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A clinical and experimental overview of sirenomelia: insight into the mechanisms of congenital limb malformations.

Garrido-Allepuz C, Haro E, González-Lamuño D, Martínez-Frías ML, Bertocchini F, Ros MA - Dis Model Mech (2011)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Biomedicina y Biotecnología de Cantabria, Universidad de Cantabria-CSIC-SODERCAN, C. Herrera Oria s/n, 39011 Santander, Spain.

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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Vascular pattern in a normal versus sirenomelia fetus. (A) Schematic drawing of the fetal umbilical cord vasculature in a normal and a sirenomelia fetus. Note the abnormally high origin of the SUA in sirenomelia and the hypoplasia of the aorta caudal to its origin. (B) Left two panels: schematic of transverse sections at the caudal level of an early normal and sirenomelia embryo. Below each section, the corresponding vascular pattern is shown in red. Ao, dorsal aorta; rpAo, recurved distal portions of aorta; UA, umbilical arteries; UV, umbilical vein; SUA, single umbilical artery; VA, vitelline artery. Right panel: a schematic lateral view of an embryo in which the great caudal vessels are shown in red and the hindgut in yellow. The broken red line indicates the level of the sections shown in the two panels to the left.
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f3-0040289: Vascular pattern in a normal versus sirenomelia fetus. (A) Schematic drawing of the fetal umbilical cord vasculature in a normal and a sirenomelia fetus. Note the abnormally high origin of the SUA in sirenomelia and the hypoplasia of the aorta caudal to its origin. (B) Left two panels: schematic of transverse sections at the caudal level of an early normal and sirenomelia embryo. Below each section, the corresponding vascular pattern is shown in red. Ao, dorsal aorta; rpAo, recurved distal portions of aorta; UA, umbilical arteries; UV, umbilical vein; SUA, single umbilical artery; VA, vitelline artery. Right panel: a schematic lateral view of an embryo in which the great caudal vessels are shown in red and the hindgut in yellow. The broken red line indicates the level of the sections shown in the two panels to the left.

Mentions: The vascular abnormalities in sirenomelia deserve particular mention owing to their possible relevance to pathogenesis (see Box 1 for a description of how disturbance in the development of vitelline and umbilical arteries might give rise to an aberrant vascular pattern). The human umbilical cord normally contains two umbilical arteries (returning deoxygenated blood from the fetus to the placenta) and a single umbilical vein (supplying oxygenated blood to the fetus). However, fetuses with sirenomelia almost invariably exhibit a single umbilical artery (SUA) instead of the normal two (Heifetz, 1984; Stevenson et al., 1986) (Fig. 3A). Moreover, this SUA has an abnormal origin, branching off the abdominal aorta quite high in the abdomen, usually immediately below the celiac branch. Below the origin of the SUA, the aorta becomes abnormally narrow and lacks a considerable number of the branches that normally supply the kidneys, large intestine and genitalia. The SUA has also been referred to as the persistent vitelline artery to indicate its possible derivation from the vitelline plexus, and to distinguish it from other cases of SUA that are found in about 1% of newborns but that have normal origin and are not related to other malformations (Martinez-Frias et al., 2008).


A clinical and experimental overview of sirenomelia: insight into the mechanisms of congenital limb malformations.

Garrido-Allepuz C, Haro E, González-Lamuño D, Martínez-Frías ML, Bertocchini F, Ros MA - Dis Model Mech (2011)

Vascular pattern in a normal versus sirenomelia fetus. (A) Schematic drawing of the fetal umbilical cord vasculature in a normal and a sirenomelia fetus. Note the abnormally high origin of the SUA in sirenomelia and the hypoplasia of the aorta caudal to its origin. (B) Left two panels: schematic of transverse sections at the caudal level of an early normal and sirenomelia embryo. Below each section, the corresponding vascular pattern is shown in red. Ao, dorsal aorta; rpAo, recurved distal portions of aorta; UA, umbilical arteries; UV, umbilical vein; SUA, single umbilical artery; VA, vitelline artery. Right panel: a schematic lateral view of an embryo in which the great caudal vessels are shown in red and the hindgut in yellow. The broken red line indicates the level of the sections shown in the two panels to the left.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3097451&req=5

f3-0040289: Vascular pattern in a normal versus sirenomelia fetus. (A) Schematic drawing of the fetal umbilical cord vasculature in a normal and a sirenomelia fetus. Note the abnormally high origin of the SUA in sirenomelia and the hypoplasia of the aorta caudal to its origin. (B) Left two panels: schematic of transverse sections at the caudal level of an early normal and sirenomelia embryo. Below each section, the corresponding vascular pattern is shown in red. Ao, dorsal aorta; rpAo, recurved distal portions of aorta; UA, umbilical arteries; UV, umbilical vein; SUA, single umbilical artery; VA, vitelline artery. Right panel: a schematic lateral view of an embryo in which the great caudal vessels are shown in red and the hindgut in yellow. The broken red line indicates the level of the sections shown in the two panels to the left.
Mentions: The vascular abnormalities in sirenomelia deserve particular mention owing to their possible relevance to pathogenesis (see Box 1 for a description of how disturbance in the development of vitelline and umbilical arteries might give rise to an aberrant vascular pattern). The human umbilical cord normally contains two umbilical arteries (returning deoxygenated blood from the fetus to the placenta) and a single umbilical vein (supplying oxygenated blood to the fetus). However, fetuses with sirenomelia almost invariably exhibit a single umbilical artery (SUA) instead of the normal two (Heifetz, 1984; Stevenson et al., 1986) (Fig. 3A). Moreover, this SUA has an abnormal origin, branching off the abdominal aorta quite high in the abdomen, usually immediately below the celiac branch. Below the origin of the SUA, the aorta becomes abnormally narrow and lacks a considerable number of the branches that normally supply the kidneys, large intestine and genitalia. The SUA has also been referred to as the persistent vitelline artery to indicate its possible derivation from the vitelline plexus, and to distinguish it from other cases of SUA that are found in about 1% of newborns but that have normal origin and are not related to other malformations (Martinez-Frias et al., 2008).

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Biomedicina y Biotecnología de Cantabria, Universidad de Cantabria-CSIC-SODERCAN, C. Herrera Oria s/n, 39011 Santander, Spain.

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.

Show MeSH
Related in: MedlinePlus