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Noonan syndrome (NS) is a genetic disorder characterised by short stature, facial dysmorphia, congenital heart defects and mildly lowered intellectual abilities. Research has mainly focused on genetic and somatic aspects, while intellectual and cognitive functioning has been documented scarcely. Also, to date studies have been primarily performed in children. This is the first study in which functioning within the major cognitive domains is systematically evaluated in a group of adults with NS and compared with a control group. Extensive neuropsychological assessment, including the domains intelligence, speed of information processing, memory (working memory, immediate recall and delayed recall), executive function and visuoconstruction, was performed in a sample of 42 patients with NS and 42 healthy controls, matched on age, sex and education level. In addition, subjective cognitive complaints were assessed with self-report questionnaires. On the domain speed of information processing patients performed worse than controls (P < 0.05). Furthermore, except for slightly better results on delayed recall in the patients with NS (P < 0.05), none of the other cognitive domains showed between-group differences. On the questionnaires, patients reported substantially more complaints about their own cognitive abilities than controls (P < 0.05). A lowered speed of information processing and relatively intact functioning in other cognitive domains characterises the cognitive profile of adult patients, in contrast to previous findings in children with NS, who seem to have more generalised cognitive deficits.
Noonan syndrome (NS) is a worldwide reported genetic disorder with an autosomal dominant inheritance pattern that was first described by Noonan and Ehmke (1963) and further elaborated upon by Noonan (1994) and Noonan and O'Connor (1995). The prevalence of NS is estimated to be between 1 in 1000 and 1 in 2500 live births (Allanson 2010; Mendez & Opitz 1985; Noonan 1994). Although clinical features may vary, NS is typically characterised by mild facial dysmorphisms including hypertelorism, ptosis, strabismus, downslanting palpebral fissures, low-set ears and a broad and sometimes webbed neck. In addition, NS is frequently associated with congenital heart defects and short stature (Allanson 2007; Van der Burgt 2007). Up to 90% of the patients have cardiac defects, particularly pulmonic valve stenosis (PVS), hypertrophic cardiomyopathy and atrial septal defects. Reported adult heights are about −2 SD, due to postnatally reduced growth (Noonan et al. 2003; Otten & Noordam 2009; Ranke et al. 1988). Other phenotypical characteristics include chest and spine deformities, cryptorchidism, lymphatic dysplasia and delayed pubertal development (Tartaglia et al. 2002; Van der Burgt 2007). Nowadays, the diagnosis is mostly established soon after birth and is based on a set of clinical criteria (Van der Burgt et al. 1994).
NS is caused by germline mutations (mutations in gametes) in the Ras-mitogen-activated protein kinase (Ras-MAPK) pathway. This signal transduction pathway is involved in cell-cycle control processes (Boutros et al. 2008; Zenker 2009). At present, while research in NS continues to identify new causative mutations, in approximately 75% of the patients a causative mutation is found in one of the following genes: PTPN11, SOS1, RAF1, KRAS, NRAS, BRAF, SHOC2, MEK1 (MAP2K1) and CBL (Tartaglia et al. 2011). Mutations in the PTPN11 gene are most common, accounting for over 50% of the cases. As the disorder is caused by germline mutations, it is inheritable (Allanson 2010). In 60% of the cases, mutations occur spontaneously (de novo) (Fakouri & Fakouri 1998; Shaw et al. 2007).
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Table 2 presents the mean raw scores, the cognitive domain scores, as well as the normative Z scores of the two groups. One patient was not able to complete the SCL-90-R; she was admitted to a psychiatric hospital elsewhere towards the end of the assessment and was not able to finalise all the questionnaires. Finally, one control did not complete the SCL-90-R and the DEX was not administered in two controls, due to time restrictions.
Table 2. Cognitive domain scores, mean raw test scores, normative Z scores and % impaired for controls and patients with NS
|Cognitive domain and tests||Patients with NS||Controls|
|Mean domain/ raw score||SD domain/raw score||Mean normative Z scorea||N (%) impaired (i.e. Z < 1.5)||Mean domain/raw score||SD domain/raw score||Mean normative Z scorea||N (%) impaired (i.e. Z < 1.5)|
|Intelligence||0.02||1.11||−0.65||9 (21%)*||−0.05||0.64||−0.70||2 (5%)|
| WAIS-III FSIQ||92.19||14.65||−0.52||9 (21%)||91.14||8.65||−0.59||4 (10%)|
| NART-IQ||88.36||13.80||−0.78||9 (21%)||88.40||8.22||−0.77||3 (8%)|
|Speed of information processing||−0.21*||1.01||−0.66||5 (12%)||0.21||0.64||−0.21||1 (2%)|
| WAIS-III digit symbol coding||66.12||17.37||−0.46||7 (17%)*||70.38||11.64||0.08||1 (2%)|
| WAIS-III symbol search||30.71||9.96||−0.59||10 (24%)*||34.19||8.30||−0.28||2 (5%)|
| Stroop I, II||58.37**||12.46||−0.93||8 (19%)||52.02||7.70||−0.44||3 (7%)|
|Working memory||0.00||1.06||−0.33||3 (7%)||−0.04||0.76||−0.38||2 (5%)|
| WAIS-III letter-number sequencing||10.20||3.10||−0.11||3 (8%)||9.12||2.18||−0.46||6 (14%)|
| WAIS-III digit span||13.55||3.44||−0.48||9 (21%)||14.29||3.04||−0.29||3 (7%)|
|Immediate recall||0.14||0.91||−0.26||5 (12%)||−0.17||0.69||−0.57||5 (12%)|
| RAVLT – immediate recall||50.05||10.38||−0.02||4 (10%)||44.74||10.31||−0.65||10 (24%)|
| Rey CFT – immediate recall||19.54||7.60||−0.45||9 (22%)||18.31||5.81||−0.49||9 (21%)|
|Delayed recall||0.18*||0.85||−0.11||5 (12%)||−0.21||0.77||−0.51||8 (19%)|
| RAVLT – delayed recall||10.69||2.97||−0.11||6 (14%)||9.31||3.17||−0.59||9 (21%)|
| Rey CFT – delayed recall||20.42||7.34||−0.06||10 (24%)||17.73||6.20||−0.43||9 (21%)|
|Executive functioning||0.10||0.91||0.01||1 (2%)||−0.10||0.60||0.30||1 (2%)|
| Tower of London||27.83||4.20||—||—||25.71||3.06||—||—|
| Stroop interference||1.78||0.36||0.01||1 (2%)||1.72||0.24||0.30||1 (2%)|
|Visuoconstruction||0.12||1.10||−0.73||12 (29%)||−0.12||0.88||−0.90||14 (33%)|
| Rey CFT – copy||30.39||5.37||−0.73||12 (29%)||29.23||4.30||−0.90||14 (33%)|
GLM multivariate analyses of variance showed an overall worse performance in the patient group (F7,76 = 2.49, P = 0.023, ηp2 = 0.19). A significant difference was found in two domains, speed of information processing (F1,82 = 5.15, P = 0.026, ηp2 = 0.059) and delayed recall (F1,82 = 4.80, P = 0.031, ηp2 = 0.055). No significant group differences were found for the domains intelligence (F1,82 = 0.120, ηp2 = 0.001), working memory (F1,82 = 0.051, ηp2 = 0.001), immediate recall (F1,82 = 3.19, ηp2 = 0.037), executive function (F1,82) = 1.31, ηp2 = 0.016) or visuoconstruction (F1,82 = 1.21, ηp2 = 0.015).
For the significant domains speed of information processing and delayed recall, separate between-group comparisons on the individual neuropsychological measures were performed (independent t-tests; Bonferroni-corrected). Regarding speed of information processing, a significantly worse performance of the patient group compared with controls was found on the Stroop CWT (t(82) = 2.81, P = 0.006, Cohen's d = 0.61), but not on WAIS-III digit symbol coding (t(71.65) = 1.32, d = 0.29) or WAIS-III symbol search (t(82) = 1.74, d = 0.38). With respect to delayed recall, post hoc analyses did not show any significant differences on the two subtests in the domain (Rey CFT-delayed recall (t(78.10) = 1.80, d = 0.40; RAVLT-delayed recall (t(82) = 2.06, d = 0.45).
Patients with NS reported significantly more subjective executive problems on the DEX (NS mean 26.5, SD = 14.0; control mean 20.5, SD = 9.6; t(70.6) = 2.25, P = 0.028, d = 0.50). They also reported significantly higher levels of complaints on the subscale cognitive-performance difficulty of the SCL-90-R (NS mean 18.4, SD = 7.4; control mean: 15.0, SD = 4.6; t(66.9) = 2.52, P = 0.014, d = 0.55). No significant difference was found between the group with NS and controls on the SCL-90-R total score (NS mean: 146.1, SD = 41.8; control mean: 132.6, SD = 34.2; t(77.0) = 1.60, d = 0.35). Correlations between DEX or cognitive-performance difficulty SCL-90-R and the domain score speed of information processing were not statistically significant (r = −0.14 and r = −0.16, respectively).
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This is the first study to examine the performance of adults with NS on all major cognitive domains, compared with that of matched controls. Patients with NS showed a significantly worse performance in the domain speed of information processing. No between-group differences were found on any of the other cognitive domains, except for a slightly better performance of patients with NS on the subdomain delayed recall. The level of complaints concerning their own cognitive capacities was significantly higher in the patients compared with controls. Patients with NS experienced more cognitive problems in their daily lives than controls, although the overall level of distress did not differ between the two groups. Also, no relation was found between the performance on measures of speed of information processing and the level of subjective complaints of distress. Concerning the background variables, slightly lowered intelligence levels were found in the adults with NS as compared with the average population, which is consistent with results of the majority of previous studies. Moreover, a higher need for special education was noted in our sample (43% of the patients with NS vs. 0% of the controls), which has been reported by others as well (Shaw et al. 2007; Van der Burgt et al. 1999; Wood et al. 1995).
Patients showed a lower speed of information processing than the control group. This finding was mainly driven by a highly significant and medium to large sized difference in performance on the Stroop CWT (reading and naming speed on part I and part II), a task that does not require psychomotor responses. Moreover, a significantly higher proportion of patients than controls showed impairments on the other two subtests for processing speed, WAIS-III-DSC and WAIS-III-SS, compared with the normative mean. Occasionally, lowered scores have been reported on time-limited tests in children with NS (Horiguchi & Takeshita 2003; Troyer & Joschko 1997; Van der Burgt et al. 1999), which have typically been interpreted as manifestations of attentional impairments. Notably, a lack of selective or sustained attention has been observed in children with NS, mainly by their parents (Lee et al. 2005; Sarimski 2000; Wood et al. 1995). Our adult group did not show deficits in selective attention as part of cognitive control (response inhibition as measured with the Stroop CWT interference score), and observation during testing did not show any signs of inattention. Possibly, the mental slowness may be associated with metabolism, in particular with the energetic limitations due to mitochondrial dysfunction that is reported to be manifest in syndromes of the Ras-MAPK pathway, including NS (Kleefstra et al. 2011). So far, however, the exact pathophysiological mechanisms for this association remain unclear, and the hypothesis of energetic limitations as a cause of speed problems is still highly speculative.
Apart from speed of information processing, patients with NS did not perform worse than controls on any of the other cognitive domains, in contrast to previous studies in children. For example, mild decrements in working memory and learning have been reported in children with NS (Horiguchi & Takeshita 2003; Troyer & Joschko 1997; Van der Burgt et al. 1999). Although measures of episodic memory function are usually thought to be intact in these children, Alfieri et al. (2011a) recently showed reduced verbal recall memory performance and normal recognition in a group of children with NS or LEOPARD syndrome. In the adults examined in this study, no differences were found between patients with NS and controls with respect to working memory or immediate recall on episodic memory tasks. The performance on the subdomain delayed recall was even slightly better in the patients with NS than in controls, although subsequent analyses did not show any subgroup differences on the individual subtests in this domain. These findings regarding memory functions seem to be in contrast with those of Alfieri et al. (2011a), and with animal studies that have shown recall problems in relation to activations in the Ras-MAPK cascade (Sweatt 2001, 2004).
Van der Burgt et al. (1999) reported weaknesses in planning and organisation abilities in children with NS, using an extensive intelligence battery. Again, these results could not be corroborated in our adult sample, as our patients with NS performed at control level on measures of working memory or executive function (planning and response inhibition). Interestingly, although no differences were found in the performance on executive tests, patients reported more subjective executive problems than controls on questionnaires. It could be argued that these complaints are associated with executive impairments that were not addressed by the current tests, such as a deficit in concept shifting. However, as our aim was to investigate all major cognitive domains, we could not examine every aspect in detail because of time limitations. Furthermore, in a previous study from our group in a smaller sample of patients with NS (n = 33) that included the Wisconsin Card Sorting Test, a widely used concept shifting task, no deficits were found compared with normative data (Wingbermühle et al. 2009). Maybe, the mental slowness we found underlies the experience of executive problems in daily life. Also, it has been shown that subjective estimates of people's own cognitive status are often incongruent with objective measures (e.g. Goverover et al. 2005; Koerts et al. 2012).
Finally, no differences were found between patients and controls on a test for visuoconstructive ability. In children with NS, research with cognitive-experimental paradigms has suggested visuomotor difficulties to be present (Horiguchi & Takeshita 2003; Lee et al. 2005; Troyer & Joschko 1997). Specifically, within the perceptual domain, the study of Alfieri et al. (2011b) showed impairments in form coherence in children with NS of varying age. It could be speculated that visuoconstruction is only compromised in NS during childhood, but no longer in adulthood. However, Alfieri used cognitive paradigms that are not applicable in clinical practice yet and their findings should be replicated with a dedicated multi-method assessment to objectify cognitive functioning of adults with NS in the domain of visuoconstruction.
In addition to the previously suggested, speculative energetic limitations, there are alternative explanations for the underlying deficit in information processing speed. For instance, heart defects may result in an increased risk for circulatory problems, with cognitive slowness as a result. In NS, however, the associated heart defects are usually fairly mild and, unless complications occur, largely asymptomatic. In line with this, Pierpont et al. (2009) did not find severity of heart defects to be associated with mental capacities in children with NS. Another, indirect, explanation for the speed problems may be in an effect of being bullied on cognition. The high rates of a bullying history in patients with NS can lead to anxiety, which may moderate cognitive development. However, recent research comparing the same patients and controls as examined in this study, did not show any differences in general levels of ‘anxiety’ (SCL-90-R subscale), although levels of social distress were significantly higher in the patients with NS (Wingbermühle et al. 2012).
Comparison of the performances of our groups with normative means shows a large number of impaired performances in various domains. It should be noted, however, that this is the case for both patients and controls, which is related to the fact that norms do not always adjust for schooling effects (Lezak et al. 2012). This emphasizes the need for the inclusion of specific control groups matched with respect to age and education level, to prevent overestimation of cognitive deficits in patients with lower intellectual ability.
Strengths of our study are the extensiveness of the neuropsychological assessments, evaluating all relevant cognitive domains, as well as the inclusion of a carefully matched control group. While a larger sample size would possibly have allowed for even more detailed subgroup analyses, it should be noted that neurobehavioural studies in NS are typically performed in smaller samples (see Table 1). Also, inspection of the effect sizes of the non-significant findings indicates that our study had sufficient statistical power resulting in reliable (non)results. Besides replication studies, preferably including more cognitive domains such as language and perception, future studies should in particular focus on the aetiological mechanisms of the mental slowness in adults with NS, which may be related to factors such as genetic influences on brain development (e.g. neuroimaging of cortical thickness and white-matter integrity) or somatic aspects (for example heart disease). As our sample consisted of patients with varying IQ levels from below average to higher ability, it would be interesting to stratify patients with NS on IQ level in future, larger studies. Moreover, there is a need for longitudinal studies to evaluate developmental change across the lifespan in NS. Systematically comparing specific patients groups with different NS mutation types is also recommended. Finally, future control groups should also include patients with other genetic disorders, preferably with Noonan-like genotypes and phenotypes (e.g. cardiofaciocutaneous syndrome, Turner syndrome), as well as young adults with a history of heart disease.
In conclusion, cognitive functioning in adults with NS is characterised by impaired speed of information processing, but not in any of the other cognitive domains, taking age and education level into account. Despite the relatively intact cognitive profile in adults with NS, patients frequently report cognitive complaints, indicating that neurocognitive and psychological assessment is important in clinical management of patients with NS. The extent and profile of cognitive impairment in adults with NS seems to be different from that of children with NS, who appear to have more generalized cognitive deficits. This may point towards a developmental delay rather than impairments that remain present during the lifespan.