Common pathogenesis for sirenomelia, OEIS complex, limb‐body wall defect, and other malformations of caudal structures

Abstract

Decades of clinical, pathological, and epidemiological study and the recent application of advanced microarray and gene sequencing technologies have led to an understanding of the causes and pathogenesis of most recognized patterns of malformation. Still, there remain a number of patterns of malformation whose pathogenesis has not been established. Six such patterns of malformation are sirenomelia, VACTERL association, OEIS complex, limb‐body wall defect (LBWD), urorectal septum malformation (URSM) sequence, and MURCS association, all of which predominantly affect caudal structures. On the basis of the overlap of the component malformations, the co‐occurrence in individual fetuses, and the findings on fetal examination, a common pathogenesis is proposed for these patterns of malformation. The presence of a single artery in the umbilical cord provides a visible clue to the pathogenesis of all cases of sirenomelia and 30%–50% of cases of VACTERL association, OEIS complex, URSM sequence, and LBWD. The single artery is formed by a coalescence of arteries that supply the yolk sac, arises from the descending aorta high in the abdominal cavity, and redirects blood flow from the developing caudal structures of the embryo to the placenta. This phenomenon during embryogenesis is termed vitelline vascular steal.

The broader phenotypic spectrum of congenital caudal abnormalities associated with mutations in the caudal type homeobox 2 gene

“…15 We propose that caudal regression syndrome, sirenomelia and persistent cloaca are part of a variable phenotypic spectrum that may also include VACTERL-like features. A common pathogenesis for these malformations has been proposed [16][17][18] and our findings may link these conditions genetically, although larger cohort studies are needed to further substantiate this.…”

NAD+ deficiency in human congenital malformations and miscarriage: A new model of pleiotropy

“…Lubinsky (2017) proposed embryonic hypocellularity as an explanation these malformations, which he also noted were associated with monozygotic twinning, maternal diabetes, some forms of aneuploidy, and certain mitochondrial disorders. Most recently, Stevenson (2021) proposed vitelline vascular steal as the common pathogenesis for sirenomelia, OEIS complex, limb‐body wall defect, and other malformations of caudal structures. All these mechanisms could be caused by NAD+ deficiency because NAD+ acts at the (intra)cellular level, and therefore affects all tissue types, all organ systems, and cellular growth and division.…”

“…The insult most likely occurs prior to 23 days gestation (9 days postconception; Blackburn & Cooley, 2006). This can result in persistent vitelline artery, believed to be the primary etiology of sirenomelia (Stevenson, 2021). Single umbilical artery (SUA) is posited to be caused either due to primary agenesis or atrophy of an existing vessel (Blackburn & Cooley, 2006).…”

Sirenomelia with associated systemic anomalies – an autopsy report in a full term neonate

“…Decades of clinical, pathological, and epidemiological research, as well as the recent use of modern microarray and gene sequencing technologies, have led to a better knowledge of the aetiology and pathogenesis of the most common malformation patterns. Nevertheless, the pathophysiology of a number of malformation types has yet to be determined, for example in the case of sirenomelia [8].…”