Letters to The Editor Related to New Topics Tremor and White Matter Lesions in Klinefelter Syndrome

A 56-year-old man, welder, was presented with a 42-year medical history of postural and action tremor of both hands. The tremor had worsened in the previous 3 years, making it impossible for him to execute more precise work in his job. He does not have any biological children. In his family, both his paternal uncle and two of his sisters had minor postural tremor (observed in the two sisters). On neurological examination, he showed 5–6 Hz upper limb rest tremor, with left side predominance, and an 11 Hz postural tremor of the four limbs, predominantly kinetic and intentional on the left. The remainder of the examination was unremarkable, namely no bradykinesia, rigidity, or gait problems were present (see supporting information video). Although he presented some atypias, a diagnosis of essential tremor was made and treatment with primidone was started without significant improvement. On the second visit to the hospital, his spouse mentioned that he was experiencing some cognitive decline (loss of initiative, memory problems, and difficulty in solving problems) and also that he had had learning difficulties in his childhood. The brain MRI identified multiple white matter T2/Flair hyperintensities in both hemispheres, confluent in the subcortical frontal areas, one small T2/FLAIR hyperintensitie in the right putamen and another on the left thalamus. None of these lesions had signs of hemorrhage at T2*, and there were no lesions on the cerebellum Figure 1. Further etiological investigation—hepatic and thyroid function, copper metabolism, immunological study, CSF and VDRL serology—did not reveal abnormalities. Neurocognitive evaluation showed below average results in multiple areas, particularly executive functions and language. Given the presence of both tremor and cognitive decline, Fragile X-associated tremor/ataxia syndrome was considered and a genetic test was performed. The FMR1 gene CGG repeats were normal, but two alleles were found. A chromosomal analysis was performed, and it confirmed the XXY karyotype; thus revealing the diagnosis of Klinefelter syndrome. With this new information, a more directed interview and examination were conducted. The patient had the characteristic elongated facial phenotype and was tall and thin. He did not have the sexual characteristics of this syndrome, except for small-volume testes. Endocrine studies demonstrated hypergonadotropic hypogonadism (normal testosterone with high levels of LH and FSH). Our case shows significant similarities to another case already reported, but is distinct in terms of imaging. It intends to underline the importance of considering Klinefelter syndrome diagnosis in the presence of tremor and cognitive decline. Tremor has been, in fact, reported as more prevalent in those patients than in the general population. This case is quite unique in terms of imaging, because of the white matter lesions are not a recognized characteristic of this syndrome, although they have already been described for the more severe variants (XXXXY). As this patient presented with lesions affecting primarily subcortical white-matter, we consider that this could theoretically explain the cognitive decline. The pathophysiological basis for the tremor is more difficult to establish. A hypothesis is that damage to corticothalamic fibers could account for it, because of the existence of cortical and subcortical oscillators taking part in tremor generation has been proposed. The damage to the nucleus of the basal ganglia and left thalamus documented in the MRI is also possibly contributory. Nevertheless, we recognize the existence of reports where tremor is present in Klinefelter syndrome patients without MRI evidence of lesion.