Phenotypic features in MECP2 duplication syndrome: Effects of age.

BACKGROUND: MECP2 Duplication syndrome (MDS) is a rare X-linked genomic disorder that is caused by interstitial chromosomal duplications at Xq28 encompassing the MECP2 gene. Although phenotypic features in MDS have been described, there is a limited understanding of the range of severity of these features, and how they evolve with age. METHODS: The cross-sectional results of N = 69 participants (ages 6 months-33 years) enrolled in a natural history study of MDS are presented. Clinical severity was assessed using a clinician-report measure as well as a parent-report measure. Data was also gathered related to the top 3 concerns of parents as selected from the most salient symptoms related to MDS. The Child Health Questionnaire was also utilized to obtain parental reports of each child's quality of life to establish disease burden. RESULTS: The results of linear regression from the clinician-reported measure show that overall clinical severity scores, motor dysfunction, and functional skills are significantly worse with increasing age. Top concerns rated by parents included lack of effective communication, abnormal walking/balance issues, constipation, and seizures. Higher levels of clinical severity were also related to lower physical health quality of life scores as reported by parents. CONCLUSIONS: The data suggest that increasing levels of clinical severity are noted with older age, and this is primarily attributable to motor dysfunction, and functional skills. The results provide an important foundation for creating an MDS-specific severity scale highlighting the most important domains to target for treatment trials and will help clinicians and researchers define clinically meaningful changes.

Characterizing the phenotypic effect of Xq28 duplication size in MECP2 duplication syndrome.

Individuals with methyl CpG binding protein 2 (MECP2) duplication syndrome (MDS) have varying degrees of severity in their mobility, hand use, developmental skills, and susceptibility to infections. In the present study, we examine the relationship between duplication size, gene content, and overall phenotype in MDS using a clinical severity scale. Other genes typically duplicated within Xq28 (eg, GDI1, RAB39B, FLNA) are associated with distinct clinical features independent of MECP2. We additionally compare the phenotype of this cohort (n = 48) to other reported cohorts with MDS. Utilizing existing indices of clinical severity in Rett syndrome, we found that larger duplication size correlates with higher severity in total clinical severity scores (r = 0.36; P = 0.02), and in total motor behavioral assessment inventory scores (r = 0.31; P = 0.05). Greater severity was associated with having the RAB39B gene duplicated, although most of these participants also had large duplications. Results suggest that developmental delays in the first 6 months of life, hypotonia, vasomotor disturbances, constipation, drooling, and bruxism are common in MDS. This is the first study to show that duplication size is related to clinical severity. Future studies should examine whether large duplications which do not encompass RAB39B also contribute to clinical severity. Results also suggest the need for creating an MDS specific severity scale.

Fetal MR imaging of posterior intracranial dural sinus thrombosis: a report of three cases with variable outcomes.

BACKGROUND: Thrombosis of fetal intracranial dural sinuses is a rare entity. A specific type of midline dural sinus thrombosis (DST) at the torcular Herophili with extension into the superior sagittal sinus (SSS) was initially seen on fetal US and was referred to fetal MRI for definite diagnosis and better delineation. OBJECTIVE: Retrospective comparison to medical literature of three cases, diagnosed at our institution, of midline fetal DST with MR imaging findings and clinical outcomes. MATERIALS AND METHODS: We reviewed MRI findings on T2-weighted images of our three cases of fetal midline DST and clinical outcomes of these fetuses and compared our findings to medical literature. The MR imaging and clinical findings of our cases extend over 6 years. They consist of three pregnant women, 31-39 years of age each with a single fetus, with fetal MR imaging performed at different gestational ages (GA). Case 1 the MR imaging was performed at 21 5/7 weeks' GA, case 2 at 24 and 33 4/7 weeks' GA, and case 3 at 22 and 25 weeks' GA. Postnatal MRI was performed in case 2 at 6 months of life and case 3 at 1 day of life. Clinical follow-up occurred during the last 6 years. RESULTS: In all of our cases, T2-W MR imaging demonstrated ballooned midline torcular Herophili with iso- to hypointense mass with or without focal eccentric area of greater hypointensity occupying the torcular Herophili with extension into the SSS. Case 3 had associated leptomeningeal dural vascular malformation overlying the left cerebral hemisphere with development of migrational disorder in the left cerebral hemisphere. Clinical outcome consisted of fetal demise in case 1, normal postnatal outcome in case 2 and severe brain damage with poor postnatal outcome in case 3. CONCLUSION: Our findings of large iso-hypointense thrombus with or without a focal eccentric area more hypointense to thrombus in a dilated torcular Herophili with extension into the SSS on T2-W images corresponds to the majority of cases of this rare type of DST in the medical literature.