VATER Association

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VATER association

Definition

VATER association describes a pattern of related birth defects in the same infant involving three or more of the following: vertebrae (spine), anus and rectum, heart, trachea (windpipe), esophagus, radius (bone of the arm), and kidneys. Infants can have any combination of features and there is a wide range of severity. Survival and medical complications depend on the extent and severity of features in each case.

Description

Quan and Smith first developed the term VATER association in 1973 to describe a similar pattern of birth defects in more than one infant. The problems at birth did not represent a certain syndrome but appeared to be associated since they were present in several babies. VATER is an acronym or abbreviation representing the first letter of each feature in the association: Vertebral (spine) abnormalities, Anal atresia (partial absence of the anus or unusual connection between anus and rectum), Tracheo-Esophageal fistula (connection between the windpipe and the tube carrying food from mouth to stomach), and Radial (bone of the forearm) or Renal (kidney) differences.

In the 1970s some researchers expanded the VATER abbreviation to VACTERL. It was expanded to include cardiac (heart) abnormalities, and limb differences in general (differences in the arms and hands). In the expanded VACTERL, "L" includes radial differences and "R" represents kidney differences only. Both VATER and VACTERL are used to describe the same association of birth defects.

The exact cause of VATER is unknown. This is because VATER is rare and because the features vary from patient to patient. Many researchers agree that the cause of VATER occurs very early in the development of the embryo in order to affect so many organ systems. It is unknown whether VATER has a single cause or multiple causes during this early development process.

In the first couple of weeks after conception, a human embryo is a clump of cells that are unspecialized and full of potential. In the third week of pregnancy the embryo undergoes a process called gastrulation. This is when the cells of the embryo begin to group together in different areas. The different cell groups begin to specialize and prepare to form different organs and body parts. The mesoderm is the group of cells that organizes and eventually forms the baby's bones, muscles, heart, blood, kidneys, and reproductive organs. In the third week of pregnancy, the notochord also develops. The notochord is the future spinal cord and gives the early embryo a center and stability. It may also have a role in organizing other cell groups. The primitive gut also organizes in the fourth week. The primitive gut undergoes more specialization and division into zones called the foregut, midgut, and hindgut. The esophagus (tube from mouth to stomach) and trachea (windpipe) develop from the foregut. The anus and rectum develop from the hindgut. The constant cell movement, grouping, and specialization is a precise process. Any interruption or damage in this early stage can affect multiple organs and body structures.

Some researchers believe the cause of VATER is a problem with gastrulation. Other researchers believe the error occurs when mesoderm cells begin to move to areas to begin specialization. Another theory is that the mesoderm receives abnormal signals and becomes disorganized. Other researchers believe more than one error occurs in more than one area of the early embryo to produce VATER. Some also believe an abnormality of the notochord is involved in the development of VATER.

One group of researchers has discovered that pregnant rats that are given a toxic drug called adriamycin have offspring with birth defects very similar to those seen in humans with VATER. This has allowed the researchers to study normal and abnormal development of the early embryo. The study of rats showed abnormal notochord development in offspring with connections of the trachea and esophagus. In those offspring, the notochord was thickened and connected unusually to the foregut. More research of this animal model will answer many questions about the development and cause of the features of VATER.

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.

Signs and symptoms

VATER has six defining symptoms. "V" represents vertebral abnormalities. Approximately 70% of individuals with VATER have some type of spine difference such as scoliosis (curvature of the spine), hemivertebrae (unusually aligned, extra, or crowded spinal bones), and sacral absence (absence of spinal bones in the pelvic area). Vertebral differences are usually in the lumbro-sacral area (the part of the spine in the small of the back and pelvis). "A" represents anal atresia which is present in about 80% of individuals with VATER. This is an unusual arrangment or connection of the anus and rectum. Imperforate anus is also common, in which the anal opening does not form or is covered. Babies with this problem cannot pass bowel movements out of the body. "TE" stands for tracheo-esophageal fistula. About 70% of babies with VATER have this problem. This is a connection between the two tubes of the throat—the esophagus (carries food from mouth to stomach) and the trachea (windpipe). This connection is dangerous because it causes breathing problems. These babies can also get food into their windpipe and choke. Lung infections are also common with this connection. Some infants may be missing part of their esophagus, causing problems with choking and feeding. These babies spit up their food because the food cannot get to the stomach.

In the original VATER association, "R" stood for radial differences and renal (kidney) problems. The radius is the forearm bone that connects to the hand on the side of the thumb. Radial differences can include an absent or underdeveloped radius. This often results in a twisted, unusual position of the arm and hand. The thumb can also be small, misplaced, or absent. Kidney problems are present in about half of individuals with VATER. These can include missing kidneys, kidney cysts, or fluid buildup in the kidneys. Some individuals also have an abnormal position of the urethra (the tube that carries urine out of the body).

The expanded VACTERL includes "C" for cardiac (heart) problems and "L" for limb differences. The heart problems are usually holes or other structural abnormalities. Limb differences usually involve the arms rather than the legs. The term includes more general differences such as extra fingers, shortened or missing fingers, and underdeveloped humerus (the bone of the upper arm). These differences often cause unusual arm or hand positions (bent or twisted) and fingers that are short, absent, or misplaced.

Many people have proposed an expanded VACTERL pattern to include differences of the reproductive system and absent sacrum. Small or ambiguous (not clearly male or female) genitalia, or misplaced reproductive parts are common in VACTERL. They tend to occur more frequently in infants with anal and kidney abnormalities. They are seen less often with esophagus and arm features. Absence of the bones of the sacrum (spine in the pelvis area) is also commonly seen in VACTERL.

Individuals with VATER have an average of seven to eight features or differences at birth. About two-thirds of features involve the lower body (intestines, genitals, urinary system, pelvis, and lower spine). One-third of features involve the upper body (arms, hands, heart, esophagus, and trachea). In addition to the typical VATER features, infants may have problems with the intestines or excess water in the brain. Intestinal problems (such as missing sections of intestine) are more common in individuals with anal or esophagus features.

Shortly after birth, infants with VATER often have failure to thrive. This involves feeding problems and difficulty gaining weight. Their development is often slow. Infants with visible signs of VATER should immediately be checked for internal signs. Quick detection of problems with the trachea, esophagus, heart, and kidneys can lead to earlier treatment and prevention of major illness. Most individuals with VATER have normal mental development and mental retardation is rare.

Diagnosis

Some features of VATER can be seen on prenatal ultrasound so that the diagnosis may be suspected at birth. Ultrasound can see differences of the vertebrae, heart, limbs, limb positions, kidneys, and some reproductive parts. Other problems that are associated with VATER on ultrasound are poor fetal growth, excessive fluid in the womb, absent or collapsed stomach, and one artery in the umbilical cord instead of the usual two. VATER features that cannot be seen on ultrasound are differences of the anus, esophagus, and trachea.

Even if VATER is suspected before birth, an infant must be examined after birth to determine the extent of features. The entire pattern of internal and external differences will determine if the infant has VATER association, another multiple birth defect syndrome, or a genetic syndrome (such as Holt-Oram syndrome, TAR syndrome, or Fanconi anemia). Since VATER overlaps with some genetic syndromes, some infants may fit the VATER pattern and still have another diagnosis. VATER only describes the pattern of related birth defects. Since the genetic causes of VATER are unknown, genetic testing is not available. A family history focusing on VATER features can help to determine if an infant has a sporadic case or a rare inherited case.

Treatment and management

Treatment for VATER involves surgery for each separate feature. Holes in the heart can be closed by surgery. Structural problems of the heart can also often be repaired. Prognosis is best for infants with small or simple heart problems. Some vertebral problems may also need surgery. If the vertebral differences cause a problem for the individual's posture, braces or other support devices may be needed.

Problems with the trachea and esophagus can also be repaired with surgery. Before surgery the infant usually needs a feeding tube for eating. This will stop the choking and spitting up. The infant may also need oxygen to help with breathing. If the trachea and esophagus are connected, the connection is separated first. Once separated, the two trachea ends and esophagus ends can be sealed together. When part of the esophagus is missing, the two loose ends are connected. If the gap between the loose ends is too big, surgery may be delayed until the esophagus grows. Some infants still have problems after surgery. They may have a difficult time swallowing or food may get stuck in their throat. They may also have asthma and frequent respiratory infections.

Surgery can also repair problems of the anus and rectum. Before surgery, a temporary opening is made from the small intestine to the abdomen. This allows the infant to have bowel movements and pass stool material. An anal opening is created with surgery. The intestines and rectum are adjusted to fit with the new anal opening. The temporary opening on the abdomen may be closed immediately after surgery or it may be closed weeks or months later. Surgeons must be very careful not to damage the nerves and muscles around the anus. If they are damaged, the individual may lose control of their bowel movements.

Differences of the hands and arms can also be improved with surgery. Infants with underdeveloped or absent radius may have a stiff elbow, stiff wrist, or twisted arm. Surgery can loosen the elbow and wrist to allow for movement. The arm can also be straightened. If needed, muscles from other parts of the body can be put into the arm. This may also improve movement. Even after surgery, individuals may not have completely normal function of the muscles and tendons of the arms and hands.

Prognosis

Prognosis for individuals with VATER association depends on the severity of features. Infants with complex heart problems or severe abnormalities of the anus, trachea, or esophagus have a poorer prognosis. Infants with several features that require surgery have a higher death rate than infants that need minor surgery or no surgery. Survival also depends on how quickly internal problems are discovered. The sooner problems with the heart, anus, trachea, and esophagus are found and repaired, the better the outlook for the infant. One study estimated that infants with VATER have a death rate 25 times higher than healthy infants. Another study estimated that up to 30% of individuals with VATER die in the newborn period.

Resources

PERIODICALS

Beasley, S.W., et al. "The Contribution of the Adriamycininduced Rat Model of the VATER Association to Our Understanding of Congenital Abnormalities and Their Embryogenesis." Pediatric Surgery International 16 (2000): 465-72.

Botto, Lorenzo D., et al. "The Spectrum of Congenital Anomalies of the VATER Association: An International Study." American Journal of Medical Genetics 71 (1997): 8-15.

Rittler, Monica, Joaquin E. Paz, and Eduardo E. Castilla. "VATERL: An Epidemiologic Analysis of Risk Factors." American Journal of Medical Genetics 73 (1997): 162-69.

Rittler, Monica, Joaquin E. Paz, and Eduardo E. Castilla. "VACTERL Association, Epidemiologic Definition and Delineation." American Journal of Medical Genetics 63 (1996): 529-36.