequence of social distress related to NF1
disease severity. Interestingly, while the rates of depression
are increased in patients with chronic pain, with depression
influencing pain and pain influencing depressive symp-
toms,27 there was no clear association between ratings of
physical complaints26 or pain23 and ratings of depression
in patients with NF1. Furthermore, while mood and anxi-
ety disorders are thought to be multifactorial in etiology,
there is a clear genetic predisposition and neurodevelop-
mental influence in the development of these conditions,28
suggesting that the neurodevelopmental sequelae of NF1
(i.e. intellectual disability, ADHD, ASD) may provide addi-
tive risk to the development of anxiety and depression in
children with NF1.
CONCLUSION
NF1 is a monogenic tumor-predisposition syndrome with
varied effects on neural structure and function, creating a
wide variety of cognitive and behavioral abnormalities. In
this regard, NF1 is associated with an overall decrease in
cognitive functioning, with a pathological shift in IQ dis-
tribution. In addition, affected individuals exhibit specific
deficits in visuospatial processing, attention, and social
functioning, which increase the rates of specific learning
disorders, ADHD, and ASD. Interestingly, similar
neurocognitive impairments have been identified in a
related class of developmental disorders caused by germline
mutations in genes that affect the Ras/MAPK (mitogen-
activated protein kinase) pathway (RASopathies; i.e. Noo-
nan syndrome, Costello syndrome, cardiofaciocutaneous
syndrome), suggesting that dysregulation of this well-
defined signal transduction pathway may be critical to the
development of cognitive and behavioral dysfunction.29
Prompt recognition of these developmental and behavioral
impairments in children with NF1 is essential for early
behavioral and academic interventions and/or timely medi-
cal treatment. Further characterization of these neurode-
velopmental impairments in children with NF1 and related
disorders (currently underway in multiple active interna-
tional clinical studies) is essential to deepen our under-
standing of how defects in the NF1 gene and associated
genes create the diversity of clinical neuropsychiatric symp-
tomatology observed in this at-risk population.
Additional information about active clinical research
studies in NF1 can be found at https://clinicaltrials.gov/.
A CK N O W L E D G M E N T S
The authors have stated that they had no interests that might be
perceived as posing a conflict or bias.

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