The natural history and genotype-phenotype correlations of TMPRSS3 hearing loss: an international, multi-center, cohort analysis.

TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype-phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.

Analysis of Factors Influencing Financial Cost and Morbidity in Nonfatal Firearm Injuries.

Representing 68% of firearm-related injuries, nonfatal firearm injuries cause substantial morbidity and are associated with high costs to patients and the health care system. A retrospective analysis was performed to evaluate 359 adults in the Southeastern United States from 2019 to 2021. IBM SPSS was used for descriptive and parametric statistical analysis. The mean total cost of stay (TCOS) was $36,639.12, length of stay (LOS) was 8.61 days, number of times to the operating room was 1.88, and number of follow-ups was 3.21. Vascular and traumatic brain injuries were associated with higher TCOS and LOS. Vascular injuries were associated with more operating room visits. Bony injuries and non-TBI neurological injuries were associated with more follow-up appointments. In this brief report, we aim to understand the effect injury types have on these factors to help inform trauma protocol development with the goal of decreasing financial burdens.

Assessing variants of uncertain significance implicated in hearing loss using a comprehensive deafness proteome.

Hearing loss is the leading sensory deficit, affecting ~ 5% of the population. It exhibits remarkable heterogeneity across 223 genes with 6328 pathogenic missense variants, making deafness-specific expertise a prerequisite for ascribing phenotypic consequences to genetic variants. Deafness-implicated variants are curated in the Deafness Variation Database (DVD) after classification by a genetic hearing loss expert panel and thorough informatics pipeline. However, seventy percent of the 128,167 missense variants in the DVD are "variants of uncertain significance" (VUS) due to insufficient evidence for classification. Here, we use the deep learning protein prediction algorithm, AlphaFold2, to curate structures for all DVD genes. We refine these structures with global optimization and the AMOEBA force field and use DDGun3D to predict folding free energy differences (∆∆GFold) for all DVD missense variants. We find that 5772 VUSs have a large, destabilizing ∆∆GFold that is consistent with pathogenic variants. When also filtered for CADD scores (> 25.7), we determine 3456 VUSs are likely pathogenic at a probability of 99.0%. Of the 224 genes in the DVD, 166 genes (74%) exhibit one or more missense variants predicted to cause a pathogenic change in protein folding stability. The VUSs prioritized here affect 119 patients (~ 3% of cases) sequenced by the OtoSCOPE targeted panel. Approximately half of these patients previously received an inconclusive report, and reclassification of these VUSs as pathogenic provides a new genetic diagnosis for six patients.

Assessing Variants of Uncertain Significance Implicated in Hearing Loss Using a Comprehensive Deafness Proteome.

Hearing loss is the leading sensory deficit, affecting ~ 5% of the population. It exhibits remarkable heterogeneity across 223 genes with 6,328 pathogenic missense variants, making deafness-specific expertise a prerequisite for ascribing phenotypic consequences to genetic variants. Deafness-implicated variants are curated in the Deafness Variation Database (DVD) after classification by a genetic hearing loss expert panel and thorough informatics pipeline. However, seventy percent of the 128,167 missense variants in the DVD are "variants of uncertain significance" (VUS) due to insufficient evidence for classification. Here, we use the deep learning protein prediction algorithm, AlphaFold2, to curate structures for all DVD genes. We refine these structures with global optimization and the AMOEBA force field and use DDGun3D to predict folding free energy differences (∆∆G Fold ) for all DVD missense variants. We find that 5,772 VUSs have a large, destabilizing ∆∆G Fold that is consistent with pathogenic variants. When also filtered for CADD scores (> 25.7), we determine 3,456 VUSs are likely pathogenic at a probability of 99.0%. These VUSs affect 119 patients (~ 3% of cases) sequenced by the OtoSCOPE targeted panel. Approximately half of these patients previously received an inconclusive report, and reclassification of these VUSs as pathogenic provides a new genetic diagnosis for six patients.

De novo variants are a common cause of genetic hearing loss.

PURPOSE: De novo variants (DNVs) are a well-recognized cause of genetic disorders. The contribution of DNVs to hearing loss (HL) is poorly characterized. We aimed to evaluate the rate of DNVs in HL-associated genes and assess their contribution to HL. METHODS: Targeted genomic enrichment and massively parallel sequencing were used for molecular testing of all exons and flanking intronic sequences of known HL-associated genes, with no exclusions on the basis of type of HL or clinical features. Segregation analysis was performed, and previous reports of DNVs in PubMed and ClinVar were reviewed to characterize the rate, distribution, and spectrum of DNVs in HL. RESULTS: DNVs were detected in 10% (24/238) of trios for whom segregation analysis was performed. Overall, DNVs were causative in at least ∼1% of probands for whom a genetic diagnosis was resolved, with marked variability based on inheritance mode and phenotype. DNVs of MITF were most common (21% of DNVs), followed by GATA3 (13%), STRC (13%), and ACTG1 (8%). Review of reported DNVs revealed gene-specific variability in contribution of DNV to the mutational spectrum of HL-associated genes. CONCLUSION: DNVs are a relatively common cause of genetic HL and must be considered in all cases of sporadic HL.

Clinical evaluation and etiologic diagnosis of hearing loss: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).

Hearing loss is a common and complex condition that can occur at any age, can be inherited or acquired, and is associated with a remarkably wide array of etiologies. The diverse causes of hearing loss, combined with the highly variable and often overlapping presentations of different forms of hearing loss, challenge the ability of traditional clinical evaluations to arrive at an etiologic diagnosis for many deaf and hard-of-hearing individuals. However, identifying the etiology of hearing loss may affect clinical management, improve prognostic accuracy, and refine genetic counseling and assessment of the likelihood of recurrence for relatives of deaf and hard-of-hearing individuals. Linguistic and cultural identities associated with being deaf or hard-of-hearing can complicate access to and the effectiveness of clinical care. These concerns can be minimized when genetic and other health care services are provided in a linguistically and culturally sensitive manner. This clinical practice resource offers information about the frequency, causes, and presentations of hearing loss and suggests approaches to the clinical and genetic evaluation of deaf and hard-of-hearing individuals aimed at identifying an etiologic diagnosis and providing informative and effective patient education and genetic counseling.

Diagnosis and management of intraoperative thyroid storm in a child with undiagnosed Graves' disease: a case report.

BACKGROUND: Thyroid storm is a life-threatening manifestation of thyrotoxicosis and presents with fever, diaphoresis, tachycardia, hypertension, and widened pulse pressure. CASE PRESENTATION: We present a case of intraoperative thyroid storm in a 12-year-old female undergoing posterior spinal fusion. Despite adequate depth of anesthesia and analgesia, the patient was persistently tachycardic and hypertensive. The surgical procedure was uneventful. A thyroid panel drawn immediately after surgery showed undetectable thyroid stimulating hormone (TSH) and high free thyroxine (T4) consistent with thyroid storm. CONCLUSIONS: Intraoperative thyroid storm in a pediatric patient is extremely rare with nonspecific clinical symptoms. Low to undetectable TSH and elevated free T4 is diagnostic.

AudioGene: refining the natural history of KCNQ4, GSDME, WFS1, and COCH-associated hearing loss.

Autosomal dominant non-syndromic hearing loss (ADNSHL) displays gene-specific progression of hearing loss, which is amenable to sequential audioprofiling. We sought to refine the natural history of ADNSHL by examining audiometric data in 5-year increments. 2175 audiograms were included from four genetic causes of ADNSHL-KCNQ4 (DFNA2), GSDME (DFNA5), WFS1 (DFNA6/14/38), and COCH (DFNA9). Annual threshold deterioration (ATD) was calculated for each gene: for the speech-frequency pure tone average, the ATD, respectively, was 0.72 dB/year, 0.94 dB/year, 0.53 dB/year, and 1.41 dB/year, with the largest drops occurring from ages 45-50 (0.89 dB/year; KCNQ4), 5-10 (1.42 dB/year; GSDME), 40-45 (0.83 dB/year; WFS1), and 50-55 (2.09 dB/year; COCH). 5-year interval analysis of audiograms reveals the gene specific natural history of KCNQ4, GSDME, WFS1 and COCH-related progressive hearing loss. Identifying ages at which hearing loss is most rapid informs clinical care and patient expectations. Natural history data are also essential to define outcomes of clinical trials that test novel therapies designed to correct or ameliorate these genetic forms of hearing loss.

Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease.

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10-8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.

Tumor detection rates in screening of individuals with SDHx-related hereditary paraganglioma-pheochromocytoma syndrome.

PURPOSE: Minimal data exist regarding the efficacy of screening protocols for individuals with SDHx germline pathogenic variants with hereditary paraganglioma-pheochromocytoma syndrome. This study aimed to evaluate the SDHx-related tumor detection rate in individuals undergoing clinical screening protocols. METHODS: A multicenter retrospective longitudinal observational study was conducted. Individuals with germline SDHx pathogenic variants underwent clinical whole-body imaging and biochemical testing. RESULTS: Two hundred sixty-three individuals with SDHx germline pathogenic variants completed 491 imaging screens. Individuals with SDHB germline pathogenic variants were most common (n = 188/263, 72%), followed by SDHD (n = 35/263, 13%) and SDHC (n = 28/263, 11%). SDHx-related tumors were found in 17% (n = 45/263) of the cohort. Most SDHx-related tumors were identified on baseline imaging screen (n = 39/46, 85%). Individuals with SDHD pathogenic variants had the highest tumor detection rate (n = 14/35, 40%). Of imaging screens identifying SDHx-related paraganglioma/pheochromocytoma, 29% (n = 12/41) had negative biochemical testing. Secondary actionable findings were identified in 15% (n = 75/491) of imaging screens. CONCLUSION: Current SDHx screening protocols are effective at identifying SDHx-related tumors. Tumor detection rates vary by SDHx gene and screening has the potential to uncover actionable secondary findings. Imaging is an essential part of the screening process as biochemical testing alone does not detect all disease.

Improved Sensitivity and Reader Confidence in CT Colonography Using Dual-Layer Spectral CT: A Phantom Study.

Background Limited cathartic preparations for CT colonography with fecal tagging can improve patient comfort but may result in nondiagnostic examinations from poorly tagged stool. Dual-energy CT may overcome this limitation by improving the conspicuity of the contrast agent, but more data are needed. Purpose To investigate whether dual-energy CT improves polyp detection in CT colonography compared with conventional CT at different fecal tagging levels in vitro. Materials and Methods In this HIPAA-compliant study, between December 2017 and August 2019, a colon phantom 30 cm in diameter containing 60 polyps of different shapes (spherical, ellipsoid, flat) and size groups (5-9 mm, 11-15 mm) was constructed and serially filled with simulated feces tagged with four different iodine concentrations (1.26, 2.45, 4.88, and 21.00 mg of iodine per milliliter), then it was scanned with dual-energy CT with and without an outer fat ring to simulate large body size (total diameter, 42 cm). Two readers independently reviewed conventional 120-kVp CT and 40-keV monoenergetic dual-energy CT images to record the presence of polyps and confidence (three-point scale.) Generalized estimating equations were used for sensitivity comparisons between conventional CT and dual-energy CT, and a Wilcoxon signed-rank test was used for reader confidence. Results Dual-energy CT had higher overall sensitivity for polyp detection than conventional CT (58.8%; 95% confidence interval [CI]: 49.7%, 67.3%; 564 of 960 polyps vs 42.1%; 95% CI: 32.1%, 52.8%; 404 of 960 polyps; P < .001), including with the fat ring (48% and 31%, P < .001). Reader confidence improved with dual-energy CT compared with conventional images on all tagging levels (P < .001). Interrater agreement was substantial (κ = 0.74; 95% CI: 0.70, 0.77). Conclusion Compared with conventional 120-kVp CT, dual-energy CT improved polyp detection and reader confidence in a dedicated dual-energy CT colonography phantom, especially with suboptimal fecal tagging. © RSNA, 2020.

Microfluidic perfusion modulates growth and motor neuron differentiation of stem cell aggregates.

Microfluidic technologies provide many advantages for studying differentiation of three-dimensional (3D) stem cell aggregates, including the ability to control the culture microenvironment, isolate individual aggregates for longitudinal tracking, and perform imaging-based assays. However, applying microfluidics to studying mechanisms of stem cell differentiation requires an understanding of how microfluidic culture conditions impact cell phenotypes. Conventional cell culture techniques cannot directly be applied to the microscale, as microscale culture varies from macroscale culture in multiple aspects. Therefore, the objective of this work was to explore key parameters in microfluidic culture of 3D stem cell aggregates and to understand how these parameters influence stem cell behavior and differentiation. These studies were done in the context of differentiation of embryonic stem cells (ESCs) to motor neurons (MNs). We assessed how media exchange frequency modulates the biochemical microenvironment, including availability of exogenous factors (e.g. nutrients, small molecule additives) and cell-secreted molecules, and thereby impacts differentiation. The results of these studies provide guidance on how key characteristics of 3D cell cultures can be considered when designing microfluidic culture parameters. We demonstrate that discontinuous perfusion is effective at supporting stem cell aggregate growth. We find that there is a balance between the frequency of media exchange, which is needed to ensure that cells are not nutrient-limited, and the need to allow accumulation of cell-secreted factors to promote differentiation. Finally, we show how microfluidic device geometries can influence transport of biomolecules and potentially promote asymmetric spatial differentiation. These findings are instructive for future work in designing devices and experiments for culture of cell aggregates.

A comparative analysis of genetic hearing loss phenotypes in European/American and Japanese populations.

We present detailed comparative analyses to assess population-level differences in patterns of genetic deafness between European/American and Japanese cohorts with non-syndromic hearing loss. One thousand eighty-three audiometric test results (921 European/American and 162 Japanese) from members of 168 families (48 European/American and 120 Japanese) with non-syndromic hearing loss secondary to pathogenic variants in one of three genes (KCNQ4, TECTA, WFS1) were studied. Audioprofile characteristics, specific mutation types, and protein domains were considered in the comparative analyses. Our findings support differences in audioprofiles driven by both mutation type (non-truncating vs. truncating) and ethnic background. The former finding confirms data that ascribe a phenotypic consequence to different mutation types in KCNQ4; the latter finding suggests that there are ethnic-specific effects (genetic and/or environmental) that impact gene-specific audioprofiles for TECTA and WFS1. Identifying the drivers of ethnic differences will refine our understanding of phenotype-genotype relationships and the biology of hearing and deafness.

Use of Antimetastatic SOD3-Mimetic Albumin as a Primer in Triple Negative Breast Cancer.

Of the deaths attributed to cancer, 90% are due to metastasis. Treatments that prevent or cure metastasis remain elusive. Low expression of extracellular superoxide dismutase (EcSOD or SOD3) has been associated with poor outcomes and increased metastatic potential in multiple types of cancer. Here, we characterize the antimetastatic therapeutic mechanisms of a macromolecular extracellular SOD3-mimetic polynitroxyl albumin (PNA, also known as VACNO). PNA is macromolecular human serum albumin conjugated with multiple nitroxide groups and acts as an SOD-mimetic. Here we show that PNA works as a SOD3-mimetic in a highly metastatic 4T1 mouse model of triple negative breast cancer (TNBC). In vitro, PNA dose dependently inhibited 4T1 proliferation, colony formation, and reactive oxygen species (ROS) formation. In vivo, PNA enhanced reperfusion time in the hypoxic cores of 4T1 tumors as measured by ultrasound imaging. Furthermore, PNA enhanced ultrasound signal intensity within the cores of the 4T1 tumors, indicating PNA can increase blood flow and blood volume within the hypoxic cores of tumors. Lung metastasis from 4T1 flank tumor was inhibited by PNA in the presence or absence of doxorubicin, a chemotherapy agent that produces superoxide and promotes metastasis. In a separate study, PNA increased the survival of mice with 4T1 flank tumors when used in conjunction with three standard chemotherapy drugs (paclitaxel, doxorubicin, and cyclophosphamide), as compared to treatment with chemotherapy alone. In this study, PNA-increased survival was also correlated with reduction of lung metastasis. These results support the hypothesis that PNA works through the inhibition of extracellular superoxide/ROS production leading to the conversion of 4T1 cells from a metastatic tumorigenic state to a cytostatic state. These findings support future clinical trials of PNA as an antimetastatic SOD3-mimetic drug to increase overall survival in TNBC patients.

ATOH1 Promotes Leptomeningeal Dissemination and Metastasis of Sonic Hedgehog Subgroup Medulloblastomas.

Medulloblastoma arising from the cerebellum is the most common pediatric brain malignancy, with leptomeningeal metastases often present at diagnosis and recurrence associated with poor clinical outcome. In this study, we used mouse medulloblastoma models to explore the relationship of tumor pathophysiology and dysregulated expression of the NOTCH pathway transcription factor ATOH1, which is present in aggressive medulloblastoma subtypes driven by aberrant Sonic Hedgehog/Patched (SHH/PTCH) signaling. In experiments with conditional ATOH1 mouse mutants crossed to Ptch1+/- mice, which develop SHH-driven medulloblastoma, animals with Atoh1 transgene expression developed highly penetrant medulloblastoma at a young age with extensive leptomeningeal disease and metastasis to the spinal cord and brain, resembling xenografts of human SHH medulloblastoma. Metastatic tumors retained abnormal SHH signaling like tumor xenografts. Conversely, ATOH1 expression was detected consistently in recurrent and metastatic SHH medulloblastoma. Chromatin immunoprecipitation sequencing and gene expression profiling identified candidate ATOH1 targets in tumor cells involved in development and tumorigenesis. Among these targets specific to metastatic tumors, there was an enrichment in those implicated in extracellular matrix remodeling activity, cytoskeletal network and interaction with microenvironment, indicating a shift in transcriptomic and epigenomic landscapes during metastasis. Treatment with bone morphogenetic protein or SHH pathway inhibitors decreased tumor cell proliferation and suppressed metastatic tumor growth, respectively. Our work reveals a dynamic ATOH1-driven molecular cascade underlying medulloblastoma metastasis that offers possible therapeutic opportunities. Cancer Res; 77(14); 3766-77. ©2017 AACR.

Can dual-energy computed tomography improve visualization of hypoenhancing liver lesions in portal venous phase? Assessment of advanced image-based virtual monoenergetic images.

PURPOSE: The purpose was to assess image quality of portal-venous phase dual-energy computed tomography (DECT) for liver lesions. METHODS: We performed 120-kVp-equivalent linear-blended (LB) and monoenergetic reconstructions from 40 to 190 keV by standard (VMI) and advanced virtual monoenergetic (VMI+) methods. Diagnostic performance, and quantitative and qualitative image analyses were assessed and compared. RESULTS: Liver contrast to noise ratio peaked at 40 keV_VMI+, while image quality and reader preference peaked at 50 keV_VMI+. 50 keV_VMI+ scored overall higher diagnostic performance: lesion sensitivity 95.4% vs. 83.3% for both 75 keV_VMI and LB. CONCLUSIONS: DECT improves assessment of hypoenhancing liver lesions on portal venous phase. 50 keV_VMI+ demonstrated the highest image quality and diagnostic performance over VMI and LB.

Cesarean-Section Scar Endometrioma: A Case Report and Review of the Literature.

Endometriomas can occur after any surgery where there is endometrial manipulation, and there are a number of reports of endometriomas developing in the abdominal wall at the site of the Pfannenstiel incision following Cesarean-section. Although this is ultimately a histopathologically-confirmed diagnosis, preoperative imaging including ultrasound, computed tomography, and magnetic resonance imaging may be helpful in the diagnosis and assessment. We report a pathology-confirmed case of Cesarean-section endometrioma with a classic, clinical presentation and imaging findings on computed tomography. A comprehensive literature review and discussion of the multi-modality imaging appearance of Cesarean-section endometrioma is also provided.

Optimization of window settings for virtual monoenergetic imaging in dual-energy CT of the liver: A multi-reader evaluation of standard monoenergetic and advanced imaged-based monoenergetic datasets.

OBJECTIVES: To evaluate optimal window settings for display of virtual monoenergetic reconstructions in third-generation dual-source, dual-energy computed tomography (DECT) of the liver. METHODS: Twenty-nine subjects were prospectively evaluated with DECT in arterial (AP) and portal venous (PVP) phases. Three reconstructed datasets were calculated: standard linearly-blended (LB120), 70-keV standard virtual monoenergetic (M70), and 50-keV advanced image-based virtual monoenergetic (M50+). Two readers assessed optimal window settings (width and level, W/L), establishing a mean for each reconstruction which was used for a blinded assessment of liver lesions. RESULTS: The optimal W/L for M50+ were significantly higher for both AP (W=429.3 ± 44.6 HU, L=129.4 ± 9.7 HU) and PVP (W=376.1 ± 14.2HU, L=146.6 ± 7.0 HU) than for LB120 (AP, W=215.9 ± 16.9 HU, L=82.3 ± 9.4 HU) (PVP, W=173.4 ± 8.9 HU, L=69.3 ± 6.0 HU) and M70 (AP, W=247.1 ± 22.2 HU, L=72.9 ± 6.8 HU) (PVP, W=232.0 ± 27.9 HU, L=91.6 ± 14.4 HU). Use of the optimal window setting for M50+ vs. LB120 resulted in higher sensitivity (AP, 100% vs. 86%; PVP, 96% vs. 63%). CONCLUSIONS: Application of dedicated window settings results in improved liver lesion detection rates in advanced image-based virtual monoenergetic DECT when customized for arterial and portal venous phases.

Detection and Clinical Significance of Sternal Lesions on Breast MRI.

The purpose of this study is to characterize sternal lesions detected on breast magnetic resonance imaging (MRI), compare MRI detection of sternal lesions with other imaging modalities (bone scan, positron emission tomography/computed tomography (PET/CT) and chest CT), and ascertain how often patient management is altered by discovery of sternal lesions. Retrospective review of 1143 breast MRIs between 2007 and 2012 identified 17 patients with sternal lesions including 15 patients with newly diagnosed breast cancer and two patients with remote history of breast cancer. Tumor size, histopathology, receptor status, nodal and distant metastasis, and images of breast MRI, and other modalities were reviewed. Sternal lesions in 9 of the 17 patients were determined to be malignant (metastasis) either by biopsy or presence of widespread metastases. Sternal lesions in 8 of the 17 were benign, confirmed by biopsy or presumed benign as not detected by other modalities. The malignant group had statistically significant larger breast cancer size (malignant: 6.4 cm; benign: 2.3 cm), a higher percentage of diffuse sternal lesions (malignant: 56%; benign: 0%), and more frequently showed rapid initial enhancing (malignant: 100%; benign: 63%) and delayed washout curves (malignant: 67%; benign: 13%). Although not statistically significant, the malignant group had a higher frequency of invasive lobular carcinoma (malignant: 44%; benign: 13%) and more lymph node involvement (malignant: 78%; benign: 50%). Breast MRI detected more sternal lesions than did bone scan, PET/CT and chest CT. Four of the 17 (24%) patients were upgraded to stage 4 due to unsuspected metastatic sternal lesions on breast MRI. In conclusion, breast MRI is more sensitive than other modalities in detecting sternal lesions. Sternal metastases occur more frequently in aggressive breast cancer and exhibit malignant-type dynamics on breast MRI. Detection of unsuspected sternal metastasis alters staging and improves patient management with more appropriate treatment.