Genetics of Sirenomelia, the Mermaid Syndrome

Sirenomelia (SML) is a rare, almost universally fatal congenital malformation presenting pathognomically with fused lower extremities and absent or malformed perineum. The classic Sirenomelia sequence includes a uniform spectrum of caudal malformations, spinal defects, and a single umbilical artery. SML is postulated to be due to a genetic predisposition, unmasked by biochemical or environmental triggers. Primary developmental defects in the formation of caudal mesoderm or embryonic caudal vessels with resultant local tissue hypoperfusion are proposed hypotheses for its pathogenesis. SML occurs sporadically in humans, presumably due to a spontaneous mutation, and is speculated to have an autosomal dominant inheritance pattern. In mutant mice, specific defects in Cyp26a1 and Bmp 7 genes are demonstrated to produce offsprings with SML. Bmp 7 is a signaling protein, which belongs to the transforming growth factor-β (TGF β) superfamily. Tsg 1, a Bmp and chordin-binding protein, functions as an activator-inhibitor of Bmp signaling in the embryonic caudal region (ECR). Loss of Bmp7 genes combined with a complete loss or half-dose of Tsg 1 is demonstrated to produce an invariable SML phenotype. SML is also demonstrated to occur with increased Retinoic acid (RA) signaling in the ECR. The Cyp26a1 gene is involved in coding for an enzyme, which expresses in ECR and degrades RA. A specific defect in this gene leads to excess local RA concentration and SML generation with a reported 20% penetrance in mutant mice. However, the mutational screening of Cyp26a1 and Bmp 7genes has failed to confirm their involvement in mankind and the molecular defect and genetic inheritability of SML in humans remain undefined.