Skeletal Radiographs Research Articles

Skeletal radiograph interpretation discrepancies in the emergency department setting: A retrospective chart review.

To determine the frequency and clinical consequences of discrepancies in skeletal radiograph interpretation between emergency and radiology doctors in an Australian ED. We reviewed the records of adult and paediatric patients assessed with skeletal radiography in an ED in Victoria, Australia over 3 months (January to March 2022). Epidemiological data, the interpretation of the radiograph by ED and radiology doctors, and clinical management of the patient were recorded to determine interpretation discrepancies and the consequences of these. There were 2359 unique skeletal radiographs in 1576 patient presentations during the study period. Of these, 140 (6%) had a discrepancy. Where a discrepancy existed, 47% of the ED interpretation reported a fracture and/or dislocation which was not present in the radiology interpretation (false positive), whereas the remaining (53%) were attributed to a missed fracture and/or dislocation (false negative). Thirty-five discrepancies (2%) required a change in patient management and were therefore clinically significant. The most commonly affected body region was the elbow, where 15% of radiographs were discrepant. Pathology was more often missed when multiple abnormalities were present on the same radiograph (odds ratio = 4.2, 95% confidence interval = 2.5-6.8). The rate of clinically significant discrepancies in the interpretation of skeletal radiographs by emergency medicine doctors is low. This data support using the ED interpretation of radiographs to guide initial management as safe practice.

The Accuracy of Radiographers Preliminary Image Evaluations of Axial Radiographs: a Prospective Longitudinal Study at Al-Hussein Hospital, Iraq

Introduction: Modern emergency departments are under increasing pressure that can only be alleviated by new approaches to meeting demand. One strategy could be the adoption of radiographer preliminary image evaluations (PIEs), which would significantly reduce the time it takes emergency teams to receive critical imagery results. The aim of this study was to examine the accuracy of radiographers’ interpretations of axial radiographs and the impact a short training program had on their image interpretation skills. Methods: Forty-one radiographers volunteered to participate in the study. From 15 January to 15 April 2023 radiographers produced PIEs for 24 axial radiographs which were compared to the radiology reports for the same images. The accuracy each of the radiographers’ PIEs were categorized as true positive, true negative, false positive and false negative, with numerical scores to enable mean accuracies to be calculated. The radiographers’ accuracy was then reassessed on the same images after they had completed a two-week training program on axial skeletal radiograph interpretation. Results: The study reported that demonstrated that most (TP) radiographer PIEs (M = 5.66, SD = 1.24) were about facial bone fracture. Moreover, this study demonstrated that most (FN/TP) radiographer PIEs (M = 3.83, SD = 1.69) were that cases about inflammatory disease of the axial spine, such as ankylosing spondylitis. In contrast, the most common cases misinterpreted were about cervical spine disorders such as diffuse idiopathic skeletal hyperostosis (DISH) (M = 2.49, SD = 1.36). Years of experience in radiography showed a positive but not statistically significant influence on accuracy. Additionally, post training mean accuracy significantly improved. Conclusion: This study found radiographers provided quite accurate PIEs for facial bone fractures when compared to the full radiology reports of the same images. The findings also highlighted specific pathologies that were frequently misinterpreted. A two-week training program was found to be effective at improving radiographers’ ability to correctly identify and describe abnormalities present in axial radiographs.

The Accuracy of Radiographers Preliminary Image Evaluations of Axial Radiographs: a Prospective Longitudinal Study at Al-Hussein Hospital, Iraq

Introduction: Modern emergency departments are under increasing pressure that can only be alleviated by new approaches to meeting demand. One strategy could be the adoption of radiographer preliminary image evaluations (PIEs), which would significantly reduce the time it takes emergency teams to receive critical imagery results. The aim of this study was to examine the accuracy of radiographers’ interpretations of axial radiographs and the impact a short training program had on their image interpretation skills. Methods: Forty-one radiographers volunteered to participate in the study. From 15 January to 15 April 2023 radiographers produced PIEs for 24 axial radiographs which were compared to the radiology reports for the same images. The accuracy each of the radiographers’ PIEs were categorized as true positive, true negative, false positive and false negative, with numerical scores to enable mean accuracies to be calculated. The radiographers’ accuracy was then reassessed on the same images after they had completed a two-week training program on axial skeletal radiograph interpretation. Results: The study reported that demonstrated that most (TP) radiographer PIEs (M 66, SD = 1.24) were about facial bone fracture. Moreover, this study demonstrated that most (FN/TP) radiographer PIEs (M = 3.83, SD = 1.69) were that cases about inflammatory disease of the axial spine, such as ankylosing spondylitis. In contrast, the most common cases misinterpreted were about cervical spine disorders such as diffuse idiopathic skeletal hyperostosis (DISH) (M = 2.49, SD = 1.36). Years of experience in radiography showed a positive but not statistically significant influence on accuracy. Additionally, post training mean accuracy significantly improved. Conclusion: This study found radiographers provided quite accurate PIEs for facial bone fractures when compared to the full radiology reports of the same images. The findings also highlighted specific pathologies that were frequently misinterpreted. A two-week training program was found to be effective at improving radiographers’ ability to correctly identify and describe abnormalities present in axial radiographs.

Improved Automated Quality Control of Skeletal Wrist Radiographs Using Deep Multitask Learning.

Radiographic quality control is an integral component of the radiology workflow. In this study, we developed a convolutional neural network model tailored for automated quality control, specifically designed to detect and classify key attributes of wrist radiographs including projection, laterality (based on the right/left marker), and the presence of hardware and/or casts. The model's primary objective was to ensure the congruence of results with image requisition metadata to pass the quality assessment. Using a dataset of 6283 wrist radiographs from 2591 patients, our multitask-capable deep learning model based on DenseNet 121 architecture achieved high accuracy in classifying projections (F1 Score of 97.23%), detecting casts (F1 Score of 97.70%), and identifying surgical hardware (F1 Score of 92.27%). The model's performance in laterality marker detection was lower (F1 Score of 82.52%), particularly for partially visible or cut-off markers. This paper presents a comprehensive evaluation of our model's performance, highlighting its strengths, limitations, and the challenges encountered during its development and implementation. Furthermore, we outline planned future research directions aimed at refining and expanding the model's capabilities for improved clinical utility and patient care in radiographic quality control.

Present and future of whole-body MRI in metastatic disease and myeloma: how and why you will do it.

Metastatic disease and myeloma present unique diagnostic challenges due to their multifocal nature. Accurate detection and staging are critical for determining appropriate treatment. Bone scintigraphy, skeletal radiographs and CT have long been the mainstay for the assessment of these diseases, but have limitations, including reduced sensitivity and radiation exposure. Whole-body MRI has emerged as a highly sensitive and radiation-free alternative imaging modality. Initially developed for skeletal screening, it has extended tumor screening to all organs, providing morphological and physiological information on tumor tissue. Along with PET/CT, whole-body MRI is now accepted for staging and response assessment in many malignancies. It is the first choice in an ever increasing number of cancers (such as myeloma, lobular breast cancer, advanced prostate cancer, myxoid liposarcoma, bone sarcoma, …). It has also been validated as the method of choice for cancer screening in patients with a predisposition to cancer and for staging cancers observed during pregnancy. The current and future challenges for WB-MRI are its availability facing this number of indications, and its acceptance by patients, radiologists and health authorities. Guidelines have been developed to optimize image acquisition and reading, assessment of lesion response to treatment, and to adapt examination designs to specific cancers. The implementation of 3D acquisition, Dixon method, and deep learning-based image optimization further improve the diagnostic performance of the technique and reduce examination durations. Whole-body MRI screening is feasible in less than 30min. This article reviews validated indications, recent developments, growing acceptance, and future perspectives of whole-body MRI.

Osteopetrosis with Typical Radiological Findings: A Report of a Rare Case

BACKGROUND: Osteopetrosis is a rare inherited disease caused by a lack of osteoclastic bone resorption, resulting in increased bone mass with insufficient mechanical strength. Patients usually present with complications such as pathologic fractures, cranial neuropathies, and bone marrow failure. Diagnosis is based on suggestive clinical and imaging findings, with genetic testing to confirm diagnosis and identify the subtype. CASE PRESENTATION: The patient is an eight-year-old girl who came to our hospital with complaints of bilateral arm swelling and visual disturbances for four years and a history of fracture of the left lower extremity two years before presentation. Physical examination revealed nontender bilateral arm swelling and a shorter left leg. The laboratory tests were within normal limits. A skeletal radiograph showed typical radiographic features of osteopetrosis. CONCLUSION: It is important to consider osteopetrosis in patients presenting with pathologic fractures and cranial neuropathies. Typical imaging findings can provide rapid diagnosis in severe cases.

Bone scan findings of Paget’s disease of bone in patients with VCP Multisystem Proteinopathy 1

Multisystem Proteinopathy 1 (MSP1) disease is a rare genetic disorder caused by mutations in the Valosin-Containing Protein (VCP) gene with clinical features of inclusion body myopathy (IBM), frontotemporal dementia (FTD), and Paget’s disease of bone (PDB). We performed bone scan imaging in twelve patients (6 females, 6 males) with confirmed VCP gene mutation six (50%) of which has myopathy alone, four (33%) with both PDB and myopathy, and two (15%) were presymptomatic carriers. We aim to characterize the PDB in diagnosed individuals, and potentially identify PDB in the myopathy and presymptomatic groups. Interestingly, two patients with previously undiagnosed PDB had positive diagnostic findings on the bone scan and subsequent radiograph imaging. Among the individuals with PDB, increased radiotracer uptake of the affected bones were of typical distribution as seen in conventional PDB and those reported in other MSP1 cohorts which are the thoracic spine and ribs (75%), pelvis (75%), shoulder (75%) and calvarium (15%). Overall, we show that technetium-99m bone scans done at regular intervals are a sensitive screening tool in patients with MSP1 associated VCP variants at risk for PDB. However, diagnostic confirmation should be coupled with clinical history, biochemical analysis, and skeletal radiographs to facilitate early treatment and prevention complications, acknowledging its limited specificity.

Demystifying the Radiography of Age Estimation in Criminal Jurisprudence: A Pictorial Review.

Skeletal radiographs along with dental examination are frequently used for age estimation in medicolegal cases where documentary evidence pertaining to age is not available. Wrist and hand radiographs are the most common skeletal radiograph considered for age estimation. Other parts imaged are elbow, shoulder, knee, and hip according to suspected age categories. Age estimation by wrist radiographs is usually done by the Tanner-Whitehouse method where the maturity level of each bone is categorized into stages and a final total score is calculated that is then transformed into the bone age. Careful assessment and interpretation at multiple joints are needed to minimize the error and categorize into age-group. In this article, we aimed to summarize a suitable radiographic examination and interpretation for bone age estimation in living children, adolescents, young adults, and adults for medicolegal purposes.

Assessing the Potential of a Deep Learning Tool to Improve Fracture Detection by Radiologists and Emergency Physicians on Extremity Radiographs

To evaluate the standalone performance of a deep learning (DL) based fracture detection tool on extremity radiographs and assess the performance of radiologists and emergency physicians in identifying fractures of the extremities with and without the DL aid. The DL tool was previously developed using 132,000 appendicular skeletal radiographs divided into 87% training, 11% validation, and 2% test sets. Stand-alone performance was evaluated on 2626 de-identified radiographs from a single institution in Ohio, including at least 140 exams per body region. Consensus from three US board-certified musculoskeletal (MSK)radiologists served as ground truth. A multi-reader retrospective study was performed in which 24 readers (eight each of emergency physicians, non-MSK radiologists, and MSK radiologists) identified fractures in 186 cases during two independent sessions with and without DLaid, separated by a one-month washout period. The accuracy (area under the receiver operating curve), sensitivity, specificity, and reading time werecompared withand without model aid. The model achieved a stand-alone accuracy of 0.986, sensitivity of 0.987, and specificity of 0.885, and high accuracy (> 0.95) across stratification for body part, age, gender, radiographic views, and scanner type. With DL aid, reader accuracy increased by 0.047 (95% CI: 0.034, 0.061; p=0.004) and sensitivity significantly improved from 0.865 (95% CI: 0.848, 0.881) to 0.955 (95% CI: 0.944, 0.964). Average reading time was shortened by 7.1s (27%) per exam. When stratified by physician type, this improvement was greater for emergency physicians and non-MSK radiologists. The DL tool demonstrated high stand-alone accuracy, aided physician diagnostic accuracy, and decreased interpretation time.

Image rejects in digital skeletal radiography in two public hospitals in Norway

IntroductionThe proportion of diagnostic images not applied for diagnostic purposes is an indicator of image quality, safety, and efficiency in radiography. Despite increased awareness, image reject is still a substantial problem and needs continued observation and targeted measures. Accordingly, the objective of this study is to estimate the extent, variation, and characteristics of image rejects, in order to improve the quality, safety, and efficiency in radiography. MethodsAll skeletal images at two digital X-ray rooms at two public hospitals in Norway were reviewed for four weeks in 2020. The number of exposed images, type of examination, and number of deleted images were registered. For each deleted image the deduced reasons for deleting the image were recorded. Results2183 and 1467 X-ray images were taken at Hospital 1 and 2 respectively. The corresponding reject rates were 14.2% and 9.1%. The reject rate varied greatly from day to day (from 0% to 22%), and the examinations with the highest reject rate were X-ray of extremities (knee, elbow, ankle, wrist) (12–25%) and of the spine (14–19%). The two clearly dominating reasons for image rejects were positioning and centering errors. ConclusionThe reject rate is high and reduces quality, safety, and efficiency of imaging services. The reasons for image rejects are typical professionally reducible errors indicating great potential for improvement. Implications for practiceMonitoring and assessing image rejects are of great importance to management, training, education, patient safety, and for quality improvement of imaging services.

Primary Plasma Cell Leukaemia with Lambda Light Chain secretion and Chromosomal abnormalities presenting as hyperleukocytosis - A case report.

Primary plasma cell leukaemia (pPCL) is a rare and lethal form of plasma cell dyscrasia that can occur either de novo (primary) or as a leukemic transformation of refractory or relapsed multiple myeloma. We report a case of pPCL with lambda light chain disease and multiple chromosomal abnormalities in a 75-year-old female who presented with generalized weakness. Her peripheral blood smear showed hyperleukocytosis with 78% circulating plasma cells. Serum protein electrophoresis (SPE) does not reveal the M band and serum immunofixation (SI) light chain analysis in serum showed an elevated lambda light chain. Skeletal radiography and PET-CT (positron emission tomography—computerized tomography) did not reveal any lytic lesions. Immunophenotypic studies reveal a CD38-positive population with negativity for T cells, B cells, myeloid markers, and a negative CD45. Fluorescent in situ hybridization (FISH) analysis results disclosed the deletion of 13q14.3 and t(11; 14). This case highlighted the usefulness of the peripheral smear findings and high fluorescent lymphocyte activity, which directed the pathologist to initiate workup for pPCL, and comprehensive laboratory biochemical and radiological evaluation further helps to confirm and differentiate pPCL from multiple myeloma. Bangladesh Journal of Medical Science Vol. 22 No. 04 October’23 Page : 932-936

Comparing Ultrasonography With Plain Radiography in the Diagnosis of Long Bone Fractures

Objective: This study was designed to compare sonography to skeletal radiography, in the diagnosis of long bone fractures. Materials and Methods: This was a cross-sectional and analytical study including 188 patients of varied ages that had 251 suspected long bone fractures. It was conducted over a 9-month period, in the emergency department of a teaching hospital, within the Swat district of Pakistan. After assessing the clinical symptoms of the fracture by an emergency orthopedic physician, sonography was followed by a radiograph performed for these referred patients. Results: Sonography shows a diagnostic accuracy of 91.23% for detecting long bone fractures, with a sensitivity and specificity of 100% and 76.84%, respectively. The positive predictive value and negative predictive value were 87.64% and 100%, respectively. Sonography was able to detect small fractures (up to 0.23 mm) that are often missed on the patient’s radiograph. Conclusion: Sonography may be useful as an initial screening imaging technique for the diagnosis of long bone fractures. The potential exists to reduce the need for unnecessary skeletal radiographs, which could reduce treatment time, cost, and ionizing radiation hazards.

Occult fractures detected on radiographs in young children with a concern for abusive head trauma.

To determine the incidence of children < 2 years old with suspected abusive head trauma, to evaluate usage of dedicated skeletal radiographs and the incidence of clinically occult fractures on dedicated skeletal radiographs. This is a retrospective single centre study of children < 2 years old with traumatic brain injury, referred to the University Hospital's Social Services Department between December 31, 2012 and December 31, 2020. Clinical and demographic data was retrieved from medical notes and imaging was reviewed by paediatric radiologists. 26 children (17 males), 2 weeks to 21 months of age (median age 3 months) were included. Eleven children (42%) had traumatic history, fourteen children (54%) had one or more bruises, eighteen children (69%) had abnormal neurological findings. 16 children (62%) had dedicated skeletal radiographs, 7 children (27%) had radiographs of part of the skeleton and 3 children (11%) had no skeletal radiographs. 5 out of 16 children (31%) with dedicated skeletal radiographs had a clinically occult fracture. 15 (83%) of clinically occult fractures had high specificity for abuse. The incidence of suspected abusive head trauma in children < 2 years old is low. Clinically occult fractures were detected in one third of children with dedicated skeletal radiographs. The majority of these fractures have high specificity for abuse. Dedicated skeletal imaging is not performed in more than one third of the children and hence fractures may be missed. Efforts should be taken to increase awareness of child abuse imaging protocols.

How to apply evidence-based practice to the use of artificial intelligence in radiology (EBRAI) using the data algorithm training output (DATO) method.

As the number of radiology artificial intelligence (AI) papers increases, there are new challenges for reviewing the AI literature as well as differences to be aware of, for those familiar with the clinical radiology literature. We aim to introduce a tool to aid in this process. In evidence-based practise (EBP), you must Ask, Search, Appraise, Apply and Evaluate to come to an evidence-based decision. The bottom-up evidence-based radiology (EBR) method allows for a systematic way of choosing the correct radiological investigation or treatment. Just as the population intervention comparison outcome (PICO) method is an established means of asking an answerable question; herein, we introduce the data algorithm training output (DATO) method to complement PICO by considering Data, Algorithm, Training and Output in the use of AI to answer the question. We illustrate the DATO method with a worked example concerning bone age assessment from skeletal radiographs. After a systematic search, 17 bone age estimation papers (5 of which externally validated their results) were appraised. The paper with the best DATO metrics found that an ensemble model combining uncorrelated, high performing simple models should achieve error rates comparable to human performance. Considering DATO in the application of EBR to AI is a simple systematic approach to this potentially daunting subject. The growth of AI in radiology means that radiologists and related professionals now need to be able to review not only clinical radiological literature but also research using AI methods. Considering Data, Algorithm, Training and Output in the application of EBR to AI is a simple systematic approach to this potentially daunting subject.

Impact of Structured Reporting of Skeletal Survey in Skeletal Dysplasia: A Single Institution Experience.

Background Structured reporting has the advantages of reducing ambiguity in written radiology reports with greater uniformity and comparability of reports amongst different institutes. It has multiple facets: structured format, structured content, and standardized language. While structured reporting initiative has been used in various radiology subspecialties such as oncology, cardiothoracic, abdominal and interventional radiology; skeletal dysplasia is a domain that remains largely untouched by this concept. Purpose To evaluate the impact of structured reporting in skeletal dysplasia. Methods and Materials This was an ethically approved pragmatic clinical trial. A defined number (75) of clinically diagnosed and/or genetically confirmed skeletal dysplasia radiographs were evaluated by two radiologists (reader A and reader B) with 5-and 7-years' experience in general radiology, respectively. A pre-defined structured reporting format for skeletal dysplasia was used as an interventional tool. Both the readers interpreted the radiographs before and after the training session. In addition to diagnosis, diagnostic confidence was noted using a semiquantitative scale. Improvement in diagnostic accuracy and diagnostic confidence after training were assessed. McNemar's test was used to assess the statistical significance of difference in proportion of correct diagnoses in pre- and post-education phases. An interrater reliability analysis using the Kappa statistic was performed to determine interobserver agreement between readers both in pre- and post-education phases. Results In the post-education phase, the proportion of accurate diagnosis improved from 48% (36/75) to 64% (48/75) for reader A, and from 44% (33/75) to 60% (45/75) for reader B as compared with the pre-education phase. Amongst the cases with a correct radiologic diagnosis, an increase in diagnostic confidence was noted in 18 cases for reader A, and 15 cases for reader B. In none of the cases, there was a reduction in diagnostic confidence after training. A McNemar's test determined that there was a statistically significant difference in the proportion of correct diagnoses in pre- and post-education phases, p < 0.001. The interobserver agreement between the readers was found to increase from Kappa = 0.33 ( p = 0.004) using non-structured reporting in pre-education phase to Kappa = 0.46 ( p < 0.001) using structured reporting in the post-education phase. Conclusion A structured reporting of skeletal survey can improve accuracy and confidence in diagnosing skeletal dysplasia.

AN INTERESTING CASE OF KNOCK KNEE

Primary hyperparathyroidism is a generalized disorder of calcium, phosphate, and bone metabolism due to an increased secretion of parathyroid hormone. The manifestations may be subtle, and the disease may have a benign course for many years or a lifetime. If the patients are symptomatic , the most commonly involved system include the renal and the skeletal system. Herein we present a case of 16 year old male who presented with complaints of multiple large joint pain and progressive deformity of both knees over the past 1 year. Physical examination revealed bilateral genu valgum. Investigations taken showed elevated serum calcium levels, parathormone levels, alkaline phosphatase levels and low levels of vitamin D. Skeletal radiograph taken showed evidence of osteitis brosa cystica along with salt and pepper appearance of the skull. USG Neck showed evidence of left parathyroid adenoma and a Tc99 Sestamibi parathyroid scintigraphy scan conrmed it. Patient underwent inferior parathyroidectomy. Post procedure, patient's parathormone levels were within the normal limits and hence was discharged with calcium and vitamin D supplements.

Computed tomography with adjusted dose for body mass index may be superior to whole-body radiography especially in elderly patients with multiple myeloma.

Whole-body skeletal radiography has traditionally been used in the management of multiple myeloma for defining treatment strategies. For several reasons, radiography has been replaced by computed tomography (CT) covering the same regions. To evaluate the body mass index (BMI) adjusted effective radiation dose from two different methods of whole-body radiologic imaging for multiple myeloma assessment. The current investigation analyses the dose to patients resulting from the two methods, conventional radiography supplemented with tomosynthesis (203 examinations) and CT (264 examinations). All patients subject to myeloma staging for 4.5 years were included in the study. Exposure parameters were collected from the PACS and conversion factors were calculated using the software packages PCXMC and VirtualDose enabling the calculation of the effective dose to each patient based on BMI. The Mann-Whitney U test was used for comparisons between groups. Patients were subject to a median effective dose of 2.5 mSv for conventional radiography and 5.1 mSv for CT, a statistically significant difference. The effective dose for whole-body CT in assessing multiple myeloma is twice as high as for whole-body skeletal survey with modern digital radiography, but at a low level and considerably less than the levels quoted in the earlier studies of ∼30 mSv when the technique was first explored.

Clinical, radiological and molecular studies in 24 individuals with Dyggve-Melchior-Clausen dysplasia and Smith-McCort dysplasia from India

BackgroundDyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC types 1 and 2) are rare spondyloepimetaphyseal dysplasias with identical radiological findings. The presence of intellectual disability in DMC and normal intellect in...

Clinician and computer: a study on doctors’ perceptions of artificial intelligence in skeletal radiography

BackgroundTraumatic musculoskeletal injuries are a common presentation to emergency care, the first-line investigation often being plain radiography. The interpretation of this imaging frequently falls to less experienced clinicians despite well-established challenges in reporting. This study presents novel data of clinicians’ confidence in interpreting trauma radiographs, their perception of AI in healthcare, and their support for the development of systems applied to skeletal radiography.MethodsA novel questionnaire was distributed through a network of collaborators to clinicians across the Southeast of England. Over a three-month period, responses were compiled into a database before undergoing statistical review.ResultsThe responses of 297 participants were included. The mean self-assessed knowledge of AI in healthcare was 3.68 out of ten, with significantly higher knowledge reported by the most senior doctors (Specialty Trainee/Specialty Registrar or above = 4.88). 13.8% of participants reported an awareness of AI in their clinical practice.Overall, participants indicated substantial favourability towards AI in healthcare (7.87) and in AI applied to skeletal radiography (7.75). There was a preference for a hypothetical system indicating positive findings rather than ruling as negative (7.26 vs 6.20).ConclusionsThis study identifies clear support, amongst a cross section of student and qualified doctors, for both the general use of AI technology in healthcare and in its application to skeletal radiography for trauma. The development of systems to address this demand appear well founded and popular. The engagement of a small but reticent minority should be sought, along with improving the wider education of doctors on AI.

A Novel De Novo Frameshift Pathogenic Variant in the FAM111B Resulting in Progressive Osseous Heteroplasia Phenotype.

Progressive osseous heteroplasia (POH) is a rare, debilitating disorder characterized by heterotopic ossification in the skin and muscles, resulting in contractures of the joints and progressive loss of function. While 60-70% of the POH patients have paternally inherited, inactivating pathogenic variants in GNAS, the remaining 30-40% have no known etiology. FAM111B pathogenic variants, located on chromosome 11q12.1, cause POIKTMP (hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis), a very rare, autosomal-dominant disorder with high frequency of de novo missense pathogenic variants, which affects multiple tissues and organs, causing extensive fibrosis and muscle adiposis, though the exact mechanism is unknown. To our knowledge, there are no reports of FAM111B associated with POH. We describe the first case of POH phenotype associated with a novel de novo frameshift pathogenic variant in the FAM111B and present an analysis of the protein structure and function caused by this genomic disruption. A 15-year-old African-American male presented with generalized calcific nodules, progressive contractures, and muscle weakness leading to immobility, beginning at 6years of age. Cutaneous examination showed generalized hard nodules varying from small to plaque-like ulcerated erupted skin lesions. Biochemical evaluation revealed 25(OH) vitamin D insufficiency (20ng/mL), and normal levels of parathyroid hormone, FGF-23, alkaline phosphatase, calcium, and phosphorus. Skeletal survey radiographs and computed tomography (CT) of the chest, abdomen, and pelvis showed extensive soft tissue and muscle heterotopic ossifications involving shoulders, axillae, trunk, abdomen, pelvis, upper and lower extremities, in a clumped, conglomerate distribution within muscle, subcutaneous fat, and in some areas extending to the skin. There was no pulmonary fibrosis on the chest CT. The clinical and radiographic findings were most consistent with POH. A trio-clinical exome sequencing revealed a de novo heterozygous likely pathogenic variant in the FAM111B (OMIM # 615584) (c.1462delT [p.Cys488Valfs*21]). The resulted frameshift change in exon 4 replaced C-terminal region with 21 alternative amino acids. Multiple, previously reported disease-associated variants appear to localize within the trypsin-like cysteine/serine peptidase domain in which this variant occurs, supporting the functional significance of this region, though none have been previously reported to be associated with POH phenotype. Our 3D protein modeling showed obliteration of predicted protein folding and structure, and elimination of the zinc-binding domain, likely severely affecting protein function. This is the first case of POH phenotype associated with a novel de novo pathogenic frameshift variant in FAM111B. Whether the frameshift change in FAM111B predicts POH remains unclear. Further evaluations are necessary to fully elucidate this finding and the potential role and mechanism by which the FAM111B variants contributes to POH phenotype.