Severe myelinopathy in 49,XXXXY syndrome

Abstract

49,XXXXY is a rare aneuploidy with neuroanatomic findings scarcely reported in the literature. Given the fact that many of its phenotypic characteristics are similar to Klinefelter patients, 49,XXXXY has been treated as a variant of Klinefelter syndrome in the past. Newer studies have shown that intellectual disabilities and cardiac sequelae are more common in 49,XXXXY making the need for more precise characterization of the disorder essential. Prior case studies have demonstrated focal (and to a lesser extent confluent) white abnormalities as well as enlarged perivascular cysts (often in clustered arrangements) in the brains of these patients, but high resolution magnetic resonance images of severe myelinopathy are infrequently documented. Presented here is an exceptional manifestation of this rare disease with substantial findings in the brain exhibiting both confluent white matter changes and diffuse perivascular cysts. Cases such as this one serve to expand the differential considerations for confluent dysmyelinating disease and improve diagnostic efficacy.

Introduction

49,XXXXY is a sex chromosome aneuploidy characterized by three extra X chromosomes arising from maternal non-disjunction in both meiosis I and meiosis II. This condition is extremely rare and occurs in only 1:85,000 to 1:100,000 live male births.¹

High-resolution 3.0 Tesla magnetic resonance imaging (MRI) has emerged as an important tool in the evaluation of the pediatric brain over the course of the last decade, however, many earlier descriptions of intracranial findings with respect to this disease were limited to computed tomography (CT) or lower resolution MRI. We present a case of 49,XXXXY in which innumerable dilated perivascular cysts were present in the setting of severe abnormal focal and confluent white matter abnormalities.

Case report

The patient is a nine-year-old male who presented with a reported history of Klinefelter syndrome, global developmental delay, communication disorder, hypotonia, and severe behavioral problems. He was born at term without complication, however, the family reported that he was unable to walk until the fourth year of age, and there was significant delay in language acquisition. The child was described as extremely moody while exhibiting impulsivity, aggression, and outbursts of violence. Recurrent headaches associated with rage attacks were reported.

MRI of the brain was performed which revealed extensive increased T2 signal throughout the bilateral supratentorial white matter with involvement of the centrum semiovale (Figure 1) and cystic dilation of the perivascular spaces (Figure 2). There was no ventriculomegaly.

Figure 1.

Axial FLAIR of the brain demonstrates dilated perivascular cysts (black arrows) superimposed on a background of extensive confluent increased signal within the centrum semiovale (white arrows). The subcortical U-fibers are spared. FLAIR: fluid-attenuated inversion recovery.

Figure 2.

Sagittal T2-weighted image of the brain depicts dilated perivascular cysts (white arrows) uniformly distributed throughout the white matter.

Additional findings in the patient included cryptorchidism, chronic constipation, and limb abnormalities including club foot.

Chromosome microarray analysis revealed the diagnosis of 49,XXXXY. Very long chain fatty acid analysis was within normal limits.

Discussion

49,XXXXY has previously been considered to be a variant of Klinefelter syndrome (47,XXY) due to multiple common features, however, 49,XXXXY should be distinguished from Klinefelter syndrome as patients with the former often have additional medical and psychological issues less common in the latter. Unlike patients with Klinefelter syndrome (KS) and other aneuploidies (48,XXYY and 48,XXXY), those with 49,XXXXY tend to be short in stature. Common findings among 49,XXXXY and 47,XXY include hypertelorism, epicanthal folds, palpebral fissures, and hooded eye lids. Other physical features seen across these disorders include dental abnormalities, clinodactyly, pes planus, lax joints, and cubitus varus.¹

Neuroimaging findings in this disorder remain scarce and diverse. Linden et al. reported CT findings of diffuse cerebral and cerebellar atrophy, prominent ventricles, and mild microcephaly in three patients² in 1995. Individual case reports by Haeusler et al., Galasso et al., Garcia-Cazorla et al., Tabarki et al., and a larger series of three patients by Hoffman et al., demonstrated magnetic resonance (MR) findings of reduced white matter volume, prominent ventricles, and increased T2 signal in the subcortical white matter ranging from multiple discreet lesions to large confluent areas.^3–7 The report by Tabarki et al. noted that the white matter changes spared the subcortical U-fibers. The largest series to date by Blumenthal et al. in 2013 included 14 patients with 49,XXXXY and confirmed that these patients had an overall reduction in brain volume and a higher rate of white matter lesions than the general population. This series also found a higher rate of thinning of the corpus callosum when compared to normal controls. Additionally, seven of the patients demonstrated dilated perivascular cysts, a finding not described in the previous series. Of the seven patients with dilated perivascular cysts, three showed evidence of focal clustering of the cysts.⁸

Patients with 49,XXXXY exhibit a higher incidence of congenital abnormalities such as heart defects, cleft palate, hip dysplasia, renal dysplasia, and radio-ulnar synostosis when compared to the other aneuploidies. Later in infancy and childhood, these patients are prone to inguinal hernias, cryptorchidism, constipation, and seizure disorders. Medical issues occurring in adolescents and adults include hypogonadism and infertility, deep vein thrombosis, pulmonary embolism, and diabetes mellitus type 2.⁹

Developmentally, learning disabilities and speech delays are present in nearly all patients as was the case in the patient presented here. Intellectual disability is extremely common with verbal intelligence quotient (IQ) more severely affected than performance IQ. Each additional chromosome has been shown to correlate with a 15-point reduction in IQ.¹⁰ Social development is also impaired, as these children demonstrate adaptive functioning deficits, emotional immaturity, impulsivity, and behavioral dysregulation at a higher rate than the general population or those with Klinefelter syndrome.¹¹ Given the effect that delayed diagnosis can have on the patient, cases such as this one highlight the importance of MRI evaluation in the approach to the child with developmental delay. Furthermore, 3.0 Tesla MRI may improve sensitivity for subtle white matter abnormalities in cases less severe than this one which may result in more comprehensive testing for the child.

Treatment of patients with 49,XXXXY is a multidisciplinary effort and requires attention given to both the medical and psychosocial aspects of the disease. A 2011 study by Samango-Sprouse et al. showed promising results with improvement of language ability and gestural communication following short course androgen replacement therapy.¹² An endocrinologist is following the patient presented here for possible testosterone supplementation after the onset of puberty.

Conclusion

49,XXXXY is a rare sex chromosome aneuploidy with severe developmental, psychosocial, and medical manifestations. Presented here is a case with severe intracranial manifestations imaged at 3.0 Tesla. 49,XXXXY should be a differential consideration in patients presenting with diffuse white matter abnormalities and extensive perivascular cysts.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.