**4. Conclusion**

Sirenomelia is a major, almost universally fatal human anomaly with obscure etiopathogenesis. An indeterminate genetic predisposition in combination with exposure to potentially adverse environmental trigger factors is thought to be instrumental in producing the phenotype. Several causal hypotheses have been forwarded, and studies in mutant mice have provided important insight into its generation at embryonic cellular and biochemical levels. Genetic aberrations in the Bmp and RA signaling pathways have been demonstrated to induce SML-like phenotype in the mutant mice. Defining the precise genetics, the roles of combined Bmp and RA signaling pathways, and the unidentified molecular defect in SML are subjects of future research on the subject.

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**Author details**

Rita Prasad Verma

Nassau University Medical Center, East Meadow, NY, USA

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: rverma2@numc.edu

provided the original work is properly cited.

*Genetics of Sirenomelia, the Mermaid Syndrome DOI: http://dx.doi.org/10.5772/intechopen.97555*

*Genetics of Sirenomelia, the Mermaid Syndrome DOI: http://dx.doi.org/10.5772/intechopen.97555*

*Congenital Anomalies in Newborn Infants - Clinical and Etiopathological Perspectives*

in caudal dysplasia in humans [48].

subjects of future research on the subject.

phenotype in humans.

**4. Conclusion**

gastrulation [1, 42–44]. The expression of Cyp26a1 takes place at the early gastrula stage in the primitive streak and the nascent mesoderm; and at the late gastrula stage in the neuropore, hindgut endoderm, and tailbud mesoderm [37, 39, 40]. RA signaling is generated by Raldh2 in the somites in association with specific growth factors. RA plays a key role in the proliferation and differentiation of precursor cells, and Cyp26a1 expression at the caudal area is pivotal in maintaining the physiologically appropriate RA levels. [45, 46] RA excess is shown to negatively regulate endothelial cell proliferation and impede vascular remodeling by inducing premature coalescence and differentiation of precursor cells. In animal models, abnormal development of umbilical and vitelline arteries in embryos similar to those in human SML was noted when pregnant rats were given RA. [47] However, despite strong evidence of Cyp26a1 being instrumental in the generation of SML phenotype, a mutational screening of the Cyp26a1 gene has not confirmed its involvement

Even though both Bmp and RA signaling pathways are critical participants in the development of caudal structural during the early embryonic stage, it is unclear if their effects are synergistic or antagonistic and whether they modulate each other's roles. RA had been shown to decrease Bmp signal duration by reducing the level of phosphorylated Smad1, an intracellular component of the Bmp signaling pathway in the developing neural tube [1, 49], whereas Bmp signaling has been demonstrated to adversely regulates RA signaling during chondrogenesis [50]. However, such effects have not been studied or confirmed to be operative in the generation of SML phenotype. The detection of possible crosstalk between the two signaling cascades might provide helpful information regarding the pathogenesis of SML

Sirenomelia is a major, almost universally fatal human anomaly with obscure etiopathogenesis. An indeterminate genetic predisposition in combination with exposure to potentially adverse environmental trigger factors is thought to be instrumental in producing the phenotype. Several causal hypotheses have been forwarded, and studies in mutant mice have provided important insight into its generation at embryonic cellular and biochemical levels. Genetic aberrations in the Bmp and RA signaling pathways have been demonstrated to induce SML-like phenotype in the mutant mice. Defining the precise genetics, the roles of combined Bmp and RA signaling pathways, and the unidentified molecular defect in SML are

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