BACKGROUND Pathogenic variants in LMNA cause a variety of progeroid disorders including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome. Six families with 11 patients harboring a pathogenic heterozygous LMNA c.1045C>T; p.R349W variant have been previously reported to have partial lipodystrophy, cardiomyopathy and focal segmental glomerulosclerosis (FSGS) suggesting a distinct progeroid syndrome. METHODS We now report 6 new patients with heterozygous LMNA p.R349W variant and review the phenotype of previously reported patients to define their unique characteristics. We also performed functional studies on the skin fibroblasts of a patient to seek underlying mechanisms of various clinical manifestations. RESULTS Of the total 17 patients, all 14 adults with the heterozygous LMNA p.R349W variant had peculiar lipodystrophy affecting the face, extremities, palms and soles with variable gain of subcutaneous truncal fat. All of them had proteinuric nephropathy with FSGS documented in 7 of them. Ten developed cardiomyopathy, and two of them died early at ages 33 and 45 years. Other common features included premature graying, alopecia, high-pitched voice, micrognathia, hearing loss and scoliosis. Metabolic complications, including diabetes mellitus, hypertriglyceridemia and hepatomegaly, were highly prevalent. This variant did not show any abnormal splicing and no abnormal nuclear morphology was noted in the affected fibroblasts. CONCLUSIONS Heterozygous LMNA p.R349W variant in affected subjects have several distinct phenotypic features and should be classified as having multisystem progeroid syndrome (MSPS). MSPS patients should undergo careful assessment at symptom onset and yearly metabolic, renal and cardiac evaluation as hyperglycemia, hypertriglyceridemia, FSGS and cardiomyopathy cause major morbidity and mortality.

IntroductionIntracranial hemorrhage (ICH) is a potentially life-threatening medical event that requires expedited diagnosis with computed tomography (CT). Automated medical imaging triaging tools can rapidly bring scans containing critical abnormalities, such as ICH, to the attention of radiologists and clinicians. Here, we retrospectively investigated the real-world performance of VeriScout™, an artificial intelligence-based CT hemorrhage detection and triage tool.MethodsGround truth for the presence or absence of ICH was iteratively determined by expert consensus in an unselected dataset of 527 consecutively acquired non-contrast head CT scans, which were sub-grouped according to the presence of artefact, post-operative features and referral source. The performance of VeriScout™ was compared with the ground truths for all groups.ResultsVeriScout™ detected hemorrhage with a sensitivity of 0.92 (CI 0.84–0.96) and a specificity of 0.96 (CI 0.94–0.98) in the global dataset, exceeding the sensitivity of general radiologists (0.88) with only a minor relative decrement in specificity (0.98). Crucially, the AI tool detected 13/14 cases of subarachnoid hemorrhage, a potentially fatal condition that is often missed in emergency department settings. There was no decrement in the performance of VeriScout™ in scans containing artefact or postoperative change. Using an integrated informatics platform, VeriScout™ was deployed into the existing radiology workflow. Detected hemorrhage cases were flagged in the hospital radiology information system (RIS) and relevant, annotated, preview images made available in the picture archiving and communications system (PACS) within 10 min.ConclusionAI-based radiology worklist prioritization for critical abnormalities, such as ICH, may enhance patient care without adding to radiologist or clinician burden.