Introduction

Neurofibromatosis Type 1 (NF1) is an autosomal dominant syndrome caused by mutations in the NF1 gene located on chromosome 17q11.2. About half of the cases are caused by de novo mutations, and the other half are inherited.1 NF1 occurs because of heterozygous pathogenetic variations in the homologous gene that codes for the common protein neurofibromin, which inhibits the RAS/MAPkinase pathway.2 NF1 causes a variety of diseases across multiple organ systems.3 The most distinguishing disease symptoms are benign nerve sheath tumors, which include cutaneous and plexiform neurofibroma (PN). Other symptoms include benign tumors and malignancies, skeletal abnormalities, cardiovascular problems, discomfort, and weariness.4 Plexiform, cutaneous, and nodular neurofibromas are among the tumors that children and adolescents with NF1 may develop. These tumors predominantly affect the neurological system and can be disfiguring. From an aesthetic perspective, patients typically exhibit thoracic deformities, scoliosis, a lower-than-expected height, macrocephaly, face dysmorphic traits resembling those of Noonan syndrome, and segmental overgrowth (elephantiasis neuromatosa).5,6

The spectrum of these potential physical manifestations encompasses psychological well-being, which in turn has a significant impact on an individual’s competence and quality of life (QoL).7

In addition to these clinical signs, NF1 has been linked to executive dysfunction, attention issues, poor emotional and social skills, and impairment in language and visuospatial ability.8 Comorbidity with other neurodevelopmental disorders, including Attention-Deficit/Hyperactivity Disorder (ADHD) and learning difficulties, may also occur.9 The neurocognitive profiles of children with NF1 can be difficult to diagnose and treat because all of these problems can co-occur in different combinations and are not mutually exclusive.

Compared to the general population, adult NF1 patients with neurofibromatosis reported significantly higher levels of perceived stress, lower levels of self-esteem, and behavioral symptoms.10 Symptoms of anxiety and depression are also more common and more severe than those of patients with life-threatening conditions like cancer.11 Furthermore, NF1 is associated with poor quality of life (QoL) and competence in both children and adults.12,13 Children and adolescents with NF1 have also been found to exhibit high rates of psychological symptoms, such as anxiety, depression, impulsivity, inattention, and social difficulties.14 The impact of NF-1 on psychological well-being and competence in pediatric populations remains an underexplored area, especially in Egypt and the Arab countries.

To our knowledge, this is the first study to describe behavioral problems and functional competence among Egyptian children with NF1 and to compare these outcomes with those of age–and sex-matched healthy controls. Also, the authors tested the association between the severity of NF1 manifestations, as measured by the Modified Ablon Scale, and behavioral outcomes and determined the prevalence of DSM-oriented psychiatric symptoms, including ADHD, affective disorders, and PTSD-related complaints, in children and adolescents with NF1 compared to healthy peers.

Methods

This is a cross-sectional descriptive case-control study that compares the psychological well-being of a group of children with NF1 (case group) attending a clinical genetics outpatient clinic at Mansoura University Children’s Hospital and a group of healthy children (control group) recruited from routine checkup outpatient pediatric clinics between March 2025 and July 2025. Healthy control children were recruited from the general pediatric outpatient clinics during visits for minor acute conditions, such as acute gastroenteritis or common upper respiratory tract infections (e.g., common cold). All control participants underwent clinical evaluation to ensure normal growth parameters and age-appropriate developmental milestones.

The sample size calculation was calculated by G*Power 3.1.9.2. (Universität Kiel, Germany). According to a previous study that used the Infant/Toddler Quality of Life Questionnaire (ITQOL), the mean score for quality of life was 81.9 ± 19 in NF-1 patients, and 92.1 ± 10.5 in healthy controls.15 The sample size was based on the following considerations: 0.66 effect size, 95% confidence level, 80% power of the study, and a group ratio of 1:1. Therefore, we recruited 38 children in each group.

Inclusion criteria: Cases with NF-1. The diagnosis of NF1 was confirmed according to the clinical criteria reported by the National Institutes of Health Consensus Statement Conference.2 Visibility and severity of NF1 manifestations were assessed using the Modified Ablon scale.16,17

The Modified Ablon Scale is a clinical tool used to assess both the severity and visibility of manifestations of Neurofibromatosis Type 1 (NF1). Severity reflects the overall clinical and functional impact of the disease, including potential effects on lifestyle, mobility, and life-threatening complications. It is categorized into three levels: mild (limited neurofibromas, mild learning or speech difficulties, mild scoliosis), moderate (numerous internal or external neurofibromas, moderate skeletal deformities, or learning difficulties affecting social function), and severe (function-threatening neurofibromas, serious internal tumors, malignancies, optic glioma, or severe skeletal abnormalities). Visibility evaluates how noticeable NF1 manifestations are during impersonal social interaction when the individual is fully dressed, excluding café-au-lait spots and freckling. It is classified into four levels: none (no observable deformities), mild (no visible tumors in exposed areas, minor skeletal features), moderate (visible neurofibromas or skeletal deformities affecting appearance), and severe (numerous facial neurofibromas, severe skeletal deformities, or vision-affecting optic glioma). Together, the scale provides a structured method to quantify both the medical burden and the social-perceptual impact of NF1.16

All children were assessed by the Arabic version of the Child Behavior Checklist (CBCL).18,19 recently validated in a normative sample of Egyptian children.20 Two age groups were recruited from 1.5–6 years old and 6–18 years old, as the child behavior checklist has 2 versions: one for preschool, which is devised for ages 1.5 to 6 years (CBCL 1 ½ -6), and one for school age, which is devised for ages 6 to 18 (CBCL 6–18).

The Child Behavior Checklist (CBCL) was used to evaluate psychosocial competence and behavioral problems in the recruited children. An Arabic-translated and validated version of the CBCL was completed by a parent and scored using a computerized scoring software system (Assessment Data Manager-version 9.1) software, Burlington, Vermont. CBCL yields four global T-scores: Competence, Internalizing Behavior Problems, Externalizing Behavior Problems, and Total Problem Behaviors. Three subscales contribute to the Competence score: Activities, Social Adaptation, and School. Eight subscales contribute to the Behavior scores: Withdrawn, Somatic Complaints, Anxious/Depressed, Social Problems, Thought Problems, Attention Problems, Delinquent Behaviors, and Aggression. The six DSM-oriented scales are: Affective Problems, anxiety problems, somatic problems, attention deficit/hyperactivity problems, oppositional defiant problems, and conduct problems.

In the present study, the role of other potentially confounding factors—including socio-environmental factors, IQ assessment, and potential neuropsychiatric comorbidities according to the DSM-5—these variables were considered through clinical assessment. They were also addressed in the first two pages of the CBCL questionnaire. Moreover, no significant differences were found regarding these factors.

In addition, to minimize bias, all participants underwent a comprehensive clinical assessment. A psychiatric evaluation was conducted for both parents and children by a qualified psychiatrist. This assessment aimed to identify any significant parental psychological distress or psychiatric conditions that could substantially influence reporting. No clinically significant parental psychopathology that could confound behavioral reporting was identified.

Patients with any other genetic, metabolic disease, or systemic diseases that can affect quality of life, such as congenital heart diseases, chronic liver diseases, malignancies, chronic kidney diseases, or autoimmune diseases, or whose parents refused to participate in the research, were excluded.

Also, as regards pharmacological therapy, number of hospitalizations, none of our cases were hospitalized or received medications for chronic illness (e.g. hypertension) as they were excluded in the exclusion criteria.

Informed and written consent was obtained from all patient caregivers before inclusion in the study and after assuring confidentiality.

This study was performed in line with the principles of the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of the Mansoura Faculty of Medicine-Institutional Research Board (Code number: R.25.02.3074).

Statistical analysis

Data analysis was performed by SPSS software, version 30 (SPSS Inc., PASW Statistics for Windows version 30, Chicago: SPSS Inc.). Qualitative data were expressed as frequencies and percentages. Quantitative data were described using median (minimum and maximum) (interquartile range) for non-normally distributed data and mean ± standard deviation for normally distributed data after testing normality using the Shapiro-Wilk test. The significance of the results obtained was judged at the (0.05) level. The chi-square test was used to compare qualitative data between groups as appropriate. Mann-Whitney U was used to compare the two studied groups for non-normally distributed data. Student’s t-test was used to compare the two independent groups for normally distributed data. Correlations were done using Pearson and Spearman coefficients for parametric and non-parametric data, respectively. Also, Bonferroni correction was applied where appropriate by adjusting the level of statistical significance according to the number of comparisons conducted. The adjusted significance threshold was used when interpreting the results.

Results

As shown in Table 1, the mean age of children (n = 38) with NF1 was 9.2 ± 4.17 years, while the control group (n = 38) had a mean age of 10.05 ± 4.27 years. This difference was not statistically significant (p = 0.387). Both groups were sex-matched (52.6% males in NF1 vs. 50% in controls; p = 0.818), ensuring comparability in baseline demographic variables.

Table 1 demographic data of the groups studied.
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Table 2 presents the main clinical features of the NF1 group. All children had ≥ 6 café-au-lait macules (100%), followed by Axillary and/or inguinal freckling 42%, while optic glioma occurred only in one case. The majority of participants had mild disease severity (81.6%) and no visible lesions (52.6%) based on the Modified Ablon scale.

Table 2 Main clinical features of the NF1 individuals included in this study.
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As illustrated in Table 3, school-aged children with NF1 showed significantly higher median scores than controls on all CBCL behavioral subscales. Moreover, composite scores for internalizing problems (69.86 ± 7.54 vs. 60.06 ± 11.32) and externalizing problems (63.28 ± 8.38 vs. 55.45 ± 9.66) were significantly elevated in NF1 children (p < 0.001). NF1 children also had lower competence scores than healthy children, including competence in activities, social adaptation, and school performance.

Table 3 The T-scores of syndrome scales in CBCL for the studied groups of school children (6–18 years old).
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School age Children with NF1 also showed significantly higher scores than healthy controls in all CBCL DSM-oriented scales (Table 4).

Table 4 The DSM-oriented scales in the studied groups of children aged 6 years to 18 years old.
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Table 5 shows that NF1 children under 6 years of age did not significantly differ from controls across CBCL domains. Median and mean scores remained within the normative range.

Table 5 The behavior scores for the studied groups of preschool children (below 6 years old).
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Regarding behavioral abnormalities and DSM-oriented scale differences according to sex among children with NF1, no statistically significant differences were observed between males and females in the age group < 6 years.

However, in the school age, a statistically significant sex-related difference was identified in the anxiety problems domain. Females demonstrated higher median anxiety scores compared to males (median [min-max]: 72 [60–75] vs. 65 [55–78], respectively), with a p-value of 0.023, indicating a significant difference between the two groups.

All other variables of psychological problems showed statistically significant positive correlations with the visibility of the NF1 lesions. In contrast, the severity scale of NF1 showed similar correlations with withdrawn/ depressed problems, social problems, thought problems, attention problems, and externalizing problems (Table 6).

Table 6 Correlation between visibility, severity scales, and behavioral problems.
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Discussion

Given the wide range of manifestations of neurofibromatosis, most of which affect the external appearance of the patient, psychosocial and mental health are supposed to be affected in many aspects. In the current study, we assessed the psychological well-being, mental health, and competence of 38 children with NF-1 using the CBCL scale and compared them with those of typically developing children. Main clinical manifestations of our cases were café-au-lait macules (100%), followed by Axillary and/or inguinal freckling (42%), neurofibroma (26%), and iris Lisch nodules (21%). Plexiform neurofibroma, short stature Z score > -3, and scoliosis occurred in 13.2% of cases. Osseous lesions occurred in 10.5% of cases. Only one case showed optic glioma, and another case had glaucoma. Using Ablon’s modified scale to assess disease severity and symptom visibility, we discovered that 6 participants (15.8%) reported severe NF1 illness symptomatology, 1 participant (2.6%) reported moderate severity, and 31 participants (81.6%) reported mild severity. As regards visibility, 6 (15.8%) participants had mild symptoms, 8 (21%) had moderate symptoms, and 4 (10.5%) had severe symptoms. Twenty subjects (52.6%) did not report any obvious manifestations of NF1.

The study findings indicate that children and adolescents with NF1 exhibited impaired psychological functioning, social behavior, and overall competence compared with healthy participants.

Regarding behavioral problems detected by the CBCL in children aged ≥6 years, the median behavioral problem scores were in the borderline to mildly affected range. This can be explained by the fact that most of our cases, 81.6%, have mild severity, and 52.6% have no visibility of NF1 lesions. But still, behavioral scores are statistically significantly higher than those of healthy children. Our study reported internalizing and externalizing symptoms, which represent two major categories of mental health problems. Internalizing symptoms are a collection of inwardly orientated emotional symptoms such as depression, anxiety, and somatic symptoms. Externalizing symptoms are a collection of outwardly focused behavioral signs such as aggression, rule-breaking, and attention troubles.21 This copes with a study done on thirty-eight NF1 children at the University of Campania, where psychological assessment revealed internalizing problems in them, anxiety (18.4%), depression (5.3%),17 Research reveals that persons with NF1 may experience internalizing and externalizing problems more severely than individuals with some other chronic diseases, including coronary artery disease and cancer,22 and when compared to individuals in general.23 Another systematic review and meta-analysis done by Liu, Dan et al provides strong evidence that individuals with NF1 experience a wide range of internalizing symptoms (depressive, anxiety, somatic, and total internalizing symptoms) and externalizing symptoms (aggression, delinquency, and total externalizing symptoms) more severely than the unaffected controls.24

The underlying biological mechanisms of mental and behavioral disorders in the NF1 population are still not completely known. However, they may be related to NF1-associated neuropathological alterations.25 On the other hand, behavioral scores in children less than 6 years were normal and similar to normal because all cases (nine cases) below 6 years were mild and showed no visibility of NF1 lesions. The behavioral disturbances appear to emerge or become more detectable in older children, likely due to the progressive nature of NF1 and increasing cognitive/social demands. The absence of a significant difference compared to controls may be attributed to the small number of participants in the preschool age group. Therefore, we emphasize that findings in preschool children should be interpreted with caution, and that future studies with larger, age-specific samples,9 particularly in early childhood, are needed to provide a clearer characterization of the early psychosocial manifestations of NF1.

A positive correlation between the visibility, severity scale of NF1 disease, and the detected behavioral problems in children with NF1 was reported in the current study.

Our findings also demonstrate significant impairment across all domains of competence, including activities, social functioning, school performance, and total competence, all of which were significantly lower compared with healthy children. Several previous studies have reported reduced competence and poorer quality of life among children with NF1. A study conducted among 38 children with NF1 at the Pediatric Neurofibromatosis Referral Center of the University of Campania “Luigi Vanvitelli” reported a lower quality of life in children with NF1, which was influenced by the visibility of NF1 lesions.17 Moreover, another study comparing the quality of life of 40 children with NF1 and 56 healthy controls revealed a significant impairment in quality of life among children with NF1.26

The current study shows social problems, somatic complaints, attention problems, aggressive behavior, and rule-breaking behavior, which are significantly higher in NF1 children than in healthy controls. Several studies showed the same results as a study done in 60 NF1 children and 60 healthy controls using the CBCL scale, and showed that children with NF1 reported anxiety problems, poorer quality of life when compared to healthy participants.12 Moreover, this has also been proven in another study that showed impairment of quality of life among 160 NF1 children in the Sophia Children’s Hospital in the Netherlands.27 The CBCL used the DSM-oriented subscales of emotional and behavioral disorders, which revealed psychiatric disorders in NF1 children with borderline to mild affection, but statistically significantly higher than healthy children. This borderline impairment can also be explained by the mild severity and non-visibility of most of our NF1 cases.

Several studies showed that NF1 patients showed mental and psychiatric problems such as affective problems, autism, ADHD, conduct problems, and PTSD. This might be attributed to genetic, biological factors, or even comorbidity, or stress of having NF1. A study conducted by Walsh and colleagues examined autism spectrum disorder (ASD) symptoms in 66 children with NF1. Among these children, 40% displayed elevated symptom levels that reached clinical significance on the Social Responsiveness Scale, and 14% exhibited levels similar to those seen in children with ASD.28 Moreover, ADHD and attention disorders were assessed in NF1 children and revealed a higher occurrence of ADHD among them, with a negative impact on social competence.9

Our study also demonstrated a significant sex difference in anxiety problems among school-age children with NF1, with higher levels observed in females. This finding is consistent with a study conducted among 38 school-aged children with NF1 to assess neuropsychiatric manifestations, which reported that female participants experienced more severe symptoms of anxiety and depression, as well as lower self-esteem, compared to males.17

Strengths and limitations

Strengths of the study include sample originality: the study focuses on an Egyptian/Arab population with NF1, filling a gap in the literature given that most studies originate from Europe or North America; use of standardized and validated tools (Arabic version of the CBCL) and presence of sex/age-matched controls.

Furthermore, combining the Child Behaviour Checklist (CBCL) with DSM-oriented items gives a strong and consistent strategy to evaluate psychological well-being in this population. The study investigates the relationships between clinical severity, the visibility of NF1-related lesions, and measures of psychological well-being and competence. This integrative approach helps us better grasp the broader psychosocial consequences of this complicated multisystem syndrome.

Nonetheless, some shortcomings in the current study should be addressed. The small sample size limits the generalizability of the findings. Although NF1 is a lifelong condition, we choose to focus on children and adolescents, which may limit recruitment. Also, the lack of confirmation of the diagnoses with the use of a standardized interview may shed uncertainty on the DSM diagnoses. A notable limitation of this study is the small sample size of the preschool subgroup (< 6 years; 9 cases and 7 controls), which resulted from age stratification required by the use of two CBCL versions. Although the overall sample size met the initial power calculation, subdivision by age reduced statistical power in younger children and increased the risk of type II error. Therefore, the absence of significant differences in the preschool group should be interpreted cautiously. Additionally, given the progressive nature of NF1, early clinical and psychosocial manifestations may be subtle or incomplete in preschool years, potentially limiting early behavioral detection. Larger, age-specific, and longitudinal studies are needed to better define early psychosocial outcomes in NF1.

Another important limitation is the restricted variability in disease severity and lesion visibility within our sample. The majority of participants had mild NF1 (81.6%), and over half had no visible lesions (52.6%), resulting in limited representation of moderate and severe cases. This constrained distribution may reduce the robustness of correlation analyses and limit the generalizability of the observed association between greater clinical severity/visibility and increased behavioral problems. Therefore, these findings should be interpreted cautiously, and future studies including a broader spectrum of NF1 severity are warranted for better clarification of this relationship.

Finally, the lack of statistical adjustment for possible confounding factors, such as socioeconomic level and parenting styles, may decrease the specificity of the findings.

Conclusion

Our study sheds insights into the psychosocial issues that children and adolescents with NF1 encounter in addition to neurological issues, physical-skeletal defects, and visual issues. Our findings also emphasize the necessity of recognizing behavioral and psychiatric symptoms in patients with NF1 to provide timely therapies. This data supports the inclusion of psychological needs in NF1 supervision and treatment, emphasizing the necessity of a multidisciplinary approach for early detection, as well as ongoing support and treatment of these disorders to improve quality of life in these children. Future research with larger, more diverse samples and longitudinal designs could help to understand these findings and inform targeted interventions.