Body Wall Defects Research Articles

Limb body wall complex: Its delineation and relationship with amniotic bands using clustering methods.

Despite the numerous reports on the limb body wall complex (LBWC), this association has never been adequately defined. Amniotic bands (AB) are frequently present but their role remains unclear. Since most reports were based on clinical and often subjective diagnoses, the aim of this work was to define LBWC and the role of AB, minimizing subjectivity. Data were obtained from the ECLAMC maternity hospitals network database. A total of 450 live and stillborn infants, born during 1967-2013, with AB or the LBWC were selected. A hierarchical cluster analysis was used to classify cases into homogeneous groups (sharing similar associated defects); robustness of the classification was confirmed with a discriminant analysis. The frequency of associated defects was compared among groups; those whose frequency differed significantly were included in a logistic regression to establish their association within each group. The cluster analysis identified two groups: a body wall defect (BWD) predominating in one, AB in the other. These groups were further divided into: BWD (cases with only BWD), AB (with only AB), BWD + AB, and NONE (with neither). Association with caudal defects and lower limb amelia was observed for BWD, with cephalic defects and upper limb amputations for BWD + AB. The results, obtained with the least possible subjectivity, indicated that BWD and BWD + AB are different conditions. Since BWD specifically associates with amelia, we propose that this defect and not any limb deficiency should be considered as inclusion criterium and that it should be included in the BWD acronym as LBWC.

Mice doubly deficient in Six4 and Six5 show ventral body wall defects reproducing human omphalocele

ABSTRACTOmphalocele is a human congenital anomaly in ventral body wall closure and may be caused by impaired formation of the primary abdominal wall (PAW) and/or defects in abdominal muscle development. Here, we report that mice doubly deficient in homeobox genes Six4 and Six5 showed the same ventral body wall closure defects as those seen in human omphalocele. SIX4 and SIX5 were localized in surface ectodermal cells and somatic mesoderm-derived mesenchymal and coelomic epithelial cells (CECs) in the PAW. Six4−/−;Six5−/− fetuses exhibited a large omphalocele with protrusion of both the liver and intestine, or a small omphalocele with protrusion of the intestine, with complete penetrance. The umbilical ring of Six4−/−;Six5−/− embryos was shifted anteriorly and its lateral size was larger than that of normal embryos at the E11.5 stage, before the onset of myoblast migration into the PAW. The proliferation rates of surface ectodermal cells in the left and right PAW and somatic mesoderm-derived cells in the right PAW were lower in Six4−/−;Six5−/− embryos than those of wild-type embryos at E10.5. The transition from CECs of the PAW to rounded mesothelial progenitor cells was impaired and the inner coelomic surface of the PAW was relatively smooth in Six4−/−;Six5−/− embryos at E11.25. Furthermore, Six4 overexpression in CECs of the PAW promoted ingression of CECs. Taken together, our results suggest that Six4 and Six5 are required for growth and morphological change of the PAW, and the impairment of these processes is linked to the abnormal positioning and expansion of the umbilical ring, which results in omphalocele.

Ringed Placenta: Changes in Placental Perfusion Associated with Increased Mortality with Ventral Body Wall Defect [18E

INTRODUCTION: Purpose is to assess perinatal morbidity/mortality among infants with ventral wall defects (VWD) and abnormal placental perfusion patterns on prenatal MRI. METHODS: A retrospective case series of pregnancies complicated by VWD (omphalocele, OEIS sequence, and bladder exstrophy) performed over a 7-year period. Maternal and infant charts were reviewed for basic demographic data, placental pathology, and neonatal outcomes. MRI studies were reviewed by 2 experts with a specialized focus in fetal MRI. RESULTS: 31 cases of VWD were noted, and 11 cases possessed a novel placental perfusion pattern of a “ringed placenta” (pattern of rings of hyperintense MR signal surrounding hypointense placental cotyledons) seen throughout the parenchyma. In cases with a ringed placenta, five of 11 (45%) survived until 6 months of age. For the control group of VWD without the ringed placenta fourteen of 20 (70%) survived until 6 months of age. The relative risk for stillbirth/neonatal demise vs stillbirth/demise within 24hrs was 1.32 vs. 2.3 in VWD with the ringed placenta. Over 50% of infant demises with abnormal placental findings and 25% of normal placenta finding were found to be small for gestational age (SGA) at birth, while all of the surviving infants were within normal range birth weight for gestational age. CONCLUSION: Compared to those pregnancies without the “ringed placenta, cases of VWD with the ringed placenta had a higher rate of death and were more likely to be SGA at birth. We did not find an increased risk of extremely low birth weights. Further study is needed to characterize this finding.

SPECC1L: A Novel Cytoskeletal Regulator of Epithelial Organization in Craniofacial Morphogenesis

Craniofacial anomalies are extremely common among birth defects, with clefts of the lip and palate affecting approximately 1/700 live‐births. While many contributory genes have been identified, a large proportion of the genetic component of this complex disease is unknown. Thus, there is a continued need to identify additional genes and to understand underlying pathogenetic mechanisms. We first identified heterozygous SPECC1L mutations in two patients with atypical facial clefts and cleft palate. New heterozygous missense SPECC1L mutations have been identified in two autosomal dominant Opitz G/BBB syndrome families with hypertelorism and cleft palate, and in two patients with Teebi hypertelorism syndrome, underscoring the importance of SPECC1L in craniofacial development. To understand the role of SPECC1L, we have generated several mouse models with null and hypomorphic (truncation, in‐frame deletion, missense) mutations. Mutants for these alleles manifest a range of structural malformations, including exencephaly, cleft palate and ventral body wall defects. The homozygous null mutants die by embryonic day 9.5 (E9.5) with an open neural tube and failure of cranial neural crest cells to delaminate from the neuroectoderm. We have shown that the latter is due to increased expression of adherens junction markers in the neuroectoderm and reduced PI3K‐AKT signaling. Homozygous mutants for a hypomorphic allele that results in SPECC1L truncation die perinatally and show midline subepidermal blebbing with no cleft palate. Specc1lnull/hypo compound mutants with moderate SPECC1L deficiency show palate elevation defects at E14.5, which resolve within one embryonic day such that only a few mutants are born with cleft palate. However, these compound mutants show abnormal organization of the oral periderm of palatal shelves and occasional oral adhesions at E13.5. Consistent with these periderm anomalies, SPECC1L expression in the palate requires IRF6, thus making it a novel member of the IRF6/GRHL3 pathway in periderm development. Lastly, homozygous mouse mutants carrying human Opitz G/BBB patient mutation (T397P) show highly penetrant cleft palate, indicating a gain‐of‐function that specifically affects palatogenesis. Given the broad phenotypic spectrum of Specc1l allelic series mutants, our studies indicate that SPECC1L regulates epithelial organization at various stages and in multiple tissues throughout embryonic development.Support or Funding InformationThis research is supported by NIH/NIDCR R01DE026172.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A Case of Bilateral Craniofacial Cleft From Amniotic Band Syndrome

Amniotic band syndrome [ABS] or amniotic disruption complex is defined as a destructive process of fetal damage in a random non symmetrical distribution, which is not attributable to aberrations in normal embryologic development processes .The mechanism has been considered to be initiated in rupture of the amnion, with the fetus then coming into contact with the chorionic surface of the amniotic membrane ,to which it adheres or becomes entwined by fibrous strands .As the fetus grows ,The tethered regions are progressively distorted, leading to constrictions, amputations ,Slash defects, and body wall or cranial defects .The severity varies from a single constrictive ring of a digit to lethal thoraco abdominal eviscerations or craniofacial distruction.ABS is a rare disorder in which bands of mesoderm that emanate from the chorionic side of the amnion and insert on the fetal body can lead to a wide variety of disfiguring and disabling malformations[1,2] . ABS results in the amputation of the fingers or limbs, associated with a wide spectrum of congenital anomalies usually involving the trunk and craniofacial regions including the skull. AbBS is in general sporadic and the incidence is approximately 1 in 15,000 live birth. Characterized by a destructive fetal process that is initiated by rupture of the amnion. Proposed as a sequel of intrauterine rupture of the amnion resulting in oligohydramnios and passage of fetus to chorionic cavity .The fetus subsequently becomes adherent to intertwined in, and tethered by fibrous mesodermic bands .As the fetus grows, its anatomy is distorted .This may lead to cranial or body wall defects or and although been reports of associated malformations of internal structures. [3, 4] ABS that involves craniofacial region may present as cleft lip or palate , oblique or transverse facial cleft .These craniofacial anomalies in ABS are typically often bizarre and frequently non-embryological .The exact cause of ABS is still unknown .This lack of direct evidence has led to the proposal of two main etiological theories. The extrinsic and the intrinsic 4. The extrinsic theory states that the band of ruptured amnion causes an extrinsic compression which then results in constriction rings and other deformities of the developing fetus, while the intrinsic theory holds that germ cell deficiencies result in the malformation of the affected parts [4]. Treatment is usually carried out after birth when plastic and reconstructive surgery is considered to treat the resulting deformities. [4, 5] (Ethiopian Journal of Reproductive Health 2016; 8:50-55)

Exposure to sub-lethal dose of a combination insecticide during early embryogenesis influences the normal patterning of mesoderm resulting in incomplete closure of ventral body wall of chicks of domestic hen.

Pesticide exposure to the non target groups especially during embryonic development has quite often resulted in congenital malformations. A commercially available combination insecticide (Ci, 50% chlorpyrifos and 5% cypermethrin) is known to induce ventral body wall defects (VBWDs) wherein abdominal viscera protrude out of the ventral body wall. Herein, an attempt was made to understand the mechanistic insight into Ci induced VBWDs. For this, before incubation, the chick embryos were dosed with the test chemical and then at different developmental stages of incubation, they were monitored for the changes in the expression of certain genes, which are indispensable for the ventral body wall closure since they regulate the cell fate, proliferation and survival. Concurrently, histopathological changes during the embryonic development were examined to corroborate the above observations. The results of mRNA profiling revealed a significant downregulation of Shh on day 4 and upregulation on day 10, while bmp4, Pitx2, E-cadherin, Wnt11, Wnt6, Pxn, MyoD1, Caspase-3, AHR, Cyp3A4, showed a significant upregulation on day 4 and/or on day 10. N-cadherin, fgf8, bmp1 showed no significant changes. The possible means by which these skewed expression patterns of regulatory molecules culminated into the VBWD are discussed.

Sequence variants identification at the KCNQ1OT1:TSS differentially Methylated region in isolated omphalocele cases

BackgroundOmphalocele is a congenital midline ventral body wall defect that can exist as isolated malformation or as part of a syndrome. It can be considered one of the major and most frequent clinical manifestation of Beckwith-Wiedemann Syndrome (BWS) in case of loss of methylation at KCNQ1OT1: Transcription Star Site-Differentially Methylated Region (TSS-DMR) or in presence of CDKN1C mutations. The isolated form of the omphalocele accounts approximately for about the 14% of the total cases and its molecular etiology has never been fully elucidated.MethodsGiven the tight relationship with BWS, we hypothesized that the isolated form of the omphalocele could belong to the heterogeneous spectrum of the BWS associated features, representing an endophenotype with a clear genetic connection. We therefore investigated genetic and epigenetic changes affecting BWS imprinted locus at 11p15.5 imprinted region, focusing in particular on the KCNQ1OT1:TSS DMR.ResultsWe studied 21 cases of isolated omphalocele detected during pregnancy or at birth and identified the following rare maternally inherited variants: i) the non-coding variant G > A at nucleotide 687 (NR_002728.3) at KCNQ1OT1:TSS-DMR, which alters the methylation pattern of the imprinted allele, in one patient; ii) the deletion c.624-629delGGCCCC at exon 1 of CDKN1C, with unknown clinical significance, in two unrelated cases.ConclusionsTaken together, these findings suggest that KCNQ1OT1:TSS-DMR could be a susceptibility locus for the isolated omphalocele.

Complex malformations involving the fetal body wall – definition and classification issues

The objective of the study is to analyse the sonographic features, cytogenetic results and pregnancy outcomes in complex malformations involving the body wall in a large cohort of fetuses with regard to different definitions proposed in the literature. A retrospective study on 96 fetuses with complex malformations comprising ventral wall, craniofacial structures, limbs and umbilical cord that were evaluated between 1997 and 2015. The most common sonographic finding was an extensive ventral wall defect (95.8%; 92/96) comprising liver (94.6%; 87/92), intestine (82.6%; 76/92), heart (17.4%; 16/92) and bladder (8.7%; 8/92). Acrania and encephalocoele were observed in 24 and 9 fetuses (25.0%, 24/96; 9.4%, 9/96), respectively. Limb anomalies were present in 54 fetuses (56.3%; 54/96). Rudimentary or absent umbilical cord was observed in 62 fetuses (64.6%; 62/96). In 79 fetuses, there were additional multiple structural anomalies detected prenatally. None of the currently used definitions encompasses all possible phenotypes of body wall defects present in our cohort. Chromosomal aberrations were seen in 8 out of 60 cases with conclusive cytogenetic result (13.3%, 8/60). Chromosomal anomalies are common, and karyotyping should be offered. There is a need for a more rigorous classification of complex malformations in order to better understand the underlying pathophysiology. © 2017 John Wiley & Sons, Ltd.

LDT classification and therapeutic strategy of congenital body wall defects

Repairing body wall defects is a critical step in the treatment of some congenital deformities, and this procedure may need the help from plastic surgeons. Although there are many articles about congenital deformities, body wall defects of these malformations are rarely studied as independent targets. In this article, the authors present an LDT classification for congenital body wall defects according to the position of the defects, the tissue layers involved, and the surgical urgency, each of which is represented by letters L, D, and T, respectively. That is, the defects in different areas (L), full-thickness (D1), or partial (D0A, D0B) defects, defects needing instant repair (T2), semi-elective repair (T1), or elective repair (T0). Based on this classification system, the authors have performed body wall reconstruction on two pairs of thoraco-omphalopagus twins, one pair of ischiopagus tetrapus twins, and an infant and an adult, both of whom were diagnosed with pentalogy of Cantrell associated with ectopia cordis. Except for one pair of thoraco-omphalopagus twins who died after emergency separation, all the other patients survived. Another pair of thoraco-omphalopagus twins suffered from wound dehiscence and partial flap necrosis, respectively, after surgery. An expanded polytetrafluoroethylene mesh in one sister of the ischiopagus twins was removed because of infection. LDT classification not only can help doctors categorise different congenital body wall defects rapidly and easily, but can also guide the reconstruction of these defects. It may have clinical value to plastic surgeons to some extent.

The modern methods of X-Ray based diagnostic in cases of ectopia cordis associated with pentalogy of Cantrell

Pentalogy of Cantrell with ectopia cordis is an extremely rare and lethal congenital anomaly included congenital hearth disease (CHD), midline supraumbilical abdominal wall defect, defect of lower sternum part, deficiency of the anterior diaphragm, a defect in the diaphragmatic pericardium. The complexity of this syndrome is usually incompatible with life. Depending on the location of the protruding heart and on the extent of the body wall defect, ectopia cordis may be grouped into cervical, thoracic, thoracoabdominal, or abdominal types. The heart mostly uncovered, covered with a serous membrane less often, and covered with skin rare. Depending on combination defects pentalogy of Cantrell classified for 3 different classes by Toyama (classified in 1972): 1 class – complete syndrome (all five defects), 2 class – probable syndrome (included intracardial defect and ventral abdominal wall defect) 3 class – incomplete syndrome (with various combinations of defects present, including a sternal abnormality). Presented clinical case newborn pentalogy of Cantrell first Toyama class. We used X-Ray for firstly diagnostic, for visualization CHD was performed CT. For postnatal diagnostic CHD are used Echo and CT. CT allows graphically to see the type of CHD and predict a surgical treatment. The strategy of surgical treatment and further prognose are depend on combination of anomalies within the framework of pentalogy of Cantrell. By CT we determined atresia of the pulmonary artery with major aorto-pulmonary collateral arteries (MAPCA), ventricular and atrial septal defects.

Discordant Anomalies with Combined Features of Pentalogy of Cantrell and OEIS Complex: A Case Report in Monochorionic Twins

ABSTRACTIntroduction: Ventral body wall defects have various manifestations. Among others, pentalogy of Cantrell (PC) and omphalocele exstrophy imperforate anus spinal abnormalities (OEIS) complex are defects that involve upper and lower anterior midline of body wall, respectively. Although both entities are in a spectrum of ventral body wall defects, the combination of PC and OEIS complex has not been described. Case Report: In this report, we describe an unusual case of congenital ventral body wall defect with combined features of PC and OEIS complex, which discordantly occurred in monochorionic monoamniotic twins. Conclusion: PC and OEIS complex may be related regarding their embryologic origins. The combination may represent the most severe manifestation of ventral body wall defects.

Calreticulin Is Required for TGF-β-Induced Epithelial-to-Mesenchymal Transition during Cardiogenesis in Mouse Embryonic Stem Cells.

SummaryCalreticulin, a multifunctional endoplasmic reticulum resident protein, is required for TGF-β-induced epithelial-to-mesenchymal transition (EMT) and subsequent cardiomyogenesis. Using embryoid bodies (EBs) derived from calreticulin-null and wild-type (WT) embryonic stem cells (ESCs), we show that expression of EMT and cardiac differentiation markers is induced during differentiation of WT EBs. This induction is inhibited in the absence of calreticulin and can be mimicked by inhibiting TGF-β signaling in WT cells. The presence of calreticulin in WT cells permits TGF-β-mediated signaling via AKT/GSK3β and promotes repression of E-cadherin by SNAIL2/SLUG. This is paralleled by induction of N-cadherin in a process known as the cadherin switch. We show that regulated Ca2+ signaling between calreticulin and calcineurin is critical for the unabated TGF-β signaling that is necessary for the exit from pluripotency and the cadherin switch during EMT. Calreticulin is thus a key mediator of TGF-β-induced commencement of cardiomyogenesis in mouse ESCs.

Discordant malformation in a monozygotic pregnancy: abdominoschisis and sirenomelia

Abstract Congenital malformations occur in up to 10% of monochorionic twins and are usually discordant. Body wall defect (BWD) is a rare entity of very low prevalence, defined as a combination of various malformations, including fetal body mutilations of thoracic and/or abdominal organs that can be caused by amniotic rupture early in embryonic development. Sirenomelia is a form of caudal regression syndrome that presents with lower limb fusion, among other anomalies. In this report, we will present a second trimester monochorionic diamniotic pregnancy, with BWD-abdominoschisis in one fetus and sirenomelia in the other one. Amniotic bands could not be found. Of particular importance in respect to both malformations is the timing of the insult that could have caused both anomalies.

44 - Is balloon kyphoplasty safe and effective for cancer-related vertebral compression fractures with posterior vertebral body wall defects?

44 - Is balloon kyphoplasty safe and effective for cancer-related vertebral compression fractures with posterior vertebral body wall defects?

Transgelin-expressing myofibroblasts orchestrate ventral midline closure through TGFβ signalling.

Ventral body wall (VBW) defects are among the most common congenital malformations, yet their embryonic origin and underlying molecular mechanisms remain poorly characterised. Transforming growth factor beta (TGFβ) signalling is essential for VBW closure, but the responding cells are not known. Here, we identify in mouse a population of migratory myofibroblasts at the leading edge of the closing VBW that express the actin-binding protein transgelin (TAGLN) and TGFβ receptor (TGFβR). These cells respond to a temporally regulated TGFβ2 gradient originating from the epithelium of the primary body wall. Targeted elimination of TGFβR2 in TAGLN+ cells impairs midline closure and prevents the correct subsequent patterning of the musculature and skeletal components. Remarkably, deletion of Tgfbr2 in myogenic or chondrogenic progenitor cells does not manifest in midline defects. Our results indicate a pivotal significance of VBW myofibroblasts in orchestrating ventral midline closure by mediating the response to the TGFβ gradient. Altogether, our data enable us to distinguish highly regulated epithelial-mesenchymal signalling and successive cellular migration events in VBW closure that explain early morphological changes underlying the development of congenital VBW defects.

Downregulation of AP-2α Gene Expression in the Cadmium-Induced Ventral Body Wall Defect in the Chick Model

Downregulation of AP-2α Gene Expression in the Cadmium-Induced Ventral Body Wall Defect in the Chick Model

The prevalence of amnion rupture sequence, limb body wall defects and body wall defects in Alberta 1980-2012 with a review of risk factors and familial cases.

Prevalence rates of amnion rupture sequence, limb body wall defect, and body wall defects vary widely. Comparisons are difficult due to small case numbers and the lack of agreement of definition, classification, and pathogenesis. This study reports the prevalence of cases classified in five distinct categories. The Alberta Congenital Anomalies Surveillance System data on live births, stillbirths, and terminations of pregnancy (<20 weeks gestation) occurring between 1980 through 2012 with the ICD-10 Royal College of Paediatrics and Child Health Adaptation codes used for congenital constriction bands (Q79.80) and body wall complex (Q89.7) were reviewed. During the 33-year-study period, there were 153 eligible cases ascertained from 1,411,652 live births and stillbirths, giving a prevalence of 1.08/10,000 total births. There were more males (52%) than females (45%) and 3% were of unknown sex. The average maternal age, birth weight, and gestation was 27 years, 2,701 g, and 35 weeks, respectively. Limb deficiencies occurred in 78% of cases. Amniotic bands with limb deficiency was the most common phenotype (48%). Digital limb deficiency was the most frequent type (56%); however, cases with body wall defects had more severe types of limb deficiencies. The upper limbs only were affected more times (44%), and there was no side preference. Most cases are sporadic but a number of familial occurrences have been reported although some have insufficient documentation and others misdiagnosed. A review of putative risk factors gives conflicting results. © 2016 Wiley Periodicals, Inc.

Chick embryo as an animal model for ventral body wall defects

Chick embryo as an animal model for ventral body wall defects

Is balloon kyphoplasty safe and effective for cancer-related vertebral compression fractures with posterior vertebral body wall defects?

Balloon kyphoplasty (BKP) is a percutaneous treatment for cancer-related vertebral compression fractures (VCF). Posterior vertebral body wall (PVBW) involvement is considered a contraindication for BKP. This study assesses whether BKP is safe and effective for cancer-related VCFs involving the PVBW. This study analyzed data on 158 patients with 228 cancer-related VCFs who underwent BKP. One hundred and twelve patients had VCFs with PVBW defects, and 46 had VCFs with no PVBW defect. Outcomes were assessed preoperatively and at 3 months. In the PVBW defect group, mean pain score decreased from 7.5 to 3.6 (P < 0.001), EQ5D increased from 0.39 to 0.48 and Oswestry Disability Index (ODI) decreased from 50 to 42. Cement leaks occurred in 31%. In the PVBW intact group, mean pain decreased from 7.3 to 3.3 (P < 0.001), EQ5D increased from 0.35 to 0.48 (P < 0.001), and ODI decreased from 53 to 50. Cement leaks occurred in 20%. No significant difference was observed in functional improvements between groups. Radiographically kyphotic angle and anterior and middle vertebral body heights were significantly worse in the PVBW defect group (P < 0.05). BKP can alleviate pain and improve QoL and function in patients with cancer-related VCFs with PVBW defects with no appreciable increase in risk. J. Surg. Oncol. 2016;113:835-842. © 2016 Wiley Periodicals, Inc.

Thoracoschisis secondary to a mesenchymal hamartoma associated with diaphragmatic eventration

Abstract Thoracoschisis is an extremely rare congenital anomaly associated with limb body wall defect and diaphragmatic hernia. We describe a case of a female infant who was noted at birth to have tissue coming through a left sided thoracic defect next to an accessory nipple. The stomach bubble was displaced superiorly on radiographs. At surgery the tissue was attached to the left lateral lobe of the liver and was protruding through the chest wall via an intercostal defect below an eventrated diaphragm. The tissue was resected and the defect closed. Pathological examination was consistent with a mesenchymal hamartoma. The diaphragm may have formed abnormally in this case due to the presence of the mesenchymal hamartoma in this location.