Neurobehavioral phenotype of Klinefelter syndrome

A defined genetic syndrome with neurobehavioral components offers an unusua l paradigm for the correlation of genetic defects with neurodevelopmental a bnormalities. The power of the combination of detailed behavioral, neuroana tomical, and genetic studies has been demonstrated in studies of other cond itions involving the sex chromosomes, such as Fragile X syndrome (Mazzocco [2000] Ment Retard Develop Disabil Res Rev. 6:96-106) and Turner syndrome ( Ross [2000] Ment Retard Develop Disabii Res Rev. 6.135-141). Although the b ehavioral and neurologic difficulties that have been identified in Klinefel ter syndrome (KS) are in most cases milder than the consequences of many ot her genetic syndromes, the deficits in KS cause significant: morbidity, rep resenting a more common, but poorly understood, subtype of those with learn ing disabilities. Both as children and as adults, KS subjects appear to off er a powerful genetic model for the study of language and language-based le arning disabilities. Although it has been proposed that the language-based learning difficulties of KS boys are similar to those of nonaneuploidic dys lexics [Bender et al., 1986; Geschwind et al., 1998], this is not yet well established. The co-morbid frontal-executive dysfunction observed in KS is also a likely contributor to learning difficulties and, perhaps, social cog nition, in many KS patients. it is also proposed that altered left-hemisphe re functioning, whether causing, or due to, altered functional and anatomic al cerebral dominance, is at the core of KS subjects' language problems. Al though X chromosomal loci can provide only part of the picture, the study o f KS subjects, a population with a relatively homogeneous etiology for dysl exia/dysphasia and frontal-executive dysfunction, offers many advantages ov er such a study in the general population, in which both dyslexia and atten tional disorders are quite genetically heterogeneous [Decker and Bender, 19 88; Pennington, 1990; Grigorenko et al., 1997; Geschwind et al., 1998]. Fur thermore, the interaction of genetic factors and hormonal influences in the cognitive phenotypes described remains an unexplored area for future inves tigation. (C) 2000 Wiley-Liss, Inc.