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Due to advancements in ultrasound techniques, the focus of antenatal ultrasound screening is moving towards the first trimester of pregnancy. The early first trimester however remains in part, a 'black box', due to the size of the developing embryo and the limitations of contemporary scanning techniques. Therefore there is a need for images of early anatomical developmental to improve our understanding of this area. By using new imaging techniques, we can not only obtain better images to further our knowledge of early embryonic development, but clear images of embryonic and fetal development can also be used in training for e.g. sonographers and fetal surgeons, or to educate parents expecting a child with a fetal anomaly. The aim of this review is to provide an overview of the past, present and future techniques used to capture images of the developing human embryo and fetus and provide the reader newest insights in upcoming and promising imaging techniques. The reader is taken from the earliest drawings of da Vinci, along the advancements in the fields of in utero ultrasound and MR imaging techniques towards high-resolution ex utero imaging using Micro-CT and ultra-high field MRI. Finally, a future perspective is given about the use of artificial intelligence in ultrasound and new potential imaging techniques such as synchrotron radiation-based CT to increase our knowledge regarding human development. ispartof: SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY vol:131 pages:78-92 ispartof: location:England status: published

Contains fulltext : 287837.pdf (Publisher’s version ) (Open Access) The Medical School of Padua (Italy) contributed profoundly to the study of teratology. Many famous physicians and professors of medicine, such as Liceti, Vallisneri, Morgagni, and Malacarne, have studied and investigated these anomalies to better understand the causes and to find a potential explanation, often preserving the specimens for future studies. The present study highlights some historical cases of conjoined twins and a conjoined triplet preserved at the Morgagni Museum of Human Anatomy to show the development of medical theories in the teratological field between the 18th and early 19th century. This approach will provide insights into different study methods and ideas of some of the most famous scholars working in Padua at that time. The current article focuses on rare cases, both human and animal, that were encountered by physicians who worked in the Veneto area in the late 18th and early 19th century. Their detailed descriptions are not only of historical but also of contemporary dysmorphological value.

Contains fulltext : 291894.pdf (Publisher’s version ) (Open Access) The collection of the Narrenturm in Vienna houses and maintains more than 50,000 objects including approximately 1200 teratological specimens; making it one of the biggest collections of specimens from human origin in Europe. The existence of this magnificent collection-representing an important resource for dysmorphology research, mostly awaiting contemporary diagnoses-is not widely known in the scientific community. Here, we show that the Narrenturm harbors a wealth of specimens with (exceptionally) rare congenital anomalies. These museums can be seen as physical repositories of human malformation, covering hundreds of years of dedicated collecting and preserving, thereby creating unique settings that can be used to expand our knowledge of developmental conditions that have to be preserved for future generations of scientists.

The ventricular walls of the human heart comprise an outer compact layer and an inner trabecular layer. In the context of an increased pre‐test probability, diagnosis left ventricular noncompaction cardiomyopathy is given when the left ventricle is excessively trabeculated in volume (trabecular vol >25% of total LV wall volume) or thickness (trabecular/compact (T/C) >2.3). Here, we investigated whether higher spatial resolution affects the detection of trabeculation and thus the assessment of normal and excessively trabeculated wall morphology. First, we screened left ventricles in 1112 post‐natal autopsy hearts. We identified five excessively trabeculated hearts and this low prevalence of excessive trabeculation is in agreement with pathology reports but contrasts the prevalence of approximately 10% of the population found by in vivo non‐invasive imaging. Using macroscopy, histology and low‐ and high‐resolution MRI, the five excessively trabeculated hearts were compared with six normal hearts and seven abnormally trabeculated and excessive trabeculation‐negative hearts. Some abnormally trabeculated hearts could be considered excessively trabeculated macroscopically because of a trabecular outflow or an excessive number of trabeculations, but they were excessive trabeculation‐negative when assessed with MRI‐based measurements (T/C, Jensen et al. show that higher spatial resolution may affect the sensitivity of diagnostic measurements of noncompaction and in addition could allow for novel measurements such as counting of trabeculations.

Contains fulltext : 235748.pdf (Publisher’s version ) (Open Access) Several teratologic collections containing specimens with malformations and syndromes are maintained in a number of Dutch anatomical museums. Technically, these are not works of art or antiquities. However, many have been depicted in illustrations of such high quality that they merit discussion here. We review a selection of specimens and their artistic portrayals which find their origin in four Dutch teratological collections. These museum specimens are more than just intriguing objects for the inquisitive museum visitor. As we will substantiate, these specimens-and their artistic depictions-can be used to find and describe rarely occurring birth defects, provide etiopathogenetic information and are a source of novel diagnosis. Additionally, we briefly discuss the ethical aspects and motivations of exhibiting these specimens, as these collections have to be protected meticulously by the new generation of museum professionals, who eventually determine what kind of past our future will have. It is therefore imperative that these collections of antique specimens are treasured as their importance is easily overlooked.

Purpose The aim of this study was to investigate whether post-mortem computed tomography (PMCT) provides additional information regarding the cause of death and underlying diseases in a general practitioners’ (GP), out-of-hospital population. Methods and materials Bodies donated to our anatomy department between January 2014 and January 2018, who consecutively underwent a total body PMCT and had given permission for retrieval of their medical records during life, were included. PMCT scans were assessed by a radiologist and compared with the cause of death as stated in the medical records. Discrepancies were analyzed with an adjusted Goldman classification. Results Ninety-three out of the 274 scanned donors during the inclusion period had given consent for the retrieval of their medical records, of which 79 GP’s responded to the request thereof (31 men, 48 women, average age 72.8 years, range 36–99). PMCT identified 49 (62%) cases of cancer, 10 (12.7%) cardiovascular diseases, 8 (10.1%) severe organ failures, 5 (6.3%) cases with signs of pneumonia, 2 (2.5%) other causes, and 7 (8.9%) cases without an (underlying) definitive cause of death. Eleven major discrepancies on the Goldman classification scale, with possible relevance to survival between PMCT and GP records, were identified. Conclusion PMCT can have added value for the detection of additional findings regarding the cause of death in an out-of-hospital, GP’s population, especially to identify or exclude major (previously non-diagnosed) underlying diseases.

Background MRI and CT have been extensively used to study fetal anatomy for research and diagnostic purposes, enabling minimally invasive autopsy and giving insight in human fetal development. Novel (contrast-enhanced) microfocus CT (micro-CT) and ultra-high-field (≥ 7.0 T) MRI (UHF-MRI) techniques now enable micron-level resolution that combats the disadvantages of low-field MRI and conventional CT. Thereby, they might be suitable to study fetal anatomy in high detail and, in time, contribute to the postmortem diagnosis of fetal conditions. Objectives (1) To systematically examine the usability of micro-CT and UHF-MRI to study postmortem human fetal anatomy, and (2) to analyze factors that govern success at each step of the specimen preparation and imaging. Method MEDLINE and EMBASE were systematically searched to identify publications on fetal imaging by micro-CT or UHF-MRI. Scanning protocols were summarized and best practices concerning specimen preparation and imaging were enumerated. Results Thirty-two publications reporting on micro-CT and UHF-MRI were included. The majority of the publications focused on imaging organs separately and seven publications focused on whole body imaging, demonstrating the possibility of visualization of small anatomical structures with a resolution well below 100 μm. When imaging soft tissues by micro-CT, the fetus should be stained by immersion in Lugol’s staining solution. Conclusion Micro-CT and UHF-MRI are both excellent imaging techniques to provide detailed images of gross anatomy of human fetuses. The present study offers an overview of the current best practices when using micro-CT and/or UHF-MRI to study fetal anatomy for clinical and research purposes. Key Points • Micro-CT and UHF-MRI can both be used to study postmortem human fetal anatomy for clinical and research purposes. • Micro-CT enables high-resolution imaging of fetal specimens in relatively short scanning time. However, tissue staining using a contrast solution is necessary to enable soft-tissue visualization. • UHF-MRI enables high-resolution imaging of fetal specimens, without the necessity of prior staining, but with the drawback of long scanning time.

Since the multi-site closure theory was first proposed in 1991 as explanation for the preferential localizations of neural tube defects, the closure of the neural tube has been debated. Although the multi-site closure theory is much cited in clinical literature, single-site closure is most apparent in literature concerning embryology. Inspired by Victor Hamburgers (1900-2001) statement that "our real teacher has been and still is the embryo, who is, incidentally, the only teacher who is always right", we decided to critically review both theories of neural tube closure. To verify the theories of closure, we studied serial histological sections of 10 mouse embryos between 8.5 and 9.5 days of gestation and 18 human embryos of the Carnegie collection between Carnegie stage 9 (19-21 days) and 13 (28-32 days). Neural tube closure was histologically defined by the neuroepithelial remodeling of the two adjoining neural fold tips in the midline. We did not observe multiple fusion sites in neither mouse nor human embryos. A meta-analysis of case reports on neural tube defects showed that defects can occur at any level of the neural axis. Our data indicate that the human neural tube fuses at a single site and, therefore, we propose to reinstate the single-site closure theory for neural tube closure. We showed that neural tube defects are not restricted to a specific location, thereby refuting the reasoning underlying the multi-site closure theory. Clin. Anat. 30:988-999, 2017. © 2017 Wiley Periodicals, Inc.

This study presents a reference for the dimensions of the tarsal sinus and canal in healthy adults in different foot positions to facilitate understanding of the kinematics of the subtalar joint, the effect of an implant, and other clinical issues. In a 3D CT stress test on 20 subjects, the right foot was forced into a neutral and eight different extreme foot positions while CT scans were obtained. The bones were segmented in the neutral foot position. The kinematics of the bones in the extreme positions were determined relative to the neutral position. The dimensions of the tarsal sinus and canal were calculated by determining the radii of the maximal inscribed spheres at 20 equidistant locations along an axis in 3D surface models of the tali and calcanei in each foot position. The radii were small on the medial side and increased laterally. Medial from the middle, the radii were small and not significantly different among the various foot positions. At the lateral side, the dimensions were affected mainly by eversion or inversion and less by dorsiflexion or plantarflexion. The pattern was reproducible among subjects, but there were between-subject differences. The dimensions are mostly determined by rotation in the frontal plane. A pivot point was found medial from the middle. These data serve as a reference and model for predicting the effect of sinus implants and understanding such clinical problems as sinus tarsi syndrome. Between-subjects differences have to be taken into account. Clin. Anat. 30:1049-1057, 2017. © 2017 Wiley Periodicals, Inc.

Oral-facial-digital syndrome type 1 (OFD1; OMIM# 311200) is an X-linked dominant ciliopathy caused by mutations in the OFD1 gene. This condition is characterized by facial anomalies and abnormalities of oral tissues, digits, brain, and kidneys. Almost all affected patients are female, as OFD1 is presumed to be lethal in males, mostly in the first or second trimester of pregnancy. Live born males with OFD1 are a rare occurrence, with only five reported patients to date. In four patients the presence of a congenital heart defect (CHD) was observed. Here, we report an affected male fetus with a hemizygous de novo mutation in OFD1 (c.2101C>T; p.(Gln701*)). Ultrasound examination demonstrated severe hydrocephalus, a hypoplastic cerebellum and a hypoplastic left ventricle of the heart. The pregnancy was terminated at 16 weeks of gestation because of poor prognosis. Post-mortem examination of the fetus confirmed severe hypoplasia of the left ventricle of the heart. We emphasize that CHDs should be included in the phenotypic spectrum of OFD1 in males. This justifies molecular analysis of OFD1 when CHD is encountered prenatally in combination with one or more phenotypic features previously described in the OFD1 gene alteration spectrum. The underlying pathogenesis of CHD in OFD1 (and other ciliopathies) probably involves dysfunction of the primary cilia regarding coordination of left-right signalling during early heart development. Whether these CHDs wholly or partly result from defective left right signalling, in which different types of cilia are known to play a critical role, remains a topic of research.

Contains fulltext : 174217.pdf (Publisher’s version ) (Open Access) OBJECTIVES: To determine the advantages of radiological imaging of a collection of full-term teratological fetuses in order to increase their scientific and educational value. BACKGROUND : Anatomical museums around the world exhibit full-term teratological fetuses. Unfortunately, these museums are regularly considered as "morbid cabinets". Detailed dysmorphological information concerning the exhibited specimens is often lacking. Moreover, fetuses with severe and complex congenital anomalies are frequently diagnosed incompletely, incorrectly or not at all. METHODS: In order to verify diagnoses and to enrich their educational and scientific value, we imaged 41 out of the 72 teratological specimens present in the collection of our Anatomy and Pathology Museum in Nijmegen (The Netherlands) by means of magnetic resonance imaging (MRI) and computed tomography (CT). Additionally, contemporary dysmorphological insights and 3D models are implemented in the teratology education of medical students and residents. CONCLUSIONS: Full-term teratological fetuses have become increasingly rare and deserve a prominent place in every anatomical museum; they are suitable for contemporary teratological research and education. Modern radiological techniques markedly enhance their scientific and didactic value. TEACHING POINTS: * To explore the scientific and educational potential of institutionalised teratological collections * To understand the additional value of radiological imaging in diagnosing teratological specimens * To learn about the specific settings of MRI parameters when scanning fixed specimens * To recognise specific internal dysmorphology in several congenital anomalies.

The first human mutations in GATA6 were described in a cohort of patients with persistent truncus arteriosus, and the phenotypic spectrum has expanded since then. This study underscores the broad phenotypic spectrum by presenting two patients with de novo GATA6 mutations, both exhibiting complex cardiac defects, pancreatic, and other abnormalities. Furthermore, we provided a detailed overview of all published human genetic variation in/near GATA6 published to date and the associated phenotypes (n = 78). We conclude that the most common phenotypes associated with a mutation in GATA6 were structural cardiac and pancreatic abnormalities, with a penetrance of 87 and 60%, respectively. Other common malformations were gallbladder agenesis, congenital diaphragmatic hernia, and neurocognitive abnormalities, mostly developmental delay. Fifty‐eight percent of the mutations were de novo, and these patients more often had an anomaly of intracardiac connections, an anomaly of the great arteries, and hypothyroidism, compared with those with inherited mutations. Functional studies mostly support loss‐of‐function as the pathophysiological mechanism. In conclusion, GATA6 mutations give a wide range of phenotypic defects, most frequently malformations of the heart and pancreas. This highlights the importance of detailed clinical evaluation of identified carriers to evaluate their full phenotypic spectrum.

Contemporary papers and book chapters on nephrology open with the assumption that human kidney development passes through three morphological stages: pronephros, mesonephros, and metanephros. Current knowledge of the human pronephros, however, appears to be based on only a hand full of human specimens. The ongoing use of variations in the definition of a pronephros hampers the interpretation of study results. Because of the increased interest in the anamniote pronephros as a genetic model for kidney organogenesis we aimed to provide an overview of the literature concerning kidney development and to clarify the existence of a pronephros in human embryos. We performed an extensive literature survey regarding vertebrate renal morphology and we investigated histological sections of human embryos between 2 and 8 weeks of development. To facilitate better understanding of the literature about kidney development, a referenced glossary with short definitions was composed. The most striking difference between pronephros versus meso- and metanephros is found in nephron architecture. The pronephros consists exclusively of non-integrated nephrons with external glomeruli, whereas meso- and metanephros are composed of integrated nephrons with internal glomeruli. Animals whose embryos have comparatively little yolk at their disposal and hence have a free-swimming larval stage do develop a pronephros that is dedicated to survival in aquatic environments. Species in which embryos do not have a free-swimming larval stage have embryos that are supplied with a large amount of yolk or that develop within the body of the parent. In those species the pronephros is usually absent, incompletely developed, and apparently functionless. Non-integrated nephrons were not identified in histological sections of human embryos. Therefore, we conclude that a true pronephros is not detectable in human embryos although the most cranial part of the amniote excretory organ is often confusingly referred to as pronephros. The term pronephros should be avoided in amniotes unless all elements for a functional pronephros are undeniably present.

Objective: Post-mortem computed tomography (PMCT) is an established method for disease, complications, and cause of death determination in both clinical and forensic cases. By adding intravascular infusion of contrast medium, computed tomography angiography (PMCTA) provides additional information on vascular structures and hemorrhages. When easily applicable and low in costs, this technique would be more frequently applied and of additional value to clinical and educational purposes, particularly in forensic scientific context. Materials and Methods: PMCTA was performed on 10 bodies of the anatomy department. First, a metal T-piece was inserted into the femoral artery as part of standard practice for conservation. Secondly, surplus contrast medium with sodium chloride was infused into the body through a catheter tube set attached to the metal T-piece, using a readily available enteroclysis pump from our radiology department. Results: With added costs of approximately € 266 (personnel and materials) and an additional procedure time of 15-20 minutes, successful infusion of contrast mixture was achieved with the enteroclysis pump. Partial or complete opacification was measured in 89% of arteries, with enhancement of soft tissue visualization. Conclusion: This study successfully evaluated an inexpensive and easy to use method to perform PMCTA for post-mortem investigations.

Supplemental material, DS_10.1369_0022155419878416 for Similarities Between Stem Cell Niches in Glioblastoma and Bone Marrow: Rays of Hope for Novel Treatment Strategies by Vashendriya V.V. Hira, Barbara Breznik, Miloš Vittori, Annique Loncq de Jong, Jernej Mlakar, Roelof-Jan Oostra, Mohammed Khurshed, Remco J. Molenaar, Tamara Lah and Cornelis J.F. Van Noorden in Journal of Histochemistry & Cytochemistry

Estimation of the postmortem interval in advanced postmortem stages is a challenging task. Although there are several approaches available for addressing postmortem changes of a (human) body or its environment (ecologically and/or biochemically), most are restricted to specific timeframes and/or individual and environmental conditions. It is well known, for instance, that buried bodies decompose in a remarkably different manner than on the ground surface. However, data on how established methods for PMI estimation perform under these conditions are scarce. It is important to understand whether and how postmortem changes are affected under burial conditions, if corrective factors could be conceived, or if methods have to be excluded for respective cases. We present the first multi-methodological assessment of human postmortem decomposition carried out on buried body donors in Europe, at the Amsterdam Research Initiative for Sub-surface Taphonomy and Anthropology (ARISTA) in the Netherlands. We used a multidisciplinary approach to investigate postmortem changes of morphology, skeletal muscle protein decomposition, presence of insects and other necrophilous animals as well as microbial communities (i.e., microbiomes) from August to November 2018 associated with two complete body exhumations and eight partial exhumations. Our results clearly display the current possibilities and limitations of methods for PMI estimation in buried remains and provide a baseline for future research and application.

Contains fulltext : 168015pub.pdf (Publisher’s version ) (Open Access) Most congenital conditions have low prevalence, but collectively they occur in a few percent of all live births. Congenital conditions are rarely encountered in anthropological studies, not least because many of them have no obvious effect on the skeleton. Here, we discuss two groups of congenital conditions that specifically affect the skeleton, either qualitatively or quantitatively. Skeletal dysplasias (osteochondrodysplasias) interfere with the histological formation, growth and maturation of skeletal tissues leading to diminished postural length, but the building plan of the body is unaffected. Well- known skeletal dysplasias represented in the archeological record include osteogenesis imperfecta and achondroplasia. Dysostoses, in contrast, interfere with the building plan of the body, leading to e.g. missing or extraskeletal elements, but the histology of the skeletal tissues is unaffected. Dysostoses can concern the extremities (e.g., oligodactyly and polydactyly), the vertebral column (e.g., homeotic and meristic anomalies), or the craniofacial region. Conditions pertaining to the cranial sutures, i.e., craniosynostoses, can be either skeletal dysplasias or dysostoses. Congenital conditions that are not harmful to the individual are known as anatomical variations, several of which have a high and population-specific prevalence that could potentially make them useful for determining ethnic origins. In individual cases, specific congenital conditions could be determinative in establishing identity, provided that ante-mortem registration of those conditions was ensured. Clin. Anat. 29:878-891, 2016. (c) 2016 The Authors Clinical Anatomy published by Wiley Periodicals, Inc. on behalf of American Association of Clinical Anatomists.

Files of the Dutch bureau of missing persons at the North Sea (BVPN) were investigated to analyse the process that led to identification of human bodies recovered from the North Sea between 1980 and 2013. Of the 94 cases that were analysed 41.5% was identified by the family, 23.4% by the use of DNA and 17% by the use of the dental status. The linking pin for the identification was the place where the body was found (14.9%), the general appearance (12.8%), jewellery (11.6%) and media attention (9.6%). In only a few cases the DNA or fingerprint database was used for identification. When a person is not reported missing the identification is problematic because of the lack of antemortem data. National and international databases of people who have gone missing, can help solve this problem.

Contains fulltext : 174200pub.pdf (Publisher’s version ) (Closed access) The Peter the Great Museum of Anthropology and Ethnography (Kunstkamera) in Saint Petersburg is the oldest museum in Russia. It keeps the remains of the anatomical collection of the world-famous 17th century Dutch anatomist Frederik Ruysch. This unique collection was bought and shipped in 1717 by Czar Peter the Great, and presently still comprises more than 900 specimens, a modest number of which concerns specimens with congenital anomalies. We searched for teratological clues in the existing collection and in all his descriptions and correspondence regarding specimens and cases he encountered during his career as doctor anatomiae and chief instructor of the surgeons and midwives in Amsterdam. A total of 63 teratological specimens and case descriptions were identified in this legacy, including some exceedingly rare anomalies. As it turns out, Ruysch was the first to describe several of the conditions we encountered, including intracranial teratoma, enchondromatosis, and Majewski syndrome. Although his comments pose an interesting view on how congenital anomalies were scientifically perceived in early 18th century Europe, Ruysch mostly refrained from explaining the causes of the conditions he encountered. Instead, he dedicated himself to careful descriptions of his specimens. Almost 300 years after his demise, Ruysch's legacy still impresses and inspires both scientists and lay men. (c) 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

Background: Recent studies reported an association between prenatal propylthiouracil exposure and birth defects, including abnormal arrangement across the left-right body axis, suggesting an association with heterotaxy syndrome. Methods: This case-control and case-finding study used data from 1981 to 2013 from the EUROCAT birth defect registry in the Northern Netherlands. First, we explored prenatal exposures in heterotaxy syndrome (cases) and Down syndrome (controls). Second, we describe the specific birth defects in offspring of mothers using propylthiouracil (PTU) prenatally. RESULTS: A total of 66 cases with heterotaxy syndrome (incidence 12.1 per 100,000 pregnancies) and 783 controls with Down syndrome (143.3 per 100,000 pregnancies) were studied. No differences in intoxication use during pregnancy were found between cases and controls, including smoking (28.0% vs. 22.7%; p = 0.40), alcohol (14.0% vs. 26.9%; p = 0.052), and recreational drugs (0 vs. 0.3%; p = 1.00). We found an association between heterotaxy syndrome and prenatal drug exposure to follitropin-alfa (5.6% vs. 1.1%; p = 0.04), and drugs used in nicotine dependence (3.7% vs. 0.2%; p = 0.02). Five mothers used PTU during pregnancy and gave birth to a child with trisomy 18, renal abnormalities, or hypospadias and cardiac defects. Conclusion: This study identified follitropin-alfa and drugs used in nicotine dependence as possible teratogens of heterotaxy syndrome. Our data suggest the possibility that there is an increased risk of birth defects (including renal, urological, and cardiac abnormalities) in children born among mothers taking PTU prenatally, but not for heterotaxy syndrome. (C) 2016 Wiley Periodicals, Inc.

The origin of the cardiovascular system of vertebrates is inferred from comparisons of basal chordates but must also encompass bewildering discrepancies. Basal chordates like lancelets (cephalochordates) have a vascular pattern similar to that of a vertebrate embryo, but without a recognizable heart or myocardium. Instead, the ‘venous’ part of their circulation contains contractile vessels, located upstream and downstream of the liver. Tunicates (urochordates) have a tubular heart containing cardiomyocytes and enclosed by a pericardium. Their circulation is open and the dominant pacemaker activity can be at either end of the heart tube, causing blood flow to reverse periodically. Recent molecular investigations have proved that urochordates rather than cephalochordates are the closest living relatives of vertebrates. This implies that the cardiovascular peculiarities of lancelets may be primitive ancestral qualities and that the original building plan of the vertebrate circulation featured a post-hepatic as well as a pre-hepatic cardiac pump.

Congenital muscle diseases, such as myopathies or dystrophies, occur relatively frequently, with estimated incidences of up to 4.7 per 100 000 newborns. To diagnose congenital diseases in the early stages of pregnancy, and to interpret the results of increasingly advanced in utero imaging techniques, a profound knowledge of normal human morphological development of the locomotor system and the nervous system is necessary. Muscular development, however, is an often neglected topic or is only described in a general way in embryology textbooks and papers. To provide the required detailed and updated comprehensive picture of embryologic muscular anatomy, three‐dimensional (3D) reconstructions were created based on serial histological sections of a human embryo at Carnegie stage 23 (8 weeks of development, crown–rump length of 23.8 mm), using amira reconstruction software. Reconstructed muscles, tendons, bones and nerves were exported in a 3D‐PDF file to permit interactive viewing. Almost all adult skeletal muscles of the trunk and limbs could be individually identified in their relative adult position. The pectoralis major muscle was divided in three separate muscle heads. The reconstructions showed remarkable highly developed extraocular, infrahyoid and suprahyoid muscles at this age but surprisingly also absence of the facial muscles that have been described to be present at this stage of development. The overall stage of muscle development suggests heterochrony of skeletal muscle development. Several individual muscle groups were found to be developed earlier and in more detail than described in current literature.

The anatomical collection of the Anatomical Museum of Leiden University Medical Center (historically referred to as Museum Anatomicum Academiae Lugduno-Batavae) houses and maintains more than 13,000 unique anatomical, pathological and zoological specimens, and include the oldest teratological specimens of The Netherlands. Throughout four centuries hundreds of teratological specimens were acquired by more than a dozen collectors. Due to the rich history of this vast collection, teratological specimens can be investigated in a unique retrospective sight going back almost four centuries. The entire 19th century collection was described in full detail by Eduard Sandifort (1742-1814) and his son Gerard Sandifort (1779-1848). Efforts were made to re-describe, re-diagnose and re-categorize all present human teratological specimens, and to match them with historical descriptions. In the extant collection a total of 642 human teratological specimens were identified, including exceptional conditions such as faciocranioschisis and conjoined twins discordant for cyclopia, and sirenomelia. Both father and son Sandifort differed in their opinion regarding the causative explanation of congenital anomalies. Whereas, their contemporaries Wouter Van Doeveren (1730-1783) and Andreas Bonn (1738-1817) both presented an interesting view on how congenital anomalies were perceived and explained during the 18th and 19th centuries; the golden age of descriptive teratology. Although this enormous collection is almost 400 years old, it still impresses scientists, (bio)medical students, and laymen visiting and exploring the collections of the Museum Anatomicum in Leiden, The Netherlands.

Since the multi-site closure theory was first proposed in 1991 as explanation for the preferential localizations of neural tube defects, the closure of the neural tube has been debated. Although the multi-site closure theory is much cited in clinical literature, single-site closure is most apparent in literature concerning embryology. Inspired by Victor Hamburgers (1900-2001) statement that "our real teacher has been and still is the embryo, who is, incidentally, the only teacher who is always right", we decided to critically review both theories of neural tube closure. To verify the theories of closure, we studied serial histological sections of 10 mouse embryos between 8.5 and 9.5 days of gestation and 18 human embryos of the Carnegie collection between Carnegie stage 9 (19-21 days) and 13 (28-32 days). Neural tube closure was histologically defined by the neuroepithelial remodeling of the two adjoining neural fold tips in the midline. We did not observe multiple fusion sites in neither mouse nor human embryos. A meta-analysis of case reports on neural tube defects showed that defects can occur at any level of the neural axis. Our data indicate that the human neural tube fuses at a single site and, therefore, we propose to reinstate the single-site closure theory for neural tube closure. We showed that neural tube defects are not restricted to a specific location, thereby refuting the reasoning underlying the multi-site closure theory. Clin. Anat. 30:988-999, 2017. © 2017 Wiley Periodicals, Inc.

The aim of this study was to determine whether effects of repetitive freeze-thaw cycles, with various thawing temperatures, on human muscle tissue can be quantified using postmortem computed tomography (PMCT) technology. An additional objective was to determine the preferred thawing temperature for muscle tissue in this study. Human cadaver upper extremities were divided into two different thawing temperature groups and underwent a series of four freeze-thaw cycles in total. Axial CT scans were performed after each cycle. CT attenuation (in Hounsfield units, HU) was measured in four muscles of the upper extremities. HU values changed significantly with the introduction of each subsequent freeze-thaw cycle. Moreover, the changes in HU values were different for each thawing group. There was a significant increase of HU values in both groups between t

The most impressive phenotypic appearance of sirenomelia is the presence of a 180°-rotated, axially positioned, single lower limb. Associated gastrointestinal and genitourinary anomalies are almost always present. This rare anomaly is still the subject of ongoing controversies concerning its nosology, pathogenesis, and possible genetic etiology. Sirenomelia can be part of a syndromic continuum, overlapping with other complex conditions including caudal dysgenesis and VATER/VACTERL/VACTERL-H associations, which could all be part of a heterogeneous spectrum, and originate from an early defect in blastogenesis. It is imaginable that different "primary field defects," whether or not genetically based, induce a spectrum of caudal malformations. In the current study, we review the contemporary hypotheses and conceptual approaches regarding the etiology and pathogenesis of sirenomelia, especially in the context of concomitant conditions. To expand on the latter, we included the external and internal dysmorphology of one third trimester sirenomelic fetus from our anatomical museum collection, in which multiple concomitant but discordant anomalies were observed compared with classic sirenomelia, and was diagnosed as VACTERL-H association with sirenomelia. Birth Defects Research 109:791-804, 2017. © 2017 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc. ispartof: Birth defects research vol:109 issue:10 pages:791-804 ispartof: location:United States status: published

Recent studies reported an association between prenatal propylthiouracil exposure and birth defects, including abnormal arrangement across the left-right body axis, suggesting an association with heterotaxy syndrome.This case-control and case-finding study used data from 1981 to 2013 from the EUROCAT birth defect registry in the Northern Netherlands. First, we explored prenatal exposures in heterotaxy syndrome (cases) and Down syndrome (controls). Second, we describe the specific birth defects in offspring of mothers using propylthiouracil (PTU) prenatally.A total of 66 cases with heterotaxy syndrome (incidence 12.1 per 100,000 pregnancies) and 783 controls with Down syndrome (143.3 per 100,000 pregnancies) were studied. No differences in intoxication use during pregnancy were found between cases and controls, including smoking (28.0% vs. 22.7%; p = 0.40), alcohol (14.0% vs. 26.9%; p = 0.052), and recreational drugs (0 vs. 0.3%; p = 1.00). We found an association between heterotaxy syndrome and prenatal drug exposure to follitropin-alfa (5.6% vs. 1.1%; p = 0.04), and drugs used in nicotine dependence (3.7% vs. 0.2%; p = 0.02). Five mothers used PTU during pregnancy and gave birth to a child with trisomy 18, renal abnormalities, or hypospadias and cardiac defects.This study identified follitropin-alfa and drugs used in nicotine dependence as possible teratogens of heterotaxy syndrome. Our data suggest the possibility that there is an increased risk of birth defects (including renal, urological, and cardiac abnormalities) in children born among mothers taking PTU prenatally, but not for heterotaxy syndrome. Birth Defects Research (Part A) 106:573-579, 2016. © 2016 Wiley Periodicals, Inc.

Sex estimation techniques are frequently applied in forensic anthropological analyses of unidentified human skeletal remains. While morphological sex estimation methods are able to endure population differences, the classification accuracy of metric sex estimation methods are population-specific. No metric sex estimation method currently exists for the Dutch population. The purpose of this study is to create Dutch population specific sex estimation formulae by means of osteometric analyses of the proximal femur. Since the Netherlands lacks a representative contemporary skeletal reference population, 2D plane reconstructions, derived from clinical computed tomography (CT) data, were used as an alternative source for a representative reference sample. The first part of this study assesses the intra- and inter-observer error, or reliability, of twelve measurements of the proximal femur. The technical error of measurement (TEM) and relative TEM (%TEM) were calculated using 26 dry adult femora. In addition, the agreement, or accuracy, between the dry bone and CT-based measurements was determined by percent agreement. Only reliable and accurate measurements were retained for the logistic regression sex estimation formulae; a training set (n = 86) was used to create the models while an independent testing set (n = 28) was used to validate the models. Due to high levels of multicollinearity, only single variable models were created. Cross-validated classification accuracies ranged from 86% to 92%. The high cross-validated classification accuracies indicate that the developed formulae can contribute to the biological profile and specifically in sex estimation of unidentified human skeletal remains in the Netherlands. Furthermore, the results indicate that clinical CT data can be a valuable alternative source of data when representative skeletal collections are unavailable.

The Museum Vrolik collection of anatomical specimens in Amsterdam, The Netherlands, comprises over 5,000 specimens of human and animal anatomy, embryology, pathology, and congenital anomalies. Recently, we rediagnosed a subset of the collection comprising dried human trunk skeletons and cranial base preparations presenting with homeotic transformations (vertebral phenotypic shifts) and numerical vertebral anomalies. We identified 11 trunk skeletons with either anterior or posterior homeotic transformations (AHT or PHT), 5 trunk skeletons with either less or more than the normal number of vertebrae, and well over a hundred cranial base preparations with either AHT (atlas-assimilation) or PHT (occipital vertebra). We found that, although homeotic transformations and numerical anomalies are distinct conditions, both can be described in terms of mismatch between homeotic patterning and morphological segmentation of the paraxial mesoderm. Therefore these two processes are perhaps not as tightly linked as they may seem on the basis of recent molecular studies. In homeotic transformations there is a constant mismatch between homeotic patterning and morphological segmentation throughout the affected region of the vertebral column. In numerical anomalies there is a variable mismatch between homeotic patterning and morphological segmentation, either because of stretching or squeezing of the homeotic pattern or because of oligo- or polysegmentation of the presomitic mesoderm (PSM). Homeotic transformations of the axial skeleton have an incidence of about 1%-5%, apart from their occurrence in malformation syndromes. Of the various etiological possibilities, explaining their frequent but mostly sporadic occurrence, maternal hyperthermia seems an attractive candidate.

The complete mitochondrial DNA (mtDNA) sequences for 63 Dutch pedigrees with Leber hereditary optic neuropathy (LHON) were determined, 56 of which carried one of the classic LHON mutations at nucleotide (nt) 3460, 11778, or 14484. Analysis of these sequences indicated that there were several instances in which the mtDNAs were either identical or related by descent. The most striking example was a haplogroup J mtDNA that carried the 14484 LHON mutation. Four different but related mitochondrial genotypes were identified in seven of the Dutch pedigrees with LHON, including six of those described by van Senus. The control region of the founder sequence for these Dutch pedigrees with LHON matches the control-region sequence that Macmillan and colleagues identified in the founder mtDNA of French Canadian pedigrees with LHON. In addition, we obtained a perfect match between the Dutch 14484 founder sequence and the complete mtDNA sequences of two Canadian pedigrees with LHON. Those results indicate that these Dutch and French Canadian 14484 pedigrees with LHON share a common ancestor, that the single origin of the 14484 mutation in this megalineage occurred before the year 1600, and that there is a 14484/haplogroup J founder effect. We estimate that this lineage--including the 14484 LHON mutation--arose 900-1,800 years ago. Overall, the phylogenetic analyses of these mtDNA sequences conservatively indicate that a LHON mutation has arisen at least 42 times in the Dutch population. Finally, analysis of the mtDNA sequences from those pedigrees that did not carry classic LHON mutations suggested candidate pathogenic mutations at nts 9804, 13051, and 14325.

The Museum Vrolik collection of the Department of Anatomy and Embryology of the Academic Medical Center, University of Amsterdam, founded by Gerardus Vrolik (1775–1859) and his son Willem Vrolik (1801–1863), consists of more than 5,000 specimens of human and animal anatomy, embryology, pathology, and congenital anomalies. Recently, the collection of congenital anomalies, comprising 360 specimens, was recatalogued and redescribed according to contemporary perspectives. The original descriptions, as far as preserved, were compared with the clinical, radiographic, and magnetic resonance imaging findings. We diagnosed 30 symmetrical conjoined twins (CTs), 11 parasitic CTs, and 16 acardiac twins. Within the group of symmetrical CTs, the following concomitant external anomalies were found in 15 specimens: neural tube defects, holoprosencephaly, cleft lip/ palate, umbilical hernia, omphalocele, cloacal exstrophy, peromelia, polydactyly, and facial abnormalities suggestive of a chromosomal abnormality. We discuss the results in the light of historical and contemporary explanations regarding conjoined twinning, including the opinions of Gerardus and Willem Vrolik and of Louis Bolk, one of their successors. Am. J. Med. Genet. 80:74–89, 1998. © 1998 Wiley-Liss, Inc.

The Museum Vrolik collection of the Department of Anatomy and Embryology of the University of Amsterdam, founded by Gerardus Vrolik (1775-1859) and his son Willem Vrolik (1801-1863), consists of more than five thousand specimens of human and animal anatomy, embryology, pathology, and congenital anomalies. Recently, the collection of congenital anomalies was recatalogued and redescribed according to contempory syndromological views. The original descriptions, as far as preserved, were compared with the clinical and radiographical findings. In 18 specimens the following skeletal dysplasias were diagnosed: achondrogenesis, achondroplasia, Blomstrand chondrodysplasia, Majewski syndrome, osteodysplastic primordial dwarfism, osteogenesis imperfecta type I, osteogenesis imperfecta type II, and thanatophoric dysplasia with and without cloverleaf skull. Radiography did not yield a diagnosis in 4 specimens. The use of additional diagnostical techniques, such as MRI and CT scanning and fluorescence in situ hybridization in these specimens, is currently being investigated.

To identify factors that influence the quality of postmortem magnetic resonance (MR) images of musculoskeletal (MSK) structures as described in the literature, and to evaluate the extent to which these MR images are affected. Four useful studies were retrieved from a PubMed and EMBASE search, covering the literature up to 1 March 2012. Three additional studies were included after a manual search from reference lists. Four human studies and three animal studies are considered in this review. Postmortem MRI quality can be affected by storage temperature, repeated freezing and thawing and fixation. Provided there was an adequate, but above-freezing storage temperature, postmortem changes in fresh cadavers did not appear to affect the MR image quality of MSK structures up to 14 days after death. Image contrast, signal intensities, and relaxation times are temperature-dependent, regardless of whether the specimen was fresh or postmortem for up to 7 days. Bad image quality can occur owing to accelerated autolysis. Freezing and thawing did not affect image quality, unless repeated too often, or whenever a heating pad was used to speed up the thawing process. Conventional formalin-based fixation leads to swelling of soft tissue and fluid accumulation in joints, and therefore to deteriorated images, with image quality just sufficient to visualize gross anatomy. Various factors were identified that affect postmortem MR image quality of MSK structures. Postmortem MR image quality was good, except for images of the fixated specimen. Freezing is the preferred method of conservation for specimens that are to be subjected to postmortem MRI

The Beckwith-Wiedemann syndrome (BWS) is a growth disorder for which an increased frequency of monozygotic (MZ) twinning has been reported. With few exceptions, these twins are discordant for BWS and for females. Here, we describe the molecular and phenotypic analysis of 12 BWS twins and a triplet; seven twins are MZ, monochorionic and diamniotic, three twins are MZ, dichorionic and diamniotic and three twins are dizygotic. Twelve twins are female. In the majority of the twin pairs ( 11 of 13), the defect on chromosome 11p15 was hypomethylation of the paternal allele of DMR2. In 5 of 10 twins, there was additional hypomethylation of imprinted loci; in most cases, the loci affected were maternally methylated, but in two cases, hypomethylation of the paternally methylated DLK1 and H19 DMRs was detected, a novel finding in BWS. In buccal swabs of the MZ twins who share a placenta, the defect was present only in the affected twin; comparable hypomethylation in lymphocytes was detected in both the twins. The level of hypomethylation reached levels below 25%. The exchange of blood cells through vascular connections cannot fully explain the degree of hypomethylation found in the blood cell of the non-affected twin. We propose an additional mechanism through which sharing of aberrant methylation patterns in discordant twins, limited to blood cells, might occur. In a BWS-discordant MZ triplet, an intermediate level of demethylation was found in one of the non-affected sibs; this child showed mild signs of BWS. This finding supports the theory that a methylation error proceeds and possibly triggers the twinning process. European Journal of Human Genetics (2009) 17, 1625-1634; doi:10.1038/ejhg.2009.77; published online 10 June 2009

A hitherto unknown combination of multiple bifid ribs, as seen in Gorlin syndrome (GS), interpedicular fusion and apparent malsegmentation of vertebral laminae at various upper thoracic levels was found in the skeleton of a newborn infant. This specific combination of anomalies is also seen in the mouse open brain (opb) mutant. Since the genes involved in GS (Patched2) and opb (rab23) both play an essential role in the hedgehog signaling pathway, it is likely that the cause of the anomalies presented here is to be sought in impaired functioning of this pathway. © 2006 Wiley-Liss, Inc.

Aplasia of the trapezius muscle is a rarely encountered, mostly asymptomatic anomaly. We report a case of isolated unilateral complete trapezius aplasia that was noticed during a dissection course. Apart from isolated cases, trapezius aplasia may occur in different combinations with other muscle aplasias. We suggest that the patterns of concomitant muscle involvement are indicative of a combined occipital and cervical somitogenic origin. Clin. Anat. 19:547–549, 2006. © 2006 Wiley-Liss, Inc.

Skin biopsies in patients with pseudoxanthoma elasticum (PXE) show elastic fiber fragmentation and calcium and proteoglycans accumulation. Assuming such changes to be present in the artery wall as well, we studied the influence of such alterations on function and structure of the human common carotid artery (CCA). Indeed, elastin fragmentation and increased calcium and proteoglycans content were present in the arteries of the two PXE patients examined. Internal diameter, distension and intima-media thickness (IMT) in the CCA of PXE patients (n = 19) and controls (n = 39) were determined by ultrasound (US). Pulse pressure was assessed in the brachial artery. The distensibility and compliance coefficients as well as the Young's modulus were calculated. Diameter and pulse pressure were not significantly different in PXE patients and controls. The distensibility and compliance coefficients were significantly greater in older PXE patients than in older controls. The distensibility coefficient decreased with age in both PXE patients and in controls. Unlike in controls, the compliance coefficient did not decrease and the Young's modulus barely increased with age in PXE patients. IMT was significantly greater at both younger and older ages and the Young's modulus was significantly smaller at older ages in PXE patients than in controls. The carotid artery is thicker and more elastic in PXE patients than in control subjects; differences are most pronounced at older ages. These alterations might be explained by the elastin fragmentation and proteoglycans accumulation as observed in these patients.

A hitherto unknown combination of congenital anomalies was found in an anatomical specimen of a female neonate. External examination and additional CT and MRI studies showed thanatophoric dysplasia type II with cloverleaf skull and concomitant parietal meningoencephalocele and hypoplasia of the descending aorta. The possibilities of causal correlations are discussed. © 2003 Wiley-Liss, Inc.

Injuries to the lateral ligament complex of the ankle are common problems in acute care practice. We believe that a well-developed knowledge of the anatomy provides a foundation for understanding the basic mechanism of injury, diagnosis, and treatment, especially surgical treatment, of lateral collateral ankle ligament injury. To address this issue we performed this review with regard to the anatomy of the lateral collateral ankle ligaments. Clin. Anat. 21:619–626, 2008. © 2008 Wiley-Liss, Inc.

Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder of the optic nerves. It has been proposed that the specific mutations in the mitochondrial DNA (mtDNA) that are associated with LHON require and X-chromosomally encoded permissive factor in order to become expressed. This would explain both the preponderance of male patients and the fact that most carriers of specific mtDNA mutations remain unaffected. Although linkage studies have been negative so far, the existence of such a factor has not been ruled out. We investigated the genealogical data of 24 large LHON pedigrees and concluded that the presumed X-linked factor would be recessively inherited and that at least 57% of the affected females would be heterozygous. Therefore, these females must be the victim of nonrandom X-chromosomal inactivation (skewed lyonization). However, analysis of X-chromosomal methylation patterns in 16 LHON-affected females revealed substantial skewing in only 15%-20% of cases, which is not significantly different from the patterns in 49 controls. Moreover, we found the frequency of LHON in daughters of affected heterozygous females to be twice to three times as high as in daughters of unaffected heterozygous females, which cannot be explained by an X-chromosomally inherited factor. We concluded that the results of our investigations do not support the hypothesis that LHON is a digenic disease with an X-linked factor being the main cause of loss of vision in the presence of relevant mtDNA mutations.