An update on clinical presentation and responses to therapy of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH).

Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics and Genomics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.

Subject-specific finite element head models for skull fracture evaluation-a new tool in forensic pathology.

Post-mortem computed tomography (PMCT) enables the creation of subject-specific 3D head models suitable for quantitative analysis such as finite element analysis (FEA). FEA of proposed traumatic events is an objective and repeatable numerical method for assessing whether an event could cause a skull fracture such as seen at autopsy. FEA of blunt force skull fracture in adults with subject-specific 3D models in forensic pathology remains uninvestigated. This study aimed to assess the feasibility of FEA for skull fracture analysis in routine forensic pathology. Five cases with blunt force skull fracture and sufficient information on the kinematics of the traumatic event to enable numerical reconstruction were chosen. Subject-specific finite element (FE) head models were constructed by mesh morphing based on PMCT 3D models and A Detailed and Personalizable Head Model with Axons for Injury Prediction (ADAPT) FE model. Morphing was successful in maintaining subject-specific 3D geometry and quality of the FE mesh in all cases. In three cases, the simulated fracture patterns were comparable in location and pattern to the fractures seen at autopsy/PMCT. In one case, the simulated fracture was in the parietal bone whereas the fracture seen at autopsy/PMCT was in the occipital bone. In another case, the simulated fracture was a spider-web fracture in the frontal bone, whereas a much smaller fracture was seen at autopsy/PMCT; however, the fracture in the early time steps of the simulation was comparable to autopsy/PMCT. FEA might be feasible in forensic pathology in cases with a single blunt force impact and well-described event circumstances.

3D printed skulls in court - a benefit to stakeholders?

Forensic pathologists may use 3D prints as demonstrative aids when providing expert testimony in court of law, but the effects remain unclear despite many assumed benefits. In this qualitative study, the effects of using a 3D print, demonstrating a blunt force skull fracture, in court were explored by thematic analysis of interviews with judges, prosecutors, defence counsels, and forensic pathologists with the aim of improving the expert testimony. Five semi-structured focus groups and eight one-to-one interviews with a total of 29 stakeholders were transcribed ad verbatim and analysed using thematic analysis. The study found that a highly accurate 3D print of a skull demonstrated autopsy findings in detail and provided a quick overview, but sense of touch was of little benefit as the 3D print had different material characteristics than the human skull. Virtual 3D models were expected to provide all the benefits of 3D prints, be less emotionally confronting, and be logistically feasible. Both 3D prints and virtual 3D models were expected to be less emotionally confronting than autopsy photos. Regardless of fidelity, an expert witness was necessary to translate technical language and explain autopsy findings, and low-fidelity models may be equally suited as demonstrative aids. The court infrequently challenged the expert witnesses' conclusions and, therefore, rarely had a need for viewing autopsy findings in detail, therefore rarely needing a 3D print.

The intracranial pressure-volume relationship following decompressive hinge craniotomy compared to decompressive craniectomy-a human cadaver study.

OBJECTIVE: Decompressive hinge craniotomy (DHC) is an alternative treatment option to decompressive craniectomy (DC) for elevated intracranial pressure (ICP). The aim of this study was to characterize the difference in pressure-volume relationship between DHC and DC. METHODS: We compared the intracranial pressure-volume relationship in a human cadaver model following either DHC, DC, or fixing of the bone plate by titanium clamps. We inserted an intracranial expandable device in two human cadaver specimens, performed either DHC, DC, or bone plate fixation, and gradually increased the intracranial volume while measuring ICP. Following DHC, we also performed CT-scans at pre-defined intervals. RESULTS: Before ICP exceeded a threshold of 20 mmHg, a fixed bone plate tolerated an increase of 130 ml of intracranial volume, while DHC and DC allowed an increase of 190 ml and 290 ml, respectively. CT-derived calculations following DHC determined that the increase in intracranial volume at ICP 22 mmHg was 65 ml, the maximal increase of intracranial volume was 84 ml, the maximal bone displacement was 21 mm, and the bone plate volume to be 82 ml. Manual stress test of the hinged bone plate did not allow misalignment or intracranial displacement of the bone plate. CONCLUSION: DHC increases the intracranial volume by up to 84 ml and allows for approximately 60 ml increase of intracranial volume before ICP exceeds 20 mmHg. This indicates, when comparing with results from previous studies of herniation volumes, that DHC will be sufficient in many patients with head injury or cerebral infarction with treatment refractory intracranial hypertension.

Sensitivity and specificity of post-mortem computed tomography in skull fracture detection-a systematic review and meta-analysis.

Post-mortem computed tomography (PMCT) has been increasingly used as routine examination in forensic pathology. No recent review of the growing number of papers on the ability of PMCT to detect skull fracture exists, and original papers report sensitivities from 0.85 to 1.00. This systematic review (PROSPERO: CRD42021233264) aims to provide a meta-analysis of sensitivity and specificity of PMCT in skull fracture detection. We searched PubMed, MEDLINE and Embase for papers published between January 2000 and August 2021 reporting raw numbers, sensitivity and specificity or Abbreviated Injury Score for PMCT compared to autopsy. Papers without both PMCT and autopsy, no separate reporting of the neuro-cranium, exclusively on children, sharp trauma, gunshot or natural death as well as case reports and reviews were excluded. Two authors independently performed inclusion, bias assessment and data extraction. QUADAS-2 was used for bias assessment and a random effects models used for meta-analysis. From 4.284 hits, 18 studies were eligible and 13 included in the meta-analysis for a total of 1538 cases. All deceased were scanned on multi-slice scanners with comparable parameters. Images were evaluated by radiologists or pathologists. Intra- and inter-observer analyses were rarely reported. In summary, sensitivity of PMCT for detection of fractures in the skull base was 0.87 [0.80; 0.92] with specificity 0.96 [0.90; 0.98], and sensitivity for the vault was 0.89 [0.80; 0.94] with specificity 0.96 [0.91; 0.98]. The mixed samples are a limitation of the review.

Fractures of the neuro-cranium: sensitivity and specificity of post-mortem computed tomography compared with autopsy.

Post-mortem computed tomography (PMCT) is a routine tool in many forensic pathology departments as it is fast and non-destructive and allows less gruesome visualization than photographs, and the images are indefinitely storable. Several studies investigated congruence between PMCT and autopsy for skull fracture but registered only the presence or absence of fracture systems. The objective of this study was to determine location-specific sensitivity and specificity of PMCT for individual fracture lines in blunt force head trauma. Accurate 3D models based on PMCT data with all fracture lines visible are important for future studies on fractures, applying finite element analysis (FEA). We retrospectively sampled adult cases from 2013 to 2019 with skull fracture mentioned in the autopsy report. PMCT was on a Siemens 64-slice scanner and autopsy according to international guidelines. The location and direction of all fracture lines at autopsy and at de novo interpretation of scans were registered and compared. Ninety-nine cases with 4809 individual findings were included. Age ranged from 18 to 100 years. The overall sensitivity was 0.58, and specificity was 0.91. For individual locations, sensitivity ranged from 0.24 to 0.85, and specificity ranged from 0.73 to 1.00. Intra-observer agreement was 0.74, and inter-observer agreement ranged from 0.43 to 0.58. In conclusion, PMCT is suited for detection of fracture systems, but not for detection of all individual fracture lines. Our results differed from the existing literature due to the methodological choices of registering individual fracture lines. Future studies utilising FEA must supplement PMCT with autopsy data.

Investigation of Structural Alterations in Inherited Retinal Diseases: A Quantitative SD-OCT-Analysis of Retinal Layer Thicknesses in Light of Underlying Genetic Mutations.

Inherited retinal diseases can result from various genetic defects and are one of the leading causes for blindness in the working-age population. The present study aims to provide a comprehensive description of changes in retinal structure associated with phenotypic disease entities and underlying genetic mutations. Full macular spectral domain optical coherence tomography scans were obtained and manually segmented in 16 patients with retinitis pigmentosa, 7 patients with cone−rod dystrophy, and 7 patients with Stargardt disease, as well as 23 age- and sex-matched controls without retinal disease, to assess retinal layer thicknesses. As indicated by generalized least squares models, all IRDs were associated with retinal thinning (p < 0.001), especially of the outer nuclear layer (ONL, p < 0.001). Except for the retinal nerve fiber layer, such thinning was associated with a reduced visual acuity (p < 0.001). These advances in our understanding of ultrastructural retinal changes are important for the development of gene-, cell-, and optogenetic therapy. Longitudinal studies are warranted to describe the temporal component of those changes.

Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI).

PURPOSE: Generalized arterial calcification of infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion. METHODS: We performed deep phenotyping of 20 GACI survivors. RESULTS: Sixteen of 20 subjects presented with arterial calcifications, but only 5 had residual involvement at the time of evaluation. Individuals with ENPP1 deficiency either had hypophosphatemic rickets or were predicted to develop it by 14 years of age; 14/16 had elevated intact FGF23 levels (iFGF23). Blood phosphate levels correlated inversely with iFGF23. For ENPP1-deficient individuals, the lifetime risk of cervical spine fusion was 25%, that of hearing loss was 75%, and the main morbidity in adults was related to enthesis calcification. Four ENPP1-deficient individuals manifested classic skin or retinal findings of PXE. We estimated the minimal incidence of ENPP1 deficiency at ~1 in 200,000 pregnancies. CONCLUSION: GACI appears to be more common than previously thought, with an expanding spectrum of overlapping phenotypes. The relationships among decreased ENPP1, increased iFGF23, and rickets could inform future therapies.

Selective retina therapy (SRT) in patients with therapy refractory persistent acute central serous chorioretinopathy (CSC): 3 months functional and morphological results.

PURPOSE: Central serous chorioretinopathy (CSC) is a disease presenting with detachment of the neurosensory retina and characteristic focal leakage on fluorescein angiography. The spontaneous remission rate is 84% within 6 months. In this study, the efficacy of selective retina therapy (SRT) was examined in patients with therapy refractory persistent acute CSC defined by symptoms for at least 6 months and persistent subretinal fluid (SRF) despite eplerenone therapy. MATERIAL AND METHODS: This is a prospective, monocentric observational study in 17 eyes (16 patients, mean age 42 years, 2 female). SRT was performed with the approved R:GEN laser (Lutronic, South Korea), a micropulsed 527-nm Nd:YLF laser device, with a train of 30 pulses of 1.7 µs at 100-Hz repetition rate at the point of focal leakage determined by fluorescein angiography (FA) at baseline (BSL). Visits on BSL, week 4 (wk4), and week 12 (wk12) included best corrected visual acuity (BCVA, logMar), central retinal thickness (CRT) on spectral domain optical coherence tomography (SD-OCT), and FA. Statistical analysis was performed by pair-by-pair comparisons of multiple observations in each case with Bonferroni correction for multiple testing. (IBM SPSS Statistics 25®). RESULTS: Mean CRT at BSL was 387.69 ± 110.4 µm. CRT significantly decreased by 106.31 µm in wk4 (95%-KI: 21.42-191.2; p = 0.01), by 133.63 µm in wk12 (95%-KI: 50.22-217.03; p = 0.001) and by 133.81 µm (95%-KI: 48.88-218.75; p = 0.001) compared to BSL. Treatment success defined as complete resolution of SRF occurred at wk4 in 7/17 eyes (35.3%) and at wk12 in 10/17 eyes (58.8%). Re-SRT was performed in 7/17 eyes (41.2%) after an average of 107.14 ± 96.59 days. Treatment success after Re-SRT was observed in 4/6 eyes (66.6%, 12 weeks after Re-SRT). Mean BCVA did not change significantly from BSL to any later timepoint after adjusting for multiple testing. Notably, eyes with treatment success showed better BCVA at all timepoints and gained more letters compared to failures. CONCLUSION: Single or repetitive SRT may be an effective and safe treatment in 2 of 3 patients suffering from acute persistent CSC after 6 months of symptoms or more. We observed complete resolution of SRF in around 60% of eyes 12 weeks after first SRT treatment and also 12 weeks after Re-SRT treatment in eyes with persistent or recurrent SRF. Results on the long-term course after SRT are still pending.

Enlargement of the human adrenal zona fasciculata and chronic psychiatric illness - an autopsy-based study.

Severe mental illness (SMI) is associated with a reduced life expectancy of up to 20 years. One possible contributor to this fact is dysregulation of the hypothalamus-pituitary-adrenal (HPA)-axis. Looking at the morphology of effector organs, such as the adrenal glands themselves, could reveal insights into organ function and response to possible HPA-dysregulation. This forensic autopsy-based study investigated if there were any morphological changes in adrenal glands between decedents who had previously been submitted to a psychiatric hospital with a diagnosis of schizophrenia (n = 34), bipolar (n = 5), or depressive disorder (n = 20), any other psychiatric diagnosis (n = 36) compared with decedents who had no previous psychiatric admission (n = 40). Length of admissions to psychiatric wards and admission in the 180 days preceding death was included in regression as proxy variables for severity of illness. On the macroscopic level, we found no difference in gland weight or volume. On the microscopic level, we found a 25% increase in cross-sectional area of the zona fasciculata (ZF) in decedents who had a diagnosis of schizophrenia compared with controls (p = 0.033). Other diagnosis groups did not differ from controls. Total admission length was positively correlated with area of the ZF.Lay SummaryPeople with a severe mental disorder may be in a constant state of increased stress, which is harmful. This study looked at the adrenal gland, which produces stress hormones, to see if they were different in deceased persons who had suffered from a severe mental illness. We found that the part of the adrenal gland that produces stress hormones is larger in deceased patients who suffered from schizophrenia, but not other types of psychiatric illnesses, compared to deceased persons with no history of psychiatric illness.

Comparison of hippocampal volume measurement by autopsy and post-mortem magnetic resonance imaging.

We present an autopsy-validated, non-invasive, magnetic resonance imaging (MRI) based segmentation algorithm, for determining hippocampal volume. A segmentation algorithm was developed to assess the volume of the hippocampus. Deceased individuals with severe mental illness were used to evaluate the use of MRI imaging to determine hippocampal volume as this group has previously been associated with altered hippocampal volume diagnosed on MRI. The accuracy of the MR- scanning protocol for volume measurement was tested on a water filled phantom control with a known volume of 500 ml, and a difference of 0.08% was found. Thus the scanning protocol was deemed to have produced acceptable results when comparing volume measures of a pair of segmented hippocampi obtained at the 1 T MR scanner and a 3 T MR scanner using the software program Mimics®. The segmentation algorithm was tested by a volume comparison obtained using anterior and posterior landmarks (in situ) and the exact volume of the dissected hippocampus (ex situ). The in situ and ex situ hippocampal volumes were highly correlated; R2 was 96%, with a mean difference of 4-5%. Cases were also examined for intra- and inter-observer agreement. This study presents a validated segmentation algorithm that can be used to determine the hippocampal volume using post-mortem MR and anatomical landmarks.

Coronary artery CT calcium score assessed by direct calcium quantification using atomic absorption spectroscopy and compared to macroscopic and histological assessments.

The Agatston score (AS) is the gold standard CT calcium scoring method in clinical practice. However, the AS is an indirect method of determining calcium amount, whereas atomic absorption spectroscopy (AAS) can directly measure the calcium amount. Our primary aim was to investigate the association between the AS and the coronary calcium amount measured by AAS. Furthermore, we compared our outcome to the macroscopic and histological coronary calcification and stenosis assessment, thus allowing us to infer a clinical coronary artery status based on post-mortem findings. Deceased individuals were examined with a 64-slice multidetector CT scanner, and the AS was determined. At autopsy, the degree of CAC and stenosis was determined, and the coronary arteries were excised and weighed. The coronary arteries were decalcified in a solution that was examined using AAS to measure the calcium amount. The degree of CAC and stenosis was also assessed by a histological examination. One hundred thirty-two coronary arteries were examined, and AS was highly correlated to the coronary calcium amount, measured by AAS, (r2 = 0.72, Pearson 0.85, p < 0.0001). In cases with AS 0, AAS measurements showed zero or very low calcium amounts. AS was also correlated to macroscopic and histological calcification assessments (Spearman's rho 0.68, p < 0.0001, Spearman's rho 0.82, p < 0.0001). Furthermore, an underestimation of subclinical atherosclerosis was seen and AS 0 could not rule out stenosis.

Cardiac left ventricular myocardial tissue density, evaluated by computed tomography and autopsy.

BACKGROUND: Left ventricular mass (LVM) is an independent risk factor for the prediction of cardiac events. Its assessment is a clinically important diagnostic procedure in cardiology and may be performed by Computed Tomography (CT). The aim of this study was to assess the correlation between the cardiac left ventricular shell volume (LVShV) determined by postmortem Computed Tomography (PMCT) and the anatomic LVM obtained at autopsy and to calculate the myocardial tissue density. METHODS: A total of 109 deceased individuals were examined with a 64-slice CT scanner and LVShV was determined. At autopsy, the left ventricle was dissected and weighted. The correlation between LVShV and the anatomic LVM was analysed. Asymmetric left ventricular (LV) hypertrophy was recorded. Inter-observer variability was evaluated, and a density value for myocardial tissue was calculated. RESULTS: The mean age of the deceased was 55 ± 16 years, and 58% was men. We found 30 cases of asymmetric LV hypertrophy. A highly positive correlation existed between LVShV and anatomic LVM (r = 0.857; p < 0.0001), regardless of hypertrophy, asymmetric hypertrophy and gender. The mean difference in the inter-observer variability for LVShV assessment was - 4.4 ml (95% CI: -26.4; 17.6). A linear regression analysis was performed, resulting in a value of 1.265 g/ml for myocardial tissue density. Applying the hitherto used myocardial tissue density of 1.055 g/ml underestimated the anatomic LVM by 18.1% (p < 0.0001). CONCLUSION: PMCT is a helpful tool for the assessment of LVM, and LVShV is highly correlated with LVM as assessed by subsequent autopsy. The correlation between the two was independent of gender, hypertrophy and LV asymmetric hypertrophy. We found a higher myocardial tissue density of 1.265 g/ml compared to previous studies. We show that PMCT combined with autopsy may contribute not only to anatomical but also clinical knowledge.

The accessory magnocellular neurosecretory system of the rostral human hypothalamus.

The morphology and neurophysin expression of the magnocellular accessory neuroendocrine system located in the rostral human hypothalamus is investigated in a series of brains obtained at autopsy. The hypothalami were fixed in formalin and embedded in paraffin, or after cryoprotection, frozen for cryostat sectioning. Paraffin sections were either stained with Luxol Fast blue or immunoreacted for neurophysin I or neurophysin II, the precursor molecule for oxytocin and vasopressin. Further, 50-µm-thick serial cryostat sections were immunoreacted with the same antibodies. Both the paraventricular and supraoptic nuclei as well as the hypothalamo-hypophysial tracts exhibited strong immunoreactivity for the neurophysin antibodies. In addition, large collections of immunoreactive accessory magnocellular nuclei and single scattered neurophysin-positive neurons were located in the preoptic region between the paraventricular and supraoptic nucleus among the hypothalamo-hypophysial nerve fibers. In addition, smaller collections of neurophysin-immunoreactive neurons were located in the basal part of this region. Among the accessory magnocellular nuclei, the classical circular nucleus was identified. Accessory magnocellular neurons were often located along the blood vessels and projections of some of these neurons penetrated the vascular endothelium. The accessory magnocellular cell bodies expressed either neurophysin I or neurophysin II immunoreactivity. Summarizing, the accessory magnocellular system in the human brain is large and differs in morphology compared to the system seen in other vertebrates. The neurons of this system contain both vasopressin and oxytocin. Some neurons of the accessory neuronal systems might secrete vasopressin or oxytocin directly into the blood stream.

The Outcomes of Nonelongating Intramedullary Fixation of the Lower Extremity for Pediatric Osteogenesis Imperfecta Patients: A Meta-analysis.

BACKGROUND: Osteogenesis imperfecta is usually due to autosomal dominant mutations in type I collagen, leading to an increase in fractures and bone deformities, especially in the long bones of the lower extremities. The use of nonelongating intramedullary rods is an established surgical intervention to address such deformities. The rate of surgical complications has been reported to be as high as 187%, with revision rates as high as 90%, although exact global rates are unknown. As such, we sought to determine the published rates of (1) bone-related complications (including both fracture and deformity), (2) rod migration, and (3) complications that require reoperation. METHODS: Following the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines, 1295 studies were evaluated. After cross-referencing, and applying specific inclusion and exclusion criteria, a total of 7 studies were included in the final cohort. Data were extracted from the studies and analyzed. Random effect models determined the complication rates of intramedullary nonelongating rod procedures. RESULTS: A total of 359 primary nonelongating intramedullary rod procedures of tibiae and femurs, in patients with a mean age of 6 years (5.2 to 7.3 y), at a mean follow-up of 63 months (24 to 118 mo), were evaluated. 60% of the surgical procedures were on femurs, and 40% were on tibiae. The reoperation rate was 39.4%. The most common complication was rod migration, with a rate of 25.7%. The rate of bone-related complications was 19.5% including fractures (15.0%) and worsening bone deformity (4.3%). CONCLUSIONS: This is the first meta-analysis to identify the rates of complication and reoperation in lower limb intramedullary fixation for pediatric osteogenesis imperfecta patients. This study has shown that rod migration is the most common complication, followed by bone-related complications including fractures and deformity. Reoperations occur after nearly 40% of all procedures due to rod migration or bone-related complications. LEVEL OF EVIDENCE: Level IV-retrospective meta-analysis.

Epicardial adipose tissue volume estimation by postmortem computed tomography of eviscerated hearts.

Epicardial adipose tissue (EAT) may play a role in the development of coronary artery disease. The purpose of this study was to evaluate a method based on postmortem computed tomography (PMCT) for the estimation of EAT volume. We PMCT-scanned the eviscerated hearts of 144 deceased individuals, who underwent a medicolegal autopsy. Using Mimics® we performed segmentation of the images and obtained the volumes of EAT and myocardium. Total heart volume was calculated by adding the volumes of EAT and myocardium. Total heart weight, including EAT, myocardium and attached vessels, was measured during autopsy. Inter-observer analysis was performed on 30 randomly chosen subjects. We included 132 individuals in the results (age range: 22-94 years; 56% men). Twelve individuals were excluded due to inadequate PMCT scanning. Median EAT volume was 73.0 mL (Interquartile range; IQR: 45.6-113.7 mL) in men and 64.8 mL (IQR: 44.0-98.0 mL) in women, which accounted for 20.4 ± 10.2% and 21.9 ± 9.5% of total heart volume, respectively. This corresponded with former autopsy studies. Total heart volume measured by PMCT was highly correlated with heart weight (R2 = 90%). Mean inter-observer difference of EAT volume was -1.7 mL (95% limits of agreement: -37.0-33.6 mL), with an Intra Class Correlation of 0.91. It was possible to estimate EAT volume using PMCT on eviscerated human hearts. Our method was fast and accurate with good inter-observer agreement. This is a useful method to determine EAT at autopsy, and we will apply this method in future research.

Forensic postmortem computed tomography: volumetric measurement of the heart and liver.

PURPOSE: The purpose of this study was to investigate the utility of postmortem computed tomography (PMCT) images in estimating organ sizes and to examine the use of the cardiothoracic ratio (CTR). METHODS: We included 45 individuals (19 females), who underwent a medico-legal autopsy. Using the computer software program Mimics®, we determined in situ heart and liver volumes derived from linear measurements (width, height and depth) on a whole body PMCT-scan, and compared the volumes with ex vivo volumes derived by CT-scan of the eviscerated heart and liver. The ex vivo volumes were also compared with the organ weights. Further, we compared the CTR with the ex vivo heart volume and a heart weight-ratio (HWR). Intra- and inter-observer analyses were performed. RESULTS: We found no correlation between the in situ and ex vivo volumes of the heart and liver. However, a highly significant correlation was found between the ex vivo volumes and weights of the heart and liver. No correlations between CTR and the ex vivo heart volume nor with HWR was found. Concerning cardiomegaly, we found no agreement between the CTR and HWR. The intra- and inter-observer analyses showed no significant differences. CONCLUSIONS: Noninvasive in situ PMCT methods for organ measuring, as performed in this study, are not useful tools in forensic pathology. The best method to estimate organ volume is a CT-scan of the eviscerated organ. PMCT-determined CTR seems to be useless for ascertaining cardiomegaly, as it neither correlated with the ex vivo heart volume nor with the HWR.

Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature.

Based on the observation of reduced stature in relatives of patients with acromesomelic dysplasia, Maroteaux type (AMDM), caused by homozygous or compound heterozygous mutations in natriuretic peptide receptor-B gene (NPR2), it has been suggested that heterozygous mutations in this gene could be responsible for the growth impairment observed in some cases of idiopathic short stature (ISS). We enrolled 192 unrelated patients with short stature and 192 controls of normal height and identified seven heterozygous NPR2 missense or splice site mutations all in the short stature patients, including one de novo splice site variant. Three of the six inherited variants segregated with short stature in the family. Nine additional rare nonsynonymous NPR2 variants were found in three additional cohorts. Functional studies identified eight loss-of-function mutations in short individuals and one gain-of-function mutation in tall individuals. With these data, we were able to rigorously verify that NPR2 functional haploinsufficiency contributes to short stature. We estimate a prevalence of NPR2 haploinsufficiency of between 0 and 1/26 in people with ISS. We suggest that NPR2 gain of function may be a more common cause of tall stature than previously recognized.

Copy number variation plays an important role in clinical epilepsy.

OBJECTIVE: To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center. METHODS: We identified patients with International Classification of Diseases, ninth revision (ICD-9) codes for epilepsy or seizures and clinical CMA testing performed between October 2006 and February 2011 at Boston Children's Hospital. We reviewed medical records and included patients who met criteria for epilepsy. We phenotypically characterized patients with epilepsy-associated abnormalities on CMA. RESULTS: Of 973 patients who had CMA and ICD-9 codes for epilepsy or seizures, 805 patients satisfied criteria for epilepsy. We observed 437 copy number variants (CNVs) in 323 patients (1-4 per patient), including 185 (42%) deletions and 252 (58%) duplications. Forty (9%) were confirmed de novo, 186 (43%) were inherited, and parental data were unavailable for 211 (48%). Excluding full chromosome trisomies, CNV size ranged from 18kb to 142Mb, and 34% were >500kb. In at least 40 cases (5%), the epilepsy phenotype was explained by a CNV, including 29 patients with epilepsy-associated syndromes and 11 with likely disease-associated CNVs involving epilepsy genes or "hotspots." We observed numerous recurrent CNVs including 10 involving loss or gain of Xp22.31, a region described in patients with and without epilepsy. INTERPRETATION: Copy number abnormalities play an important role in patients with epilepsy. Because the diagnostic yield of CMA for epilepsy patients is similar to the yield in autism spectrum disorders and in prenatal diagnosis, for which published guidelines recommend testing with CMA, we recommend the implementation of CMA in the evaluation of unexplained epilepsy.