Brain & Development 33 (2011) 5261

www.elsevier.com/locate/braindev

Review article

Behavioural and cognitive phenotypes in children with

neurobromatosis type 1 (NF1): The link with the
neurobiological level
Caroline Hachon a,b, Stephanie Iannuzzi a,b, Yves Chaix a,b,c,*
b

a
Unite de Neurologie Pediatrique, Hopital des Enfants, Toulouse, France
Inserm, Imagerie Cerebrale et Handicaps Neurologiques UMR 825, CHU Purpan, Place du Dr Baylac, F-31059 Toulouse Cedex 9, France
c
Universite de Toulouse, UPS, Imagerie Cerebrale et Handicaps Neurologiques UMR 825, CHU Purpan, Place du Dr Baylac,
F-31059 Toulouse Cedex 9, France

Received 2 October 2009; accepted 27 December 2009

Abstract
Neurobromatosis type 1 (NF1) is one of the most frequent monogenetic disorder encountered in children. Approximately 50%
of children with NF1 develop learning disabilities notably for reading. Understanding the reasons of reading impairment in this
context may lead to improve therapeutic methods in NF1 and more generally in reading developmental disorders. An interesting
challenge is to disentangle the connections between the dierent levels of description proposed in the etiological approach. This
is the aim of this review based on recent advances in analysis of cognitive decits observed in children with NF1 and on results
of recent brain imaging (structural and functional) or animal model studies.
2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: NF1; Child; Reading disabilities; Cognitive impairment; Brain imagery

1. Introduction
Neurobromatosis type 1 (NF1) is a multi-systemic
autosomal dominant genetic disorder with an estimated
prevalence of 1 in 3500 [1]. The responsible gene, a tumor
suppressor gene, of this neurocutaneous disorder is
located on the long arm of chromosome 17 (17q11.2).
Its protein product, Neurobromin, plays an important
part in cell transduction involved in synaptic plasticity,
memory and learning [2,3]. Diagnosis of NF1 is based
on clinical criteria, established through a National Institutes of Health consensus in 1987 [4] revalued in 1997.
*
Corresponding author. Address: Unite de Neurologie Pediatrique,
Hopital des Enfants, 330 av de Grande Bretagne, 31059 Toulouse
Cedex 9, France. Tel.:+33 05 34 55 85 75; fax: +33 05 34 55 87 10.
E-mail address: chaix.y@chu-toulouse.fr (Y. Chaix).

The prognosis of NF1 remains unpredictable with the

possibility of complications aecting various organs.
Learning disabilities are the most frequent childrens
complications, with a frequency between 30% and 60%
depending on studies [57]. So, we can consider that
approximately one out of two children with NF1 will
show learning disabilities and academic impairment.
The last published studies take account of the pitfalls of
the rst studies, allowing to progressively improve the
knowledge of cognitive prole of NF1: these studies are
based on larger groups, with control groups, removing
NF1 children with an associated cerebral disease (tumor,
seizures, . . .) and taking the overall cognitive functioning
into account to explain the specicity of learning
disabilities.
This review will take a particular interest in cognitive
and cerebral imaging studies that have allowed the

0387-7604/$ - see front matter 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.braindev.2009.12.008

C. Hachon et al. / Brain & Development 33 (2011) 5261

improvement of the understanding of the origin of learning disabilities in NF1. The display of this review is realized according to the multi-level etiological model
propounded by Frith et al. [8] in childrens developmental
disorders. These various levels include behavioural
manifestations, cognitive impairment responsible for the
decits seen on the rst level, and on the neurobiological
level, neuro-anatomical substrates of cognitive impairment and theirs links with the NF1 genetic mutation.
This review was based on a search in PubMed and using
the following key words, Neurobromatosis type 1,
Learning disability, Cognitive decit in conjunction
with pathophysiology, genetics, brain imaging. Largely, we selected publications of the past 5 years; we also
searched the reference lists of the reviewed articles and we
considered older, classic papers and those we judged relevant to the topics of this review.
2. Behavioural level
Learning disabilities are the most frequent complications described in NF1 children. A rate near 50% was
conrmed by recent publications: for instance, 52%
among 81 children with NF1 had learning disabilities
[7,9] or 47% among 17 children in another study [10].
Coude et al. [11] reported a higher frequency of academic impairment (60% among 116 children with
NF1) but they taken in account only childs school
course and not the objective academic level of children
like in the two previous studies.
We cannot solved the problem of learning disabilities
without considering the NF1 childrens level of intelligence eciency. Indeed, its now recognized that the
overall cognitive functioning of the NF1 children is usually normal. The incidence of mental retardation
(dened as a full-scale IQ less than 70 on the Wechsler
scale) is higher than the general population but cannot
explain the incidence of learning disabilities: Hyman
et al. [7] found mental retardation between 6% and 7%
of their NF1 population; this represents 2 or 3 times
the incidence in the general population. Nevertheless
all studies converge to show a shift to the left of the
IQ curve in this population: the mean IQ of NF1 children is signicantly lower than the IQ of unaected participants (sibling or others), around 90 in the recent
studies [7,9,12,13].
Some authors initially suggested a bimodal curve in
this population [14] with two groups of children: one with
a mean IQ around 85 and the other around 100. In fact the
study of the same group [7] but on a larger cohort tended
to refute this, showing a normal distribution of the fullscale IQ with an average of 90. Among the predictive factors of lowering of IQ the same authors found a negative
eect of the socioeconomic status both in the NF1 group
and in the control group. It was widely assumed that the

53

lowering of IQ is not related to the clinical severity of

the disease, but it must be specied that most of the current studies about cognitive disorders in NF1 removed
the subjects with cerebral complication (tumor, malformation, optic glioma, seizures).
If the rst studies suggested a signicant dierence
between ability in nonverbally versus verbally mediated
functions, at the expense of the last ones [15,16], leading
some authors to propose NF1 as a model for the nonverbal learning disabilities syndrome (NLD), subsequent
studies have shown the possibility of verbal learning disabilities [1720]. In most recent studies no signicant difference between verbal and performance IQ scores in the
studied population have been found [7,9,10].
The learning disabilities aect as well reading and spelling than mathematics. According to the selected denition and considering or not the level of intelligence
eciency, the incidence of these disabilities diers.
Hyman et al. [9] proposed to distinguish two subtypes
of learning disabilities: a group with general learning disabilities (without dissociation between overall cognitive
functioning and academic achievement) and a group with
specic learning disabilities (with signicant dissociation
between overall cognitive functioning and academic
achievement). These two groups represented respectively
32% and 20% of the 52% of NF1 children with learning
disabilities in their study. In a recent work, Watt et al.
[21] found reading disorders in 67% of the 30 studied children but among them only 17% met the criteria for specic
impairment when considering discrepancy between IQ
and reading levels. Nevertheless, the distinction between
general and specic learning disabilities in this population
requires caution: discrepancy between academic achievement and cognitive functioning has been diagnosed on
full-scale IQ that did not always reect real childs cognitive functioning because of the heterogeneity of the cognitive prole. This point should be more evident now with
the use for intellectual assessment of the WISC IV scale
of which four index distributions seems rather heterogeneous in this population.
In the general population, spelling and mathematics
impairment are often associated with reading disabilities. There are few studies that had specically disentangled the relations between reading, spelling and
mathematics abilities in the NF1 population. According
to Mazzocco et al. [22] mathematics impairment in NF1
was not specic but related to reading disabilities. In
children with NF1, reading impairment concerns both
uency and reading comprehension [23].
Moreover, compared to the general population, children with NF1 have more problems with attention:
depending on the studies 3050% of the NF1 children
met the diagnosis criteria of attention decit and hyperactivity disorder (ADHD) [24]. Koth et al. [25] found,
among 32 studied families, a frequency of 42% of
ADHD among the NF1 children compared to 13%

54

C. Hachon et al. / Brain & Development 33 (2011) 5261

among their siblings, what made ADHD one of the typical features of the clinical phenotype of neurobromatosis. For Hyman et al. [7,9] the diagnosis criteria of
DSM IV for ADHD was found in 38% of the NF1 children. This co-morbidity increases if only the group with
specic learning disabilities was taken into account.
Hyman et al. [7] found this association in 45% of cases:
this was the frequency of co-morbid association (dyslexia and ADHD) in the studies about specic learning
disabilities [26]. Children with NF1 developed more
often an inattentive form of ADHD than the general
population, in which the hyperactive/impulsive form
was prevalent [27]. Mautner et al. [28] showed that
Methylphenidate improved attention and behaviour.
So the coexistence of ADHD and specic learning
impairment could contribute to the low academic
achievement in this population.
The studies specially centred on diseases psychosocial consequences showed that NF1 subjects developed
signicantly more behavioural problems than the
general population, with more aggressiveness [10,29],
anxio-depressive signs [27,29] and also more sleep disorders which seemed correlated with behavioural problems [30]. Impacts were noted on social acceptance [27]
and on social interactions [31], seeing that subjects with
NF1 seemed to display less leadership behaviour and to
be more socially sensitive-isolated than controls despite
they seemed more prosocial (helpful to others) [27]. The
perception of disease severity was correlated with clinical, behavioural and cognitive severity scores, with especially a correlation with cognitive severity score for
adolescents. Academic and learning diculties were a
major concern [31].
About this rst part, we can conclude that, on behavioural level, children with NF1 show for half a part of
them learning disabilities, particularly in the eld of
reading (speed and comprehension) and symptoms of
ADHD. What are the deciencies involved in this diculties at the cognitive level? (Fig. 1a).
3. Cognitive level
Children with NF1 exhibited a rather typical decit in
visuo-spatial abilities [23,32] that persisted once IQ
taken into account [7]. A Judgement of Line Orientation
of Benton (JLO) impairment was systematically found
among these children, making of visuo-spatial impairment one of the typical features of the cognitive phenotype [5,6,23]. The test of JLO involved visuo-spatial
abilities, working memory, visuo-attentionnal and
visuo-motor skills, all of these abilities may contribute
to the failure of this test. Schrimsher et al. [32] have
shown that the dierence between the NF1 and the control groups persisted when the attention diculties were
taken into account. Hyman et al. [7] showed that the
visuo-spatial impairment remained present when visuo-

motor skills and visual memory were controlled. These

visuo-spatial diculties could be involved in the reading
disabilities of these children.
Language disabilities were also found in the NF1
population with the possibility of decits on spoken language, aecting expressive or receptive side [17,3335].
Hyman et al. [7] reported that language impairments,
unlike the visuo-perceptual and attentionnal disabilities,
did not seem to be more important than those foreseeable
by the NF1 childrens overall cognitive functioning compared to control siblings. Nevertheless, this study did not
assess accurately the metaphonologic skills, only the
expressive and receptive language skills were evaluated.
Metaphonologic skills are essential to implement the grapho-phonemic code, rst stage on the learning of reading
and are relatively independent of the level of intelligence
eciency [36]. Denckla, as early as 1996, [37] stressed that
NF1 subjects had low scores in phoneme segmentation
and phonological memory, like those found in developmental dyslexia. The same group [18] compared 20 NF1
children, 20 control children and 20 dyslexic children.
They found similar reading and phonological awareness
impairment in the NF1 group than in the dyslexic children, but with a more general impairment of spoken language and a visuo-spatial impairment (JLO) in the NF1
group not found among the two other groups.
Children with NF1 may show a phonological skills
decit involved as well in the phonologic awareness than
in the phonological short-term memory [38]. Recently,
Watt et al. [21] have systematically examined the reading
procedure of 30 NF1 children according to the dualroute model of reading propounded by Coltheart [39].
The authors highlighted a prevalence of phonologic difculties in this population with 75% of the children
meeting the criteria of phonologic dyslexia with main
diculty on the sub-lexical procedure. The remaining
25% of children among those with reading diculties
were classied with mixed dyslexia.
Two negative results must be underlined from Hyman
et al. [7] study: on one side the lack of diculty of subjects
with NF1 compared to the control population in the
memory tasks (immediate memory, delayed memory
and recognition memory in both visual and verbal modalities); on the other side the lack of dysexecutive syndrome
when the level of intelligence eciency was taken into
account compared to control subjects and the default of
association between ADHD and dysexecutive syndrome.
Main studies interested in motor disorders have shown
ne motor coordination impairment and low motor speed
among 2030% of the NF1 children. This low speed
seemed specic to motor function and independent of
cognitive functioning [7]. Motor disabilities aected ne
and global motor functions [17] but also the visuo-motor
skills independently of attention abilities [32].
Further studies would be necessary to clarify several
points but reading disabilities in children with NF1

C. Hachon et al. / Brain & Development 33 (2011) 5261

55

N
E
U
R
O
B
I
O
L
O
G
I
C
A
L

E
N
V
I
R
O
N
M
E
N
T

C
O
G
N
I
T
I
V
E

Motor
slowness

Reading disabilities

Reduced
reading
fluency

Comprehension
deficit

ADHD

Inattentive
sub-type

B
E
H
A
V
I
O
U
R
A
L

Fig. 1

could result from a specic and simultaneous linguistic

decit with a phonological procedures impairment
and visuo-spatial decit with a perceptive and a visuomotor aspects worsened, for the last one, by the coordination diculties found in these children. Moreover, the
interactions with attentionnal diculties have to be
specied. (Fig. 1b).
4. Neurobiological level
About 50% of individuals with NF1 have macrocephaly
relative to megalencephaly [23]. Steen et al. [40] did not
nd any dierence of full-scale IQ between NF1 subjects
with or without macrocephaly. Most recent studies, using
volumetric MRI, imputed the increase of cerebral volume
to a simultaneous increase of gray matter (GM) and white
matter (WM) volume [41]. However, this increase seemed

to be more obvious concerning the WM [40,42], predominantly in the frontal [41,42] and parietal [42] regions.
Signicant positive interaction between GM right hemisphere volume and JLO and DTVMI (Developmental
Test of Visual-Motor Integration) achievement and
signicant negative interaction between GM frontal volume in the right hemisphere and ADHD [42] have been
found. So the increase of cerebral volume in NF1 subjects
did not seem to be uniform. The data gotten from morphological MRI conrmed this hypothesis. Billingsley
et al. [43] showed less leftward asymmetry of the planum
temporale in boys with NF1 than in girls with NF1 or in
controls. This lesser asymmetry was signicantly related
to specic learning impairment (i.e. with signicantly
dissociation between overall cognitive functioning and
academic achievement) concerning reading and mathematics. The same authors [12] found a signicantly

56

C. Hachon et al. / Brain & Development 33 (2011) 5261

E
N
V
I
R
O
N
M
E
N
T

N
E
U
R
O
B
I
O
L
O
G
I
C
A
L

Sustained
attention

Coordination
disorder

Linguistic impairment
specially
Phonological process

deficit

Visuo-spatial deficit
Perceptive and visuomotor impairments

Motor
slowness

Reading disabilities

Reduced
reading
fluency

Comprehension
deficit

ADHD

Inattentive
sub-type

C
O
G
N
I
T
I
V
E

B
E
H
A
V
I
O
U
R
A
L

Fig. 1 (continued)

positive interaction between particular morphologic features in right inferior frontal gyrus and phonological uency performance, some linguistic abilities, reading and
spelling in NF1 subjects.
Systematic T2-weighted brain Magnetic Resonance
Imaging (MRI) scans showed, in 4379% of NF1 subjects, depending on the study, areas of high signal intensity called Unidentied Bright Objects (UBOs).
According to the most recent studies, the frequency of
hyper intensities was around 70% [44,45]. The link
between cognitive impairment and hyper intensities
was much discussed [14,46,47], as well as their precise
nature [48]. This last study spoke for oedematous process with vacuolar myelinic changes. MR diusion
studies about 15 [49] and 50 NF1 subjects [50] showed
an increase of the apparent diusion coecient values
in the cerebral parenchyma of NF1 subjects compared
to controls, with the highest values in the UBOs. This

suggested an increase in water content of the studied

places. UBOs were principally sub cortically located,
especially in basal ganglia, thalami, cerebellum and
brainstem. Longitudinal studies showed a decrease with
age of these anomalous areas of signal intensity [51,52].
Gill et al. [52] emphasized yet that there were hemispheric hyper intensities in 18% of the NF1 subjects,
particularly seen on FLAIR sequences, located in the
hippocampus and that did not regress with age contrary
to the sub-tentorial hyper intensities. According to some
authors, more than their presence or their number, it
was the location of the UBOs that should determine
the presence of cognitive impairment: Moore et al. [46]
focused on the thalamic location and Mott et al. [53]
showed a relation between visuo-spatial trouble and
right corticalsubcortical location of the hyper intensities. Goh et al. [54] found a statistical association
between thalamic lesions and lower intellectual function,

C. Hachon et al. / Brain & Development 33 (2011) 5261

Dysfunction
Frontal areas

Dysfunction
Occipital areas

Thalamic
UBOs
E
N
V
I
R
O
N
M
E
N
T

57

Coordination
disorder

Linguistic impairment
specially
Phonological process

Cerebellar
UBOs

Sustained
attention

deficit

Visuo-spatial deficit Perceptive

and visuo-motor impairments

Motor
slowness

Reading disabilities

Reduced
reading
fluency

Comprehension
deficit

ADHD

Inattentive
sub-type

N
E
U
R
O
B
I
O
L
O
G
I
C
A
L

C
O
G
N
I
T
I
V
E

B
E
H
A
V
I
O
U
R
A
L

Fig. 1 (continued )

left globus pallidus hyper intensities and lower attention

score, and right middle cerebellar peduncle hyper intensities and lower sensori-motor score. Hyman et al. [44]
conrmed the data about thalamus in a study including
76 NF1 children: the presence of thalamic lesions was
related to a lowering of intellectual level and to lower
attention scores; on the other hand they did not nd
any relation between the presence and/or the number
of hyper intensities and cognitive impairment.
On the functional level, there has been shown in this
area an hypometabolism on a Positron Emission
Tomography (PET) scan study [55] and a decrease of
the NAA/Cho ratio on a spectroscopic MRI study
[56], speaking for an increased myelin turnover followed
by neuropil injury.
There were few functional imaging studies about NF1
and their results were somehow inconsistent [12,13,57].

In a rst study, Billingsley et al. [12] compared 15

NF1 children with 15 unaected children during phonologic tasks. The authors showed, in NF1 children, a
greater spatial extent and magnitude of activity in the
right frontal cortex relative to middle temporal and
parietal cortex during auditory phonologic processing
task, and a greater spatial extent and magnitude of
activity in the middle temporal and occipital cortex relative to frontal cortex, especially in the left part, during
the orthographic task. The authors concluded that
increased participation of the right hemisphere during
the auditory phonology task and increased posterior
cortical activity relative to frontal activity observed during the orthographic task may reect white matter disconnectivity between frontal and posterior areas
following the WM disorder noted in NF1. In a second
study [57], the authors proposed to the same children,

58

C. Hachon et al. / Brain & Development 33 (2011) 5261

Altered
NEUROFIBROMIN

Myelin
Disorder

Dysfunction
Frontal areas

Dysfunction
Occipital areas

Thalamic
UBOs
E
N
V
I
R
O
N
M
E
N
T

Coordination
disorder

Linguistic impairment
specially
Phonological process

Cerebellar
UBOs

Sustained
attention

deficit

Visuo-spatial deficit Perceptive

and visuo-motor impairments

Motor
slowness

Reading disabilities

Reduced
reading
fluency

Comprehension
deficit

ADHD

Inattentive
sub-type

N
E
U
R
O
B
I
O
L
O
G
I
C
A
L

C
O
G
N
I
T
I
V
E

B
E
H
A
V
I
O
U
R
A
L

Fig. 1 (continued)

a letter or number visual identication task (three conditions of presentation: conventional form, inverted form
or rotation in varying degrees). They showed an increase
of activity in posterior areas (middle temporal, parietal
and occipital) relative to anterior (inferior and lateral
orbital frontal) cortical regions in NF1 children compared to unaected children with a signicant positive
correlation between performance on the fMRI task
and reading scores. This correlation suggested a link
between the NF1 subjects visuo-spatial diculties and
their reading abilities. The functional anomalies of frontal regions shown in children with NF1 in this study
were linked with architectural anomalies described by
the same authors in anterior regions [12]. More recently,
Clements-Stephens et al. [13] studied the visuo-spatial
processes in 13 NF1 children and 13 unaected children
using fMRI. The authors showed in NF1 children an
inecient right hemisphere network with compensating

recruiting of left hemispheric regions. They found more

specically a decreased volume of activation in primary
visual cortex during a JLO task in children with NF1
compared to unaected ones.
On cerebral level, in the present state of knowledge,
thalamic hyper intensities should play a key role in cognitive impairment already described and motor impairment should result of basal ganglia and/or cerebellum
impairment. Although they seem inconsistent, the functional studies results should suggest connectivity pathology between anterior (frontal) and posterior (especially
occipital) cerebral areas. (Fig. 1c).
5. Genetic level
On cellular level, the NF1 gene product is a protein
called Neurobromin that acts as a brake on growth and
cellular increase, regulating an other protein expression,

C. Hachon et al. / Brain & Development 33 (2011) 5261

RAS protein. Regulating RAS, Adenylyl Cyclase and

Microtubule, Neurobromin plays a key role in cellular
transduction signal regulation involved in synaptic
plasticity, memorizing and also in learning. Actually,
modications on the number or the intensity of synaptic
connections provided neurobiological support for learning
and long term memory [2]. The knockout NF1 mouse
model conrmed that mice carrying a heterozygous null
mutation of the NF1 gene (NF1 +/ ) developed a predisposition to tumors and learning decits [58,59]. These mice
showed learning and memorizing impairment in a visuospatial task in the hidden version of the water maze (Morris
Water Maze), decit relied on hippocampal lesions. Costa
et al. [59] showed that, after a 10 days training, control
mice searched signicantly longer in the training quadrant
than NF1 +/ mice. In an interesting way, remediation
should have a positive impact, allowing to correct some
cognitive decits seeing that training continuation should
correct dierences between NF1 +/ and control mice.
Moreover, Costa et al. [59] pointed out that excessive
RAS activity secondary to Neurobromin impairment in
NF1 mice led to an increase of inhibitory process underlain
by GABA activity. The authors showed that these learning
decits can be rescued by genetic or pharmacological
manipulations that decrease RAS function, especially
using farnesyl-transferase. These works suggested the
potential eciency of anti-RAS agent, like the 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
reductase inhibitor. Li et al. [60] showed that Lovastatine,
a drug used commonly for hypercholesterolemia treatment
in human that is an HMG-CoA reductase inhibitor that
intervenes in the cholesterol synthesis, could reverse the
learning impairment in a knockout mice model. This
attractive therapeutic way was however constrained by
the recent Krab et al. [61] publication about the lack of
demonstrated eect of Lovastatine after 12 weeks of treatment on a double-blind, placebo-controlled clinical trial
about 62 NF1 children aged from 9 to 15. Nevertheless animal models suggested therapeutic tracks that were to be
explored: RAS hyperactivity or GABA over inhibition.
Animal models teach us how Neurobromin impairment may lead to learning disabilities and which therapeutic options may be tested in the future. We can
also think that gene and protein impairment shall lead
to a myelin turnover trouble even if a direct link is not
demonstrated. (Fig. 1d).
6. Future directions
The dierent explanation levels of learning disabilities
seen in NF1 have made noteworthy progresses during this
last 10 years. A number of remaining questions have to be
investigated in the following years. Among them is the
question of the respective part taken by visuo-spatial, phonological and attentionnal troubles in the origin of the
reading diculties, comparing NF1 subjects with or with-

59

out reading impairment but also children with NF1 and

children with developmental dyslexia. About visuo-spatial
impairment, the involvement of eye motor function needs
further investigations as the study of the link with coordination disorder frequently associated. At last it seems that
the assessment of intensive trainings on the cognitive and
cerebral behaviour, as already done in developmental dyslexia, is a track to explore, waiting for specic drugs.
Acknowledgments
This work was supported by a grant from the Clinical
Research Hospital Program from the French Ministry
of Health (PHRC 2008, University Hospital of Toulouse No. 08 113 01) and a Grant from the French Association Neurobromatosis and Recklinghausen (ANR)
to Dr. C. Hachon
References
[1] Kayl AE, Moore BD. Behavioral phenotype of neurobromatosis
type 1. Ment Retard Dev Disabil Res Rev 2000;6:11724.
[2] Johnston MV. Brain plasticity in pediatric neurology. Eur J
Paediatr Neurol 2003;7:10513.
[3] Johnston MV. Clinical disorders of brain plasticity. Brain Dev
2004;26:7380.
[4] Neurobromatosis. Conference statement. National Institutes of
Health Consensus Conference. Arch Neurol 1988; 45: 5758.
[5] Ozono S. Cognitive impairment in neurobromatosis type 1. Am
J Med Genet 1999;89:4552.
[6] North K. Neurobromatosis type 1. Am J Med Genet
2000;97:11927.
[7] Hyman SL, Shores A, North KN. The nature and frequency of
cognitive decits in children with neurobromatosis type 1.
Neurology 2005;65:103744.
[8] Frith U, Morton J, Leslie AM. The cognitive basis of a biological
disorder: autism. Trends Neurosci 1991;14:4337.
[9] Hyman SL, Shores A, North KN. Learning disabilities in children
with neurobromatosis type 1: subtypes, cognitive prole, and
attention-decit-hyperactivity disorder. Dev Med Child Neurol
2006;48:9737.
[10] Descheemaeker MJ, Ghesquie`re P, Symons H, Fryns JP, Legius
E. Behavioural, academic and neuropsychological prole of
normally gifted neurobromatosis type 1 children. J Intellect
Disabil Res 2005;49:3346.
[11] Coude FX, Mignot C, Lyonnet S, Munnich A. Academic
impairment is the most frequent complication of neurobromatosis type-1(NF1) in children. Behav Genet 2006;36:6604.
[12] Billingsley RL, Jackson EF, Slopis JM, Swank PR, Manhankali S,
Moore BD. Functional magnetic resonance imaging of phonologic
processing in neurobromatosis 1. J Child Neurol 2003;18:73240.
[13] Clements-Stephens AM, Rimrodt SL, Gaur P, Cutting LE.
Visuospatial processing in children with neurobromatosis type
1. Neuropsychologia 2008;46:6907.
[14] North K, Joy P, Yuille D, Cocks N, Mobbs E, Hutchins P,
et al. Specic learning disability in children with neurobromatosis type 1: signicance of MRI abnormalities. Neurology
1994;44:87883.
[15] Eliason MJ. Neurobromatosis: implications for learning and
behavior. J Dev Behav Pediatr 1986;7:1759.
[16] Eliason MJ. Neuropsychological patterns: neurobromatosis
compared to developmental learning disorders. Neurobromatosis 1988;1:1725.

60

C. Hachon et al. / Brain & Development 33 (2011) 5261

[17] Hofman KJ, Harris EL, Bryan RN, Denckla MB. Neurobromatosis type 1: the cognitive phenotype. J Pediatr 1994;124:S18.
[18] Cutting LE, Koth CW, Denckla MB. How children with
neurobromatosis type 1 dier from typical learning disabled
clinic attenders: nonverbal learning disabilities revisited. Dev
Neuropsychol 2000;17:2947.
[19] Cutting LE, Koth CW, David D, Denckla MB. Comparison of
neuropsychological proles of children with NF-1 and RD. J Int
Neuropsychol Soc 2003;9:203.
[20] Billingsley RL, Slopis JM, Swank PR, Jackson EF, Moore BD.
Cortical morphology associated with language function in neurobromatosis, type I. Brain Lang 2003;85:12539.
[21] Watt SE, Shores A, North KN. An examination of lexical and
sub-lexical reading skills in children with neurobromatosis type
1. Child Neuropsychol 2008;14:40118.
[22] Mazzocco MM. Math learning disability and math LD subtypes:
evidence from studies of Turner syndrome, fragile X syndrome,
and neurobromatosis type 1. J Learn Disabil 2001;34:52033.
[23] Levine TM, Materek A, Abel J, ODonnell M, Cutting LE.
Cognitive prole of neurobromatosis type 1. Semin Pediatr
Neurol 2006;13:620.
[24] North K, Hyman S, Barton B. Cognitive decits in neurobromatosis 1. J Child Neurol 2002;17:60512.
[25] Koth CW, Cutting LE, Denckla MB. The association of
neurobromatosis type 1 and attention decit hyperactivity
disorder. Child Neuropsychol 2000;6:18594.
[26] Chaix Y, Albaret JM, Brassard C, Cheuret E, de Castelnau P,
Benesteau J, et al. Motor impairment in dyslexia: the inuence of
attention disorders. Eur J Paediatr Neurol 2007;11:36874.
[27] Noll RB, Reiter-Purtill J, Moore BD, Schorry EK, Lovell AM,
Vannatta K, et al. Social, emotional, and behavioral functioning
of children with NF1. Am J Med Genet A 2007;143A:226173.
[28] Mautner FV, Kluwe L, Thakker SD, Leark RA. Treatment of
ADHD in neurobromatosis type 1. Dev Med Child Neurol
2002;44:16470.
[29] Kayl AE, Moore 3rd BD. Behavioral phenotype of neurobromatosis, type 1. Ment Retard Dev Disabil Res Rev 2000;6:11724.
[30] Johnson H, Wiggs L, Stores G, Huson SM. Psychological
disturbance and sleep disorders in children with neurobromatosis type 1. Dev Med Child Neurol 2005;47:23742.
[31] Sebold CD, Lovell A, Hopkin R, Noll R, Schorry E. Perception
of disease severity in adolescents diagnosed with neurobromatosis type 1. J Adolesc Health 2004;35:297302.
[32] Schrimsher GW, Billingsley RL, Slopis JM, Moore 3rd BD.
Visual-spatial performance decits in children with neurobromatosis type-1. Am J Med Genet A 2003;120:32630.
[33] Dilts CV, Carey JC, Hofman RO, Creel D, Ward K, Clark E,
et al. Children and adolescents with neurobromatosis 1: a
behavioral phenotype. J Dev Behav Pediat 1996;17:22939.
[34] Joy P, Roberts C, North K, de Silva M. Neuropsychological
function and MRI abnormalities in neurobromatosis type 1. Dev
Med Child Neurol 1995;37:90614.
[35] Mazzocco MM, Turner JE, Denckla MB, Hofman KJ, Scanlon
DC, Vellutino FR. Language and reading decits associated with
NF1: evidence for not-so-nonverbal learning disability. Dev
Neurosci 1995;11:50322.
[36] Stanovich KE, Siegel LS. Phenotypic performance prole of
children with reading disabilities. A regression-based test of the
phonological-core variable-dierence model. J Educ Psychol
1994;86:2453.
[37] Denckla MB. Neurobromatosis type 1: a model for the
pathogenesis of reading disabilities. Ment Retard Dev Disabil
Res Rev 1996;2:4853.
[38] Cutting LE, Clements AM, Lightman AD, Yerby-Hammack PD,
Denckla MB. Cognitive prole of neurobromatosis type 1:
rethinking nonverbal learning disabilities. Learn Disabilities Res
Practice 2004;19:15565.

[39] Coltheart M. Analysing developmental disorders of reading. Adv

Speech Lang Pathol 2005;7:4957.
[40] Steen RG, Taylor JS, Langston JW, Glass JO, Brewer VR,
Reddick WE, et al. Prospective evaluation of the brain in
asymptomatic children with neurobromatosis type 1: relationship of macrocephaly to T1 relaxation changes and structural
brain abnormalities. Am J Neuroradiol 2001;22:8107.
[41] Greenwood RS, Tupler LA, Whitt K, Buu A, Dombeck CB, Harp
AG, et al. Brain morphometry, T2-weighted hyperintensities and
IQ in children with neurobromatosis type 1. Arch Neurol
2005;62:19048.
[42] Cutting LE, Cooper KL, Koth CW, Mostofsky SH, Kates WR,
Denckla MB, et al. Megalencephaly in NF1. Predominantly white
matter contribution and mitigation by ADHD. Neurology
2002;59:138894.
[43] Billingsley RL, Schrimsher GW, Jackson EF, Slopis JM, Moore BD.
Signicance of planum temporale and planum parietale morphologic
features in neurobromatosis 1. Arch Neurol 2002;59:61622.
[44] Hyman SL, Gill DS, Shores EA, Steinberg A, North Kathryn. T2Hyperintensities in children with neurobromatosis type 1 and
their relationship to cognitive functioning. J Neurol Neurosurg
Psychiatry 2007;78:108891.
[45] Lopes Ferraz Filho JR, Munis MP, Soares Souza A, Sanches RA,
Goloni-Bertollo EM, Pavarino-Bertelli EC. Unidentied bright
objects on brain MRI in children as a diagnostic criterion for
neurobromatosis type 1. Pediatr Radiol 2008;38:30510.
[46] Moore BD, Slopis JM, Schomer D, Jackson EF, Levy BM.
Neuropsychological signicance of areas of high signal intensity
on brain MRIs of children with neurobromatosis. Neurology
1996;46:16608.
[47] Legius E, Descheemaeker MJ, Steyaert J, et al. Neurobromatosis
type 1 in childhood: correlation of MRI ndings with intelligence.
J Neurol Neurosurg Psychiatry 1995;59:63840.
[48] DiPaolo DP, Zimmerman RA, Rorke LB, Zackai EH, Bilniuk
LH, Yachmis AT. Neurobromatosis type 1: pathologic substrate
of high signal intensity foci in the brain. Neuroradiology
1995;195:7214.
[49] Tognini G, Ferrozzi F, Garlaschi G, Piazza P, Patti A, Virdis R,
et al. Brain apparent diusion coecient evaluation in pediatric
patients with neurobromatosis type 1. J Comput Assist Tomogr
2005;29:298304.
[50] van Engelen SJ, Krab LC, Moll HA, de Goede-Bolder A, Pluijm
SM, Catsman-Berrevoets CE, et al. Quantitative dierentiation
between healthy and disordered brain matter in patients with
neurobromatosis type I using diusion tensor imaging. Am J
Neuroradiol 2008;29:81622.
[51] Hyman SL, Gill DS, Shores EA, Steinberg A, Joy P, Gibikote
SV, et al. Natural history of cognitive decits and their
relationship to MRI T2-hyperintensities in NF1. Neurology
2003;60:113945.
[52] Gill DS, Hyman SL, Steinberg A, North KN. Age-related ndings
on MRI in neurobromatosis type 1. Pediatr Radiol
2006;36:104856.
[53] Mott SH, Mazzocco M, Hofman K, Melhem H, Reiss AL,
Denckla MB. Neurobromatosis type 1: correlation between
volumes of T2-weighted high-intensity signals (UBOs) within
neural pathways and impaired performance on judgement of line
orientation. Ann Neurol 1995;38:509.
[54] Goh WH, Khong PL, Leung CS, Wong VC. T2-weighted
hyperintensities (unidentied bright objects) in children with
neurobromatosis 1: their impact on cognitive function. J Child
Neurol 2004;19:8538.
[55] Kaplan AM, Chen K, Lawson MA, Wodrich DL, Bonstelle CT,
Reiman EM. Positron emission tomography in children with
neurobromatosis type 1. J Child Neurol 1997;12:499506.
[56] Wang PY, Kaufmann WE, Koth CW, Denckla MB, Barker PB.
Thalamic involvement in neurobromatosis type 1: evaluation

C. Hachon et al. / Brain & Development 33 (2011) 5261

with proton magnetic resonance spectroscopic imaging. Ann
Neurol 2000;47:47784.
[57] Billingsley RL, Jackson EF, Slopis JM, Swank PR, Manhankali
S, Moore BD. Functional MRI of visual-spatial processing in
neurobromatosis type 1. Neuropsychologia 2004;42:395404.
[58] Costa RM, Silva AJ. Molecular and cellular mechanisms underlying the cognitive decits associated with neurobromatosis 1. J
Child Neurol 2002;17:6226.
[59] Costa RM, Federov NB, Kogan JH, Murphy GG, Stern J, Ohno
M, et al. Mechanism for the learning decits in a mouse model of
neurobromatosis type 1. Nature 2002;415:5265230.

61

[60] Li W, Cui Y, Kushner SA, Brown RA, Jentsch JD, Frankland

PW, et al. The HMG-CoA reductase inhibitor lovastatin reverses
the learning and attention decits in a mouse model of neurobromatosis type 1. Curr Biol 2005;15:19617.
[61] Krab LC, de Goede-Bolder A, Aarsen FK, Pluijm SM, Bouman
MJ, van der Geest JN, et al. Eect of simvastatin on cognitive
functioning in children with neurobromatosis type 1: a randomized controlled trial. JAMA 2008;300:28794.