NORD gratefully acknowledges Etienne Leveille, MD Candidate, McGill University School of Medicine, Roger E. Stevenson, MD, Senior Clinical Geneticist, Greenwood Genetic Center, JC Self Research Institute of Human Genetics, for assistance in the preparation of this report.
VACTERL association is a nonrandom association of birth defects that affects multiple anatomical structures. The term VACTERL is an acronym with each letter representing the first letter of one of the more common findings seen in affected children:
(V) = (costo-) vertebral abnormalities
(A) = anal atresia
(C) = cardiac (heart) defects
(TE) = tracheal-esophageal abnormalities, including atresia, stenosis and fistula
(R) = renal (kidney) and radial abnormalities
(L) = limb abnormalities
(S) = single umbilical artery
Initially, the acronym VATER included vertebral, anal, tracheoesophageal, radial and renal anomalies was used. The acronym was subsequently redefined with the addition of (C) for cardiac defects, (L) for limb defects other than radial anomalies, and (S) for single umbilical artery. VACTERL association is currently the most frequently used term to define this condition. The cause of VACTERL association remains unknown in most patients and is likely caused by a combination of different factors (multifactorial). It is not considered a hereditary disorder and usually occurs in a single individual in any given family.
VACTERL association involves multiple anatomical defects. These defects are congenital and may be obvious at birth (e.g., anal atresia, tracheoesophageal fistula and esophageal atresia, radial defects) or not become recognized until later (e.g., cardiac, vertebral, and renal malformations). The combination of malformations may vary greatly from one child to another and an affected child will typically not have all of the malformations listed below.
Vertebral abnormalities are defects of the spinal column. These defects include missing vertebrae, malformed vertebrae (half-formed vertebrae termed hemivertebrae, butterfly-shaped vertebrae, vertebral clefts and fusion of vertebrae), missing ribs, an increased number of ribs (supernumerary ribs), rib fusions and splitting of ribs. Side-to-side curvature of the spine (scoliosis) and absence of the tailbone, the lowest bone of the spinal column (sacral agenesis), may also occur.
Anal atresia is a malformation in which the opening that connects the rectum through the anus to the exterior is closed. The closure may be a thin membrane of skin or a thicker blockage of skin and muscle. This condition, also termed imperforate anus, prevents the normal passage of bowel contents. Anal atresia may coexist with abnormalities in the lower urogenital tract.
Cardiac (Heart) Defects
A number of different cardiac defects may occur in the VACTERL association, the most common being ventricular septal defects (VSDs). The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The aorta, the main vessel of arterial circulation, carries blood away from the left ventricle to the rest of the body. A VSD is a hole in the ventricular septum and may occur anywhere in the septum. The size and location of the defect determine the severity of the symptoms. A small ventricular septal defect may close on its own (spontaneously) or become less significant as the child matures and grows. A moderately-sized defect may affect the ability of the heart to pump blood efficiently to the lungs and the rest of the body (congestive heart failure). Symptoms associated with heart failure include an abnormally rapid rate of breathing (tachypnea), wheezing, an unusually fast heartbeat (tachycardia), and failure to grow at the expected rate (failure to thrive). A large ventricular septal defect may cause life-threatening complications during infancy.
Additional congenital heart defects that have occurred in the VACTERL association include atrial septal defects (ASDs); hypoplastic left heart syndrome (a life-treating condition in which there is underdevelopment of the left ventricle, the aortic and/or mitral valve, and the ascending aorta); transposition of the great arteries (a condition in which the aorta and pulmonary artery are switched in positions); a complex malformation known as tetralogy of Fallot; and patent ductus arteriosus [a condition in which the passage between the blood vessel that leads to the lungs (pulmonary arteries) and the major artery of the body (aorta) fails to close after birth]. (For more information on those conditions, choose the name of the disorder as your search term in the Rare Disease Database.)
Tracheoesophageal Fistula and/or Esophageal Atresia
An abnormal connection between the trachea and the esophagus (tracheoesophageal fistula) is the most common birth defect in the VACTERL association. The malformation potentially allows food to be inhaled (aspirated) into the lungs, which, in turn, may result in respiratory infections (e.g., pneumonia) and failure to thrive. Esophageal atresia, a malformation in which the esophagus narrows to a thin cord or ends in a blind pouch rather than providing passage to the stomach, may also be present. These two conditions may result in breathing, feeding and swallowing difficulties.
A variety of abnormalities affecting the kidneys and urinary tract including absence of development of one or both kidneys (renal aplasia), malformation of one or both kidneys (renal dysplasia), displaced or malpositioned kidneys (renal ectopia), abnormal backflow (reflux) of urine into the tube (ureter) that carries urine to the bladder (vesicoureteral reflux), resulting in abnormal accumulation of urine in the kidneys (hydronephrosis). In addition, affected children may experience frequent urinary tract infections and the urethral opening may be abnormally positioned at the end of the penis (hypospadias).
Another major finding associated with VACTERL association is defects affecting the forearm on the thumb side (radius). These defects may include absence of the radius (radial aplasia), underdevelopment of the radius (radial hypoplasia), underdevelopment or absence of the thumb and/or the presence of an extra bone in the thumb (triphalangeal thumb). Other limb anomalies including extra digits (polydactyly), webbing of the digits (syndactyly), abnormal fusion of the two forearm bones (radioulnar synostosis) and lower limb malformations (such as clubfoot, and hypoplasia of the great toe and tibia) have been described in VACTERL association.
Other Birth Defects
Additional birth defects that have been reported to occur in a minority of affected individuals include facial asymmetry (hemifacial microsomia), abnormal shape and size of the ears, narrowing of the larynx (laryngeal stenosis), narrowing of the passages from the back of the nose to the throat that make it possible to breathe through the nose (choanal atresia), lung malformations , protrusion of part of the intestines through an abnormal opening in the muscular abdominal wall near the umbilical cord (omphalocele), intestinal misplacement and misalignment (malrotation), and tethered spinal cord. A single umbilical artery rather than the usual two arteries has been found in a minority of infants with VACTERL association. (For information on this condition, choose “tethered spinal cord” as your search term in the Rare Disease Database.)
Some infants and young children with VACTERL association may grow slower than normal. In the vast majority of patients, VACTERL association does not affect mental functioning and intelligence.
With the improvement of medical and surgical care, the patient outcomes (prognosis) of VACTERL association are much better than they were before. However, affected individuals may experience medical complications throughout life. For instance, vertebral malformations might lead to scoliosis and chronic back pain, anal atresia might be associated with incontinence and/or constipation, gastro-esophageal reflux might result from TE fistula and renal anomalies are associated with an increased risk of urinary tract infection (UTI) and renal stones (nephrolithiasis). In addition, individuals with limb abnormalities and malformation might have functional limitations.
The exact cause of VACTERL association is unknown. Clearly, the factors that lead to the widespread malformations must influence the very early stages of embryonic development. One or more VACTERL defects have occurred with greater frequency to women with diabetes than in the general population. Rarely, VACTERL association has been associated with gene alterations including duplications or deletions (copy number variation), and mitochondrial dysfunction (the mitochondria is a cellular structure responsible for energy production in the cell).
Estimates place the birth prevalence of VACTERL association at about 1 per 10,000 to 40,000 live births. The true frequency may be difficult to determine because different diagnostic criteria are used in different studies. In addition, VACTERL association is likely to be underdiagnosed, especially in children with fewer problems. Some studies have shown that males might be slightly more commonly affected than females, but no association with a specific geographic region or ethnic group has been determined. VACTERL association is generally not a heritable disease, and the risk of recurrence in another child from the same parents is low.
VACTERL association is a diagnosis made when other possible causes of birth defects have been ruled out (diagnosis of exclusion). No clearly-established set or validated diagnostic criteria has been published to date, and no laboratory test exists that can diagnose or rule out VACTERL association. At the moment, the most stringent approach defines a “secure” designation of VACTERL association in presence of at least one anomaly in all three involved body parts (i.e. limbs, thorax and pelvis/lower abdomen), and “probable” in presence of two or more anomalies in two body parts. The diagnosis is a clinical diagnosis based on the defects present and therefore starts with a complete physical examination. Other tests performed will depend on the suspected birth defects. For example, X-ray imaging might be used to detect vertebral and limb anomalies and ultrasound imaging might identify cardiac or renal defects. Laboratory and genetic tests can be useful to rule out alternative diagnoses. Some malformations seen in VACTERL association might be identified before birth with imaging techniques such as prenatal ultrasound. Importantly, the presence of a single umbilical artery should prompt evaluation for VACTERL association and other birth defects.
Although children with VACTERL association may have many complications, their malformations are usually not life threatening. The treatment of VACTERL association is directed toward the specific malformations and related symptoms that occur in each individual, which often varies greatly. Many of the structural abnormalities (radial defects, heart defects, anal atresia, etc.) can be surgically corrected. In some individuals, surgery might be necessary as early as the neonatal period. Repeat surgeries might also be needed later in life to revise or further correct structural defects.
A team approach is essential for optimal treatment of the condition. Individuals diagnosed with VACTERL association will need to be followed by a number of medical and developmental specialists depending on their individual needs. Some of the medical specialists who often follow individuals with VACTERL association include cardiologists, urologists, orthopedists, ear, nose and throat (ENT) physicians and clinical geneticists.
Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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