VATER Association Health Article

Genetic profile

The exact genetic cause of VATER association is unknown. Most cases are sporadic and do not occur more than once in the same family. This was determined by studies of families with an affected individual. Since cases are rare and most are isolated in a family, studies to find a genetic cause have been unsuccessful. Parents of a child with VATER association have a 1% or less chance of having another baby with the same condition. There have been a few reports of affected individuals with a parent or sibling showing a single feature of the VATER spectrum. There has only been one reported case of a parent and child both affected with multiple VATER features.

Most individuals with VATER association have a normal chromosome pattern. However, a few cases of chromosome differences have been reported in individuals with VATER. One child with VATER had a deletion (missing piece) on the long arm of chromosome 6. Another male infant had a deletion on the long arm of chromosome 13. There have been other children reported with a chromosome 13 deletion and VATER-like features. This infant was the first reported with the deletion to have all of the VACTERL main features. He was also the first with this chromosome deletion to have a connection between his trachea and esophagus. Another child with VATER association had an extra marker chromosome. This is a fragment of chromosomal material present in the cell in addition to the usual 46 chromosomes. This child's marker was found to contain material from chromosome 12. These cases have not led to the discovery of a gene involved in VATER.

There has only been one VATER case reported in which a genetic change was identified. That female infant died one month after birth because of kidney failure. Her mother and sister later were diagnosed with a mitochondrial disease. Mitochrondria are the structures in the cell that create energy by chemical reactions. The mitochrondria have their own set of DNA and a person inherits mitochondrial DNA from the mother only. Stored kidney tissue from the deceased infant was analyzed and she was found to have the same genetic change in her mitochondrial DNA as her mother and sister. The researchers could not prove that the gene change caused the infant's features of VATER.

There are two subtypes of VACTERL that seem to be inherited. Both types have the typical VACTERL features in addition to hydrocephaly (excess water in the brain). They are abbreviated VACTERL-H. The first subtype was described in 1975 by David and O'Callaghan and is called the David-O'Callaghan subtype. It appears to be an autosomal recessive condition. Parents of an affected child are carriers of a normal gene and a gene that causes VACTERL-H. When both parents are carriers there is a 25% chance for an affected child with each pregnancy. The second subtype is called Hunter-MacMurray and appears to be an X-linked recessive condition. In X-linked conditions, the disease-causing gene is located on the X chromosome, one of the sex-determining chromosomes. Females have two X chromosomes and males have an X chromosome and a Y chromosome. A female who carries a disease-causing gene on one of her X chromosomes shows no symptoms. If a male inherits the gene he will show symptoms of the condition. A woman who carries the VACTERL-H X-linked gene has a 25% chance of having an affected son with each pregnancy. Both of these subtypes are rare and account for a small number of VACTERL cases.

Demographics

VATER is rare, but has been reported worldwide. Exact incidence can be difficult to determine because of different criteria for diagnosis. Some studies consider two or more VATER features enough to make the diagnosis. Other studies require at least three features to diagnose VATER. Also, infants with features of VATER may have other genetic syndromes such as trisomy 13, trisomy 18, Holt-Oram syndrome, TAR syndrome, and Fanconi anemia. VATER does appear to be more frequent in babies of diabetic mothers. It is also more frequent in babies of mothers taking certain medications during pregnancy, including estroprogestins, methimazole, and doxorubicin.