Skeletal Imaging Research Articles

Dental and Skeletal Imaging in Forensic Age Estimation: Disparities in Current Approaches and the Continuing Search for Optimization.

Medical imaging for forensic age estimation in living adolescents and young adults continues to be controversial and a subject of discussion. Because age estimation based on medical imaging is well studied, it is the current gold standard. However, large disparities exist between the centers conducting age estimation, both between and within countries. This review provides an overview of the most common approaches applied in Europe, with case examples illustrating the differences in imaging modalities, in staging of development, and in statistical processing of the age data. Additionally, the review looks toward the future because several European research groups have intensified studies on age estimation, exploring four strategies for optimization: (1) increasing sample sizes of the reference populations, (2) combining single-site information into multifactorial information, (3) avoiding ionizing radiation, and (4) conducting a fully automated analysis.

Quantitative Skeletal Muscle Imaging Using 3D MR Fingerprinting With Water and Fat Separation.

Quantitative muscle MRI is a robust tool to monitor intramuscular fatty replacement and disease activity in patients with neuromuscular disorders (NMDs). To implement a 3D sequence for quantifying simultaneously fat fraction (FF) and water T1 (T1,H2O ) in the skeletal muscle, evaluate regular undersampling in the partition-encoding direction, and compare it to a recently proposed 2D MR fingerprinting sequence with water and fat separation (MRF T1 -FF). Prospective. Seventeen-vial phantom at different FF and T1,H2O , 11 healthy volunteers, and 6 subjects with different NMDs. 3T/3D MRF T1 -FF, 2D MRF T1 -FF, STEAM MRS ASSESSMENT: FF and T1,H2O measured with the 2D and 3D sequences were compared in the phantom and in vivo at different undersampling factors (US). Data were acquired in healthy subjects before and after plantar dorsiflexions and at rest in patients. Linear correlations, Bland-Altman analysis, two-way repeated measures analysis of variance (ANOVA), Student's t-test. Up to a US factor of 3, the undersampled acquisitions were in good agreement with the fully sampled sequence (R2 ≥ 0.98, T1,H2O bias ≤10 msec, FF bias ≤4 × 10-4 ) both in phantom and in vivo. The 2D and 3D MRF T1 -FF sequences provided comparable T1,H2O and FF values (R2 ≥ 0.95, absolute T1,H2O bias ≤35 msec, and absolute FF bias ≤0.003). The plantar dorsiflexion induced a significant increase of T1,H2O in the tibialis anterior and extensor digitorum (relative increase of +10.8 ± 1.7% and + 7.7 ± 1.4%, respectively, P < 0.05), that was accompanied by a significant reduction of FF in the tibialis anterior (relative decrease of -16.3 ± 4.0%, P < 0.05). Some subjects with NMDs presented increased and heterogeneous T1,H2O and FF values throughout the leg. Quantitative 3D T1,H2O and FF maps covering the entire leg were obtained within acquisition times compatible with clinical research (4 minutes 20 seconds) and a 1 × 1 × 5 mm3 spatial resolution. 2 TECHNICAL EFFICACY: Stage 2.

SMA: REGISTRIES, BIOMARKERS & OUTCOME MEASURES: P.177 Efficacy evaluation of Nusinersen for spinal muscular atrophy type I and type II using bioelectrical impedance (BIA)

Nusinersen has gained acceptance as a treatment for spinal muscular atrophy (SMA) since its introduction in 2017. We routinely evaluated Nusinersen efficacy employing the motor function rating scale, CHOP-INTEND (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders), and skeletal muscle imaging. In this study, we also used bioelectrical impedance analysis (BIA) to evaluate the efficacy of Nusinersen. The subjects were three type I and three type II SMA patients who had been treated with Nusinersen.

Differential photon waves imaging

AbstractImaging philosophy was simulated for well‐known biomedical diffuse optical imaging (DOI) methodology. It runs based on the differential photon waves. The underlying philosophy of imaging methodology takes its origin from the distance of the same molecule types. Inherently, each type of biological molecules has different molecular structure, size, and binding distance. Molecules might be water, oxy‐hemoglobin, deoxyhemoglobin, ATP, pepsin, cholesterol, protein, fats or lipids, hydroxyapatite, carbohydrates, glucose, glycogen, DNA, etc. These molecules need to be grouped for biomedical photon imaging purposes such as in hair, skull, scalp, cortex, dermis, epidermis, cerebrospinal fluid, cerebellar gray and white matter for neuroimaging; or skin, fat, water for breast imaging; optic nerve, humor aqueous for eye imaging; bones and joints for skeletal system imaging; liver, muscle, fibroadenoma breast, mucous tissue, nodule, bowel, heart, kidneys, lung, stomach, whole blood vascular system for inner organs. Among these different types of molecular structures, each type has different characteristic photon absorption and scattering coefficients for corresponding wavelength. Researchers have been using these characteristic wavelengths to reconstruct the images. They have focused on either absorption or scattering maximums of specific wavelengths for each tissue type. This is right when the molecules are investigated first, but it is a dead‐end when it goes deep tissue, since low‐power laser photons scatter randomly when they penetrate inside the tissue, immediately. Novel approach uses phase‐shifted group photon waves corresponding to the molecular distances. Single photon wavelength can be used to investigate the molecules inside the imaging media.

A Clinically Driven Task-Based Comparison of Photon Counting and Conventional Energy Integrating CT for Soft Tissue, Vascular, and High-Resolution Tasks.

Photon-counting CT detectors are the next step in advancing CT system development and will replace the current energy integrating detectors (EID) in CT systems in the near future. In this context, the performance of PCCT was compared to EID CT for three clinically relevant tasks: abdominal soft tissue imaging, where differentiating low contrast features is important; vascular imaging, where iodine detectability is critical; and, high-resolution skeletal and lung imaging. A multi-tiered phantom was imaged on an investigational clinical PCCT system (Siemens Healthineers) across different doses using three imaging modes: macro and ultra-high resolution (UHR) PCCT modes and EID CT. Images were reconstructed using filtered backprojection and soft tissue (B30f), vascular (B46f), or high-resolution (B70f; U70f for UHR) kernels. Noise power spectra, task transfer functions, and detectability index were evaluated. For a soft tissue task, PCCT modes showed comparable noise and resolution with improved contrast-to-noise ratio. For a vascular task, PCCT modes showed lower noise and improved iodine detectability. For a high resolution task, macro mode showed lower noise and comparable resolution while UHR mode showed higher noise but improved spatial resolution for both air and bone. PCCT offers competitive advantages to EID CT for clinical tasks.

CORR Insights®: Is Skeletal Imaging Essential in the Staging Workup for Conventional Chondrosarcoma?

CORR Insights®: Is Skeletal Imaging Essential in the Staging Workup for Conventional Chondrosarcoma?

Is there a utility of adding skeletal imaging to 68-Ga-prostate-specific membrane antigen-PET/computed tomography in initial staging of patients with high-risk prostate cancer?

Both bone-scan and cross-sectional imaging are indicated in the staging of high-risk prostate cancer (PCa). However, 68Ga-prostate-specific membrane antigen (PSMA)-PET/computed tomography (CT) has proven to be an excellent tracer for detection of skeletal metastases. The aim of this study was to assess if adding skeletal imaging (with 18F-Fluoride-PET/CT) to 68-Ga-PSMA-PET/CT had any impact on high-risk PCa staging. Fifty treatment-naive, histopathologically proven, high-risk (European Association of Urology) PCa patients underwent both 68-Ga-PSMA-PET/CT and 18F-Fluoride-PET/CT for staging. Fluoride-PET/CT detected significantly a higher number of skeletal metastases/patient than PSMA-PET/CT (median 4.5/patient vs 3.0; Wilcoxan-signed-rank-test, P = 0.060) and there was a significantly higher proportion of only Fluoride-avid than only PSMA-avid lesions (McNemar-test P < 0.001). No significant advantage was seen in patient-wise metrics. Most lesions missed by PSMA-PET/CT were in flat bones (25/33). serum prostate specific antigen (S.PSA) showed positive correlation with both, the number of lesions [r(PSMA)-0.555 (P = 0.006) and r(Fluoride)-0.622 (P = 0.001)] as well as tumor to background ratio (TBR) [[r-0.706 (P < 0.001) and 0.516 (P = 0.010)]. Median TBR was significantly higher in PSMA-PET/CT (22.77 vs 16.30; P < 0.001). All three patients with only Fluoride-avid lesions (also not identified in bone-scan) showed biochemical response with additional therapy. Though, Fluoride-PET/CT detected a higher absolute number of lesions than PSMA-PET/CT, no significant advantage was seen in patient-wise metrics. Fluoride-PET/CT added second-line management in only 3/50 patients, which could have been reduced to 1/50, with more sensitive evaluation of flat bones in PSMA-PET-CT. Therefore, additional skeletal imaging is not needed with 68-Ga-PSMA-PET/CT in initial staging of high-risk PCa.

Skeletal muscular relaxation time from postmortem MR imaging of adult humans

Abstract Purpose To measure T1, and T2 values of the skeletal muscle by postmortem magnetic resonance (PMMR) imaging in adult humans at 1.5 T, and to compare them with those of living human subjects. Materials and methods We performed skeletal muscular PMMR imaging on 45 deceased adults (31 men, 14 women; mean age, 55.6 years). We measured T1 and T2 values of the right and left erector spinae muscles. The PMMR imaging data were compared with those from the corresponding sites in 13 healthy subjects. The association among rectal temperature, age and sex in T1 and T2 values was assessed by multiple regression analysis. Results By skeletal muscular PMMR imaging (clinical MR imaging), the average T1 values were: right:745 ± 107 ms (820 ± 108 ms); left:930 ± 133 ms (1022 ± 116 ms), and the average T2 values were: right:62± 9 ms (43± 5 ms); left:59 ± 7 ms (42 ± 5 ms). The left-right T1 difference was due to B1 inhomogeneity. Compared with clinical skeletal muscular MR imaging, PMMR imaging demonstrated significantly shorter T1 values and longer T2 values. On PMMR imaging, T1 values were significantly influenced by rectal temperature, whereas T2 values were significantly influenced by age and sex, but not by rectal temperature. Conclusion In the skeletal muscle, PMMR imaging shows shorter T1 values and longer T2 values than clinical MR imaging. T1 values decrease with lower rectal temperature and T2 values increase with female and elder age.

Neurogenic calf amyotrophy with CK elevation by entrapment radiculopathy; clinical, radiological, and pathological analyses of 18 cases.

To characterize the clinical, radiological, and pathological manifestations of 18 cases showing neurogenic calf amyotrophy with creatine kinase (CK) elevation by entrapment radiculopathy (NCACKEER). We retrospectively reviewed and evaluated the medical records of patients who complained of weakness or atrophy of the calf muscles in our department between 2004 and 2019. We identified 18 cases fulfilling the proposed criteria of NCACKEER. We extracted neurological, laboratory, neurophysiological, and neuroradiological data from all cases. Moreover, we evaluated biopsy specimens from the gastrocnemius in four cases. Eighteen NCACKEER cases exhibited the characteristic findings that can discriminate previously known myopathies or polyneuropathies affecting distal legs. We noticed male predominance (72%) with an average age at diagnosis of 65.6years. Muscle weakness or atrophy was localized in the distal legs, with Achilles tendon reflexes absent in all cases. We observed elevated serum CK levels with a range from 237 to 2294IU/L. All electromyography (EMG) studies showed neurogenic changes in the affected muscles. Lumbar spinal MRI exhibited either spinal canal stenosis at various vertebral levels or intervertebral foraminal stenosis at L4/5 and L5/S1 in all cases with significant straightening spinal and sacral alignments. All muscle biopsy specimens showed findings of neurogenic muscular degeneration with no inflammatory infiltrations. Cases with higher CK elevation had more necrotic muscle fibers. We established the clinical characteristics of NCACKEER. Evaluations of serum CK level and skeletal muscle CT imaging are useful for screening, and lumbar spinal MRI, EMG and/or muscle biopsy are necessary for diagnostic confirmation.

Is Skeletal Imaging Essential in the Staging Workup for Conventional Chondrosarcoma?

Staging of a bone sarcoma before initiating treatment helps orthopaedic oncologists determine the intent of treatment and predicting the prognosis. As per National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines, there are no exclusive recommendations for chondrosarcoma staging. They are staged similar to other bone sarcomas even though skeletal metastases are extremely rare in chondrosarcomas. We asked: (1) What proportion of patients with a chondrosarcoma present with detectable only skeletal metastasis? (2) What proportion of patients with chondrosarcoma present with skeletal metastasis with or without concurrent pulmonary metastases? Between January 2006 to December 2017, 480 patients with histology-proven chondrosarcomas of the extremity, including clavicle, scapula, spine, and pelvis, presented to our institute. Fifty-three patients were excluded due to incomplete details about their staging. The remaining 427 were retrospectively analyzed and included in this study. Their clinical, radiological, and histopathological details were retrieved from patient files and electronic medical records. Of the 427 patients included, 53 had Grade 1 chondrosarcoma, 330 had Grade 2 chondrosarcoma, and 41 had Grade 3 chondrosarcoma. Grade was not available in three patients. All patients were staged with a thoracic CT scan and bone scan or a whole body fluorodeoxyglucose positron-emission tomography/CT (FDG PET/CT). Patients with a suspected or documented metastasis were reviewed again by an experienced radiologist and a nuclear medicine expert for the purpose of this study. A total of 8% (35 of 427) of patients with chondrosarcoma had isolated lung metastases at the time of initial staging. These included 9% (31 of 330) of patients with Grade 2 chondrosarcomas and 10% (4 of 41) of patients with Grade 3 chondrosarcomas. No patient with a Grade 1 chondrosarcoma had detectable lung metastases. The primary study endpoint was the number of patients who had a diagnosis of skeletal or skeletal and lung metastases as identified by the staging modalities. Three patients with Grade 2 chondrosarcoma had only skeletal metastasis. No patients with Grade 1 or Grade 3 chondrosarcoma had detectable bone metastases. Combined lung and bone metastases were seen in only two patients with Grade 2 chondrosarcoma. Our study found that the incidence of bony metastasis in conventional chondrosarcomas is extremely low. Considering the present results, we believe skeletal scanning may be overused in current staging algorithms. We do not have survival outcomes to know if detecting these few patients with skeletal lesions at initial presentation would be important in the absence of symptoms, but our data suggest that omitting skeletal imaging from the staging work-up of conventional chondrosarcomas should be considered. It may be reserved for patients with documented pulmonary metastases. Level IV, diagnostic study.

Usefulness of magnetic resonance enterography in detecting signs of sacroiliitis in young patients with inflammatory bowel disease

BackgroundArthritis is often an underestimated extraintestinal manifestation in pediatric inflammatory bowel disease (IBD), including sacroiliitis, whose early signs are well detectable at magnetic resonance imaging (MRI). Magnetic resonance enterography (MRE) is an accurate imaging modality for pediatric IBD assessment.We studied the possibility to detect signs of sacroiliac inflammation in a group of children with IBD who underwent MRE for gastrointestinal disease evaluation.MethodsWe retrospectively reviewed MRE scans performed in pediatric patients with IBD. We looked for signs of sacroiliitis taking the ASAS (Assessment of SpondyloArthritis international Society) criteria as a model. Presence of bone marrow edema (using T2W sequences with fat suppression), diffusion restriction in Diffusion Weighted Imaging (DWI) or Diffusion Weighted Imaging with Background Suppression (DWIBS), and dynamic contrast enhancement were evaluated. Each SI joint was divided into 4 quadrants: upper iliac, lower iliac, upper sacral, and lower sacral. Two blinded observers with experience in pediatric and skeletal imaging independently evaluated the images. Cases upon which there was a disagreement were evaluated by the two reviewing radiologists and a third radiologist with similar experience together.ResultsWe enrolled 34 patients (24 males and 10 females, with mean age at scanning 14.3 years, median 15.3 years; 2 affected by ulcerative colitis, 32 by Crohn’s disease) for a total of 59 examinations performed at the time of their first diagnosis or at symptom exacerbations. No patient complained of musculoskeletal symptoms, neither had pathological findings at articular examination. At the time of MRE 25 patients were under treatment for their IBD. Five patients had radiological signs of SI inflammation at MRE, albeit of mild degree. All patients with SI joint edema also had a restricted diffusion in DWIBS or DWI and almost everyone had contrast media uptake.ConclusionsSacroiliitis is one of the extraintestinal manifestation associated with IBD; it is often asymptomatic and clinically underdetected, with an unrelated progression with respect to the underlying IBD. MRE offers the possibility to study SI joints in young patients with IBD who undergo MRE for the investigation of their intestinal condition. Furthermore, we observed that gadolinium enhancement does not improve diagnostic specificity in sacroiliiitis detection.

A valuable modality: skeletal scintigraphy imaging

Laura Quiney, IMV Imaging, discusses the pros and cons of this established diagnostic tool

Genetics of Skeletal Disorders.

Bone and mineral diseases encompass a variety of conditions that involve altered skeletal homeostasis and are frequently associated with changes in circulating calcium, phosphate, or vitamin D metabolites. These disorders often have a genetic etiology and comprise monogenic disorders caused by a single-gene mutation, which may be germline or somatic, or an oligogenic or polygenic condition involving multiple genetic variants. Single-gene mutations causing Mendelian diseases are usually highly penetrant, whereas the gene variants contributing to oligogenic or polygenic disorders are each associated with smaller effects with additional contributions from environmental factors. The detection of monogenic disorders is clinically important and facilitates timely assessment and management of the patient and their affected relatives. The diagnosis of monogenic metabolic bone disorders requires detailed clinical assessment of the wide variety of symptoms and signs associated with these diseases. Thus, clinicians should undertake a systematic approach commencing with careful history taking and physical examination, followed by appropriate laboratory and skeletal imaging investigations. Finally, clinicians should be familiar with the range of molecular genetic tests available to ensure their appropriate use and interpretation. These considerations are reviewed in this chapter.

Multi-factorial age estimation: A Bayesian approach combining dental and skeletal magnetic resonance imaging

PurposeTo study age estimation performance of combined magnetic resonance imaging (MRI) data of all four third molars, the left wrist and both clavicles in a reference population of females and males. To study the value of adding anthropometric and sexual maturation data. Materials and methodsThree Tesla MRI of the three anatomical sites was prospectively conducted from March 2012 to May 2017 in 14- to 26-year-old healthy Caucasian volunteers (160 females, 138 males). Development was assessed by allocating stages, anthropometric measurements were taken, and self-reported sexual maturation data were collected. All data was incorporated in a continuation-ratio model to estimate age, applying Bayes’ rule to calculate point and interval predictions. Two performance aspects were studied: (1) accuracy and uncertainty of the point prediction, and (2) diagnostic ability to discern minors from adults (≥18 years). ResultsCombining information from different anatomical sites decreased the mean absolute error (MAE) compared to incorporating only one site (P<0.0001). By contrast, adding anthropometric and sexual maturation data did not further improve MAE (P=0.11). In females, combining all three anatomical sites rendered a MAE equal to 1.41 years, a mean width of the 95% prediction intervals of 5.91 years, 93% correctly classified adults and 91% correctly classified minors. In males, the corresponding results were 1.36 years, 5.49 years, 94%, and 90%, respectively. ConclusionAll aspects of age estimation improve when multi-factorial MRI data of the three anatomical sites are incorporated. Anthropometric and sexual maturation data do not seem to add relevant information.

SCN4A p.R675Q Mutation Leading to Normokalemic Periodic Paralysis: A Family Report and Literature Review

Objective: To investigate the clinical features, skeletal muscle imaging, and muscle pathological characteristics of normokalemic periodic paralysis (NormoKPP) caused by mutation of SCN4A gene p.R675Q.Methods: The clinical data, skeletal muscle imaging, pathological data, and gene test results of a family with NormoKPP were collected in detail in October 2018. The previous literature was reviewed and used for comparative analysis.Results: The proband was a 28-year-old male with paroxysmal weakness of both lower limbs for 14 years. Limb weakness was mainly manifested in the proximal extremities of both lower limbs, which occurred two to three times a year. The muscle weakness of each attack lasted for 1–2 weeks and gradually recovered. The blood potassium levels were normal. The abnormal signals of the posterior thigh muscle group and the medial calf muscle group could be seen on the magnetic resonance imaging (MRI) of the skeletal muscle, and the target-fiber could be seen in some muscle fibers in muscle pathology. The father of the proband and his brother had the same symptoms. In the same family, 10 people received genetic testing. The results showed that five had a mutation of SCN4A gene p.R675Q. The mutation gene came from the father of the proband.Conclusion: NormoKPP is a clinically rare form of sodium ion channel disease. The clinical manifestations, skeletal muscle imaging, and pathological changes are different from the common hypokalemic periodic paralysis. SCN4A gene detection is an important means for the diagnosis of NormoKPP.

Improvement of image quality applying iterative scatter correction for grid-less skeletal radiography in trauma room setting.

Iterative reconstruction is well established for CT. Plain radiography also takes advantage of iterative algorithms to reduce scatter radiation and improve image quality. First applications have been described for bedside chest X-ray. A recent experimental approach also provided proof of principle for skeletal imaging. To examine clinical applicability of iterative scatter correction for skeletal imaging in the trauma setting. In this retrospective single-center study, 209 grid-less radiographs were routinely acquired in the trauma room for 12 months, with imaging of the chest (n = 31), knee (n = 111), pelvis (n = 14), shoulder (n = 24), and other regions close to the trunk (n = 29). Radiographs were postprocessed with iterative scatter correction, doubling the number of images. The radiographs were then independently evaluated by three radiologists and three surgeons. A five-step rating scale and visual grading characteristics analysis were used. The area under the VGC curve (AUCVGC) quantified differences in image quality. Images with iterative scatter correction were generally rated significantly better (AUCVGC = 0.59, P < 0.01). This included both radiologists (AUCVGC = 0.61, P < 0.01) and surgeons (AUCVGC = 0.56, P < 0.01). The image-improving effect was significant for all body regions; in detail: chest (AUCVGC = 0.64, P < 0.01), knee (AUCVGC = 0.61, P < 0.01), pelvis (AUCVGC = 0.60, P = 0.01), shoulder (AUCVGC = 0.59, P = 0.02), and others close to the trunk (AUCVGC = 0.59, P < 0.01). Iterative scatter correction improves the image quality of grid-less skeletal radiography in the clinical setting for a wide range of body regions. Therefore, iterative scatter correction may be the future method of choice for free exposure imaging when an anti-scatter grid is omitted due to high risk of tube-detector misalignment.

Radiation dosimetry considerations for skeletal survey imaging of multiple myeloma

PurposeThis paper aims to review the dosimetry and utility of currently implemented imaging modalities for assessment of multiple myeloma and consider the role of tin filtration computed tomography (CT) as a potential replacement to current standard practice. MethodsRadiation output of tin CT was measured experimentally and used for software-based dose calculation. Resultant effective dose was then compared to calculated planar radiography doses and published doses of other imaging modalities. ResultsBased on example patient parameters used for modalities and 14 projection planar radiography site protocols, doses are comparable between planar radiography and tin filtration CT (approximately 0.9 and 1.0 mSv respectively). Both studies carried a reduced radiation burden compared to Expected Pathologically Increased Contrast-CT (EPIC-CT), FDG-PET and MIBI SPECT/CT (5.7, 11.1–20.0 and 13.0 mSv respectively). ConclusionTin filtered CT provided visualisation of multiple myeloma at doses comparable to planar radiography and where available may be a suitable alternative, following due consideration of patient specific justification and optimisation in line with best practice.

Facial Gender Affirmation Surgery: Craniomaxillofacial Imaging.

Facial procedures directed at gender affirmation are uniquely tailored to the individual patient and may affect soft tissue and skeletal structures over the entire face-from the chin through the upper forehead. Complete photographic and radiographic documentation that addresses these areas is important from the perspectives of surgical planning, evaluation of outcomes, research purposes, and communication between patient and provider, and amongst treating professionals. This work outlines pertinent skeletal anatomy that is uniquely addressed in gender affirmation procedures and means by which it can be effectively imaged. It provides historical insight into the evolution of computerized-tomography-based imaging. The authors provide detailed protocols for photodocumentation and computerized-tomography based skeletal imaging at their center.

RINT1 Bi-allelic Variations Cause Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities

Pediatric acute liver failure (ALF) is life threatening with genetic, immunologic, and environmental etiologies. Approximately half of all cases remain unexplained. Recurrent ALF (RALF) in infants describes repeated episodes of severe liver injury with recovery of hepatic function between crises. We describe bi-allelic RINT1 alterations as the cause of a multisystem disorder including RALF and skeletal abnormalities. Three unrelated individuals with RALF onset ≤3 years of age have splice alterations at the same position (c.1333+1G>A or G>T) in trans with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del) in RINT1. ALF episodes are concomitant with fever/infection and not all individuals have complete normalization of liver function testing between episodes. Liver biopsies revealed nonspecific liver damage including fibrosis, steatosis, or mild increases in Kupffer cells. Skeletal imaging revealed abnormalities affecting the vertebrae and pelvis. Dermal fibroblasts showed splice-variant mediated skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay. Fibroblasts also revealed decreased RINT1 protein, abnormal Golgi morphology, and impaired autophagic flux compared to control. RINT1 interacts with NBAS, recently implicated in RALF, and UVRAG, to facilitate Golgi-to-ER retrograde vesicle transport. During nutrient depletion or infection, Golgi-to-ER transport is suppressed and autophagy is promoted through UVRAG regulation by mTOR. Aberrant autophagy has been associated with the development of similar skeletal abnormalities and also with liver disease, suggesting that disruption of these RINT1 functions may explain the liver and skeletal findings. Clarifying the pathomechanism underlying this gene-disease relationship may inform therapeutic opportunities.

The Impact of Childhood Obesity on Skeletal Health and Development.

Increased risk of fracture identified in obese children has led to a focus on the relationship between fat, bone, and the impact of obesity during skeletal development. Early studies have suggested that despite increased fracture risk, obese children have a higher bone mass. However, body size corrections applied to account for wide variations in size between children led to the finding that obese children have a lower total body and regional bone mass relative to their body size. Advances in skeletal imaging have shifted the focus from quantity of bone in obese children to evaluating the changes in bone microarchitecture that result in a change in bone quality and strength. The findings suggest that bone strength in the appendicular skeleton does not appropriately adapt to an increase in body size which results in a mismatch between bone strength and force from falls. Recent evidence points to differing influences of fat compartments on skeletal development—visceral fat may have a negative impact on bone which may be related to the associated adverse metabolic environment, while marrow adipose tissue may have an independent effect on trabecular bone development in obese children. The role of brown fat has received recent attention, demonstrating differences in the influence on bone mass between white and brown adipose tissues. Obesity results in a shift in growth and pubertal hormones as well as influences bone development through the altered release of adipokines. The change in the hormonal milieu provides an important insight into the skeletal changes observed in childhood obesity.