Abstract: Sirenomelia, also known as sirenomelia sequence, is a severe malformation of the
lower body characterized by fusion of the legs and a variable combination of
visceral abnormalities. The causes of this malformation remain unknown, although
the discovery that it can have a genetic basis in mice represents an important step
towards the understanding of its pathogenesis. Sirenomelia occurs in mice lacking
Cyp26a1, an enzyme that degrades retinoic acid (RA), and in mice that develop
with reduced bone morphogenetic protein (Bmp) signaling in the caudal
embryonic region. The phenotypes of these mutant mice suggest that sirenomelia
in humans is associated with an excess of RA signaling and a deficit in Bmp signaling
in the caudal body. Clinical studies of sirenomelia have given rise to two main
pathogenic hypotheses. The first hypothesis, based on the aberrant abdominal
and umbilical vascular pattern of affected individuals, postulates a primary vascular
defect that leaves the caudal part of the embryo hypoperfused. The second
hypothesis, based on the overall malformation of the caudal body, postulates a
primary defect in the generation of the mesoderm. This review gathers
experimental and clinical information on sirenomelia together with the necessary
background to understand how deviations from normal development of the caudal
part of the embryo might lead to this multisystemic malformation
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