Measurement accuracy of prototype non-contrast, compressed sensing-based, respiratory motion-resolved whole heart cardiovascular magnetic resonance angiography for the assessment of thoracic aortic dilatation: comparison with computed tomography angiography.

BACKGROUND: Patients with thoracic aortic dilatation who undergo annual computed tomography angiography (CTA) are subject to repeated radiation and contrast exposure. The purpose of this study was to evaluate the feasibility of a non-contrast, respiratory motion-resolved whole-heart cardiovascular magnetic resonance angiography (CMRA) technique against reference standard CTA, for the quantitative assessment of cardiovascular anatomy and monitoring of disease progression in patients with thoracic aortic dilatation.  METHODS: Twenty-four patients (68.6 ± 9.8 years) with thoracic aortic dilatation prospectively underwent clinical CTA and research 1.5T CMRA between July 2017 and November 2018. Scans were repeated in 15 patients 1 year later. A prototype free-breathing 3D radial balanced steady-state free-precession whole-heart CMRA sequence was used in combination with compressed sensing-based reconstruction. Area, circumference, and diameter measurements were obtained at seven aortic levels by two experienced and two inexperienced readers. In addition, area and diameter measurements of the cardiac chambers, pulmonary arteries and pulmonary veins were also obtained. Agreement between the two modalities was assessed with intraclass correlation coefficient (ICC) analysis, Bland-Altman plots and scatter plots. RESULTS: Area, circumference and diameter measurements on a per-level analysis showed good or excellent agreement between CTA and CMRA (ICCs > 0.84). Means of differences on Bland-Altman plots were: area 0.0 cm2 [- 1.7; 1.6]; circumference 1.0 mm [- 10.0; 12.0], and diameter 0.6 mm [- 2.6; 3.6]. Area and diameter measurements of the left cardiac chambers showed good agreement (ICCs > 0.80), while moderate to good agreement was observed for the right chambers (all ICCs > 0.56). Similar good to excellent inter-modality agreement was shown for the pulmonary arteries and veins (ICC range 0.79-0.93), with the exception of the left lower pulmonary vein (ICC < 0.51). Inter-reader assessment demonstrated mostly good or excellent agreement for both CTA and CMRA measurements on a per-level analysis (ICCs > 0.64). Difference in maximum aortic diameter measurements at baseline vs follow up showed excellent agreement between CMRA and CTA (ICC = 0.91). CONCLUSIONS: The radial whole-heart CMRA technique combined with respiratory motion-resolved reconstruction provides comparable anatomical measurements of the thoracic aorta and cardiac structures as the reference standard CTA. It could potentially be used to diagnose and monitor patients with thoracic aortic dilatation without exposing them to radiation or contrast media.

Correcting versus resolving respiratory motion in free-breathing whole-heart MRA: a comparison in patients with thoracic aortic disease.

BACKGROUND: Whole-heart magnetic resonance angiography (MRA) requires sophisticated methods accounting for respiratory motion. Our purpose was to evaluate the image quality of compressed sensing-based respiratory motion-resolved three-dimensional (3D) whole-heart MRA compared with self-navigated motion-corrected whole-heart MRA in patients with known thoracic aorta dilation. METHODS: Twenty-five patients were prospectively enrolled in this ethically approved study. Whole-heart 1.5-T MRA was acquired using a prototype 3D radial steady-state free-precession free-breathing sequence. The same data were reconstructed with a one-dimensional motion-correction algorithm (1D-MCA) and an extradimensional golden-angle radial sparse parallel reconstruction (XD-GRASP). Subjective image quality was scored and objective image quality was quantified (signal intensity ratio, SIR; vessel sharpness). Wilcoxon, McNemar, and paired t tests were used. RESULTS: Subjective image quality was significantly higher using XD-GRASP compared to 1D-MCA (median 4.5, interquartile range 4.5-5.0 versus 4.0 [2.25-4.75]; p < 0.001), as well as signal homogeneity (3.0 [3.0-3.0] versus 2.0 [2.0-3.0]; p = 0.003), and image sharpness (3.0 [2.0-3.0] vs 2.0 [1.25-3.0]; p < 0.001). SIR with the 1D-MCA and XD-GRASP was 6.1 ± 3.9 versus 7.4 ± 2.5, respectively (p < 0.001); while signal homogeneity was 274.2 ± 265.0 versus 199.8 ± 67.2 (p = 0.129). XD-GRASP provided a higher vessel sharpness (45.3 ± 10.7 versus 40.6 ± 101, p = 0.025). CONCLUSIONS: XD-GRASP-based motion-resolved reconstruction of free-breathing 3D whole-heart MRA datasets provides improved image contrast, sharpness, and signal homogeneity and seems to be a promising technique that overcomes some of the limitations of motion correction or respiratory navigator gating.

Clinical and genomic evaluation of 201 patients with Phelan-McDermid syndrome.

This study is the first to describe age-related changes in a large cohort of patients with Phelan-McDermid syndrome (PMS), also known as 22q13 deletion syndrome. Over a follow-up period of up to 12 years, physical examinations and structured interviews were conducted for 201 individuals diagnosed with PMS, 120 patients had a focused, high-resolution 22q12q13 array CGH, and 92 patients' deletions were assessed for parent-of-origin. 22q13 genomic anomalies include terminal deletions of 22q13 (89 %), terminal deletions and interstitial duplications (9 %), and interstitial deletions (2 %). Considering different age groups, in older patients, behavioral problems tended to subside, developmental abilities improved, and some features such as large or fleshy hands, full or puffy eyelids, hypotonia, lax ligaments, and hyperextensible joints were less frequent. However, the proportion reporting an autism spectrum disorder, seizures, and cellulitis, or presenting with lymphedema or abnormal reflexes increased with age. Some neurologic and dysmorphic features such as speech and developmental delay and macrocephaly correlated with deletion size. Deletion sizes in more recently diagnosed patients tend to be smaller than those diagnosed a decade earlier. Seventy-three percent of de novo deletions were of paternal origin. Seizures were reported three times more often among patients with a de novo deletion of the maternal rather than paternal chromosome 22. This analysis improves the understanding of the clinical presentation and natural history of PMS and can serve as a reference for the prevalence of clinical features in the syndrome.

22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan-McDermid syndrome.

PURPOSE: Phelan-McDermid syndrome is a developmental disability syndrome with varying deletions of 22q13 and varying clinical severity. We tested the hypothesis that, in addition to loss of the telomeric gene SHANK3, specific genomic regions within 22q13 are associated with important clinical features. METHODS: We used a customized oligo array comparative genomic hybridization of 22q12.3-terminus to obtain deletion breakpoints in a cohort of 70 patients with terminal 22q13 deletions. We used association and receiver operating characteristic statistical methods in a novel manner and also incorporated protein interaction networks to identify 22q13 genomic locations and genes associated with clinical features. RESULTS: Specific genomic regions and candidate genes within 22q13.2q13.32 were associated with severity of speech/language delay, neonatal hypotonia, delayed age at walking, hair-pulling behaviors, male genital anomalies, dysplastic toenails, large/fleshy hands, macrocephaly, short and tall stature, facial asymmetry, and atypical reflexes. We also found regions suggestive of a negative association with autism spectrum disorders. CONCLUSION: This work advances the field of research beyond the observation of a correlation between deletion size and phenotype and identifies candidate 22q13 loci, and in some cases specific genes, associated with singular clinical features observed in Phelan-McDermid syndrome. Our statistical approach may be useful in genotype-phenotype analyses for other microdeletion or microduplication syndromes.

Association between deletion size and important phenotypes expands the genomic region of interest in Phelan-McDermid syndrome (22q13 deletion syndrome).

BACKGROUND: The clinical features of Phelan-McDermid syndrome (also known as 22q13 deletion syndrome) are highly variable and include hypotonia, speech and other developmental delays, autistic traits and mildly dysmorphic features. Patient deletion sizes are also highly variable, prompting this genotype-phenotype association study. METHODS: Terminal deletion breakpoints were identified for 71 individuals in a patient cohort using a custom-designed high-resolution oligonucleotide array comparative genomic hybridisation platform with a resolution of 100 bp. RESULTS: Patient deletion sizes were highly variable, ranging from 0.22 to 9.22 Mb, and no common breakpoint was observed. SHANK3, the major candidate gene for the neurologic features of the syndrome, was deleted in all cases. Sixteen features (neonatal hypotonia, neonatal hyporeflexia, neonatal feeding problems, speech/language delay, delayed age at crawling, delayed age at walking, severity of developmental delay, male genital anomalies, dysplastic toenails, large or fleshy hands, macrocephaly, tall stature, facial asymmetry, full brow, atypical reflexes and dolichocephaly) were found to be significantly associated with larger deletion sizes, suggesting the role of additional genes or regulatory regions proximal to SHANK3. Individuals with autism spectrum disorders (ASDs) were found to have smaller deletion sizes (median deletion size of 3.39 Mb) than those without ASDs (median deletion size 6.03 Mb, p=0.0144). This may reflect the difficulty in diagnosing ASDs in individuals with severe developmental delay. CONCLUSIONS: This genotype-phenotype analysis explains some of the phenotypic variability in the syndrome and identifies new genomic regions with a high likelihood for causing important developmental phenotypes such as speech delay.

United States head circumference growth reference charts: birth to 21 years.

OBJECTIVE: To produce a more reliable, continuous set of occipitofrontal head circumference (OFC) growth reference charts for males and females from birth to adulthood in the United States. STUDY DESIGN: After investigating the strengths and shortcomings of previous reports, we combined the most recent statistically reliable reports of OFC growth reference data into a locally weighted regression analysis to estimate percentile curves. We used cross-sectional prospective local pediatric data to validate our results. RESULTS: We present new age- and sex-appropriate US OFC growth charts from birth to adulthood that include 3rd and 97th percentile cutoff values. Our local pediatric data validate that our new proposed OFC growth charts' assessment of attained OFC growth is comparable with previous references. CONCLUSIONS: We have eliminated disagreements between multiple current references by unifying previously reported US OFC data into a single set of smoothed male and female growth reference charts from birth to adulthood. This will reduce confusion or errors in interpretation of normal versus abnormal measurements currently encountered by primary care clinicians and subspecialists when using OFC growth charts for the US pediatric population.