Assessment of cognitive and adaptive behaviour among individuals with congenital insensitivity to pain and anhidrosis
Abstract
Aim Individuals with congenital insensitivity to pain with anhidrosis (CIPA) are reported to have mental retardation* but to our knowledge no detailed study on the subject has ever been published. The present study assessed and documented cognitive and adaptive behaviour among Arab Bedouin children with CIPA.
Methods Twenty-three Arab Bedouin children (12 females, 11 males) with CIPA aged between 3 and 17 years (mean 9y 7mo, SD 4y 2mo) were assessed. They were compared with 19 healthy siblings of the affected children aged between 5 and 13 years (mean 8y 11mo, SD 2y 10m). All of the children in the comparison group, but only half of the CIPA group, were attending school. The children were evaluated using a standardized, non-verbal intelligence test, the Leiter International Performance Scale – Revised, and an adaptive behaviour questionnaire, the Vineland Adaptive Behaviour Scales, 2nd edition.
Results Based on scores on the intelligence test and the adaptive behaviour scale, children with CIPA functioned in the mental retardation range (mean IQ scores: CIPA group 53.8, comparison group 83.32 [p<0.001]; adaptive behaviour: CIPA group 68.1, comparison group 104.88 [p<0.001]). IQ was significantly higher among the children with CIPA aged up to 7 years 11 months than among the older children 73.83 vs 45.21 (p<0.001).
Interpretation As a group, the younger children with CIPA may be functioning above the mental retardation range. We propose that early intervention addressing these children’s needs and developing an appropriate educational system, might improve their outcome.
List of Abbreviations
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- CIPA
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- Congenital insensitivity to pain with anhidrosis
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- Leiter-R
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- Leiter International Performance Scale – Revised
The cognitive functioning of children with congenital insensitivity to pain with anhidrosis (CIPA) has been assumed to be in the mental retardation range,1 but to our knowledge no large study to evaluate this assumption has ever been conducted. The present research evaluated the cognitive and adaptive behavioural status of Arab Bedouin children with CIPA, living in southern Israel, to determine if this assumption is true.
CIPA is a rare autosomal recessive, multisystem disease, involving the central nervous system (CNS),2 the peripheral nervous system, and the musculoskeletal, endocrine, ophthalmic, oral, and immunological systems. It is one of five inherited diseases known as hereditary sensory and autonomic neuropathies (HSAN) types 1 to 5; CIPA is HSAN type 4 (HSAN4).
Individuals with CIPA experience anhidrosis due to a lack of sweat gland innervation that leads to recurrent episodes of unexplained fever.3–6 They have a 1926-ins-T mutation in the tyrosine kinase A receptor (TrkA) gene, which is a receptor for nerve growth factor, resulting in a defective signal of nerve growth factor to growing sympathetic and sensory neurons and causing their apoptosis.3,7,8
Peripheral neurological damage is illustrated in skin biopsies from individuals with CIPA, in which the number of subcutaneous non-myelinated type C fibres is reduced, but the number of large nerve fibres is unaltered.1 The major clinical characteristic of the disease is insensitivity to pain, leading to self-mutilation, including tongue and finger biting and multiple fractures.2,9,10 Many children with CIPA exhibit symptoms of severe attention-deficit–hyperactivity disorder (ADHD).
Method
A case–control design was used for this study. Ethics approval for the research was granted by the Ethics in Human Research Committee at Soroka University Medical Centre, Israel.
Participants
The study population comprised 23 Arab Bedouin children* with CIPA, aged 3 to 17 years, who were followed in the Paediatric Day Centre at Soroka University Medical Centre in Be’er-Sheva Israel between 2006 and 2008. Children were included in the study group if (1) they tested positive for the CIPA mutation (1926-ins-T mutation on chromosome 1) and (2) were aged between 3 and 21 years. The comparison group included 19 children who were (1) a healthy sibling (from the same mother) of a child in the study group and (2) were aged between 3 and 21 years and of a similar age to their affected sibling. We used siblings as a comparison group to eliminate confounding factors that could influence the study results, such as maternal academic background and socioeconomic status. The parents of participants gave written consent allowing their child with CIPA and a healthy sibling to be evaluated.
Assessment of intelligence
A non-verbal intelligence test, the Leiter International Performance Scale – Revised11 (Leiter-R), was selected to assess intellectual functioning. This test is minimally influenced by formal education and language and was chosen both because no intelligence test has yet been standardized for the Arab Bedouin population in Israel and because many children with CIPA do not attend school. In addition, as the age range for the test is 2 to 21 years, it is appropriate for use with all the children in our study. The test includes items measuring reasoning, visual abilities, and information processing using symbols and pictures. The Leiter-R test comprises two parts: the Visualization and Reasoning Battery, and the Attention and Memory Battery. The Attention and Memory Battery was not administered because of its length and difficulties in administration; this battery requires a higher level of concentration and focus than was possible for the children in our sample during the testing sessions. The Visual and Reasoning Battery of the Leiter-R provides a Full-scale IQ or a brief IQ (comprising four subtests). The brief IQ was used when a child was able to sustain attention for a short time only.
Assessment of adaptive behaviour
The Vineland Adaptive Behaviour Scales, 2nd edition (Vineland 2), was selected to assess adaptive and maladaptive behaviour.12 The scale is a questionnaire which is administered as a semistructured interview. The parent is asked about the child’s behaviour in five domains, a maladaptive behaviour scale and four domains that measure adaptive behaviour: communication, daily living skills, socialization, and motor skills (for children <4y). Each item on the adaptive questionnaire is scored 0 if the child never performs the behaviour or never performs it independently, 1 if the child sometimes performs the behaviour independently or partially performs the behaviour independently, and 2 if the child usually performs the behaviour independently. Each of the first four domains (three for children >4y) yields a score, and their combination yields the adaptive behaviour composite score. The mean score on each of the domains and the composite score is 100 (SD 15). For each of the items on the maladaptive scale, the item is scored 0 if no symptoms are apparent, 1 if the child exhibits symptoms occasionally or 2 if the child exhibits symptoms frequently. Severity on the maladaptive domain is defined by three levels: average maladaptive behaviour (score 1–17), increased maladaptive behaviour (18–20), and significant maladaptive behaviour (21–24). For our study, to specifically assess ADHD symptomatology, independent judges selected three items from the maladaptive scale which addressed symptoms of hyperactivity, impulsivity, and attention. The combination of these items constituted the ADHD Index (maximum ADHD Index score=6).
Statistical analysis
The main statistical analysis compared the study and control groups using the SPSS program PASW Statistics 17 (http://www.spss.com/software/statistics/). Demographic, intelligence, and adaptive behaviour results were compared in a univariant analysis which included a χ2 test for categorical variables and an independent t-test for continuous variables. Pearson’s correlation was used to find the correlation between brief and Full-scale IQ scores. The threshold for statistical significance was p<0.05; significance tests were two tailed.
Results
A total of 23 children with CIPA were tested in the study group and 19 healthy siblings were tested for the comparison group. The mean age of the study group (9y 7mo) was not statistically different from the mean age of the comparison group (8y 11mo). Fifty-two per cent of the study group (n=12) attended school, compared with 100% (n=19) of the comparison group (Table I). The Full-scale and the brief IQ scores on the Leiter-R yielded a Pearson’s correlation of 0.98 (95% confidence interval 0.95–0.99) with p<0.01. This high correlation allowed us to use the brief IQ score (for which there are scores for all children in the study population) for statistical comparisons.
| Parameter | Comparison group (n=19) | Study group (n=23) | p value |
|---|---|---|---|
| Mean age (SD) | 8y 11mo (2y 9mo) | 9y 7mo (4y 2mo) | 0.5 |
| Sex M/F | 7/12 | 12/11 | 0.4 |
| Number of children in a school system (%) | 19 (100) | 12 (52.2) | <0.05 |
Our main hypothesis was that children with CIPA function in the mental retardation range and that they would be found to function at a lower level than children in the comparison group, on both the cognitive and adaptive behaviour scales. In fact, statistically significant differences in all adaptive behaviour domains and intelligence testing were found (Table II). Scores on both the intelligence test and the overall adaptive behaviour scale were less than 2SDs below the mean, and suggest a diagnosis of mental retardation.13 In addition to these analyses, the ADHD Index was evaluated to ascertain the status of the children regarding hyperactivity and attention (Table II).
| Parameter | Study group (n=23) | Comparison group (n=19) | 95% confidence interval of the difference | p value | |
| Lower | Upper | ||||
| Leiter-R, mean 100 (SD 15) | |||||
| Brief IQ | 53.8 (15.2) | 83.3 (15.5) | −39.9 | −19.2 | <0.001 |
| Full IQ | 58.2 (16.1) | 79.9 (17.8) | −36.3 | −4.7 | <0.001 |
| Adaptive behaviour scores – Vineland 2, mean 100, (SD 15) | |||||
| Communication | 70.6 (10.3) | 111.5 (8.79) | −47.3 | −33.6 | <0.001 |
| Daily living skills | 65.2 (15.6) | 106.9 (8.3) | −48.75 | −30.5 | <0.001 |
| Socialization | 74.8 (9.6) | 100.8 (11.4) | −33.3 | −18.6 | <0.001 |
| Adaptive behaviour composite | 68.1 (9.9) | 104.8 (10.9) | −42.74 | 28.1 | <0.001 |
| Maladaptive behaviour score | 19.8 (3.1) | 14.2 (2.1) | 3.6 | 7.5 | <0.001 |
| Maladaptive index (maximal score 6) | 0.22 (0.17) | 5 (0.17) | 3.8 | 5.6 | <0.001 |
- Leiter-R, Leiter International Performance Scale – revised.
The differences between the children with CIPA and their healthy siblings were marked and statistically significant. Almost all of the children with CIPA (21/23) were assessed by their parents as having significant symptoms in each of the three areas (hyperactivity, impulsivity, and attention). In contrast, only one child in the comparison group was reported to have significant symptoms in these areas. To test whether school attendance was a reason for the differences between the study and comparison groups, two subgroups in the study were compared: children who were enrolled in an educational system (n=12) and children who were not (n=11; many children with CIPA do not attend school because of inadequate facilities to address their special needs).
No statistically significant difference was found between the two groups (Table III). To test the impact of age on behaviour and cognition, we compared IQ and adaptive behaviour scores for age in two age groups: children above and children below 8 years (Table IV). We found that IQ was higher among the younger children (mean 73.83) than in the older children (45.21), a difference that was statistically significant (p<0.05). This younger group would not qualify for the diagnosis of mental retardation as their cognitive functioning was not less than 2SDs below the mean (Table IV).
| Parameter | Attend school system (n=12) | Do not attend school (n=11) | p value |
|---|---|---|---|
| Leiter-R, mean 100 (SD 15) | |||
| Brief IQ | 58.70 (15.1) | 48.90 (11.6) | 0.15 |
| Full IQ | 62.75 (14.8) | 51.00 (10.9) | 0.21 |
| Vineland Adaptive behaviour scores, mean 100, (SD 15) | |||
| Communication | 72.50 (13.7) | 68.70 (5.8) | 0.42 |
| Socialization | 74.20 (10.0) | 75.50 (10.1) | 0.76 |
| Daily living skills | 69.2 (14.6) | 57.8 (11.9) | |
| Adaptive behaviour composite | 69.50 (12.0) | 66.70 (7.4) | 0.53 |
| Maladaptive behaviour score | 19.60 (3.2) | 20 (1.6) | 0.77 |
- Leiter-R, Leiter International Performance Scale – revised.
| Parameter | Age ≤7y 11mo | Age ≥8y | p value | |||
|---|---|---|---|---|---|---|
| Study group (n=9) | Comparison group (n=8) | Study group (n=14) | Control group (n=11) | Study group | Control group | |
| Leiter-R, mean 100 (SD 15) | ||||||
| Brief IQ | 73.8 (5.7) | 88.5 (14.9) | 45.2 (5.7) | 79.5 (7.9) | <0.001 | 0.21 |
| Full IQ | ||||||
| 74.6 (8.3) | 95.2 (18.0) | 48.0 (9.6) | 69.6 (3.4) | <0.001 | 0.014 | |
| Vineland Adaptive behaviour scores, mean 100, (SD 15) | ||||||
| Communication | 71.6 (10.0) | 111.5 (4.2) | 69.9 (10.0) | 111.6 (3.1) | 0.7 | 0.9 |
| Socialization | 75.7 (6.3) | 101.7 (14.5) | 74.2 (6.3) | 100.2 (3.2) | 0.7 | 0.7 |
| Daily living skills | 69.5 (17.3) | 108.7 (5.1) | 62.4 (17.3) | 105.7 (4.2) | 0.3 | 0.9 |
| Adaptive behaviour composite | 68.6 (8.9) | 103.1 (14.7) | 67.7 (8.9) | 106.1 (3.1) | 0.8 | 0.5 |
| Maladaptive behaviour score | 19.7 (3.5) | 14.2 (2.9) | 19.8 (3.5) | 14.3 (0.86) | 0.9 | 0.9 |
Discussion
To our knowledge, this study is the first to evaluate the cognitive and adaptive behaviour status of a substantial group of children with CIPA with the same genetic mutation and to compare them with a group of healthy siblings. As hypothesized, the IQ scores of children with CIPA were significantly lower than those of the comparison group (Table II). In addition, the adaptive behaviour scores of children with CIPA were significantly lower than those of the comparison group. Not only were the scores lower, but they were in the mental retardation range, a finding that concurs with previous reports. Furthermore, our data pointed to a higher frequency of ADHD symptoms among children with CIPA.
CIPA, being a multisystem disease, is known to have some CNS involvement.3,7,14 It may be that a neurodegenerative process which has not yet been discovered, is associated with the disease and may be the cause of the mental retardation observed. Future studies are necessary to elucidate the CNS structural or functional changes that might contribute to the cognitive deficits among children with CIPA.
An unexpected finding of the study was an inverse relation between age and IQ among the CIPA group: the older the child with CIPA, the lower the IQ score. One possible explanation is that the reduced cognitive functioning in older children may result from the effects of the multiple injuries, recurrent episodes of hyperpyrexia, or infections that the child with CIPA typically experiences.3,4,9
Although, theoretically, education minimally affects intelligence, it may be possible that education has some effect on the IQ scores among children with CIPA. Although the difference between children attending school and those who do not did not reach statistical significance, this may be because of the small sample size.
The younger study children were not functioning in the mental retardation range. This suggests that their scores may reflect a developmental delay, which could be ameliorated by special adaptive education. We propose that early intervention addressing these children’s needs and developing an appropriate educational system at an early age might improve the outcome.
A prospective study to determine the influence of education on the cognitive and adaptive behaviour scores of children with CIPA would be an important step to assess the possibility that early intervention will improve outcome.
A limitation of our study is that it used a small study population. In addition, we included only one genetic mutation of a population in the Negev, and we cannot say whether our results will be true for other mutations as well as other populations with CIPA around the world; future research will be necessary to address this question
What this paper adds
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Cognitive and adaptive behavior among children with CIPA are significantly lower compared with healthy siblings
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Children with CIPA present with a high frequency of ADHD symptoms
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An inverse relation between IQ and age was found among children with CIPA, the older the child with CIPA, the lower is the IQ score
