Genetic factors in esophageal atresia, tracheo-esophageal fistula and the VACTERL association: Roles for FOXF1 and the 16q24.1 FOX transcription factor gene cluster, and review of the literature

• Published in: European journal of medical genetics Vol. 53; no. 1; pp. 6 - 13
• Main Author: Shaw-Smith, Charles
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Masson SAS 01-01-2010; Elsevier
• Subjects: 16q24.1 microdeletion; Abnormalities, Multiple - genetics; Animals; Chromosome Mapping; Chromosomes, Human, Pair 16; Esophageal atresia; Esophageal Atresia - genetics; Forkhead Transcription Factors - genetics; FOXF1; Hedgehog Proteins - genetics; Humans; Limb Deformities, Congenital - genetics; Medical Education; Mice; Sonic hedgehog; Tracheo-esophageal fistula; Tracheoesophageal Fistula - genetics; VACTERL association; Esophageal atresia; Sonic hedgehog; 16q24.1 microdeletion; FOXF1; Tracheo-esophageal fistula; VACTERL association
• ISSN: 1769-7212; 1878-0849
• DOI: 10.1016/j.ejmg.2009.10.001

Abstract Esophageal atresia with/without tracheo-esophageal fistula is a relatively common malformation, occurring in around 1 in 3500 births. In around half of cases, additional malformations are present, forming either a syndrome of known genetic aetiology, or a recognised association, of which the VACTERL association (Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal and Limb malformations) is the most recognised. Recently, microdeletions of the FOX gene cluster at 16q24.1, comprising four genes, FOXF1 , MTHFSD , FOXC2 and FOXL1 , were reported to cause a phenotype resembling VACTERL association, with vertebral anomalies, gastro-intestinal atresias (esophageal, duodenal and anal), congenital heart malformations, and urinary tract malformations, as well as a rare lethal developmental anomaly of the lung, alveolar capillary dysplasia. This article reviews these new data alongside other genetic causes of syndromic esophageal atresia, and also highlights information from relevant mouse models, particularly those for genes in the Sonic Hedgehog pathway.