Publications by authors named "Christina Jacobsen"

48 Publications

Autopsies in pandemics - a perspective on barriers and benefits. Is it time for a revival?

APMIS 2021 Mar 1. Epub 2021 Mar 1.

Department of Forensic Medicine, Section of Forensic Pathology, University of Copenhagen, Copenhagen, Denmark.

Influenza virus and coronavirus pandemics regularly sweep the globe, at great cost of health and economy. Our aim was to conduct a PubMed search for autopsy studies on influenza and coronavirus to investigate the contribution of autopsies during pandemics, focussing on autopsy methods and procedures and the role of autopsy findings in pandemics. The retrieved autopsy studies generally relied on microscopy, polymerase chain reaction (PCR), immunostaining and electron microscopy. Most were small and reported on lung effects, including diffuse alveolar damage (DAD), pneumonia and tracheobronchitis. Antibiotic therapy has diminished a role for bacterial pneumonia, whereas obesity is an emerging risk factor. Autopsy studies have provided new insights into coronavirus disease 2019 (COVID-19) treatments like anti-coagulative therapy. Unfortunately, autopsies during pandemics are hampered by lack of guidelines, facilities and expertise for handling potentially infectious corpses and by widely varying recommendations for personal protective equipment and procedures. The Department of Forensic Pathology, at the Forensic Institute, at the University of Copenhagen in Denmark has, in collaboration with the Department of Pathology, Rigshospitalet, Copenhagen, initiated a prospective observational study on COVID-19-related deaths encompassing postmortem imaging, standardized autopsy procedures/reporting and extensive tissue sampling for histological, chemical, microbiological and genetic analysis. The study involves a diverse array of research groups at the University of Copenhagen, and the clinical field.
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http://dx.doi.org/10.1111/apm.13111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013917PMC
March 2021

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

Graefes Arch Clin Exp Ophthalmol 2020 Nov 18. Epub 2020 Nov 18.

University Eye Hospital, Medical School Hannover, Carl-Neuberg-Str.1, 30625, Hannover, Germany.

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.
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http://dx.doi.org/10.1007/s00417-020-04999-9DOI Listing
November 2020

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

Genet Med 2021 Feb 2;23(2):396-407. Epub 2020 Oct 2.

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

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.
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http://dx.doi.org/10.1038/s41436-020-00983-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867608PMC
February 2021

Single-Cell RNA Sequencing of Calvarial and Long-Bone Endocortical Cells.

J Bone Miner Res 2020 10 20;35(10):1981-1991. Epub 2020 Jul 20.

Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA, USA.

Single-cell RNA sequencing (scRNA-Seq) is emerging as a powerful technology to examine transcriptomes of individual cells. We determined whether scRNA-Seq could be used to detect the effect of environmental and pharmacologic perturbations on osteoblasts. We began with a commonly used in vitro system in which freshly isolated neonatal mouse calvarial cells are expanded and induced to produce a mineralized matrix. We used scRNA-Seq to compare the relative cell type abundances and the transcriptomes of freshly isolated cells to those that had been cultured for 12 days in vitro. We observed that the percentage of macrophage-like cells increased from 6% in freshly isolated calvarial cells to 34% in cultured cells. We also found that Bglap transcripts were abundant in freshly isolated osteoblasts but nearly undetectable in the cultured calvarial cells. Thus, scRNA-Seq revealed significant differences between heterogeneity of cells in vivo and in vitro. We next performed scRNA-Seq on freshly recovered long bone endocortical cells from mice that received either vehicle or sclerostin-neutralizing antibody for 1 week. We were unable to detect significant changes in bone anabolism-associated transcripts in immature and mature osteoblasts recovered from mice treated with sclerostin-neutralizing antibody; this might be a consequence of being underpowered to detect modest changes in gene expression, because only 7% of the sequenced endocortical cells were osteoblasts and a limited portion of their transcriptomes were sampled. We conclude that scRNA-Seq can detect changes in cell abundance, identity, and gene expression in skeletally derived cells. In order to detect modest changes in osteoblast gene expression at the single-cell level in the appendicular skeleton, larger numbers of osteoblasts from endocortical bone are required. © 2020 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.4052DOI Listing
October 2020

Clinical forensic medicine in Eastern Denmark: Organisation and assessments.

Med Sci Law 2020 04 24;60(2):150-158. Epub 2020 Feb 24.

Department of Forensic Medicine, University of Copenhagen, Denmark.

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http://dx.doi.org/10.1177/0025802419898338DOI Listing
April 2020

Predictors of completion and outcome of exercise challenge tests in childhood asthma.

Pediatr Allergy Immunol 2020 07 4;31(5):574-578. Epub 2020 Mar 4.

Department of Pediatric and Adolescent Medicine, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

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http://dx.doi.org/10.1111/pai.13224DOI Listing
July 2020

Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.

J Clin Endocrinol Metab 2020 05;105(5)

Clinical Research Branch, National Institute of Environmental Health Sciences, Durham, North Carolina.

Context: The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in humans led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed.

Objective: The objective of this work is to determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures.

Methods: We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients.

Results: All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to 2 GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male patient.

Conclusions: Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with but may not depend on olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.
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http://dx.doi.org/10.1210/clinem/dgaa065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108682PMC
May 2020

[Experiences of aggression and violence against ophthalmologists].

Ophthalmologe 2020 Aug;117(8):775-785

Universitätsklinik für Augenheilkunde, Medizinische Hochschule Hannover (MHH), Hannover, Deutschland.

Background: The media have reported an increased willingness of patients and relatives to use violence against medical personnel. So far a few studies have been carried out on this topic and the data situation is correspondingly weak. Ophthalmologists in particular have close contact with patients at the slit lamp and are often alone with patients.

Methods: A questionnaire was developed based on the perception of prevalence of aggression scale (POPAS) questionnaire and the survey on aggression and violence among general practitioners. In autumn 2018, all members of the German Ophthalmological Society (DOG) and the Professional Association of Ophthalmologists (BVA) received an invitation by e‑mail to complete the questionnaire online.

Results: Of the 9411 ophthalmologists contacted a total of 1508 (age 49 ± 12 years) took part in the survey (16%). Of the respondents 806 (53.7%) were female and 1139 (75.5%) participants worked in practices. A total of 1264 (83.3%) ophthalmologists had experienced aggression/violence in their work, 986 (65%) respondents had already experienced verbal assaults without threats, 363 (24.1%) doctors reported experiences with threats of physical violence and 30 (2%) participants had received medical treatment for severe physical violence. Sexual intimidation/harassment was affirmed by 322 (21.4%) of respondents, of whom 243 (75.5%) were female and 533 (47.9%) doctors felt that aggressive/violent behavior had increased in the last 5 years.

Conclusion: The high number of participants indicates the high relevance of the topic. The survey produced astonishing results, which should lead to further discussion and action to improve the safety of employees.
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http://dx.doi.org/10.1007/s00347-020-01039-zDOI Listing
August 2020

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

Forensic Sci Med Pathol 2020 03 30;16(1):119-122. Epub 2019 Oct 30.

Department of Forensic Pathology, Institute of Forensic Medicine, University of Copenhagen, Frederik V's vej 11, 2100, Copenhagen East, Denmark.

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; R 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.
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http://dx.doi.org/10.1007/s12024-019-00188-1DOI Listing
March 2020

Combination therapy in the Col1a2 mouse model of Osteogenesis Imperfecta reveals an additive effect of enhancing LRP5 signaling and inhibiting TGFβ signaling on trabecular bone but not on cortical bone.

Bone 2020 02 21;131:115084. Epub 2019 Oct 21.

Divisions of Endocrinology and Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA. Electronic address:

Enhancing LRP5 signaling and inhibiting TGFβ signaling have each been reported to increase bone mass and improve bone strength in wild-type mice. Monotherapy targeting LRP5 signaling, or TGFβ signaling, also improved bone properties in mouse models of Osteogenesis Imperfecta (OI). We investigated whether additive or synergistic increases in bone properties would be attained if enhanced LRP5 signaling was combined with TGFβ inhibition. We crossed an Lrp5 high bone mass (HBM) allele (Lrp5) into the Col1a2 mouse model of OI. At 6-weeks-of-age we began treating mice with an antibody that inhibits TGFβ1, β2, and β3 (mAb 1D11), or with an isotype-matched control antibody (mAb 13C4). At 12-weeks-old, we observed that combining enhanced LRP5 signaling with inhibited TGFβ signaling produced an additive effect on femoral and vertebral trabecular bone volumes, but not on cortical bone volumes. Although enhanced LRP5 signaling increased femur strength in a 3-point bending assay in Col1a2 mice, femur strength did not improve further with TGFβ inhibition. Neither enhanced LRP5 signaling nor TGFβ inhibition, alone or in combination, improved femur 3-point-bending post-yield displacement in Col1a2 mice. These pre-clinical studies indicate combination therapies that target LRP5 and TGFβ signaling should increase trabecular bone mass in patients with OI more than targeting either signaling pathway alone. Whether additive increases in trabecular bone mass will occur in, and clinically benefit, patients with OI needs to be determined.
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http://dx.doi.org/10.1016/j.bone.2019.115084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232829PMC
February 2020

Expression of vasopressin mRNA in the hypothalamus of individuals with a diagnosis of schizophrenia.

Brain Behav 2019 09 13;9(9):e01355. Epub 2019 Jul 13.

Faculty of Health and Medical Sciences, Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark.

Objective: This study investigates the expression of mRNA encoding vasopressin in the hypothalamus of autopsy brains of individuals diagnosed with schizophrenia.

Methods: Ten brains of individuals with schizophrenia and 10 brains from individuals without any disease were examined during autopsy. The hypothalamic block was dissected and immersion fixed in paraformaldehyde, sucrose substituted, frozen, and cut into 20-µm-thick coronal cryostat sections. The sections were hybridized with an S-35-labeled DNA antisense oligo probe and after washing covered by an X-ray film. The hybridization signals on the films were transferred to a computer and densitometrically quantified.

Results: The densitometry signals showed a statistically significant lower mRNA expression (53% decrease; p = 0.014) in the paraventricular nucleus of the individuals with schizophrenia compared to the controls. In the supraoptic nucleus, the decrease in the group with schizophrenia was 39% compared to the controls, but this decrease was not statistically significant (p = 0.194).

Conclusions: Our results show a low expression of mRNA encoding vasopressin in the paraventricular nucleus of the individuals with schizophrenia. We suggest that vasopressin is not directly involved in the pathogenesis of schizophrenia, but might influence schizophrenic symptoms via vasopressin receptors located in the social behavioral neural network in the forebrain.
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http://dx.doi.org/10.1002/brb3.1355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749484PMC
September 2019

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

Stress 2020 01 19;23(1):69-76. Epub 2019 Jul 19.

Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark.

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 ( = 34), bipolar ( = 5), or depressive disorder ( = 20), any other psychiatric diagnosis ( = 36) compared with decedents who had no previous psychiatric admission ( = 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 ( = 0.033). Other diagnosis groups did not differ from controls. Total admission length was positively correlated with area of the ZF.People 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.
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http://dx.doi.org/10.1080/10253890.2019.1641485DOI Listing
January 2020

Retinoic-acid-induced osteogenesis of hiPSCs.

Nat Biomed Eng 2019 07;3(7):504-506

Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1038/s41551-019-0422-3DOI Listing
July 2019

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

BMC Med Imaging 2019 04 12;19(1):29. Epub 2019 Apr 12.

Section of Forensic Pathology, Department of Forensic Medicine, University of Copenhagen, Frederik V's vej 11, 1 sal, 2100, Copenhagen, Denmark.

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.
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http://dx.doi.org/10.1186/s12880-019-0326-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461811PMC
April 2019

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

Int J Legal Med 2019 Sep 4;133(5):1485-1496. Epub 2019 Jan 4.

Section of Forensic Pathology, Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark.

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, (r = 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.
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http://dx.doi.org/10.1007/s00414-018-01998-8DOI Listing
September 2019

The accessory magnocellular neurosecretory system of the rostral human hypothalamus.

Cell Tissue Res 2018 08 16;373(2):487-498. Epub 2018 Mar 16.

Department of Forensic Medicine, Section of Forensic Pathology, Faculty of Health and Medical Sciences, Frederik V's Vej 11, 2100, Copenhagen, Denmark.

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.
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http://dx.doi.org/10.1007/s00441-018-2818-xDOI Listing
August 2018

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

Forensic Sci Med Pathol 2017 Dec 2;13(4):468-472. Epub 2017 Nov 2.

Department of Forensic Medicine, Section of Forensic Pathology, University of Copenhagen, Frederik V's vej 11, 2100, Copenhagen East, Denmark.

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 (R = 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.
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http://dx.doi.org/10.1007/s12024-017-9930-1DOI Listing
December 2017

Corrigendum: SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.

Nat Genet 2017 05;49(6):969

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http://dx.doi.org/10.1038/ng0617-969cDOI Listing
May 2017

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

J Pediatr Orthop 2017 Jul/Aug;37(5):e313-e316

*Department of Orthopaedic Surgery, SUNY Downstate Medical Center, Brooklyn, NY †Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD ‡Department of Pediatrics, Boston Children's Hospital, Divisions of Endocrinology and Genetics, & Harvard Medical School, Boston, MA.

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.
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http://dx.doi.org/10.1097/BPO.0000000000000970DOI Listing
November 2017

SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.

Nat Genet 2017 Feb 9;49(2):238-248. Epub 2017 Jan 9.

Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.
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http://dx.doi.org/10.1038/ng.3743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473428PMC
February 2017

Application of anti-Sclerostin therapy in non-osteoporosis disease models.

Bone 2017 03 22;96:18-23. Epub 2016 Oct 22.

Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA, United States; Division of Endocrinology, Boston Children's Hospital, Boston, MA, United States; Division of Genetics, Boston Children's Hospital, Boston, MA, United States; Department of Pediatrics, Harvard Medical School, Boston, MA, United States. Electronic address:

Sclerostin, a known inhibitor of the low density lipoprotein related protein 5 and 6 (LRP5 and LRP6) cell surface signaling receptors, is integral in the maintenance of normal bone mass and strength. Patients with loss of function mutations in SOST or missense mutations in LRP5 that prevent Sclerostin from binding and inhibiting the receptor, have significantly increased bone mass. This observation leads to the development of Sclerostin neutralizing therapies to increase bone mass and strength. Anti-Sclerostin therapy has been shown to be effective at increasing bone density and strength in animal models and patients with osteoporosis. Loss of function of Sost or treatment with a Sclerostin neutralizing antibody improves bone properties in animal models of Osteoporosis Pseudoglioma syndrome (OPPG), likely due to action through the LRP6 receptor, which suggests patients may benefit from these therapies. Sclerostin antibody is effective at improving bone properties in mouse models of Osteogenesis Imperfecta, a genetic disorder of low bone mass and fragility due to type I collagen mutations, in as little as two weeks after initiation of therapy. However, these improvements are due to increases in bone quantity as the quality (brittleness) of bone remains unaffected. Similarly, Sclerostin antibody treatment improves bone density in animal models of other diseases. Sclerostin neutralizing therapies are likely to benefit many patients with genetic disorders of bone, as well as other forms of metabolic bone disease.
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http://dx.doi.org/10.1016/j.bone.2016.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328800PMC
March 2017

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

Forensic Sci Med Pathol 2016 Dec 28;12(4):510-516. Epub 2016 Sep 28.

Department of Forensic Medicine, Section of Forensic Pathology, University of Copenhagen, Frederik V's vej 11, 2100, Copenhagen East, Denmark.

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.
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http://dx.doi.org/10.1007/s12024-016-9810-0DOI Listing
December 2016

Enhanced Wnt signaling improves bone mass and strength, but not brittleness, in the Col1a1(+/mov13) mouse model of type I Osteogenesis Imperfecta.

Bone 2016 09 11;90:127-32. Epub 2016 Jun 11.

Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA, United States; Department of Genetics, Harvard Medical School, Boston, MA, United States; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, United States.

Osteogenesis Imperfecta (OI) comprises a group of genetic skeletal fragility disorders. The mildest form of OI, Osteogenesis Imperfecta type I, is frequently caused by haploinsufficiency mutations in COL1A1, the gene encoding the α1(I) chain of type 1 collagen. Children with OI type I have a 95-fold higher fracture rate compared to unaffected children. Therapies for OI type I in the pediatric population are limited to anti-catabolic agents. In adults with osteoporosis, anabolic therapies that enhance Wnt signaling in bone improve bone mass, and ongoing clinical trials are determining if these therapies also reduce fracture risk. We performed a proof-of-principle experiment in mice to determine whether enhancing Wnt signaling in bone could benefit children with OI type I. We crossed a mouse model of OI type I (Col1a1(+/Mov13)) with a high bone mass (HBM) mouse (Lrp5(+/p.A214V)) that has increased bone strength from enhanced Wnt signaling. Offspring that inherited the OI and HBM alleles had higher bone mass and strength than mice that inherited the OI allele alone. However, OI+HBM and OI mice still had bones with lower ductility compared to wild-type mice. We conclude that enhancing Wnt signaling does not make OI bone normal, but does improve bone properties that could reduce fracture risk. Therefore, agents that enhance Wnt signaling are likely to benefit children and adults with OI type 1.
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http://dx.doi.org/10.1016/j.bone.2016.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985001PMC
September 2016

Quantitative analysis of myocardial tissue with digital autofluorescence microscopy.

J Pathol Inform 2016 11;7:15. Epub 2016 Apr 11.

Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background: The opportunity offered by whole slide scanners of automated histological analysis implies an ever increasing importance of digital pathology. To go beyond the importance of conventional pathology, however, digital pathology may need a basic histological starting point similar to that of hematoxylin and eosin staining in conventional pathology. This study presents an automated fluorescence-based microscopy approach providing highly detailed morphological data from unstained microsections. This data may provide a basic histological starting point from which further digital analysis including staining may benefit.

Methods: This study explores the inherent tissue fluorescence, also known as autofluorescence, as a mean to quantitate cardiac tissue components in histological microsections. Data acquisition using a commercially available whole slide scanner and an image-based quantitation algorithm are presented.

Results: It is shown that the autofluorescence intensity of unstained microsections at two different wavelengths is a suitable starting point for automated digital analysis of myocytes, fibrous tissue, lipofuscin, and the extracellular compartment. The output of the method is absolute quantitation along with accurate outlines of above-mentioned components. The digital quantitations are verified by comparison to point grid quantitations performed on the microsections after Van Gieson staining.

Conclusion: The presented method is amply described as a prestain multicomponent quantitation and outlining tool for histological sections of cardiac tissue. The main perspective is the opportunity for combination with digital analysis of stained microsections, for which the method may provide an accurate digital framework.
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http://dx.doi.org/10.4103/2153-3539.179908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837794PMC
May 2016

Bone mineral properties in growing Col1a2(+/G610C) mice, an animal model of osteogenesis imperfecta.

Bone 2016 06 13;87:120-9. Epub 2016 Apr 13.

Weill Cornell Medical College, New York, NY, United States; Mineralized Tissues Laboratory, Hospital for Special Surgery, New York, NY, United States. Electronic address:

The Col1a2(+/G610C) knock-in mouse, models osteogenesis imperfecta in a large old order Amish family (OOA) with type IV OI, caused by a G-to-T transversion at nucleotide 2098, which alters the gly-610 codon in the triple-helical domain of the α2(I) chain of type I collagen. Mineral and matrix properties of the long bones and vertebrae of male Col1a2(+/G610C) and their wild-type controls (Col1a2(+/+)), were characterized to gain insight into the role of α2-chain collagen mutations in mineralization. Additionally, we examined the rescuability of the composition by sclerostin inhibition initiated by crossing Col1a2(+/G610C) with an LRP(+/A214V) high bone mass allele. At age 10-days, vertebrae and tibia showed few alterations by micro-CT or Fourier transform infrared imaging (FTIRI). At 2-months-of-age, Col1a2(+/G610C) tibias had 13% fewer secondary trabeculae than Col1a2(+/+), these were thinner (11%) and more widely spaced (20%) than those of Col1a2(+/+) mice. Vertebrae of Col1a2(+/G610C) mice at 2-months also had lower bone volume fraction (38%), trabecular number (13%), thickness (13%) and connectivity density (32%) compared to Col1(a2+/+). The cortical bone of Col1a2(+/G610C) tibias at 2-months had 3% higher tissue mineral density compared to Col1a2(+/+); Col1a2(+/G610C) vertebrae had lower cortical thickness (29%), bone area (37%) and polar moment of inertia (38%) relative to Col1a2(+/+). FTIRI analysis, which provides information on bone chemical composition at ~7μm-spatial resolution, showed tibias at 10-days did not differ between genotypes. Comparing identical bone types in Col1a2(+/G610C) to Col1a2(+/+) at 2-months-of-age, tibias showed higher mineral-to-matrix ratio in trabeculae (17%) and cortices (31%). and in vertebral cortices (28%). Collagen maturity was 42% higher at 10-days-of-age in Col1a2(+/G610C) vertebral trabeculae and in 2-month tibial cortices (12%), vertebral trabeculae (42%) and vertebral cortices (12%). Higher acid-phosphate substitution was noted in 10-day-old trabecular bone in vertebrae (31%) and in 2-month old trabecular bone in both tibia (31%) and vertebrae (4%). There was also a 16% lower carbonate-to-phosphate ratio in vertebral trabeculae and a correspondingly higher (22%) carbonate-to-phosphate ratio in 2month-old vertebral cortices. At age 3-months-of-age, male femurs with both a Col1a2(+/G610C) allele and a Lrp5 high bone mass allele (Lrp5+/A214V) showed an improvement in bone composition, presenting higher trabecular carbonate-to-phosphate ratio (18%) and lower trabecular and cortical acid-phosphate substitutions (8% and 18%, respectively). Together, these results indicate that mutant collagen α2(I) chain affects both bone quantity and composition, and the usefulness of this model for studies of potential OI therapies such as anti-sclerostin treatments.
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http://dx.doi.org/10.1016/j.bone.2016.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862917PMC
June 2016

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

Hum Mutat 2015 Apr 16;36(4):474-81. Epub 2015 Mar 16.

Genome Institute of Singapore, Singapore.

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.
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http://dx.doi.org/10.1002/humu.22773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382411PMC
April 2015

Copy number variation plays an important role in clinical epilepsy.

Ann Neurol 2014 Jun 13;75(6):943-58. Epub 2014 Jun 13.

Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology and Neurogenetics Program, Department of Neurology, Boston Children's Hospital, and Harvard Medical School, Boston, MA.

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.
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http://dx.doi.org/10.1002/ana.24178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487364PMC
June 2014

Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations.

J Clin Endocrinol Metab 2014 Aug 24;99(8):E1510-8. Epub 2014 Apr 24.

Program in Developmental Endocrinology and Genetics (O.N., J.C.L., J.B.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Center for Molecular Medicine and Pediatric Endocrinology Unit, Department of Women's and Children's Health (O.N.), Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Program in Biological and Biomedical Sciences (M.H.G.), Harvard Medical School, Boston, Massachusetts 02115; Connecticut Children's Medical Center (N.D.), Hartford, Connecticut 06106; Children's Hospital of Pittsburgh (J.P., D.F.), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224; Division of Endocrinology (M.H.G., C.J., J.N.H., A.D.), Boston Children's Hospital, Boston, Massachusetts 02115; Department of Genetics (M.H.G., J.N.H.), Harvard Medical School, Boston, Massachusetts 02115; and Program in Medical and Population Genetics (J.N.H., A.D.), Broad Institute, Cambridge, Massachusetts 02142.

Context: Many children with idiopathic short stature have a delayed bone age. Idiopathic short stature with advanced bone age is far less common.

Objective: The aim was to identify underlying genetic causes of short stature with advanced bone age.

Setting And Design: We used whole-exome sequencing to study three families with autosomal-dominant short stature, advanced bone age, and premature growth cessation.

Results: Affected individuals presented with short stature [adult heights -2.3 to -4.2 standard deviation scores (SDS)] with histories of early growth cessation or childhood short stature (height SDS -1.9 to -3.5 SDS), advancement of bone age, and normal endocrine evaluations. Whole-exome sequencing identified novel heterozygous variants in ACAN, which encodes aggrecan, a proteoglycan in the extracellular matrix of growth plate and other cartilaginous tissues. The variants were present in all affected, but in no unaffected, family members. In Family 1, a novel frameshift mutation in exon 3 (c.272delA) was identified, which is predicted to cause early truncation of the aggrecan protein. In Family 2, a base-pair substitution was found in a highly conserved location within a splice donor site (c.2026+1G>A), which is also likely to alter the amino acid sequence of a large portion of the protein. In Family 3, a missense variant (c.7064T>C) in exon 14 affects a highly conserved residue (L2355P) and is strongly predicted to perturb protein function.

Conclusions: Our study demonstrates that heterozygous mutations in ACAN can cause a mild skeletal dysplasia, which presents clinically as short stature with advanced bone age. The accelerating effect on skeletal maturation has not previously been noted in the few prior reports of human ACAN mutations. Our findings thus expand the spectrum of ACAN defects and provide a new molecular genetic etiology for the unusual child who presents with short stature and accelerated skeletal maturation.
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http://dx.doi.org/10.1210/jc.2014-1332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121031PMC
August 2014