Apart from general cognitive outcome, language and academic difficulties are the most widely studied cognitive domain in individuals with KS. There are now a number of studies in the literature that describe the language and reading difficulties, in particular, of children and adults with KS.
Language difficulties have been identified in 70–80% of children with KS starting at an early age. This finding has been relatively robust, being shown in prospectively ascertained samples [Leonard et al., 1979
; Ratcliffe, 1982
; Walzer et al., 1982
; Bender et al., 1983a
; Graham et al., 1988
]. A study by Robinson et al. which looked at children identified with KS from a cohort of 40,000 births at a public hospital in Denver, CO, also noted that children with KS had delays in speech that were identifiable as early as 24 months of age [Robinson et al., 1979
]. These studies were significant because they tested children prior to school age, and thus showed that speech and language problems preceded the academic achievement deficits that they would demonstrate at later ages. These early studies showed that difficulties with articulation, phonemic processing, and word retrieval, in addition to more general delayed expressive language skills, were common in children with KS.
Although most of the studies have identified expressive speech and language difficulties as primary, receptive language deficits have also been noted. Problems with phonemic discrimination, processing speed, and comprehension of grammatical and morphological aspects of language have been reported [Graham et al., 1988
; Walzer et al., 1990
; Bender et al., 1993
]. Netley and Rovet also showed a significant difference between patients with KS and controls on a sentence verification task, where participants had to judge the veracity of sentences of varying linguistic complexity relative to a picture stimulus [Netley and Rovet, 1982b
]. In their 2004 review of the literature, Geschwind and Dykens noted that auditory processing and verbal memory are core cognitive deficits that underlie many of the linguistic deficits seen in patients with KS [Geschwind and Dykens, 2004
]. Thus, tasks with increased perceptual discrimination or short term memory demands are usually the ones where patients with KS struggle most.
Language difficulties in adolescence and adulthood have been identified in cohorts of patients followed longitudinally, or tested cross-sectionally at later ages. Bender et al. showed that adolescents with KS had significantly worse auditory memory, confrontation naming, and verbal fluency skills than matched controls [Bender et al., 1989
]. In the Toronto longitudinal study [Rovet et al., 1995
], children with KS were followed from age 6 to age 20. The study showed depressed verbal conceptual ability on IQ testing, with significant deficits in subtests measuring auditory memory, language comprehension, and expressive abilities. In this cohort, children with KS were deficient in comprehending and using syntactic information to judge the veracity of sentences [Netley and Rovet, 1982b
]. Finally, studies conducted with unselected samples of adults have also shown impairment in verbal memory, verbal fluency, and confrontation naming (word retrieval) ability [Geschwind et al., 1998
; Boone et al., 2001
Another quite consistent finding reported in the literature on individuals with KS has been the extent to which these patients demonstrate deficits in academic achievement throughout their academic careers. Early studies that looked at the proportion of patients receiving special education support reported significantly elevated numbers of children with KS having academic difficulties in school, particularly in the literacy and spelling domains [Pennington et al., 1982
; Robinson et al., 1986
]. Approximately 50–75% of boys demonstrate a specific reading disability at some point in their development [Bender et al., 1986b
; Graham et al., 1988
As studies began to look more systematically at the academic achievement of children with KS, some have noted that the achievement gap is not constrained to the literacy domain. In the Toronto longitudinal study, the authors reported significantly lower achievement of children with KS compared to sibling controls on tests of word decoding, reading comprehension, spelling, written language skills, arithmetic, and math problem solving [Rovet et al., 1996
]. Additionally, their performance on the standardized achievement tests declined relative to age and grade expectations, such that by the last time point (18–20 years of age), they were performing more than five grade levels behind the control group for reading and arithmetic skills. Thus, the academic deficits were not solely in the area of literacy, as some other studies have found, but also included problems in math calculation and problem solving, suggesting that at least a subgroup of children with KS demonstrate a more generalized learning disability profile.
Early studies that looked at the proportion of patients receiving special education support reported significantly elevated numbers of children with KS having academic difficulties in school, particularly in the literacy and spelling domains …
Similar to the oral language difficulties discussed earlier, academic difficulties of patients with KS can also persist into adulthood. In a study by Geschwind et al., ~ 70% of adult participants showed evidence of reading disability [Geschwind et al., 1998
]. Similar deficits in the literacy domain were reported by Boone et al. although in this study single word decoding was not as impaired, relatively speaking, as has been noted in the pediatric studies [Boone et al., 2001
Although the preponderance of the evidence points to a specific cognitive profile in patients with KS, with verbal and language based skills being relative weaknesses, it is also important to note that there is significant variability among participants in these studies. For example, while the participants with KS in the Toronto longitudinal study showed a stable pattern of verbal conceptual skill weakness (VIQ) compared to nonverbal reasoning skills (PIQ) over time, other studies have reported different results. For example, a recent study by Ross et al. in 2008 that reported on the neurocognitive and academic achievement of 50 boys ranging in age from 4–18 years of age, there was no discrepancy between verbal and nonverbal reasoning skills, with both of these scores for the group being in the average to low average range [Ross et al., 2008
]. Surprisingly, the academic achievement of the Ross et al. cohort was also in the average range on measures of single word decoding, spelling, and arithmetic. Furthermore, when the sample was broken down into younger (<10 years) and older patients (>10 years), academic performance did not seem to decline with age in any of the academic domains. A similar profile, where verbal conceptual skills were on par with nonverbal reasoning skills was seen in the testing of adolescent patients followed longitudinally in the Denver sample [Bender et al., 1993
There are inconsistent findings in the language domain as well. Although receptive language skills have been reported as deficient in some studies, Graham et al. reported that children with KS scored within the normal range relative to age norms on all receptive language measures except for one measuring syntactic comprehension [Graham et al., 1988
]. Bender et al. also noted no significant difference on the Token Test, which measures the ability to understand and process directions of increasing length and syntactical complexity [Bender et al., 1986a
The recent study by Ross et al. also reports some inconsistent findings [Ross et al., 2008
]. It is noteworthy that the sample size of this study is one of the largest reported to date in the pediatric age group. Although it has some limitations (e.g., lack of a control group, mixture of clinical and prenatal ascertainment), the larger N provides some extra reassurance that findings are not spurious. Contrary to previous studies, Ross et al. did not find evidence of expressive or receptive vocabulary problems in their cohort of patients. Furthermore, word retrieval skills on phonemic as well as semantic verbal fluency tasks were also normal. They did find that the patients with KS had difficulty with rapid naming skills (but only with colors and objects, and not when naming digits or letters), as well as on tasks measuring higher order language comprehension and formulation. Unfortunately, the latter tests do not measure syntactic or morphological competency as cleanly, thus precluding any conclusion about this particular cohort's skills in these more basic language skills.
Overall, the variability of results across studies is not that surprising. Apart from the likelihood that the disorder itself can have variable phenotypic expression, there are also several methodological factors in the way the syndrome has been studied that likely contribute to the variability in the literature. The latter include the small sample size of most of the studies, use of different types of control groups, the wide age range of the participants in many of the cohorts studied, the disparate batteries of tests that have been used to measure constructs of interest, and variability in the consistency with which possible mediating factors were controlled. In some studies, significant differences between children with KS and a control group were found, but the scores of the group with KS were not that discrepant from age norms. Statistical comparisons can often be misleading when sample sizes are small; reporting of effect sizes would be useful in this regard, but few studies do so. In addition, it is important to note that there can be multiple reasons for a child's deficient performance on a particular task, especially for those tasks that are overdetermined.
Other important factors that have not been consistently controlled in previous studies, but that may mediate the neurocognitive outcome of patients with KS include the amount of special education or tutoring intervention children in the KS group received; whether or not they were naive to testosterone treatment; parental education and SES differences, and family history of speech, language or reading disability. The latter is particularly critical given the deficits being documented have genetic underpinnings in nonaneuploidy populations. Subgroups of individuals with KS may in fact be inheriting a genetic predisposition from allelic variations of genes on nonsex chromosomes that affect verbal and reading deficits, in addition to the effects of having an extra X chromosome. Understanding how background genetic influences add to, or interact, with sex-chromosome aneuploidy is important; yet, none of the studies to date have documented whether there are differences in outcome between patients with KS with and without a family history of speech, language, reading, or attentional disorders.
Apart from the likelihood that the disorder itself can have variable phenotypic expression, there are also several methodological factors in the way the syndrome has been studied that likely contribute to the variability in the literature.
Some of the studies in the literature have attempted to show that the cognitive profile in patients with KS with reading deficits is similar to that of children with dyslexia who do not have sex-chromosome aneuploidy [Bender et al., 1986a
; Graham et al., 1988
]. However, studies to date have not attempted to test cognitive models of reading and language deficits in KS. Various models now exist for language and reading disability in nonaneuploidy populations with specific combinations of endophenotypes accounting for, and predicting, language and reading outcome over time [Pennington, 2006
; Pennington and Bishop, 2009
]. Endophenotypes that have been found to be significant in such models include phonological representations/awareness, phonological memory, verbal, and nonverbal processing speed, as well as nonverbal IQ. Protective factors also need to be measured and analyzed; for example, it has also been recently reported that children with language disorder (who have no history of speech sound disorder) and whose rapid automatized naming is within normal limits are at less risk for developing dyslexia [Bishop et al., 2009
]. Testing these types of models in KS would allow for a more robust understanding of whether the same underlying cognitive factors are indeed responsible for symptom level phenotypes. Finally, with advances in functional brain imaging, as well as genotyping and gene expression testing, the next wave of research in KS should integrate findings across various levels of analysis, allowing for a more complete story to unfold regarding the interplay among genetic, neurobiological, cognitive, and environmental etiological factors that contribute to the clinical phenotype.