TSC and NF1 are the most common genetic disorders with cutaneous and neurological involvement. They present many challenges in management due to their heterogeneous presentation and large inter and intra-familial clinical variability. Although their genetic basis and phenotype are different, they are both tumor-prone disorders resulting from the dysregulation of components of the convergent RAS/MAPK and PI3K/AKT/mTOR pathways (27)(28)(29).
In both disorders the prevalence of neuropsychiatric problems is relevantly higher than in the general population and impact quality of life (23)(4). However, these issues are not always addressed adequately, as physicians are usually more concerned about life-threating complications of both diseases. Moreover, neuropsychiatric evaluation is time-consuming and needs specialized staff. As a result, neuropsychiatric complications may remain underdiagnosed even in expert centers (26).
The TAND-Checklist was developed to provide healthcare professionals with a tool to easily screen neuropsychiatric involvement in patients with TSC. The checklist explores the frequency of a wide range of neuropsychiatric manifestations and the multiple dimensions of the involvement on different levels: behavioral, psychiatric, intellectual, academic, neuropsychological and psychosocial (24). As these aspects can be impaired also in NF1 patients, we hypothesized that the checklist could be useful for screening neuropsychiatric needs in this population as well.
The TAND Checklist showed a wide range of neuropsychiatric issues in our TSC cohort. More than half of the parents reported temper tantrums, difficulty in paying attention and concentrating, impulsivity, scholastic difficulties, attention and executive skills deficits in their children. This profile is in line with the results of TAND data from the large-scale international TOSCA study (30). The interesting aspect is the result of the study of TAND in the epilepsy subgroups. In the TSC cohort 69.0% of the patients had a history of epilepsy (38.1% were seizure free at the time of evaluation and the remaining 30.9% had active epilepsy with variable seizure frequency). We found a statistically significant correlation between epilepsy severity and TAND, except for anxiety, extreme shyness, mood swings, aggressive outbursts, temper tantrums, self-injury, poor eye contact, rigidity, overactivity/hyperactivity, difficult paying attention, restlessness, impulsivity, difficulties with eating, sleep difficulties, academic difficulties (spelling and mathematics) and neuropsychological problems (dual-tasking, visuo-spatial tasks, executive skills, getting disoriented). These last features that are highly reported also in patients with no history of epilepsy, may be considered associated with the disease itself and deserve a deeper consideration both in terms of diagnosis and care in all TSC affected individuals (30). As we expected, disease-related variables of epilepsy have a significant impact on depressed mood, absent or delayed onset of language, repetitive language and behavior, difficult relationship with peers, and specific neuropsychological domains. The severity of epilepsy, in particular with early onset and poorly controlled seizures, is strongly associated with cognitive impairment and ASD (31)(32)(33). On the other hand, TSC patients without epilepsy did not report any feature associated with ASD. Our findings are in line with the study recently published by Toldo et al. (34), which identified a major impact of early-onset epilepsy on ASD features of TAND in a group of 32 Italian children with TSC, and a higher risk of developing anxious and depressive disorders in individuals with a less severe neurological phenotype.
By administering the TAND-Checklist to an age- and gender-matched sample of patients with NF1, we observed difficulties in attention and concentration, impulsivity and anxiety in more than 50% of the patients. Temper tantrums, overactivity/hyperactivity, academic difficulties, executive skill deficits, low self-esteem and very high level of stress in families were reported in more than 30% of children and adolescents with NF1.
Attention problems and ADHD represent well-known behavioral problems in NF1 children as approximately one-third to one-half of children with NF1 fulfill the criteria for ADHD (12). In line with data from the literature, the TAND-Checklist found frequent ADHD-like features: difficulty in paying attention and concentrating in 59.5%, impulsivity in 52.4%, overactivity/hyperactivity in 38.1% and poor attention in 59.5%. These aspects do not show a clear correlation with the disease severity according to the modified version of Riccardi medical severity scale. Of note however, this scale does not include cognitive and behavioral characteristics more directly involved in general adaptive functioning in daily-life (35).
Moreover, regardless of having a comorbid diagnosis of ADHD, children with NF1 show several signs of executive dysfunction compared with typically developing children (36). Riva et al. (37) found that children with NF1 have specific executive deficits that have an impact on real-life situations. This data is confirmed by our findings from the TAND-checklist applied to NF1, which show the presence of poor executive skills in 38.1% of the patients with NF1.
With regard to emotional and behavioral problems, some studies have evaluated children and adolescents with NF1 through the parents' compilation of Child Behavior Checklist (CBCL) questionnaires. Rietman et al. (20) showed that on 183 subjects 32% fell in the clinical range, considering Total scores. Graf et al. (21) identified problems predominantly in the internalizing domain of anxiety, depression, social withdrawal and somatic complaints. Studies investigating anxiety in children and adolescents with NF1 have found a higher predisposition to developing an anxiety disorder, but have relied on relatively small sample sizes (38). In our cohort of NF1 patients 50.0% were reported to have anxiety symptoms, and no statistically significant differences were noted in the three severity subgroups. Only 15 patients with NF1 had received a formal psychiatric assessment, and 7/15 (46.6%) received a diagnosis of ADHD and 5/15 (33.3%) had been diagnosed with anxious or mood disorders. It is therefore possible that the TAND-Checklist is useful to identify more NF1 children with dysfunctional behavioral or psychological problems who may benefit from a full behavioral and neuropsychological assessment.
Regarding academic performances, children and adolescents with NF1 commonly perform more poorly at school than how their intellectual abilities would predict (14). In our sample scholastic difficulties were reported in all domains (reading, writing, spelling and mathematics). Taken together, 41.7% had one or a combination of deficits. Almost all of them received personalized plans and compensatory measures at school, and 21.4% were formally assessed and classified as Specific Learning Disorder.
Taken together, the results of the TAND-Checklist applied to NF1 are congruent with the medical literature, are useful to outline a profile of the neuropsychiatric involvement in NF1 and to collect patients’ needs.
In addition, it is noteworthy that parents showed a great interest in this screening tool, asked pertinent questions to the examiner, collaborated with enthusiasm and 21.4% declared the need for a supplementary in-depth analysis of their children’s neuropsychiatric problems, mostly at the behavioral level.
Lastly, we compared the frequencies of the neuropsychiatric manifestations resulting from the checklist in the two conditions. Individuals with TSC were reported to have a greater neuropsychiatric involvement in all the investigated levels.
Cognitive assessment was performed in all TSC and NF1 participants and, as expected, patients with TSC performed lower than patients with NF1. Indeed, the mean IQ in the NF1 cohort was 94 with only 9.5% having mild ID, whereas the mean IQ in the TSC cohort was 74 with 37.7% having various degrees of ID. We found aggressive outburst to be statistically significantly higher in the TSC group. Aggression is common in TSC and is usually associated with stereotyped and repetitive behaviors, low mood, hyperactivity, impulsivity and repetitive use of language, in subjects with intellectual disabilities (39).
We demonstrated statistically significant differences also in the behavioral manifestations of ASD, which are more common in the TSC patients: absent or delayed onset of language, repetitive language, poor eye contact and repetitive behaviors.
It is known that ASD in TSC can be present in 40–50% of the patients (8)(40) being one of the most characteristic disease trait. On the other hand, prevalence rates of clinical ASD symptoms in children with NF1, based on screening instruments, are between 13–29% (41)(42) with a statistically significant comorbidity with symptoms of ADHD. A recent study by Eijk et al. (19) used standardized diagnostic methods and found a prevalence of clinical ASD of 10.9%. No one in our NF1 cohort had formal diagnosis of ASD, and the features commonly associated with ASD (such as absent or delayed onset of language, repetitive language, poor eye contact, difficulties in relationship with peers and repetitive behaviors) were reported in less than 15% of the patients.
Individuals with NF1 were recognized to have more difficulties, though non statistically significant, in anxiety, depressed mood and low self-esteem. It can be difficult to investigate these aspects in TSC, given the high rate of ID in this population, and anxiety or depression symptoms can manifest with behavioral changes over time (7). On the other hand, patients with NF1 have a higher mean IQ and are more aware of their illness.
It is noteworthy that the two samples, despite the differences in IQ levels, had almost identical high rates of ADHD-like symptomatology (overactivity/hyperactivity, difficulty paying attention or concentrating, impulsivity, poor attention and poor executive skills) and of scholastic difficulties (reading, writing, spelling and mathematics). All these features are confirmed to be frequently associated with the disease and deserve a deeper consideration both in terms of diagnosis and care in all TSC and NF1 children.