Caudal Dysgenesis Research Articles

Birth defects associated with perturbations in preimplantation, gastrulation, and axis extension: from conjoined twinning to caudal dysgenesis

Congenital malformations represent approximately 3 in 100 live births within the human population. Understanding their pathogenesis and ultimately formulating effective treatments are underpinned by knowledge of the events and factors that regulate normal embryonic development. Studies in model organisms, primarily in the mouse, the most prominent genetically tractable mammalian model, have equipped us with a rudimentary understanding of mammalian development from early lineage commitment to morphogenetic processes. In this way, information provided by studies in the mouse can, in some cases, be used to draw parallels with other mammals, including human. Here, we provide an overview of our current understanding of the general sequence of developmental events from early cell cleavages to gastrulation and axis extension occurring in human embryos. We will also review some of the rare birth defects occurring at these stages, in particular those resulting in conjoined twinning or caudal dysgenesis.

Sirenomelia: Case Reports and Current Concepts of Pathogenesis

We present 2 cases of sirenomelia and highlight the recent theories about its pathogenesis. Both cases had a large aberrant abdominal umbilical artery (AAUA) arising from the aorta, suggesting vascular steal as the pathophysiology. However, the bilateral upper limb defects noted in 1 case, the reported 10% association of holoprosencephaly and anencephaly, and the reports of sirenomelia with normal umbilical arteries point to the alternative caudal dysgenesis (CD) theory. This proposes that an insult at the early blastogenic stage interferes with the formation of the notochord, resulting in abnormal development of caudal structures, an AAUA, and occasional neural tube defects. We have also analyzed the implications of the similarities between sirenomelia/CD and the VATER association; the increased risk of CD but not sirenomelia in infants of diabetic mothers; the fact that sirenomelia, holoprosencephaly, and the VATER association are all more common in monozygotic twins; the experimental production of sirenomelia in mice; and the possible genetic implications of the co-occurrence of sirenomelia and CD.

Sirenomelia

Sirenomelia, also known as the 'mermaid malformation/syndrome', is a rare, serious congenital anomaly characterized by variable degrees of fusion of the lower limbs and associated severe malformations of the lower vertebral and genitourinary systems. In this report, we describe a series of African patients with sirenomelia. We present the clinical and radiological features of four black South African patients and illustrate some of the rarer associated abnormalities, which include asymmetrical upper limb defects, not confined to the radial ray. The clinical phenotypic overlap between caudal dysgenesis, VACTERL association and sirenomelia in our patients is highlighted, lending support to the theory that these entities may be different manifestations of a single pathogenic process.

A Fetus with Hemifacial Microsomia and Sirenomelia. The Same Mesodermal Defect Spectrum?

Sirenomelia is the most severe malformation complex affecting the human caudal pole, although its etiology is unclear, a primary defect of blastogenesis has been proposed. Studies consider sirenomelia as the most severe form of caudal dysgenesis, VACTERL association, or axial mesodermal dysplasia, although others still support the idea of a different pathologic entity. We report the prenatal, clinical, and pathologic features of a fetus with cleft lip and palate, microtia, cardiac, renal and intestinal malformations, radial aplasia, and sirenomelia. Karyotype, chromosomal breakage studies, and SHH sequence analysis were normal. The occurrence of cephalic, midline-paramedial, and caudal malformations in the same patient imply the diagnosis of hemifacial microsomia and sirenomelia. These entities are part of the same mesodermal malformation spectrum and the clinical presentation depends on environmental and genetic interactions in embrionic development. Future clinical and genome wide studies will help to better delineate this spectrum.

Trisomy 2 mosaicism with caudal dysgenesis, Hirschsprung disease, and micro-anophthalmia

American Journal of Medical Genetics Part AVolume 155, Issue 4 p. 928-930 Research Letter Trisomy 2 mosaicism with caudal dysgenesis, Hirschsprung disease, and micro-anophthalmia† Paolo Prontera, Paolo Prontera Medical Genetics Unit, Department of Clinical and Experimental Medicine, University of Perugia and “S. Maria della Misericordia” Hospital, Perugia, ItalySearch for more papers by this authorGabriela Stangoni, Gabriela Stangoni Neonatology Unit, “S. Maria della Misericordia” Hospital, Perugia, ItalySearch for more papers by this authorCarmela Ardisia, Carmela Ardisia Medical Genetics Unit, Department of Clinical and Experimental Medicine, University of Perugia and “S. Maria della Misericordia” Hospital, Perugia, ItalySearch for more papers by this authorDaniela Rogaia, Daniela Rogaia Medical Genetics Unit, Department of Clinical and Experimental Medicine, University of Perugia and “S. Maria della Misericordia” Hospital, Perugia, ItalySearch for more papers by this authorAmedea Mencarelli, Amedea Mencarelli Medical Genetics Unit, Department of Clinical and Experimental Medicine, University of Perugia and “S. Maria della Misericordia” Hospital, Perugia, ItalySearch for more papers by this authorEmilio Donti, Corresponding Author Emilio Donti genetica@unipg.it Medical Genetics Unit, Department of Clinical and Experimental Medicine, University of Perugia and “S. Maria della Misericordia” Hospital, Perugia, ItalyUniversità e Azienda Ospedaliera di Perugia, Sezione di Genetica Medica, Via E. dal Pozzo, 06123 Perugia, Italy.Search for more papers by this author Paolo Prontera, Paolo Prontera Medical Genetics Unit, Department of Clinical and Experimental Medicine, University of Perugia and “S. Maria della Misericordia” Hospital, Perugia, ItalySearch for more papers by this authorGabriela Stangoni, Gabriela Stangoni Neonatology Unit, “S. Maria della Misericordia” Hospital, Perugia, ItalySearch for more papers by this authorCarmela Ardisia, Carmela Ardisia Medical Genetics Unit, Department of Clinical and Experimental Medicine, University of Perugia and “S. Maria della Misericordia” Hospital, Perugia, ItalySearch for more papers by this authorDaniela Rogaia, Daniela Rogaia Medical Genetics Unit, Department of Clinical and Experimental Medicine, University of Perugia and “S. Maria della Misericordia” Hospital, Perugia, ItalySearch for more papers by this authorAmedea Mencarelli, Amedea Mencarelli Medical Genetics Unit, Department of Clinical and Experimental Medicine, University of Perugia and “S. Maria della Misericordia” Hospital, Perugia, ItalySearch for more papers by this authorEmilio Donti, Corresponding Author Emilio Donti genetica@unipg.it Medical Genetics Unit, Department of Clinical and Experimental Medicine, University of Perugia and “S. Maria della Misericordia” Hospital, Perugia, ItalyUniversità e Azienda Ospedaliera di Perugia, Sezione di Genetica Medica, Via E. dal Pozzo, 06123 Perugia, Italy.Search for more papers by this author First published: 17 March 2011 https://doi.org/10.1002/ajmg.a.33817Citations: 6 † How to Cite this Article: Prontera P, Stangoni G, Ardisia C, Rogaia D, Mencarelli A, Donti E. 2011. Trisomy 2 mosaicism with caudal dysgenesis, Hirschsprung disease and micro-anophthalmia. Am J Med Genet Part A 155:928–930. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume155, Issue4April 2011Pages 928-930 RelatedInformation

Bilateral Renal Agenesis/Hypoplasia/Dysplasia (BRAHD): Postmortem Analysis of 45 Cases with Breakpoint Mapping of Two De Novo Translocations

BackgroundBilateral renal agenesis/hypoplasia/dysplasia (BRAHD) is a relatively common, lethal malformation in humans. Established clinical risk factors include maternal insulin dependent diabetes mellitus and male sex of the fetus. In the majority of cases, no specific etiology can be established, although teratogenic, syndromal and single gene causes can be assigned to some cases.Methodology/Principal Findings45 unrelated fetuses, stillbirths or infants with lethal BRAHD were ascertained through a single regional paediatric pathology service (male∶female 34∶11 or 3.1∶1). The previously reported phenotypic overlaps with VACTERL, caudal dysgenesis, hemifacial microsomia and Müllerian defects were confirmed. A new finding is that 16/45 (35.6%; m∶f 13∶3 or 4.3∶1) BRAHD cases had one or more extrarenal malformations indicative of a disoder of laterality determination including; incomplete lobulation of right lung (seven cases), malrotation of the gut (seven cases) and persistence of the left superior vena cava (five cases). One such case with multiple laterality defects and sirelomelia was found to have a de novo apparently balanced reciprocal translocation 46,XY,t(2;6)(p22.3;q12). Translocation breakpoint mapping was performed by interphase fluorescent in-situ hybridization (FISH) using nuclei extracted from archival tissue sections in both this case and an isolated bilateral renal agenesis case associated with a de novo 46,XY,t(1;2)(q41;p25.3). Both t(2;6) breakpoints mapped to gene-free regions with no strong evidence of cis-regulatory potential. Ten genes localized within 500 kb of the t(1;2) breakpoints. Wholemount in-situ expression analyses of the mouse orthologs of these genes in embryonic mouse kidneys showed strong expression of Esrrg, encoding a nuclear steroid hormone receptor. Immunohistochemical analysis showed that Esrrg was restricted to proximal ductal tissue within the embryonic kidney.Conclusions/SignificanceThe previously unreported association of BRAHD with laterality defects suggests that renal agenesis may share a common etiology with heterotaxy in some cases. Translocation breakpoint mapping identified ESRRG as a plausible candidate gene for BRAHD.

Caudal dysgenesis and sirenomelia‐single centre experience suggests common pathogenic basis

Abnormally formed lower limbs with varying degrees of fusion are the major feature of sirenomelia whereas maldeveloped lower limbs without fusion are found in association with caudal dysgenesis (CD). The relationship between these two entities has been a topic of debate for many years. The presence of a single umbilical artery originating from the abdominal aorta was considered a major feature distinguishing sirenomelia from CD. Based on this finding, the vascular steal theory was put forward as the causative mechanism of sirenomelia. CD and sirenomelia were considered to be two entirely different entities with distinct pathogenic mechanisms. However, it is now clear that a single umbilical artery can be found in some patients of CD and normal umbilical arteries in some patients of sirenomelia. The hypothesis of primary deficiency of caudal mesoderm caused by early developmental disruption suggests that sirenomelia and CD are two ends of a spectrum of maldevelopment of caudal mesoderm. In this paper we report on the clinical and pathological features of 16 patients of CD and 9 patients of sirenomelia from our institution and review the literature. This series of cases is notable for the significant association with neural tube defects, refining the renal and urogenital pathology associated with these conditions, and supporting the concept of a continuum of the disease spectrum.

Caudal regression in adrenocortical dysplasia (acd) mice is caused by telomere dysfunction with subsequent p53-dependent apoptosis

Adrenocortical dysplasia (acd) is a spontaneous autosomal recessive mouse mutation that exhibits a pleiotropic phenotype with perinatal lethality. Mutant acd embryos have caudal truncation, vertebral segmentation defects, hydronephrosis, and limb hypoplasia, resembling humans with Caudal Regression syndrome. Acd encodes Tpp1, a component of the shelterin complex that maintains telomere integrity, and consequently acd mutant mice have telomere dysfunction and genomic instability. While the association between genomic instability and cancer is well documented, the association between genomic instability and birth defects is unexplored. To determine the relationship between telomere dysfunction and embryonic malformations, we investigated mechanisms leading to the caudal dysgenesis phenotype of acd mutant embryos. We report that the caudal truncation is caused primarily by apoptosis, not altered cell proliferation. We show that the apoptosis and consequent skeletal malformations in acd mutants are dependent upon the p53 pathway by genetic rescue of the limb hypoplasia and vertebral anomalies with p53 null mice. Furthermore, rescue of the acd phenotype by p53 deficiency is a dosage-sensitive process, as acd/acd, p53(-/-) double mutants exhibit preaxial polydactyly. These findings demonstrate that caudal dysgenesis in acd embryos is secondary to p53-dependent apoptosis. Importantly, this study reinforces a significant link between genomic instability and birth defects.

Wnt signaling in caudal dysgenesis and diabetic embryopathy

Congenital defects are a major complication of diabetic pregnancy, and the leading cause of infant death in the first year of life. Caudal dysgenesis, occurring up to 200-fold more frequently in children born to diabetic mothers, is a hallmark of diabetic pregnancy. Given that there is also an at least threefold higher risk for heart defects and NTDs, it is important to identify the underlying molecular mechanisms for aberrant embryonic development. We have investigated gene expression in a transgenic mouse model of caudal dysgenesis, and in a pharmacological model using situ hybridization and quantitative real-time PCR. We identified altered expression of several molecules that control developmental processes and embryonic growth. The results from our models point towards major implication of altered Wnt signaling in the pathogenesis of developmental anomalies associated with embryonic exposure to maternal diabetes.

Caudal dysgenesis, sirenomelia, and situs inversus totalis: A primitive defect in blastogenesis

Caudal dysgenesis (CD) constitutes a heterogeneous spectrum of congenital caudal anomalies, including varying degrees of agenesis of the vertebral column, as well as anorectal and genitourinary anomalies. Sirenomelia, characterized by a fusion of the lower limbs, could represent the most severe end of this spectrum. The two main debated pathogenic hypotheses are an aberrant vascular supply versus a primary axial mesoderm defect. We present the autopsy findings of two fetuses of non-diabetic mothers, with normal karyotype. Both fetuses presented situs inversus associated with a CD, in one case consisting of sirenomelia, establishing a very rare association profile that might be random. This association also suggests the occurrence of a common pathogenic mechanism, in accordance to recent genetic data, such as displayed in the Kif3A murine mutation phenotype. Some cases of sirenomelia and CD could represent developmental field defects of blastogenesis involving the caudal mesoderm, rather than being related to vascular insufficiency.

Bifid tongue: A rare feature associated with infants of diabetic mother syndrome

Infants born to diabetic mothers (IDM) are well documented to have a higher rate of congenital malformations. Sacral agenesis/hypogenesis and caudal dysgenesis are classically linked to maternal diabetes, but many other types of anomalies are more frequent. In this case report, we describe a male infant born to a diabetic mother who in addition to other typical congenital abnormalities was born with an impressive bifid tongue. Accompanying congenital anomalies include unilateral microphthalmia, bilateral microtia, cleft palate, micropenis with unilateral cryptorchidism, bilateral radial hypoplasia, unilateral pre-axial polydactyly, and mid-line central nervous system defects including arhinencephaly and pituitary hypoplasia. Review of the literature reveals an additional case of an infant with a bifid tongue born to a diabetic mother [Comess et al., 1969]. In conclusion, bifid tongue without oral hamartoma, a rare congenital anomaly, can be an associated finding in IDM.

Fetal Caudal Dysgenesis after Maternal Cardiopulmonary Bypass in Pregnancy

Fetal Caudal Dysgenesis after Maternal Cardiopulmonary Bypass in Pregnancy

IMAGe association and congenital adrenal hypoplasia: No disease-causing mutations found in the ACD gene

The spontaneous mouse mutant adrenocortical dysplasia ( acd) is characterized by defects in the adrenals, kidneys, and gonads of adult mutant mice and by caudal dysgenesis and vertebral segmentation defects in acd embryos. This association of defects mirrors those identified in patients with known or suspected abnormalities in adrenocortical development, including adrenal hypoplasia congenita and IMAGe association. The identification of the Acd gene in mice has prompted the study of its human homolog ACD, which has recently been shown to be a regulator of telomere length. Sequencing of ACD in 15 patients revealed no coding mutations, but three novel SNPs were identified.

Defects in Yolk Sac Vasculogenesis, Chorioallantoic Fusion, and Embryonic Axis Elongation in Mice with Targeted Disruption of Yap65

YAP is a multifunctional adapter protein and transcriptional coactivator with several binding partners well described in vitro and in cell culture. To explore in vivo requirements for YAP, we generated mice carrying a targeted disruption of the Yap gene. Homozygosity for the Yap(tm1Smil) allele (Yap-/-) caused developmental arrest around E8.5. Phenotypic characterization revealed a requirement for YAP in yolk sac vasculogenesis. Yolk sac endothelial and erythrocyte precursors were specified as shown by histology, PECAM1 immunostaining, and alpha globin expression. Nonetheless, development of an organized yolk sac vascular plexus failed in Yap-/- embryos. In striking contrast, vasculogenesis proceeded in both the allantois and the embryo proper. Mutant embryos showed patterned gene expression domains along the anteroposterior neuraxis, midline, and streak/tailbud. Despite this evidence of proper patterning and tissue specification, Yap-/- embryos showed developmental perturbations that included a notably shortened body axis, convoluted anterior neuroepithelium, caudal dysgenesis, and failure of chorioallantoic fusion. These results reveal a vital requirement for YAP in the developmental processes of yolk sac vasculogenesis, chorioallantoic attachment, and embryonic axis elongation.

Urogenital and caudal dysgenesis in adrenocortical dysplasia ( acd ) mice is caused by a splicing mutation in a novel telomeric regulator

Adrenocortical dysplasia (acd) is a spontaneous autosomal recessive mouse mutant with developmental defects in organs derived from the urogenital ridge. In surviving adult mutants, adrenocortical dysplasia and hypofunction are predominant features. Adults are infertile due to lack of mature germ cells, and 50% develop hydronephrosis due to ureteral hyperplasia. We report the identification of a splice donor mutation in a novel gene, which is the mouse ortholog of a newly discovered telomeric regulator. This gene (Acd) has recently been characterized as a novel component of the TRF1 protein complex that controls telomere elongation by telomerase. Characterization of Acd transcripts in mutant animals reveals two abnormal transcripts, consistent with a splicing defect. Expression of a wild-type Acd transgene in acd mutants rescues the observed phenotype. Most mutants die within 1-2 days of life on the original genetic background. Analysis of these mutant embryos reveals variable, yet striking defects in caudal specification, limb patterning and axial skeleton formation. In the tail bud, reduced expression of Wnt3a and Dll1 correlates with phenotypic severity of caudal regression. In the limbs, expression of Fgf8 is expanded in the dorsal-ventral axis of the apical ectodermal ridge and shortened in the anterior-posterior axis, consistent with the observed loss of anterior digits in older embryos. The axial skeleton of mutant embryos shows abnormal vertebral fusions in cervical, lumbar and caudal regions. This is the first report to show that a telomeric regulator is required for proper urogenital ridge differentiation, axial skeleton specification and limb patterning in mice.

The Adrenocortical Dysplasia (acd) Mouse: Mutation in a Novel Gene Causes a Pleiotropic Phenotype of Urogenital Defects and Caudal Dysgenesis

The adrenocortical dysplasia (DW/J‐acd/J) mouse is a spontaneous autosomal recessive mutant with developmental defects in organs derived from the urogenital ridge: the kidneys, gonads, and adrenals. Adrenocortical dysplasia and hypofunction are predominant features in surviving adult mice. Adult female mutant mice exhibit subnormal fertility secondary to an overall decrease in folliculogenesis in the ovary, and males are completely infertile due to germ cell degeneration in the testes. Fifty percent of adult acd mutant mice develop hydronephrosis due to ureteral hyperplasia. On the original genetic background, most mutants die within 1–2 days of life. Analysis of acd mutant embryos on this genetic background reveals variable, yet striking defects in caudal specification, limb patterning, and axial skeletal formation. We have identified a splice donor site mutation in a novel gene (Acd) in acd mutant mice. Characterization of Acd transcripts produced in acd mutant tissues reveals two abnormal transcripts and lack of any detectable normal transcript, consistent with a splicing defect. Expression of a beta‐actin‐driven Acd cDNA transgene rescues the mutant phenotype and provides genetic confirmation of the etiologic role of the Acd gene in the observed adrenal dysplasia. Surprisingly, the Acd gene is the mouse ortholog of a newly discovered telomeric regulator, which has recently been characterized by others as a novel component of the protein complex that controls telomere elongation by telomerase. Further studies are in progress to evaluate for evidence of genomic instability in acd mutant animals and to define the molecular mechanisms leading to urogenital and caudal dysgenesis in acd mutant embryos.

Collaborative strategies for unraveling the complexity of birth defects

Thisarticle summarizesa presentation by one of the authors(CAH) to the Fifth Annual Meeting of the Diabetes in Pregnancy Study Group of North America. Dr Hobbs, MD, PhD, the Director of the Arkansas Center for Birth Defects Research and Prevention, presented an overview of the collaborative strategies developed for investigating the etiology of birth defects. A multidisciplinary group of scientists and clinicians explores current hypotheses in diabetic embryopathy, drawing upon expertise in experimental biology, genetic epidemiology, genomics, metabolomics and translational research. The prevalence rate of birth defects among infants of diabetic mothers isashigh as 11%, despite the knowledge that maternal metabolic control iss trongly correlated with the risk of malformations. Specifically, caudal dysgenesis, renal anomalies, heart and neural tube defectsand situsabnormalitiesoccur more often among infantsof diabetic women than non-diabetic women. Researchers are also working to discover the underlying mechanisms that make some women with diabetes more susceptible than others to having infants with birth defects.

A surviving infant with sirenomelia (mermaid syndrome) associated with absent bladder

The authors report a case of a surviving infant with sirenomelia (Mermaid syndrome). The child is now 4 years of age. The authors believe that this is only the fourth reported case of an infant with sirenomelia surviving beyond the neonatal period and the first associated with absent bladder. The abnormal distal aorta shown in this case supports the theory that sirenomelia is an extreme form of caudal dysgenesis rather than occurring secondary to vascular steal.

Caudal dysgenesis in Islet-1 transgenic mice.

Maternal diabetes during pregnancy is responsible for the occurrence of diabetic embryopathy, a spectrum of birth defects that includes heart abnormalities, neural tube defects, and caudal dysgenesis syndromes. Here, we report that mice transgenic for the homeodomain transcription factor Isl-1 develop profound caudal growth defects that resemble human sacral/caudal agenesis. Isl-1 is normally expressed in the pancreas and is required for pancreas development and endocrine cell differentiation. Aberrant regulation of this pancreatic transcription factor causes increased mesodermal cell death, and the severity of defects is dependent on transgene dosage. Together with the finding that mutation of the pancreatic transcription factor HLXB9 causes sacral agenesis, our results implicate pancreatic transcription factors in the pathogenesis of birth defects associated with diabetes.

Carbon monoxide-induced axial skeletal dysmorphogenesis in the chick embryo.

Congenital axial skeletal defects affect two to three individuals per 1,000 live births. Without strong evidence for heritability, the cause is assumed to be multi-factorial. Carbon monoxide (CO), an increasingly prevalent environmental toxicant, is a potential environmental component in the etiology of these defects. The chick embryo is a useful model for the characterization and assessment of the mechanism(s) of action of basic developmental mechanisms. We have determined a critical period and dose for CO teratogenicity and established a model of CO-induced axial skeletal dysmorphogenesis in the chick embryo. The resulting phenotypes reveal a spectrum of axial skeletal defects ranging from minor defects of the vertebral canal and inter-vertebral discs, to thoraco-lumbar scoliosis, to a tailless phenotype reminiscent of caudal dysgenesis syndrome. These axial skeletal defects have been related to earlier developmental defects in somitogenesis, including errors in segmentation and epithehalization and the expression of the somitic epithelialization factor, Paraxis. We have examined patterns of cell death and apoptosis in CO exposed chick embryos to assess the target tissue(s) involved in the teratogenicity of CO. With respect to the embryonic axis, the neural tube was found to be the most sensitive to CO-induced apoptosis, followed by the somitic mesoderm and Hensen's node. We hypothesize that the somitic defects and the resulting axial skeletal dysmorphogenesis are caused by disrupted neural tube or ectoderm functions related to somite formation and maintenance. We also hypothesize that CO-induced dysmorphogenesis at this critical period of somitogenesis is caused by the overabundance of CO acting endogenously as a cellular signal, while coincidentally exerting its influence as a toxicant of oxygen delivery or utilization.