Tremor-Like Myoclonus Associated with Klinefelter Syndrome in a Child

Klinefelter syndrome (KS) is a rare genetic disorder (0.1–0.2% of the population) characterized by the presence of two or more X chromosomes in males. It leads to hypogonadism and infertility, and also to some intellectual disability and psychiatric disturbances.[1] Some studies reported a higher prevalence of unspecific action tremor in KS in adult patients compared with controls.[2]

We report a 7-year-old boy who presented with a 3-year history of tremor. There was no family history of genetic disorder or tremor. He was born full term and walked at the age of 14 months. Language acquisition was delayed and learning difficulties required educational support and speech therapy. On examination, his height was 138 cm (> 4 standard deviation [SD]) and his weight was 46 kg (> 7 SD). He also had morphological abnormalities: obesity, adiposity, small testes, fingers, and toes clinodactyly. A neurological examination showed difficulties in global and fine motor tasks, and a mild bilateral postural and action tremor of the upper limbs. He was not receiving any drug at the time of the examination.

The polymyographic recording showed irregular, sometimes rhythmic (9–10 cycles/second), with intermediate duration bursts (80–250 ms). The pattern was consistent with positive subcortical myoclonus and postural and action tremor with mixed frequencies of 5 and 9 Hz ([Fig. 1]).

Fig. 1 Polymyographic recordings of right upper limb showing the irregular polygraphic pattern of myoclonus and tremor in Klinefelter syndrome. Positive myoclonus recorded during calculation (94–112 ms) at rest (A), or during wrist extension (86–120 ms) (B). Rhythmic (9–10 cycles/second) myoclonus during wrist extension resulting in a 9 Hz tremor on the Acc (C). A 5 Hz postural tremor was recorded on the Acc, during shoulder abduction with elbow flexion and wrist extension; the lack of a clear relationship between repetitive myoclonus (80–250 ms) on FDI EMG and tremor on Acc suggests the coexistence of a more proximal rhythmic activity (D). The rather long duration of the myoclonus—above 80 ms—highly suggests a subcortical generator. Acc, accelerometer; ECR, extensor carpi radialis; FCR, flexor carpi radialis; FDI, first dorsal interosseous . *, positive myoclonus; °, tremor.

A 1.5 T field strength brain magnetic resonance imaging was normal, including 3-mm thick fluid-attenuated inversion recovery, T1, T2, diffusion sequences and specific analysis of hypothalamic–pituitary–adrenal axis. Testicular echography, bone age, metabolic (cholesterol and triglyceride concentrations, glycohemoglobin A_1C [HBA_1C]) and hormonal (testosterone, follicle-stimulating hormone, and luteinizing hormone concentrations) tests were normal. The neuropsychological assessment found poor executive functioning and language skills, in the absence of intellectual disability. The combination of an early and severe obesity, minor motor disorders, and learning disabilities had led to discuss three diagnoses: Klinefelter, Prader–Willi, or fragile X syndromes. Karyotype analysis established the diagnosis of KS, showing XXY aneuploidy.

The child's condition remained stable over 3 years. A regular biannual follow-up was made, including clinical and biological (cholesterol and triglyceride concentrations, HBA_1C) survey. The hormonal profile will be controlled at the age of puberty. Now, he benefits of educational support and diet care. He received no drug targeting tremor over the disease course.

KS is the most frequent sex chromosome abnormality among males. It is characterized by varying degrees of cognitive, social, and behavioral difficulties. In adulthood, primary testicular failure with small testes, hypergonadotropic hypogonadism, tall stature, and eunuchoid body proportions can also be observed.[1] [3] Diagnosis is often delayed because physical abnormalities may be discrete before puberty. The tremor has been reported in adults with KS, mostly as a postural and action tremor that resembles essential tremor.[2] [4] [5] A 27-year-old patient has been reported with jerky movements occurring in the whole body and predominantly in both hands during the action. His upper limb polymyographic recording revealed irregular and pseudorhythmic (8 Hz) bursts (50–100 ms) consistent with myoclonus. The cortical study revealed no cortical features (no cortical drive on electroencephalogram–electromyogram coherence analysis, no giant somatosensory-evoked potentials, or C-reflexes).[6] Despite the lack of neurophysiological features supporting a cortical origin, the authors did not clearly define myoclonus as a subcortical one. Although our case report suggests a subcortical origin to tremor and myoclonus in KS as well, their pathophysiology is not clearly elucidated to date. The link between KS movement disorders and the lack of testosterone might be considered but is not predictable. The effect of testosterone on tremor has been reported as positive in one patient,[7] negative in one,[4] and neutral in three others.[2]

Early detection of KS is recommended to prevent complications related to hypogonadism, learning difficulties, and psychosocial problems.

In addition, KS may be added to the list of possible causes of myoclonus. Clinical clues to this diagnosis in a child are a delay in language acquisition predominating on expressive skills, learning difficulties, tall stature, small testes, and gynecomastia. The polymyographic recording is useful to distinguish rhythmic myoclonus from tremor in this setting.[6] Neurophysiological studies of homogenous and well-defined groups of Klinefelter patients with either tremor or myoclonus could provide valuable knowledge on the pathophysiology of these movement disorders.

Note

Domitille Gras and Elodie Hainque have contributed equally to the article.

• References

• 1 Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E. Klinefelter's syndrome. Lancet 2004; 364 (9430) 273-283
• 2 Koegl-Wallner M, Katschnig-Winter P, Pendl T , et al. Tremor associated with Klinefelter syndrome—a case series and review of the literature. Parkinsonism Relat Disord 2014; 20 (3) 323-327
• 3 Aksglaede L, Link K, Giwercman A, Jørgensen N, Skakkebaek NE, Juul A. 47,XXY Klinefelter syndrome: clinical characteristics and age-specific recommendations for medical management. Am J Med Genet C Semin Med Genet 2013; 163C (1) 55-63
• 4 Burdick DJ, Griffith A, Agarwal P. A case of tremor in Klinefelter syndrome worsened by testosterone administration. Parkinsonism Relat Disord 2015; 21 (4) 419
• 5 Harlow TL, Gonzalez-Alegre P. High prevalence of reported tremor in Klinefelter syndrome. Parkinsonism Relat Disord 2009; 15 (5) 393-395
• 6 Buijink AWG, Koelman JHTM, Meissner A, Stegenga ME, van Rootselaar A-F. Klinefelter syndrome associated myoclonus. Parkinsonism Relat Disord 2014; 20 (11) 1315-1316
• 7 Kinoshita H, Ohkubo T, Kaneko M , et al. Tremor in Klinefelter's syndrome improved by testosterone administration. J Neurol 2009; 256 (11) 1924-1925