Inherited Deletion of 1q, Hyperparathyroidism and Signs of Y-chromosomal Influence in a Patient with Turner Syndrome

We report a detailed phenotypic, cytogenetic and molecular characterization of a patient prenatally diagnosed with Turner syndrome (TS). In addition to having typical TS clinical characteristics including webbed neck, high arched palate and coarctation of the aorta, the patient had features less frequently seen in TS. These included recurrent parathyroid adenomas, growth along the 75th-90th centiles on the TS height curve despite minimal treatment with growth hormone, behavioral problems and evidence of gonadal dysgenesis with testicular-like structures, such as seminiferous tubules lined by Sertoli cells and a contiguous nodule of Leydig cells. While fluorescence in situ hybridization (FISH) failed to detect Y-chromosome material in gonadal tissue or blood samples, chromosomal microarray analysis (CMA) confirmed X monosomy and a 4.69 Mb copy number loss on 1q31.2q31.3 (bp 192,715,814 to 197,401,180). This region contains the CDC73 gene which has been associated with hyperparathyroidism-jaw tumor syndrome, features of which include recurrent, functional parathyroid adenomas and behavioral issues. This case illustrates how atypical features in a TS patient, such as robust growth and recurrent parathyroid adenomas, may suggest an underlying molecular etiology that should be explored by additional genetic diagnostic modalities. It is therefore appropriate in such cases to conduct further genetic testing, such as CMA and FISH, to explore other diagnostic possibilities and possibly prevent further complications

Early brain vulnerability in Wolfram syndrome.

Wolfram Syndrome (WFS) is a rare autosomal recessive disease characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, deafness, and neurological dysfunction leading to death in mid-adulthood. WFS is caused by mutations in the WFS1 gene, which lead to endoplasmic reticulum (ER) stress-mediated cell death. Case studies have found widespread brain atrophy in late stage WFS. However, it is not known when in the disease course these brain abnormalities arise, and whether there is differential vulnerability across brain regions and tissue classes. To address this limitation, we quantified regional brain abnormalities across multiple imaging modalities in a cohort of young patients in relatively early stages of WFS. Children and young adults with WFS were evaluated with neurological, cognitive and structural magnetic resonance imaging measures. Compared to normative data, the WFS group had intact cognition, significant anxiety and depression, and gait abnormalities. Compared to healthy and type 1 diabetic control groups, the WFS group had smaller intracranial volume and preferentially affected gray matter volume and white matter microstructural integrity in the brainstem, cerebellum and optic radiations. Abnormalities were detected in even the youngest patients with mildest symptoms, and some measures did not follow the typical age-dependent developmental trajectory. These results establish that WFS is associated with smaller intracranial volume with specific abnormalities in the brainstem and cerebellum, even at the earliest stage of clinical symptoms. This pattern of abnormalities suggests that WFS has a pronounced impact on early brain development in addition to later neurodegenerative effects, representing a significant new insight into the WFS disease process. Longitudinal studies will be critical for confirming and expanding our understanding of the impact of ER stress dysregulation on brain development

Upstream Dysfunction of Somatomotor Functional Connectivity After Corticospinal Damage in Stroke

none11siBackground. Recent studies have shown that focal injuries can have remote effects on network function that affect behavior, but these network-wide repercussions are poorly understood. Objective. This study tested the hypothesis that lesions specifically to the outflow tract of a distributed network can result in upstream dysfunction in structurally intact portions of the network. In the somatomotor system, this upstream dysfunction hypothesis predicted that lesions of the corticospinal tract might be associated with functional disruption within the system. Motor impairment might then reflect the dual contribution of corticospinal damage and altered network functional connectivity. Methods. A total of 23 subacute stroke patients and 13 healthy controls participated in the study. Corticospinal tract damage was quantified using a template of the tract generated from diffusion tensor imaging in healthy controls. Somatomotor network functional integrity was determined by resting state functional connectivity magnetic resonance imaging. Results. The extent of corticospinal damage was negatively correlated with interhemispheric resting functional connectivity, in particular with connectivity between the left and right central sulcus. Although corticospinal damage accounted for much of the variance in motor performance, the behavioral impact of resting connectivity was greater in subjects with mild or moderate corticospinal damage and less in those with severe corticospinal damage. Conclusions. Our results demonstrated that dysfunction of cortical functional connectivity can occur after interruption of corticospinal outflow tracts and can contribute to impaired motor performance. Recognition of these secondary effects from a focal lesion is essential for understanding brain-behavior relationships after injury, and they may have important implications for neurorehabilitation.mixedCarter, Alex R.; Patel, Kevin R.; Astafiev, Serguei V.; Snyder, Abraham Z.; Rengachary, Jennifer; Strube, Michael J.; Pope, Anna; Shimony, Joshua S.; Lang, Catherine E.; Shulman, Gordon L.; Corbetta, MaurizioCarter, Alex R.; Patel, Kevin R.; Astafiev, Serguei V.; Snyder, Abraham Z.; Rengachary, Jennifer; Strube, Michael J.; Pope, Anna; Shimony, Joshua S.; Lang, Catherine E.; Shulman, Gordon L.; Corbetta, Maurizi

Mean (±SD) age and gender distribution and clinical variables for control groups and WFS group for DTI scans.

<p>Abbreviation. HC: healthy controls; T1C: diabetic controls; WFS: Wolfram Syndrome group; SD: standard deviation.</p><p>There were no differences between groups for age (p = .24) or gender (p = .28) but there was a significant. difference in duration of diabetes between T1C and WFS (p = .001).</p

Voxel-based morphometry (VBM) findings.

<p>Gray and white matter clusters where WFS have lower volumes than controls. (A) Gray matter clusters included right cerebellum (p = .0008), and left cerebellum (p = .0125), while (B) white matter clusters included a large cluster consisting of much of the cerebellum, brainstem, and subcortex (p<.001), and a small cluster in the parietal-occiptal cortex (p = .0239). Glass brain (all results shown collapsed on a single slice) view shown on left, and the significant cluster on an average MR overlay is shown on the right. Cross hairs are placed in the voxel with a peak t value in the cluster.</p

Regional subcortical brain volumes by significance level.

<p>Regions were segmented in Freesurfer. Left and right volumes were averaged and are shown on the right side of the brain only. The brainstem, cerebellar gray matter and cerebellar white matter were significantly reduced in the WFS compared to controls and survived Bonferroni multiple comparison correction (in red; p<.0038). In addition, the thalamus and pallidum were also reduced in WFS compared to controls, but did not survive correction (p<.05, in yellow). Finally, the corpus callosum, hippocampus, amygdala, caudate, putamen and accumbens were not different between groups (p>.05, in purple).</p

Volume of brainstem segments by diagnosis and age.

<p>(A) The WFS group has reduced volumes in all three brainstem segments after adjusting for intracranial volume. A repeated measures general linear model analysis found a segmental volume by diagnosis interaction (F(4,112) = 7.6, p<.001). Volume in the WFS group was significantly different from the control groups for all three segments (*), but the effect was most striking in the pons. (B) The pons appeared to be reduced in volume in almost all WFS individuals even after adjusting for intracranial volume. This figure shows the relationship between pontine volume and age. HC  =  healthy controls; T1C  =  diabetic controls; WFS  =  Wolfram group.</p