Mitochondrial Factors and VACTERL Association-Related Congenital Malformations

Abstract

VACTERL/VATER association is a group of congenital malformations characterized by at least 3 of the following findings: vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities. To date, no unifying etiology for VACTERL/VATER association has been established, and there is strong evidence for causal heterogeneity. VACTERL/VATER association has many overlapping characteristics with other congenital disorders that involve multiple malformations. In addition to these other conditions, some of which have known molecular causes, certain aspects of VACTERL/VATER association have similarities with the manifestations of disorders caused by mitochondrial dysfunction. Mitochondrial dysfunction can result from a number of distinct causes and can clinically manifest in diverse presentations; accurate diagnosis can be challenging. Case reports of individuals with VACTERL association and confirmed mitochondrial dysfunction allude to the possibility of mitochondrial involvement in the pathogenesis of VACTERL/VATER association. Further, there is biological plausibility involving mitochondrial dysfunction as a possible etiology related to a diverse group of congenital malformations, including those seen in at least a subset of individuals with VACTERL association.

The etiology of VACTERL association: Current knowledge and hypotheses

“…There is strong evidence that a proportion of VACTERL has a genetic basis, but the evidence about a genetic basis for all or even most affected patients is mixed. Evidence for a genetic basis for the condition includes the fact that genetic causes continue to be found, though only in a small fraction of patients per cause and per cohort investigated (Saisawat et al, ; Shi et al, ; Siebel & Solomon, ). This is logical if one assumes strong etiological heterogeneity, which current evidence supports.…”

“…Third, along these lines, though mentioned separately here because of a hypothesized distinct disease mechanism, mitochondrial explanations have been reported in a very small proportion of cases. According to this causation hypothesis—and assuming that these findings were not coincidental—features of VACTERL association in individuals with molecularly‐proven mitochondrial anomalies could be because of impaired energy production as well as the overproduction of reactive oxygen species and free radicals early in embryonic development (Siebel & Solomon, ).…”

An Approach to the Identification of Anomalies and Etiologies in Neonates with Identified or Suspected VACTERL (Vertebral Defects, Anal Atresia, Tracheo-Esophageal Fistula with Esophageal Atresia, Cardiac Anomalies, Renal Anomalies, and Limb Anomalies) Association

“…7, 54–56 Although VACTERL association is usually sporadic, a relatively small number of familial cases have been described, and there may be an over-representation of VACTERL-type anomalies in relatives of probands. 57, 58 A thorough family history can help with the differential diagnosis (e.g., the possibility of other conditions may be raised) and can help inform discussions regarding recurrence risks.…”

Vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association with Mayer-Rokitansky-Küster-Hauser syndrome in co-occurrence: two case reports and a review of the literature

“…Several copy number variations (CNVs) have been reported (thoroughly reviewed by Brosens et al [46]), of which recurrent de novo CNVs have been reported at 8q24.3 ( GLI4 ) and 17q23 ( TBX2 / TBX4 ). Finally, a few cases of VACTERL association and mitochondrial dysfunction have been reported [47]. To-date, the only well-established environmental cause of VACTERL association in humans is maternal diabetes mellitus [1].…”