Role of environmental factors in axial skeletal dysmorphogenesis

Alexander, Peter G.; Tuan, Rocky S.

doi:10.1002/bdrc.20179

Cited by 38 publications

(25 citation statements)

References 173 publications

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“…Nevertheless, teratogens are very discrete in their nature, and determination of true teratogenic mechanisms remains complicated. Many potential mechanisms, pathogenetic routes, and ultimate morphological outcomes are present, which makes it very difficult to elucidate certain teratogens that induce congenital anomalies (reviewed by Alexander and Tuan, ; Alexander et al, ). Although some studies apparently report a relationship between sirenomelia and certain drugs, these findings are statistically weak and can very well be coincidental findings.…”

Section: Teratogenically Induced Sirenomeliamentioning

confidence: 99%

Sirenomelia: A Multi‐systemic Polytopic Field Defect with Ongoing Controversies

Kim

Morava

Klein

et al. 2017

Birth Defects Research

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The most impressive phenotypic appearance of sirenomelia is the presence of a 1808-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. Key words: blastogenesis; caudal dysgenesis; mermaid syndrome; anatomical museum; sirenomelia; teratology; VACTERL; VACTERL-H; VATER IntroductionThe most obvious phenotypic characteristic in sirenomelia (also called: symmelia or mermaid syndrome) is the single axially positioned lower limb. However, sirenomelia can be seen as a (lethal) multi-system condition based on a polytopic field defect with a wide phenotypical variability and frequently observed co-occurring with musculoskeletal, central nervous system, cardiopulmonary and other visceral anomalies, in addition to the almost always present gastrointestinal and genitourinary anomalies (reviewed by Gabriele and Gianpaolo, 2013). Sirenomelia is still the subject of debate, due to its ongoing controversies regarding its etiopathogenesis. Sirenomelia shows a heterogeneous phenotypic variability and overlap with caudal regression syndrome/sacro-coccygeal dysgenesis (Duhamel, 1961;Stocker and Heifetz, 1987;Adra et al., 1994), small pelvic outlet syndrome (Currarino and Weinberg, 1991), VATER/ VACTERL (Young et al., 1986;Sch€ uler and Salzano, 1994;Jain et al., 2002;Moosa et al., 2012), and VACTERL-H associations (Onyeije et al., 1998). There have been several attempts to classify these receptacles of caudal malformations, unfortunately without satisfying results. Clearly, diagnostic overlap exists between these conditions and the interpretation of their etiopathogenetic origin.The purpose of this study is to give an overview of multiple facets of this dysmorphological puzzle and review what is known about the co-occurrence of sirenomelia and other birth defects, in particular those assigned to the VACTERL(-H) spectrum. The existing literature on these conditions is supplemented by one additional case of sirenomelia with ...

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Section: Teratogenically Induced Sirenomeliamentioning

confidence: 99%

Sirenomelia: A Multi‐systemic Polytopic Field Defect with Ongoing Controversies

Kim

Morava

Klein

et al. 2017

Birth Defects Research

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“…Instead, there is likely a strong environmental influence on its development. In particular, maternal exposure to a wide range of environmental conditions early in gestation has been implicated in the generation of vertebral defects (Alexander and Tuan, 2010). Such defects are not usually the result of defective bone formation, rather they arise from the failure of an earlier developmental process.…”

Section: Introductionmentioning

confidence: 99%

A Mechanism for Gene-Environment Interaction in the Etiology of Congenital Scoliosis

Sparrow

Chapman

Smith

et al. 2012

Cell

192

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Congenital scoliosis, a lateral curvature of the spine caused by vertebral defects, occurs in approximately 1 in 1,000 live births. Here we demonstrate that haploinsufficiency of Notch signaling pathway genes in humans can cause this congenital abnormality. We also show that in a mouse model, the combination of this genetic risk factor with an environmental condition (short-term gestational hypoxia) significantly increases the penetrance and severity of vertebral defects. We demonstrate that hypoxia disrupts FGF signaling, leading to a temporary failure of embryonic somitogenesis. Our results potentially provide a mechanism for the genesis of a host of common sporadic congenital abnormalities through gene-environment interaction.

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“…Other authors have proposed that vertebral malformations are caused by exposure to environmental toxins during the gestational period, but most appear to be simple structural defects unaccompanied by genetic damage. Less than 5% of patients appear to develop these anomalies as a result of gene mutations 9 . A single hemivertebra without other congenital malformations is sporadic, and associated karyotype abnormalities have a very low incidence 10 .…”

Section: Discussionmentioning

confidence: 99%