**3. Pathogenesis**

Although unsubstantiated, it is believed that SML is an autosomal-dominant genetic condition in humans, and each case is the result of a new spontaneous mutation. It is speculated that the syndrome is induced by a combination of genetic and environmental influences. The most accepted non-genetic hypotheses for the pathogenesis of SML are the vascular steal phenomenon and defective blastogenesis. These two theories are not mutually exclusive as any deficiency in blastogenesis could potentially lead to fetal vascular and visceral maldevelopment. Genetically, SML phenotype has been demonstrated in mutant mice with both gain-of-function of retinoic acid (RA) signaling and loss-of-function of bone morphogenetic protein (Bmp) signaling [11].

#### **3.1 Non-genetic theories**

### *3.1.1 Vascular steal hypothesis*

SML is characterized by an anomalous single umbilical artery that diverts blood away from the caudal fetal limb buds to the placenta, thereby compromising the regional blood supply during the early developmental period. In the early fetal

stage, the vitelline artery complex serves as an embryonic vascular network that supplies the yolk sac. [2, 11] In SML, the umbilical vasculature develops abnormally and connects to the vitellus in an anomalous way, resulting in the formation of a large aberrant aorta-like vessel that originates from the vitelline artery high in the future abdominal cavity. The normal aortic branches, such as the celiac artery, are either separated from this abnormal abdominal aorta or are absent or hypoplastic. This large anomalous vessel functions as a single umbilical artery and diverts blood away from the lower part of the fetus to the placenta, thus severely limiting the blood and nutrients supply to the mesoderm of the caudal fetal body. In autopsies, the tissues dependent upon the lower branches of this aberrant steal aorta are found to be malformed or in different stages of incomplete or arrested development. However, case reports of SML with two umbilical arteries have been described, and an aberrant single umbilical artery, which was considered as the hallmark of SML and a major differentiating feature from caudal dysgenesis, is now not considered to be so [2, 15, 17–19].
