1. Top of page
  2. Abstract
  3. What this paper adds
  4. Defining the constructs
  5. Method
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References
  10. Supporting Information

Aim  This systematic review aimed to pull together the findings from research into behavioural systems and attention in children with neurofibromatosis type 1 (NF1) and to identify areas that need further study.

Method  Relevant papers were identified through searches of electronic databases (MEDLINE, PsycINFO, EMBASE) and manual searches through reference lists. In total, 5746 articles were identified and 57 met the inclusion criteria. The data were synthesized using the narrative approach, as the studies varied considerably in terms of participants and measures.

Results  The results of the review showed that intelligence, academic skills, visuospatial skills, social competence, and attention are impaired in children with NF1. Evidence of deficits in memory, motor functioning, language, and executive functions was less clear.

Interpretation  Research has made marked progress in outlining the behavioural phenotype of NF1. However, although the general areas of impairment are becoming better known, the exact nature of the impairment is still not understood in many areas of behaviour. Care needs to be taken with the way in which behavioural constructs are defined and measured, and the variability of problems in NF1 is a particular challenge. Nevertheless, research is steadily moving towards comprehensive understanding of behaviour in children with NF1.


Children’s Behavior Checklist


Judgement of Line Orientation


Neurofibromatosis type 1


Rapid Automatized Naming

What this paper adds

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Defining the constructs
  5. Method
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References
  10. Supporting Information
  •  The paper provides the first systematic review on behaviour in children with NF1.
  •  It places the currently available studies of behaviour in children with NF1 within a theoretical framework.
  •  It identifies areas for further study.

Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders with a prevalence in the UK of 1 per 4560 live births.1 The main disease feature in childhood is the emergence of multiple café-au-lait spots (flat coffee-coloured skin lesions) and skinfold freckling. The most common complications in childhood are different deficits of cognition and behaviour, which affect the majority of children with NF1. Children with NF1 are also at a higher risk of a number of much rarer physical complications that can affect virtually every system of the body2 and include disfiguring plexiform neurofibromas, scoliosis, pseudarthrosis, and optic nerve gliomas.

The cognitive and behavioural problems associated with NF1 are a major impairment to children’s functioning at school and are issues that repeatedly come up in clinical practice as causing great distress to parents. The IQ of children with NF1 is usually within the normal range although somewhat lower than that of their unaffected siblings or community comparisons. More than 70% of children with NF1 perform more poorly at school than would be expected given their intellectual abilities.3 Furthermore, only a small proportion of children with NF1 are diagnosed with attention-deficit–hyperactivity disorder (ADHD),4 although experimental studies using clinical diagnostic criteria for ADHD suggest that the incidence of this disorder among children with NF1 is up to 40 to 50%.3

Issues concerning learning and various behaviour problems (such as difficulties with attention, peer relationships, and challenging behaviours) are among the most common complaints by parents of children with NF1 that emerge in our clinic work. Questions concerning learning and behaviour problems also make up the vast majority of the workload of neurofibromatosis advisors in the UK (funded through the national patient association, the Neuro Foundation). It is likely that this is at least in part because children with NF1 often have noticeable problems in several areas of functioning, although they do not dramatically fail in any one area. Also, there is tremendous variation between children with NF1, which means that an individualized approach to the difficulties experienced by children with the disorder is necessary. Understanding the different kinds of problems of cognitive and behavioural functioning resulting from NF1 is, therefore, of key importance in children’s clinical care. Although research investigating these questions has been ongoing for approximately two decades, studies to date vary widely in design, measures used, and participant groups, which makes it difficult to form an overall view of the current state of knowledge.

Defining the constructs

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Defining the constructs
  5. Method
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References
  10. Supporting Information

In this review, we follow the conceptualization of Lezak et al.,5 who suggest that behaviour consists of three systems: cognition (information handling), executive functions (how behaviour is expressed), and emotionality (feelings and motivation). In addition, they identify ‘mental activity variables’ (attention, consciousness, and activity rate; the last two are not discussed in this review), which also affect the overall behaviour of the individual. Cognitive functions are usually associated with specific areas or skills; in contrast, executive functions, emotionality, and mental activity variables affect behaviour in a more global manner. The definitions of executive function, attention, and emotionality will be discussed below.

We will start with the different classes of cognitive functions identified by Lezak et al.5: receptive and expressive functions (including linguistic, visuospatial, and motor functioning), thinking, and memory. Executive function and attention will then be discussed. Finally, we will review research on emotionality in the context of behaviour problems and social competence (since emotionality plays a part in social functioning). Intellectual functioning will be considered together with thinking processes, mainly for the practical reason that different subtests of intelligence test batteries provide the main source of data for measuring various thinking skills. Academic performance in general will be discussed in conjunction with linguistic functions, as the majority of work has centred on reading.

There have been several reviews concerning behaviour in children with NF1. Most of these have attempted to detail the cognitive profile of NF1 and have also briefly reviewed the potential connections between the cognitive problems and brain structural deficits and/or animal work done on NF1.6–9 Some have more specifically focused on the neurobiological, molecular, and cellular levels of cognition.10–12 The psychosocial aspects of NF1 have received less attention, although they have been briefly reviewed.6,8,10 These reviews have given the field of NF1 research several useful updates over the last 15 years, and directed future research efforts. However, there has not yet been a systematic review of all studies that have been published on the behaviour of children with NF1.

The aim of this systematic review is to pull together the findings from research into the behavioural systems of children with NF1 and to identify areas that need further study. Consolidating the available research evidence in the context of a systematic review was considered important in order to address issues such as the reasons behind underachievement at school by children with NF1 and to identify the gaps that still remain in our knowledge.


  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Defining the constructs
  5. Method
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References
  10. Supporting Information

Eligibility criteria

All empirical studies involving children with NF1 aged 6 to 16 years were included in the review. This age range was selected because we were particularly interested in how NF1 affects children’s functioning in skills related to education and the school environment. Studies were included if their outcome variables measured cognition, executive function, emotion, attention, or social functioning, and both studies using a comparison group and norm comparisons were included. We included only empirical studies using quantitative methods, published in peer-reviewed journals. Case studies were excluded because of the high potential for bias in these designs. The few studies published in languages other than English were not included owing to lack of translation resources.

We included treatment studies if they reported baseline data for all the participants together and studies that focused on the relationship between cognition and brain structure/function (e.g. T2 hyperintensities [T2H]) if they reported results for the entire group of children with NF1. In this review, we did not discuss the relationship between brain structure and functioning in children with NF1, as these have very recently been comprehensively reviewed by Payne et al.11

Information sources

Literature relevant to this review was obtained from the following electronic databases: MEDLINE (1946 to date), PsycINFO (1806 to date) and EMBASE (1974 to date). The databases were last searched on 12 May 2012.


For the MEDLINE search, the following MESH headings were used (combined with the OR function): cognition, executive function, attention deficit and disruptive behaviour disorders, attention, memory, learning, behaviour, motor skills, learning disorders, cognition disorders, memory disorders, mental disorders, speech disorders, language development disorders. The following keywords/phrases were used (combined with the OR function): motor skills, social skills, executive function, attention, memory, cogniti$, learning, behaviour, school, education, language. All the used MESH headings and keywords were then combined with the OR function, and the resulting search combined with the MESH headings of neurofibromatosis 1/neurofibromatosis type 1/NF1/Recklinghausen$ (using the AND function). The search terms were purposefully wide because, although many specific deficits and problems associated with NF1 have been investigated in detail, others have been less well characterized and/or researched and possibly the subject of only one study. We wanted to ensure that we did not miss studies this way and chose to be overinclusive in the search rather than risk failing to include relevant studies.

The same search terms were used (with appropriate modifications) to search the PsycINFO and EMBASE databases. The electronic searches were complemented by manually searching the reference lists of the identified articles.

Study selection

The titles and abstracts of all the articles retrieved by the search were scanned by the first author and papers that were obviously irrelevant were eliminated. These included papers that did not concern children and did not contain measures of cognition, behaviour, or learning, as well as papers in languages other than English. The selected full-text articles were accessed and papers not fulfilling the inclusion criteria were eliminated. The first round of the selection process was done by the first author and then verified by the other authors. The inclusion of non-peer-reviewed papers and studies not published in English were discussed among the authors and decided against. The data were then systematically extracted by the first author. A data extraction form in Microsoft Access, developed for this study, was used to ensure that the same details were obtained from all papers (Fig. S1, supporting information). The second author (EH) read all the selected papers and corroborated the extracted data. Any disagreements were discussed and resolved; these constituted a few cases in which one of the authors had included a finding but the other one had not.

Synthesis of results

The studies on behaviour in children with NF1 vary considerably in terms of the measures used (a large number of different measures have been employed), inclusion/exclusion criteria (e.g. excluding children with tumours or very low IQs), and recruitment methods. This variation was considered when choosing the most appropriate method for synthesizing the results.13 To perform a meta-analysis, we would ideally have liked to see a number of studies with similar design aspects to use the same measures in several common aspects of cognition and behaviour. Areas in which more controversy exists about the presence of deficits (e.g. executive function, memory, or language) were considered especially important.

Inspection of the different measures used across studies revealed that two measures were used in a large proportion of the studies: the Wechsler Intelligence Scale for Children (WISC; Revised, 3rd and 4th editions) and the Judgement of Line Orientation (JLO) test appeared in 38 and 20 studies, respectively. Given that the findings concerning the WISC and the JLO test are the least controversial in the literature, a meta-analysis using these outcome measures was not considered to significantly add to the current knowledge base.

Three other measures had been used in eight to 10 studies (Grooved Pegboard, the Children’s Behavior Checklist [CBCL], and Beery Visual–Motor Integration Test). However, the studies varied in terms of their methods for participant recruitment, selection of comparison participants, and inclusion/exclusion criteria, and the three aspects of cognition and behaviour they measured did not form a coherent whole. Therefore, a meta-analysis using these measures would have produced a somewhat disjointed report and would still need to have been supplemented by a narrative analysis to cover all the aspects of neurocognitive function that would not have featured in the meta-analysis. The rest of the measures were only used in one to three studies each.

Overall, therefore, a meta-analysis of the data was not considered to be the most informative way to synthesize the data; instead, the narrative review approach was thought to give the flexibility to best deal with the variability.14


  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Defining the constructs
  5. Method
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References
  10. Supporting Information

Our search produced 5746 papers. These were scanned and 5650 papers were excluded as they did not fulfil the inclusion criteria for this review. Ninety-six articles were retrieved in full, and of these, 39 were excluded (participants in five papers were either children younger than school age or adults; relevant data were not reported in 27 papers, six papers turned out to be reviews or commentaries, and one paper was a case study). A total of 57 papers that satisfied our selection criteria were identified.

Oral language

Comprehension and expression

Several studies have demonstrated that children with NF1 have deficits in their linguistic development (vocabulary, expressive, and receptive language),3,15–17 while some studies have demonstrated only deficits in expressive, not receptive, language.18–20 Phonological skills have also been found to be implicated;18,19,21 however, similar deficits are not always shown, for example Eldridge et al.,22 Billingsley et al.,23 Moore et al.,24,25 and Cutting and Levine.21 It is important to note, however, that the study by Eldridge et al.22 included only 13 participants with NF1 and may have failed to show significant differences because of inadequate power. The studies by Moore et al.24,25 and Billingsley et al.,23 on the other hand, used composite measures of several tests (verbal fluency test, the Rapid Automatized Naming [RAN] test, and the Test of Auditory Analysis Skills). This may have masked more subtle difficulties in only one of the tests only. Results on the RAN test have in general been unreliable.18,19 This may be because, although the test measures skills associated with reading and linguistic abilities, it has been suggested to involve other cognitive skills as well and is thus not a straightforward measure of linguistic skills. Similarly, verbal fluency does not seem to be significantly affected in children with NF13,16,26–28 and is also likely to measure executive functions alongside linguistic skills.16 Finally, it is worth noting that both Cutting et al.18 and Hyman et al.3 found that differences between children with NF1 and comparison children disappeared once IQ was entered into the analyses as a covariate.

Speech production

This aspect of language ability has not been extensively studied, despite the fact that children with NF1 often receive speech therapy (for example, Hyman et al.3 found that 44% of children with NF1 had received speech therapy, compared with 4% of typically developing children). However, Alivuotila et al.29 recently conducted a study focusing on speech quality in Finnish adults and children with NF1. Their results in children suggested that children with NF1 experienced difficulties in a range of aspects of speech: they performed significantly worse than comparison children in the areas of voice quality, regulation of pitch, rhythm (intonation differences and sequencing of syllables), sentence stress, nasal voice, and various speech sounds. However, there were no differences in fluency and intelligibility. These results may be, in part, language dependent, as languages vary in terms of phonemic and syllabic structure, stress, and rhythm, so it would be important to replicate the results in other languages. For example, the speech sounds that children find challenging are likely to vary depending on the phonological characteristics of the language in question.

Academic skills

Reading and spelling

A few studies have specifically focused on the relationship between linguistic abilities and literacy skills. Cutting and Levine21 found that comparison children scored significantly better on all phonological and reading comprehension measures than children with both NF1 and reading difficulties (NF1+RD). Children with NF1 but no reading difficulties (NF1noRD) scored better than those in the NF1+RD group on phonological memory and awareness and reading comprehension, but not on rapid naming. Differences between comparison children and NF1noRD children were not reported. Watt et al.28 investigated the reading subskills of children with NF1 and found that two-thirds of the children demonstrated problems in at least one subskill and, of these, 75% fulfilled criteria for phonological dyslexia. Non-word reading was associated with verbal skills, spelling, verbal comprehension, and verbal fluency. Billingsley et al.30 found impairments in auditory and orthographic tasks, even though children with NF1 did not differ from comparison children in terms of baseline speed.

Academic achievement

Reading problems in NF1 have to be considered in the context of learning problems in general. These are one of the main problems caused by NF1 in childhood. North et al.20 found that 65% of their sample of children with NF1 had impairment in at least one area of academic performance (>2y behind chronological age in reading/spelling, >1.96 standard deviation [SD] below population norm in mathematics). Hyman et al.3 reported this figure to be 52% (performance more than 1SD below norm), and Krab et al.17 found the prevalence of difficulties to be as high as 75% (based on ‘learning efficacy’). Overall, the majority of studies that have investigated academic skills show that children with NF1 do worse on most academic tasks than their siblings, comparison children, or standardized norms.3,15–17,19,22,24,31–36 The exact pattern of deficits depends to a degree on the measures used, which vary from one study to the next (e.g. Wechsler Individual Achievement Test or the Woodcock–Johnson Battery).

Research findings are somewhat variable because the way in which learning problems have been defined varies from study to study. Some studies just note if children with NF1 perform significantly worse than comparison children or norms. Some report learning deficits if there is a significant discrepancy between achievement scores and the individual’s IQ. However, some authors, for example Levine and colleagues,7 argue that in NF1 it is possible to underdiagnose learning problems via this method; if the IQ of an individual is already lowered, it may be harder to demonstrate the necessary discrepancy. They advocate the importance of overall performance levels as well as IQ-related performance. Hyman et al.3 do this using the discrepancy method (predicted achievement method that takes into account the correlation between ability and achievement scores) and reported generally lowered performance. Finally, Krab et al.17 used scores from the Dutch government-run programme of academic performance tests. Krab et al.17 converted the children’s achievement scores to age-equivalent scores and then compared these with the children’s chronological age to calculate their ‘learning efficacy’. Children whose learning efficacy was more than 1SD below average (i.e. <85%) were considered to have learning deficits. The deficit was considered specific if the child’s IQ was within 1SD from the mean (i.e. >85). According to this method, 39% of children had general learning deficits, 39% had specific learning deficits and 22% had no learning deficits. The fact that most studies still agreed in their findings demonstrated the robustness of learning problems in NF1. However, a more detailed understanding of the nature of learning problems in NF1 requires these differences in methodology to be taken into account.

Visuospatial functioning

Visuospatial deficits are perhaps the best-established characteristic of the cognitive profile of NF1 in childhood. The first detailed study describing learning deficits in NF1, by Eliason,37 found that the majority of children with NF1 suffered from visuoperceptual (non-verbal learning problems), although this label did not comprehensively explain all aspects of the functioning in these children. A number of studies have investigated this further, using a variety of measures that focus on the perception of angulation (e.g. the JLO test), visual organization (e.g. the Hooper Visual Organization Test), and object recognition (e.g. Benton Visual Form Discrimination Test and the Birmingham Object Recognition Battery). Children with NF1 have been found to perform significantly more poorly on visuoperceptual tasks than sibling comparisons,3,15–18,22–24,36,38–41 as well as scoring at least 1SD below standardized norms.27,42 There are some conflicting findings though: Clements-Stephens et al.33 found that, although children with NF1 scored significantly more poorly than comparison children on the JLO test and on two perceptual subtests of the Developmental Test of Visual Perception, there were no significant differences between the groups on the Hooper Visual Organization Test; Descheemaeker et al.35 failed to show a substantial deficit in visuomotor skills alone; and De Winter et al.43 found that children with NF1 demonstrated larger deficits on pure visuoperceptual tasks (the JLO test, recognition–discrimination task) than tasks requiring visuomotor components as well. However, in the studies of both Clements-Stephens et al.33 and Descheemaeker et al.35 sample size was fairly small, so the failure to find a statistically significant difference may be due to inadequate power in these studies. Brewer et al.,32 using hierarchical agglomerative clustering analysis, found that 14% of the children with learning problems in their sample fell into what they called the ‘visuospatial constructionally deficient group’, having special problems in the visuospatial constructional and fine motor coordination domains. This is a surprisingly small proportion, suggesting that it is not very common for visuospatial problems to be the only NF1-related cognitive problems of a child with NF1.

It seems that the JLO test captures particularly well the type of visuospatial impairment common in NF1; for example, Hyman et al.3 found that 56% of children with NF1 scored at least 1SD lower than comparison children, and Krab et al.17 and Moore et al.24 also found sizable deficits in the performance of children with NF1 on this particular task. Schrimsher et al.39 administered several different visuospatial tests to children with NF1, as well as comparison children. They then performed a discriminant function analysis and found the JLO test to be the best predictor of group membership. However, as pointed out by Levine,7 it is possible that the JLO test taps into other aspects of cognitive performance, in addition to visuoperceptual function, that makes it sensitive to deficits in NF1, such as executive function.18

Motor control and coordination, visuomotor function

Motor performance is closely related to visuospatial function, as pointed out, for example, by Levine et al.7 Parent reports of poor coordination and clumsiness are common in clinical practice, and Krab et al.17 found that over 40% of children receive remedial teaching to improve their motor performance at school, whereas in the study by Hyman et al.,3 53% of children with NF1 were found to have poor handwriting, according to parental reports (in contrast to 6% of children in a comparison group). Motor performance has been measured by tasks such as the Grooved Pegboard, the Beery Visual–Motor Integration Test, the Rey Complex Figure test, subtests from the Amsterdam Neuropsychological Tasks battery, the prism task, and the Bruininks–Oseretsky Test. Children with NF1 appear to struggle with both their fine and gross motor skills.3,16,17,19,20,35,36,38,44–51 Gilboa et al.52 studied handwriting, a skill that is often reported to be a problem for children with NF1, and showed that children with NF1 scored significantly lower on all measures of the Six-Trait Writing Model test (ideas, organization, word choice, sentence fluency, conventions, and total score) than comparison participants.

However, not all studies have found impairment on motor tasks: Bawden et al.42 and Billingsley et al.23 did not find impaired performance on the Grooved Pegboard; Eldridge et al.22 did not find an impairment in the Beery Visual–Motor Integration test; Krab et al.48 failed to show a significant difference on the Prism Adaptation test; and Moore et al.25 found no significant differences on any of the measures they used, although children with NF1 had lower scores than comparison participants. Also, although the handwriting of children with NF1 in the study by Gilboa et al.52 was less legible, less well-organized, and included more letter corrections and illegible letters than the handwriting of comparison children, these differences did not reach statistical significance.

There are some possible explanations for the variability in the results. Motor function, executive, and visuospatial skills are closely connected, and, in the case of handwriting, linguistic skills would also play a part; these are not isolated skills that can be measured discretely. Instead, it would be necessary to measure all these skills within one study and to investigate their interrelationships to differentiate their contribution to overall performance. Furthermore, children with NF1 have been documented to have decreased mineral density, bone strength, and muscle mass,53 and may have reduced muscle force.54 It is possible that these deficits affect children’s performance in motor tasks as well as their motor functioning in everyday life. More research into these connections is needed.

Intelligence and thinking

Intelligence as a construct has been defined a number of times in different contexts. An editorial statement of 52 researchers in 1994 defined it as: ‘A very general mental capability that, among other things, involves the ability to reason, plan, solve problems, think abstractly, comprehend complex ideas, learn quickly and learn from experience. It is not merely book learning, a narrow academic skill, or test-taking smarts. Rather, it reflects a broader and deeper capability for comprehending our surroundings—“catching on,”“making sense” of things, or “figuring out” what to do.’55

Relying solely on measurements of intelligence or IQ would no doubt lead to oversimplification of children’s abilities. The skills and experiences that influence an individual’s performance on intelligence tests are too diverse to comprehensively summarize in one or a few composite scores. However, from a clinical point of view it is useful to determine an individual’s general level of functioning and the pattern of strengths or weaknesses. These can then be investigated further if necessary. Furthermore, intelligence tests are composed of a number of subtests that measure various thinking skills, which are one aspect of the cognitive skills of the individual.

Cognitive processes measured by IQ tests: thinking skills

Lezak et al.’s5 conceptualization of cognitive functions includes thinking (involving different ways to mentally organize or manipulate information). Many of the subtests of standard IQ tests involve reasoning and concept formation, and therefore shed light on the skills of children with NF1 in these specific areas of cognition.

Verbal concept formation can be measured with the similarities subtest of the WISC. Hyman et al.,3 Ferner et al.,56 Hofman et al.,16 and Mazzocco et al.19 all found that children with NF1 performed significantly worse on this subtest than sibling comparisons, while Krab et al.17 did not find marked lowering, although they did not report statistical comparisons for their whole group against a normative sample. Furthermore, 45% of children with NF1 scored more than 1SD below their sibling on this task.

Reasoning skills are measured by several of the WISC subtests: comprehension (verbal reasoning), picture completion, and picture arrangement (visuoperceptual reasoning) and arithmetic (mathematical reasoning). Picture arrangement was the only subtest on which Hyman et al.3 did not find children with NF1 to be impaired, while Mazzocco et al.19 did not find significant differences between children with NF1 and siblings on any of these four subtests. Their participant numbers were small, however so this may in part explain the lack of significant differences. Hofman et al.16 report results only for the arithmetic subtest, and showed that children with NF1 were not impaired. Ferner et al.56 do not report results for any of these four subtests. Finally, in the study by Krab et al.,17 children with NF1 did not seem to particularly struggle with picture completion or picture arrangement, but performed less well on arithmetic and comprehension.

IQ profile of children with NF1

The full-scale IQ of the majority of children with NF1 is in the normal range, although somewhat lower than children in normative samples or comparison groups (usually around 90, instead of the normative mean of 100).3,17–20,22,23,27,33,36,40,42,44,56–61 Only around 6% to 7% of children with NF1 have an IQ lower than 70,3,36,56 compared with only 2% of a normative population. The mean verbal and performance IQ of the participants with NF1 is usually significantly lower than that of comparison participants. Despite the apparent robustness of these findings, some studies have failed to demonstrate significant differences in IQ between children with NF1 and comparison children or norms.15,16,24,25,31 Apart from the studies by Moore and colleagues,24,25 all studies that failed to find an IQ difference between children with NF1 and comparison participants included only small numbers of participants, and the results may therefore be due to lack of power or, alternatively, biased sampling. Although several studies have looked at discrepancies between verbal and performance IQ, a consensus on the matter has not been reached, as different studies have found either no discrepancy or discrepancies to different extents.3,36,60 Indeed, North et al.8 suggested that the discrepancies are of ‘questionable significance’.

There is disagreement with regards to the exact IQ profile of children with NF1. Some studies have found that children with NF1 perform significantly more poorly on almost all subtests of the WISC3,16,56 with the exception of arithmetic16 and picture arrangement.3 The results of Mazzocco et al.19 were somewhat less conclusive; they found significant differences between all the verbal comprehension subtests except comprehension, while on only one perceptual/organization subtest, block design, were significant differences between children with NF1 and their siblings detected. In addition, digit span was significantly different between the two groups. Krab et al.17 do not report the significance of the comparisons between the NF1 group and a normative sample, but the children’s performance is close to the expected normative mean (mean standard scores over 9, mean 10) on similarities, picture completion, picture arrangement, and coding. Their results are therefore not entirely dissimilar from the findings of Hofman et al.16


Memory is the ability to ‘retain information and utilize it for adaptive purposes’.62 Memory functions are often divided to declarative memory (explicit memory, semantic, and episodic memories) and implicit memory (procedural memory and implicit item-specific memory). A distinction between verbal and non-verbal memory is also drawn.

In general, studies focusing on memory have given mixed results. Bawden et al.42 used the Warrington Recognition Memory test and the Verbal and Nonverbal Selective Reminding Tests, and found that children with NF1 were impaired on the recall measure of Selective Reminding tests and on the long-term storage score of Verbal Selective Reminding. Billingsley et al.23 found deficits in verbal but not spatial memory, while Moore et al.24 did not find significant differences on the memory measures (although they did not look at the verbal/non-verbal subtests separately). Hyman et al.3,36 found no significant differences between the NF1 and sibling groups on the verbal or visual memory tests they used (the Continuous Visual Memory Test and the California Verbal Learning Test for Children). Likewise, Krab et al.17 found that children with NF1 were not markedly impaired on the Rey Auditory Verbal Learning Test and Descheemaeker et al.35 found no significant impairment on the 15 words of Rey (immediate or delayed recall). Ullrich et al.40 found no differences between NF1 and comparison groups on the California Verbal Learning Test for Children. A slightly more consistent finding concerns the delayed recall condition of the Rey Osterrieth Complex Figure test, which has been used to measure memory; children with NF1 tend to perform poorly on delayed recall.16,17,35,42

Ullrich et al.40 studied visuospatial learning and memory by devising a computerized, virtual reality task equivalent to the Morris Water Maze task, performance on which is known to be impaired in the NF1 mouse model. With a visible target, there were no differences between the children with NF1 and comparison participants in speed and direction. However, when the target was hidden from view, children with NF1 spent significantly less time than sibling comparisons searching the correct quadrant. It is worth noting that children who performed poorly on the working memory tasks were especially impaired on the virtual maze task, which may indicate that this task too may involve an executive function component. Overall, however, Ullrich et al.’s40 study provides an example of a task that is ecologically valid (i.e. it approximates a real-life setting). However, the sample size was very small and therefore the results should be replicated with a larger sample.

Executive function and attention

Lezak et al.5 define executive functions as capacities that enable a person to successfully engage in ‘independent, purposive, self-serving behaviour’, and Gioia et al.63 further add that executive functions guide and manage cognitive and emotional functions, especially in the context of new situations or problems. Executive functions include working memory, planning, organization, inhibitory processes, categorization, flexibility, rule deduction, and divided and sustained attention.64–66

Because executive functions encompass several functions, there is a great deal of variety in the focus and measures that different studies have adopted to investigate whether executive functions are affected by NF1. Some have concentrated on working memory; Ferner et al.56 used a working memory task (the Sternberg Memory Test) and found that the NF1 participants made more errors than comparison children, although the reaction times of the two groups did not significantly differ. Children with NF1 performed more poorly than their siblings on the CANTAB Spatial Working Memory task40 and on the working memory task from the Amsterdam Neuropsychological Tasks battery.45

Many of the studies on children with NF1 have investigated the planning aspects of executive functions; overall their findings suggest that this aspect of executive function is impaired in children with NF1. Hyman et al.3 and Pride et al.27 found that children with NF1 performed significantly more poorly than siblings on tasks of executive functioning (including the Tower of London and the Children’s Category Test). Over 70% of the children were more than 1SD below the norm on the Tower of London test. Roy et al.58 studied the planning abilities of children with NF1 and obtained similar results, demonstrating that the NF1 group performed more poorly than comparison participants on all measures of planning skills.

Inhibitory control is another facet of executive function affected in children with NF1.45,47 Ferner et al. found that children with NF1 were impaired on the Stroop task; in around 20% of the NF1 participants, mean performance on this task was 2SD below the mean for comparison participants. Moreover, both Huijbregts et al.45 and Rowbotham et al.47 showed that cognitive control is important (defined as an equivalent of executive function, but also encompassing the level of complexity required to perform a task). Children with NF1 performed particularly poorly on tasks of working memory and inhibitory control when the demand for cognitive control increased; the effect on motor tasks was less clear. Rowbotham et al.47 found that the performance of children with NF1 deteriorated more substantially than that of comparison participants when processing load increased. Children with NF1 also made more errors when flexibility was required. In contrast to the findings discussed above, Krab et al.17 and Descheemaeker et al.35 found no marked deficits in executive functioning (Wisconsin Card Sorting Task, Stroop task), although children with NF1 performed slightly below the norm.

Traditionally, executive functions have been measured directly. However, a questionnaire instrument, the Behaviour Rating Inventory of Executive Function, can also be used and is argued to be more ecologically valid than specific psychometric tests. Pride et al.27 found that children with NF1 scored poorly on the shift, emotional control, and monitor subscales, as well as the Global Executive Composite and Behavioural Regulation Index. Payne et al.26 reported significantly lower scores in the NF1 group than in the comparison group on all the scores of the Behaviour Rating Inventory of Executive Function. Notably, these differences remained significant even after controlling for verbal IQ.

According to Lezak et al.,5 attentional functions are processes concerning the way in which the individual responds to stimuli and they do not have a unique behavioural end product as such. They have limited resources,67 are organized in a hierarchical manner, and take place sequentially.68

As with executive functions, attention problems in children with NF1 have been addressed by using neuropsychological tests to directly measure the deficits that children with NF1 have and by investigating how attention problems affect children’s behaviour and functioning in their daily life (using various questionnaire measures). A number of studies3,17,19,28,35,56 (although not Dilts et al.15) have shown that children with NF1 are impaired on attention tasks. Hyman et al.3 found that children with NF1 were impaired only on the sustained and switching attention tasks of the Tea-Ch battery, not on all subtests. Pride et al.27 and Watt et al.28 replicated this result, although Payne et al.26 found that children were impaired on all of the screening measures on the Tea-Ch battery. Gilboa et al.69 used a virtual reality paradigm in which they embedded a version of the continuous performance task into a computer-based classroom simulation with typical distracters (auditory and visual). They found that children with NF1 made more commission errors and had fewer total correct hits than comparison children. The children’s performance also correlated negatively with their inattention/cognitive problems score on the Conners’ Parent Rating Scale.

The majority of studies that have measured attention symptomatology with functional questionnaires have found that a substantial number of children with NF1 scored highly enough on these questionnaires to meet the researchers’ criteria for ADHD.16,21,22,33,40,58,70,71 Overall, approximately one-third to one-half of children with NF1 fulfilled the criteria set for ADHD (or poor attention) according to the research criteria employed by different studies. Koth et al.70 showed that ADHD was much more common in children with NF1 than in their siblings (or parents). However, it is important to note that scoring high on a questionnaire is not enough to warrant a diagnosis (especially as the questionnaires that are utilized vary widely in quality), and additional observational, interview, and psychometric measures would always be employed before arriving at a formal diagnosis. This procedure has been most closely followed in a research context by Hyman et al.,3 who used a combination of parents’ and teachers’ Conners’ questionnaire scores, as well as children’s performance on the psychometric tasks and observations during the assessment. In addition, Mautner et al.72 used a diagnostic interview to investigate ADHD in their sample of 93 children, of whom 49.5% were diagnosed with the disorder.

Emotionality, behaviour problems, and social competence

Lezak et al.5 point out that emotionality plays an important part in determining the behaviour of an individual. Emotionality is the ‘observable behavioural and physiological component of emotion’73 and emotion is a system that allows the individual to respond to events rapidly and appropriately.74 Emotion is associated with mood, temperament, disposition, motivation, and personality.75 Emotions guide our thoughts and actions and regulate our behaviour, and therefore help us to appropriately adapt to our environment.76 Emotion regulation involves processes such as cognitive appraisal (reading and understanding social cues, perception of affect, predicting one’s own and others’ actions); expression of emotions (communicating feelings to others during social interaction); socialization of emotions (reinforcement to express certain emotional displays in certain contexts); and modulation of emotions and mood states (in response to internal states, environmental demands and the social context77). Various cognitive and executive functions are involved in several aspects of emotion regulation, which means that deficits in cognition and/or executive function can potentially affect an individual’s abilities to regulate his/her emotions. Other factors that can potentially affect emotion regulation78 are child temperament, emotional development, language delay, general developmental delay, overactivity, parental depression, environmental stress, parental management techniques, and parental history.

Emotion and behaviour problems

Behaviour problems are an issue that many parents of children with NF1 bring up in clinic. Research investigating the type and prevalence of behaviour problems in children with NF1 has mainly used different questionnaires. The findings from the CBCL across studies suggest that, when rated by parents, children with NF1 have a significantly higher score on the total problems scale of the CBCL than comparison children or the CBCL norms.15,79–81 Descheemaeker et al.35 found that, although the mean scores for the group of children with NF1 in their study were in the normal range overall, 35% of the children were rated in the ‘at risk’ or ‘clinical’ ranges by parents whereas only 2% of typically developing children would be expected to fall into the ‘clinical’ range. The studies also showed that children with NF1 scored significantly higher than the norms on internalizing, externalizing, and thought problems.79,81 The children in the study by Dilts et al.15 scored significantly more highly than comparison children on anxious/depressed, internalizing, and attention problems. The teacher ratings for the CBCL differ from the parent ratings in that teachers rated children with NF1 significantly higher than the norms on total problem behaviours and internalizing problems; however, there were no differences when comparisons were made between siblings and children with NF1.79 Dilts et al.,15 on the other hand, found that teachers rated children with NF1 significantly higher on anxious/depressed problems than they did comparison children. Huijbregts and de Sonneville82 and Johnson et al.,4 using the Strengths and Difficulties Questionnaire, found that children with NF1 had significantly more conduct and emotional problems than children in the comparison group, and a significantly higher proportion of children with NF1 than norms scored in the ‘clinical’ range on all the subscales of the CBCL apart from prosocial behaviour.4 In contrast, Noll et al.80 found that there were no differences between children with NF1 and comparison children on ratings of depression and loneliness.

Social competence: social problems and social skills

Social competence is not discussed by Lezak et al.5 as one of the three fundamental systems contributing to behaviour. We have included it in this review because social competence is an important aspect contributing to an individual’s overall function. In defining social competence, we follow Rose-Krasnor’s83 model, which emphasizes the importance of effectiveness in social interactions as key in social competence. She sees social competence as situation specific and influenced by the systems affecting behaviour: cognitive and executive functions, emotionality, and attention. A child’s developing skills in the areas of motor, memory, linguistic, executive, and other functions will affect his or her competence. Thus, developmental problems in any of these areas are likely to have repercussions on the child’s social competence.

Studies investigating social competence in children with NF1 have usually focused on measuring either social problems (undesirable behaviours such as clinginess, acting young) or social skills (socially acceptable learnt behaviours, e.g. giving a compliment84), or abilities such as perspective taking, empathy, and social problem-solving.85 Both social skills and social problems contribute to a child’s social competence. The majority of data concerning the social skills and social problems of children with NF1 have come from questionnaires: data from the CBCL, the Strengths and Difficulties Questionnaire, the Social Skills Rating System (SRSS), and the Social Responsiveness Scale all suggest that social problems are common in children with NF1.15,79–82 Huijbregts and de Sonneville82 also showed that children with NF1 scored significantly more highly than comparison children on autistic traits (Social Responsiveness Scale); group differences were largest for this variable. Finally, Noll et al.80 reported that teachers perceived children with NF1 as more prosocial than comparison classmates (using the Revised Class Play instrument). In contrast, Barton and North79 found no significant differences on social skills (measured by the SRSS) between children with NF1 and their siblings on any of the variables they looked at.

Studies have also measured social competence more directly. Barton and North79 studied the association of social skills (from the SRSS ratings) and social outcomes, based on the social problem and the social competence scores from the CBCL (e.g. taking part in sports, hobbies, clubs, and teams). They found that children with NF1 scored significantly lower than their siblings on all social competence scales, thus replicating the results of Dilts et al.15 and Barton and North79 also found that parents’ and teachers’ ratings were correlated with the ratings of social competence and the behavioural correlates of social skills: better social skills were associated with significantly fewer social problems and better social competence. Noll et al.80 investigated social behaviour and peer acceptance in children with NF1 through peer and teacher ratings. Results from the Revised Class Play instrument (peers/teachers asked to assign roles to different children within the classroom) suggested that children with NF1 were perceived by both teachers and peers as more sensitive and isolated, less well liked, displayed less leadership behaviour, were selected less often as best friends, and had fewer reciprocal friendships than comparison children. Interestingly, children with NF1 did not have lower self-ratings on the Revised Class Play than children without NF1. Thus, overall, evidence from various sources seems to agree that children with NF1 have poorer social competence than comparison children.

The reasons for the poorer social competence of children with NF1 warrant more research. Barton and North79 did not find IQ or academic achievement to be related to social competence, whereas Huijbregts et al.86 found that there was a significant difference between the social skills of children with NF1 and comparison children, which disappeared once cognitive processing abilities had been accounted for. However, it is important to note that Huijbregts et al.86 used a composite measure of cognitive processing, whereas Barton and North79 used IQ and academic achievement as measures. Another potential factor is the severity of physical NF1 symptoms. These, however, do not appear to consistently affect the social competence of children with NF1 as Barton and North79 found that, in children’s self-ratings, children with moderate/severe NF1 had poorer social skills, while neither Huijbregts and de Sonneville82 nor Johnson et al.81 demonstrated this association.

More recently, Huijbregts et al.86 investigated whether children with NF1 have deficits in social information processing (e.g. recognition of faces, facial expressions and emotions, or top-down processes involving stored knowledge for adjusting one’s behaviour).86 Huijbregts et al.86 investigated whether children with NF1 are impaired in their ability to process social information using tasks from the Amsterdam Neuropsychological Tasks battery that tapped face and emotion recognition. They found that, in general, children and young people with NF1 are slower and more variable in their performance when asked to recognize faces in front and in profile, to identify fear, and to match emotions. This would suggest that children with NF1 may have difficulties when bottom-up encoding of social information is required. Importantly, however, using cognitive control (tasks of inhibitory control and working memory) as a covariate in the analyses reduced the significance of group differences on processing of social stimuli; differences remained significant in fear recognition, accuracy of emotion matching, accuracy in recognizing frontal faces, and stability in recognizing faces in profile.86 The authors consequently argued that cognitive control is involved in the processing of social information.

How are different systems of function related?

Different aspects of behaviour are always connected and operate together. For example, an appropriate emotional response in a novel social situation requires processing of sensory cues, appraisal of the situation, planning of response, and inhibition of inappropriate responses. Although neuropsychological tests and paradigms attempt to measure discreet aspects of cognition and behaviour, it is very difficult to have measures that would not require the use of other skills in addition to the particular one that is measured.

Processing skills affecting behaviour problems

A few studies have used different ‘processing skills’ (combination of cognitive and executive skills) as covariates in analyses investigating group differences on various outcomes between children with NF1 and comparison children. Huijbregts and de Sonneville82 found that differences in rates of conduct problems between children with NF1 and comparison children disappeared when social information processing (tasks on identifying and matching facial expressions from the Amsterdam Neuropsychological Tasks) was used as a covariate. A similar effect was produced by adding cognitive processing (processing speed, cognitive control, and social communication) as a covariate to an analysis of emotional difficulties (as measured by the Strengths and Difficulties Questionnaire). Although cognitive processing did explain a significant amount of variance in autistic traits, group differences remained significant after covarying for cognitive processing. These studies would suggest that the problems that children with NF1 have in emotional functioning may at least in part be due to their problems with certain aspects of cognitive processing, not their emotional function per se. Likewise, social information processing skills may potentially underlie conduct problems. It is important to note, though, that the results of these types of analyses obviously depend on how ‘processing skills’ are defined and measured in the study. However, this approach begins to tease out the relationships between different cognitive and behavioural skills and outcomes.

Does IQ explain findings on cognition/behaviour?

IQ is regarded to be an index of the general level of cognitive functioning of an individual. Some studies have included IQ as a covariate in their analyses and have considered differences between NF1 and comparison groups that remain significant after controlling for IQ to be especially robust. These include Salford tracking errors and Stroop errors;56 reading, spelling, planning, perception (both visuospatial and visuoperceptual), and sustained attention;3 visuospatial skills and long-term memory;17 and measures of planning abilities58 (mazes, Tower of London, and Rey Osterrieth Figure). Finally, Payne et al.26 used verbal IQ as a covariate in an analysis of results from the Behaviour Rating Inventory of Executive Function, and discovered that children with NF1 scored more highly than comparison children on all Behaviour Rating Inventory of Executive Function problem index scores, even after verbal IQ was controlled for. Cutting et al.18 used IQ as a covariate but discovered that all significant differences between children with NF1 and comparison children disappeared as a result. It is important to note that there is an ongoing debate about whether IQ should be used as a covariate when investigating cognitive outcomes in children with neurodevelopmental disorders. This will be considered in more detail in the discussion below.


  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Defining the constructs
  5. Method
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References
  10. Supporting Information

We will first summarize the findings in the different areas of behaviour and the areas where research is still required. We will then address various issues that need to be considered when evaluating the research as well as the limitations of this review. Finally, we will put the findings in the context of clinical care for children with NF1.

Cognitive skills, intelligence, and academic performance

Visuospatial (or visuoperceptual) skills have been found to be impaired in almost all studies that have looked at abilities such as angulation, visual organization, and object recognition. In particular, studies using the JLO test have usually found sizable deficits in children with NF1. The majority of studies have also found that children with NF1 have deficits of both fine and gross motor function. Some studies have failed to agree with these findings, however, suggesting that a more careful evaluation of motor skills in children with NF1 is necessary. Evidence on the skills of children with NF1 in the areas of memory and thinking (reasoning and concept formation), and on the exact nature of linguistic skill difficulties, is more contradictory. Visuospatial skills have been mentioned in previous reviews as one area in which children with NF1 clearly struggle.6,7,9,10,87 Kayl et al.6, in addition, point out that visuoperceptual deficits often go hand in hand with difficulties in perceiving social situations accurately, which is common in children with NF1.

Several areas of cognitive functioning require more research. Areas of linguistic skills that have not received research attention are discourse (tasks such as storytelling and describing activities) and grammatical abilities. There has also been no research into the pragmatic language skills of children with NF1. This might be especially revealing given the high levels of autistic spectrum symptomatology found in these children. There are also several aspects of memory that have not been investigated in the context of children with NF1, such as story recall, incidental learning, and prospective learning (remembering to execute a planned action). Given the problems that children with NF1 have with organization and planning, the last two might well be particularly impaired. Furthermore, several areas of cognitive functioning have been the object of only one study so far, such as active visual learning and speech production.

The studies included in this review have consistently found that the vast majority of children with NF1 have intelligence in the normal range, although their mean IQ is usually somewhat lower (in the low 90s) than that of the normative population or sibling comparisons. Five studies failed to find the IQ of children with NF1 to be significantly affected. However, several of these studies included relatively small numbers of participants (<20), and the higher IQ of the participants may be explained by selection bias. Variables such as parent educational levels or socio-economic status of the families are often not reported, so it is difficult to estimate the degree to which these might have affected the results.

Academic skills are affected in the majority of children with NF1, and both specific and general learning problems are found in children with NF1. The high incidence of learning problems can be regarded an established finding in children with NF1, and has featured in previous reviews on children with NF1.6,7,9,10,87 These problems have been defined in a variety of ways, however, which needs to be taken into account when interpreting them. Levine et al.7 highlight the importance of investigating the component processes of different academic skills. Reading has received more attention than the other academic skills in this respect.

Executive function and attention

Most studies of executive function have found deficits in different tasks involving planning and working memory. Increased cognitive load and higher demand of flexibility seem to be particularly detrimental to the performance of children with NF1,45,47 although these findings require further experimental confirmation. In general, as observed by Ozonoff,9 studies have tended to include just a few tests of executive function in their batteries, and more thorough exploration of the spared/impaired functions is still required. Problems with organizational skills are often mentioned in clinical work and in the literature,20,26,27 and these would benefit from further investigation. Aspects of executive function that have not been studied in detail include self-regulation (productivity, the ability to follow plans to fruition) and effective performance (an individual’s ability to monitor, self-correct and regulate the intensity of action). Both of these skills are important in adaptive behaviour and goal achievement. A further issue that needs investigation, raised by Cutting et al.,87 for example, is the way in which impaired executive function may affect performance in other areas of behaviour, for example academic achievement and motor function.

Problems with attention have been identified as one of the key characteristics of NF1 in several previous reviews.6,7,10,87 Indeed, studies that have set clinical criteria for diagnosis of ADHD have found that a substantial number of children with NF1 fulfil the criteria. These criteria, however, vary widely between studies, and this needs to be considered when evaluating the results. Studies measuring attention directly have found that it is impaired in children with NF1; Hyman et al.3 and Pride et al.27 have suggested that switching and sustained attention are particularly affected in NF1, although Payne et al.26 found deficits in all aspects of attention (sustained, switching, and selective attention).

An important challenge for future studies is to determine in more detail the types of attentional problems that children with NF1 have. The results of studies conducted to date suggest that inattention is a particular problem. Both Gilboa et al.69 and Payne et al.26 found that children with NF1 displayed inattentive behaviour significantly more often than comparison sibling participants. Gilboa et al.69 reported that the inattention scale was the only one on which children with NF1 significantly differed from comparison children. These connections require more investigation. The prevalence of inattention (as opposed to hyperactivity) problems, in particular, could in part explain why children with NF1 underachieve at school: hyperactivity is easily picked up because of its disruptive nature, whereas children with concentration problems but causing no havoc in the classroom may be left to their own devices, which contributes to their underachievement at school.

Finally, attention problems in NF1 are on a continuum, and therefore some children are likely to have problems with different aspects of attention severe enough to impair their function, even though they may fail to fulfil diagnostic criteria of ADHD. This is an issue that should be considered when discussing attention problems in the context of NF1.

Emotionality, behaviour problems, and social competence

Overall, children with NF1 appear to display higher frequency of different emotional and behaviour problem symptomatology than comparison children or normative samples. These rates are fairly high in some studies, and tie in with the high rates of ADHD. However, some areas of behaviour problems have received limited or no attention in research so far; for example, a number of parents of children with NF1 mention problems with sleeping (especially getting to sleep) and ‘faddy’ eating. These are common problems in young children in general, and therefore it would be important to find out whether there are specific issues connected to NF1 that make these problems more frequent in children with NF1. Overall, it is notable that not many discrete behaviour problems (such as conduct disorders, anxiety disorders, and so on) have been associated with children with NF1 despite the apparently elevated symptomatology in this group. It is difficult to say whether this is due to the extreme variability of these symptoms in children with NF1, or whether these symptoms are just considered part of a child’s NF1, instead of a discrete problem independent of NF1 as such.

Studies investigating social competence in children with NF1 suggest that they do indeed show higher rates of social problems and peer problems than comparison children. The deficits that children with NF1 show in face and emotion perception constitute one potential mechanism for this. In contrast, the evidence for the deficient social skills of children with NF1 is less consistent; nevertheless, children with NF1 score lower on social competence scales of the CBCL, indicating that they are involved in fewer clubs, after-school activities, hobbies, and so on. Finally, ratings by other children and teachers reveal that children with NF1 are less well liked, have fewer reciprocal friendships, and are selected as best friends less often.

The findings of this review agree with those of previous reviews,6,10 although we expand on the subject considerably. Kayl et al.6 suggest several potential contributing factors, such as the symptomatology of NF1 (e.g. tumours, disfigurement, learning problems, and ADHD), central nervous system abnormalities, and problems in visual perception. The last two have not been investigated, and the results concerning disorder severity and behavioural problems are mixed.81,82,88 In general, much more work will be needed to elucidate the reasons for psychosocial problems in NF1.

In addition, there are several areas related to social competence that need further study. More studies on social information processing are needed, both to replicate the current findings on processing facial expressions and to extend this work. Examples of potential areas of investigation are skills such as understanding of gestures and tone of voice, or higher-order processes, for example theory of mind. The work of Huijbregts and de Sonneville82 on the relationship between different aspects of cognitive processing and behavioural problems or social competence is promising and should be expanded. Finally, given the high prevalence of autism symptomatology found by Huijbregts and de Sonneville,82 executive function problems (the connection mentioned by Ozonoff82), and the suggestion of linguistic problems in NF1, the possibility of a raised prevalence of autistic spectrum symptomatology should be looked into in more detail.

Are there subgroups of different cognitive profiles in NF1?

The heterogeneity of the phenotypical manifestation of NF1 needs to be considered when developing remedial approaches for children with NF1. Because of the variability in the affected skills within and between individuals with NF1, it is possible that there is no one universal ‘cognitive profile’ of NF1. Indeed, several studies have tried to identify different subgroups of children with NF1. Hyman et al.36 and Krab et al.17 divided children with NF1 into groups according to their learning difficulties and then compared the cognitive profiles of these groups. Brewer et al.32 used a hierarchical agglomerative clustering analysis to classify the 74 children in their study who met the cut-off for academic impairment, according to the type of cognitive problems they displayed. These studies3,17,32 identified a group struggling with several areas of learning (32%/39% of the children in the studied sample in each study), as well as a group of less severely impaired children. Findings concerning the cognitive profiles of various groups, however, are somewhat difficult to interpret because of the use of different measures and depending on whether or not the comparisons include comparison groups. Cutting and Levine21 took a similar approach with regards to reading problems, and compared children with NF1 with and without reading problems with children with reading problems who were not diagnosed with NF1. They found that children with NF1 and reading problems scored similarly on phonological awareness, RAN, and reading comprehension as children who have reading problems but not NF1. There were no differences in oral language measures. The children with NF1 and reading problems performed significantly more poorly on visuospatial measures than children with NF1 and no reading problems, or healthy comparison children.

Finally, studies of the cognitive profiles of children with NF1 with and without comorbid ADHD found that a larger proportion of children with NF1 and ADHD had a specific learning problem than children with NF1 who did not have comorbid ADHD, although there was no increased risk of executive function deficits.36 Children with NF1 and comorbid ADHD had the lowest social competence scores and scored highly on attention problems, aggressive behaviour, social problems, and both internalizing and externalizing problems.79 In contrast, Roy et al.58 found that children with NF1 and ADHD performed more poorly on only one measure of planning (Tower of London moves score), and that deficits in planning may thus be only partially due to ADHD.

In general, these findings demonstrate that categorizing children with NF1 in different ways according to the type of outcomes (learning problems, ADHD status) can reveal different patterns of cognitive weaknesses. However, we do not yet understand the potential causal relationships between learning problems and cognitive profiles, nor do we know if these differences in cognitive profiles are clinically important.

Methodological issues

Some methodological issues are particularly relevant for studies on behaviour in NF1.

Recruitment and representativeness

Methods of recruitment raise the issue of representativeness of participants. Several studies recruited at least a portion of their participants via patient associations or by placing advertisements in newspapers, and, although this method is likely to provide compliant participants, these may well differ from families who do not have the inclination, time, or resources to be active in patient associations. Recruitment through clinics, on the other hand, will probably mean missing out participants who have mild NF1. Furthermore, the success of any recruitment method depends on parental consent.89

Goodman and Yude89 argue that issues such as recruitment methods and ascertainment level matter less than is often assumed. In their study on childhood hemiplegia they found that neither ascertainment level nor comprehensiveness of recruitment made a difference regarding demographic, medical, cognitive, or behavioural variables. However, this result is likely to depend on the condition in question, and should be applied with caution to a disorder that is phenotypically as variable as NF1. Representativeness may also be more of an issue for studies with fairly low participant numbers, as is the case of several (especially older) studies into behaviour and NF1.

In general, it would be vital to request studies to report detailed information about their sampling strategies; only a limited number of studies described their sampling in detail, specifying how many participants refused, were not reachable, and so on. This information would be important for getting a comprehensive idea of the final sample in relation to the patient population. In the future, it would also be important to do a population-based study in NF1, although even then one would still be limited by the issue of parental consent.

IQ as a covariate

The majority of studies have not controlled for differences in IQ in their analyses. The studies that do report comparisons with and without IQ covariates show that many of the differences between groups disappear once IQ is controlled for. Several studies have found group differences in executive functions (e.g. planning, response inhibition) to remain even after IQ has been added to the model; findings for other constructs are less consistent, but this would be expected since not many studies have included IQ covariates and these studies have not all employed the same measures.

Whether IQ should be controlled for, and in what kind of experimental design, has been the subject of debate. Ozonoff,9 for example, advocates the use of sibling comparison groups or IQ-matched groups instead of comparing children with NF1 with published norms. Dennis et al.90 have recently refuted this view, however, suggesting that using comparison groups matched for IQ will mean that either the NF1 or the comparison group will be unrepresentative and the results therefore impossible to interpret. Dennis et al.90 also argue that IQ should not be used as a covariate in studies of neurodevelopmental disorders at all, both for statistical reasons and because it produces ‘overcorrected and anomalous’ findings. Furthermore, if there is shared variance between IQ and the variable of interest (e.g. linguistic measures), using IQ as a covariate may reduce real group differences and thus bias results. Although the debate is still ongoing, it is important to consider these issues in the context of NF1, especially given the limitations of IQ as a measure (discussed in Emotionality, behaviour problems, and social competence section).

Comparison groups

Studies have used different comparison groups: siblings, community comparisons, normative data, or a mixture of these. As reviewed in detail by Levine et al.7 and Ozonoff9, for example, using different comparison groups answers slightly different theoretical questions. However, no study has yet systematically compared the effects of using different types of comparison, although some studies do report both normative comparisons and comparisons between the NF1 group and a sibling comparison group. However, comparison with norms can be problematic when the participants differ from normative data on attributes such as socio-economic status, for example. Also, high-quality norms are not available for all measures used in the literature. Erdoğan-Bakar et al.38 found some differences between the performance of sibling comparisons and community comparisons, and Cutting et al.18 showed that results on visual skills in children with NF1 differed depending on whether the comparison was made pair-wise between siblings or group-wise between a group of children with NF1 and a comparison group. These findings are far from conclusive, however, and therefore a more thorough investigation of the issue is in order.

Constructs and measures

On the whole, studies often do not include systematic consideration of the behavioural constructs they are investigating. There are numerous psychometric instruments available for measuring a particular behavioural construct, and consideration should be exercised in choosing the appropriate one(s). Many of the cognitive constructs used to delineate the behavioural profile of NF1 in childhood are themselves complex and not easy to define or measure. Constructs also overlap by definition, for example visuospatial, visuomotor, and motor coordination skills and executive function. A good example of this overlap in terms of measures is the Figure of Rey test; performance in this test is affected by all the aforementioned skills. Executive functions, in particular, affect performance across the board; a good example of this is executive function problems impairing achievement at school. We have discussed lack of definition with regards to constructs such as learning problems or diagnostic criteria for ADHD, and these have been acknowledged in the literature before. However, rigour in defining terms should be extended to all the measured constructs.

As Table SI reveals, studies have used a wide variety of different psychometric instruments to measure behaviour in NF1. There are many practical reasons for this; studies have been conducted in different countries at different times, so different measures have been available. In addition, cognitive measures develop over time, and therefore more recent studies are in the position to use more recent, more thoroughly normed, and often more accurate measures. It is possible, in fact, that the differences in the particular measures used and their quality in part explains the variability in findings.

Several studies have included fairly comprehensive batteries of a number of cognitive functions; this has been important for getting an idea of the breadth of the cognitive impairment in NF1. However, it would also be important to conduct studies that examine different behavioural constructs in more detail and with reference to the theoretical framework behind the construct in question. This means that studies will have to be more focused, as otherwise testing batteries would become too lengthy for participants to manage in a reasonable amount of time.


We acknowledge that this review has some limitations. We chose not to include the so-called ‘grey literature’, that is studies that are ongoing and not yet published or which have not been published for some other reason. The reason for this was primarily that these types of publications are not peer reviewed. We are aware that it has been argued that the exclusion of grey literature biases a review, because it is possible that effects are larger in published studies.91 However, this argument has been primarily formulated in the context of clinical trials, in which the result is usually an intervention effect. In this type of context, finding a smaller or non-significant effect suggests that the trial was less successful (or a downright failure), which may make publication more difficult. However, the studies we have reviewed ask research questions about the behavioural profile of NF1. The results are thus less clearly a failure or a success; instead, they contribute to the knowledge base in general.

In addition, we had decided to exclude studies in languages other than English, as there were no resources to translate these. However, the small number of non-English studies we came across in our searches were mostly either case studies or reviews.

Clinical importance and future directions

Children with NF1 have deficits in many areas of behaviour such as visuospatial functioning, attention, intelligence, academic achievement, and social competence. In this, our findings largely agree with previous reviews. However, evidence pertaining to other areas of behaviour, such as executive and motor functioning, memory, and various linguistic skills, remains more contradictory.

In terms of future directions, several steps are important for furthering our knowledge about behaviour in children with NF1. Firstly, investigation of the very complex, multifaceted behavioural constructs has to be more systematic. For example, a number of different instruments, often measuring slightly different aspects of executive functions, have been used without careful consideration of the theoretical constructs involved. This may well be one of the reasons why evidence concerning executive skills in children with NF1 is still inconclusive. Related to this is the fact that various aspects of the behavioural constructs that have been studied in children with NF1 are related (for example, motor, visuospatial, and executive functions). Investigating the relationships between them will help in determining the nature of deficits in NF1. It is also important to acknowledge that some deficits may have wide-ranging but non-specific effects on, for example, function, executive skills, and attention. It may be impossible to specify the exact causal relationship between deficit and function, and more information about the neurocognitive functioning of children with NF1 is certainly required for this.

Secondly, although discussed in several previous reviews, there are as yet no published studies on remedial programmes designed to tackle the poor performance of children with NF1 in various academic areas. Some drug treatment trials exist72,92 or are in progress at the moment, attempting to remedy the effects of the gene mutation causing NF1. However, currently there is no evidence suggesting that, for example, remedial approaches to reading problems in children without NF1 would not work for children with NF1, and therefore this is an avenue worth pursuing.

Thirdly, it would be useful to develop ecologically valid paradigms to assess the skills of children with NF1, as they would give an opportunity to assess their function in more complex, real-life situations. Gilboa et al.69 and Ullrich et al.40 have developed some such paradigms using computer technologies; the results are promising though need replication. These types of paradigms, combined with more traditional neuropsychological tests, have the potential to further elucidate the behavioural phenotype.

Put together with research to determine how the different deficits in behaviour are related to the brain abnormalities in NF111 and emerging knowledge of behaviour in preschool age groups,93,94 these findings are likely to put us in a position that enables more comprehensive understanding of how NF1 affects the different facets of behaviour in childhood. We will also be able to better determine the specific aspects of behaviour that are indicators of future problems. Furthermore, it will be possible to start identifying which behaviours and functions manifest as a direct causal effect of NF1, and behaviours and functions that may just be associated with NF1. It is important to note, though, that clinically this is probably less important, as interventions would be the same independent of the nature or lack of the causal relationship in question.

Together, these developments will naturally have positive implications on earlier and more efficient identification of children who struggle at school and on the development of various remedial programmes to address the wide and varied spectrum of problems that children with NF1 can have.


  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Defining the constructs
  5. Method
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References
  10. Supporting Information

We are grateful for the Manchester Biomedical Research Centre for funding Dr Lehtonen. We particularly thank Mary Ingram at the University of Manchester for her expert advice on literature searches.


  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Defining the constructs
  5. Method
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References
  10. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Defining the constructs
  5. Method
  6. Results
  7. Discussion
  8. Acknowledgements
  9. References
  10. Supporting Information
dmcn4399_sm_FigureS1.pdf108KSupporting info item
dmcn4399_sm_TableS1.docx70KSupporting info item

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