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.