Recurrent constellations of embryonic malformations re-conceptualized as an overlapping group of disorders with shared pathogenesis

Aaron P. Adam, Cynthia J. Curry, Judith G. Hall, Kim M. Keppler-Noreuil, Margaret P. Adam, William B. Dobyns

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Several recurrent malformation associations affecting the development of the embryo have been described in which a genetic etiology has not been found, including LBWC, MURCS, OAVS, OEIS, POC, VACTERL, referred to here as “recurrent constellations of embryonic malformations” (RCEM). All are characterized by an excess of reported monozygotic discordant twins and lack of familial recurrence. We performed a comprehensive review of published twin data across all six phenotypes to allow a more robust assessment of the association with twinning and potential embryologic timing of a disruptive event. We recorded the type of twinning, any overlapping features of another RCEM, maternal characteristics, and the use of ART. Statistically significant associations included an excess of monozygotic twins and 80% discordance rate for the phenotype across all twins. There was an 18.5% rate of ART and no consistently reported maternal adverse events during pregnancy. We found 24 instances of co-occurrence of two RCEM, suggesting a shared pathogenesis across all RCEM phenotypes. We hypothesize the following timing for RCEM phenotypes from the earliest perturbation in development to the latest: LBWC, POC, OEIS, VACTERL, OAVS, then MURCS. The RCEM group of conditions should be considered a spectrum that could be studied as a group.

Original languageEnglish (US)
Pages (from-to)2646-2661
Number of pages16
JournalAmerican Journal of Medical Genetics, Part A
Volume182
Issue number11
DOIs
StatePublished - Nov 1 2020

Bibliographical note

Funding Information:
The authors have no conflicts of interest to declare. This study was based on a literature review and therefore we did not generate original data that would be appropriate to deposit in a public repository database. However, we have included all raw data in Tables S1 and S2 for reference.

Keywords

  • VACTERL/VACTERL association
  • cloacal exstrophy
  • oculo-auriculo-vertebral spectrum
  • pentalogy of Cantrell
  • recurrent constellations of embryonic malformations (RCEM)
  • twins

PubMed: MeSH publication types

  • Journal Article

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