Information on the following diseases can be found in the Related Disorders section of this report:

• REAR syndrome
• Townes-Brocks syndrome
• Holt-Oram syndrome

VACTERL association is a rare disorder affecting multiple organ systems. Affected children have multiple problems apparent at birth (congenital birth defects) and some of them could be observed on prenatal ultrasound. Additional characteristics of VACTERL association do not develop or are not apparent until later during life. The diagnosis of VACTERL association is usually made based on the presence of at least three of the characteristic findings. The specific symptoms present will vary greatly from one child to another. Affected children will not have all of the symptoms listed below.

Vertebral Abnormalities
Vertebral abnormalities are defects of the spinal column. Children with VACTERL association may have malformed vertebrae (missing vertebrae, hemivertebrae, "butterfly" vertebrae, vertebral clefts and fusions) and ribs (absent ribs, supernumerary ribs, rib fusions and splitting). In some cases, abnormal 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
Some children with VACTERL association may have a condition in which a thin covering blocks the anal opening or the passage that normally connects the anus and the lowest part of the large intestine (rectum) fails to develop, a condition is known as anal atresia or imperforate anus. This condition prevents the normal passage of bowel contents. Involvement of the rectum/anus relates to a major risk for genital anomalies, which are usually more serious in boys.

Cardiac Defects
The most common heart defect in children with VACTERL association is 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 may occur in any portion of the ventricular 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 may include an abnormally rapid rate of breathing (tachypnea), wheezing, an unusually fast heartbeat (tachycardia), failure to grow at the expected rate (failure to thrive), and/or other findings. A large ventricular septal defect may cause life-threatening complications during infancy.

Additional congenital heart defects associated with the disorder may 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; patent ductus arteriosus, a condition in which the passage (ductus) between the blood vessel that leads to the lungs (pulmonary artery) and the major artery of the body (aorta) fails to close after birth; transposition of the great arteries, a condition in which the aortic and pulmonary arteries are in one another's normal positions; and a condition known as tetralogy of Fallot. (For more information on this disorder, choose tetralogy of Fallot as your search term in the Rare Disease Database.)

Tracheoesophageal Fistula and/or Esophageal Atresia
Children with VACTERL association often have an abnormal connection between the windpipe and the tube that carries food from the throat to the stomach (tracheoesophageal fistula) potentially causing food to be inhaled (aspirated) into the lungs, which, in turn, may result in respiratory infections (e.g., pneumonia) and failure to thrive. In addition, esophageal atresia may be present. Esophageal atresia is a condition in which the tube (esophagus) that normally carries food from the mouth to the stomach narrows to a thin cord or ends in a pouch rather than providing passage to the stomach. These two conditions may result in feeding and swallowing difficulties.

Renal Abnormalities
Children with VACTERL association often have a variety of abnormalities affecting the kidneys and urinary tract including lack 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 not be at the end of the penis (hypospadias).

Limb Anomalies
Another major finding associated with VACTERL association are defects affecting the lower arm bone on the thumb side (radius). These defects may include failure of the radius to grow (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 tumb). In addition, affected children may have other limb anomalies including extra fingers (polydactyly), webbing of the fingers (syndactyly), abnormal fusion of the two forearm bones (radiaoulnar synostosis) and lower limb malformations (such as clubfoot, and hypoplasia of the great toe and tibia).

Some infants with VACTERL association may experience growth deficiencies and failure to thrive. In some cases, a single umbilical artery instead of the normal two may be present. In most cases of VACTERL association mental functioning and intelligence are unaffected.

Additional abnormalities that have been reported to occur in some individuals with VACTERL association include mild facial asymmetry (hemifacial microsomia), ear anomalies, narrowing of the voice box (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), incomplete lobation of the lungs, protrusion of part of the intestines through an abnormal opening in the muscular abdominal wall near the umbilical cord (omphalocele), intestinal malrotation, and a condition called tethered spinal cord syndrome. (For information on this condition, choose tethered spinal cord as your search term in the Rare Disease Database.)

The exact cause of VACTERL association is unknown. No specific genetic or environmental cause has been identified. The vast majority of cases of VACTERL association occur randomly, for no apparent reason (sporadically). In rare cases, VACTERL association has occurred in more than one family member.

Some researchers believe that abnormalities occurring in VACTERL association may result from defects in the middle (mesodermal) layer of the primary layers of the embryo during fetal development due to a variety of reasons. More specifically, VACTERL association results from an insult, heterogeneous in nature, which affects the embryo in the early prenatal life.

One or more VACTERL features have occurred with greater frequency to women with diabetes than in the general population.

Multiple VACTERL features could be also observed in chromosomal disorders, in particular Trisomy 18 syndrome.

One estimate places the incidence of VACTERL association at 1.6 per 10,000 live births. The true frequency of may be difficult to determine because many cases may be misdiagnosed or undiagnosed, especially children with fewer problems. Although many features of VACTERL association are apparent at birth, some features will not be apparent for weeks, months, or perhaps years. The recurrence risk of VACTERL association for parents with one affected child is about two-three percent. No specific test in actually available for prenatal diagnosis.
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Symptoms of the following disorders can be similar to those of VACTERL association. Comparisons may be useful for a differential diagnosis:

VACTERL with hydrocephalus is an extremely rare genetic disorder in which the multisystem features of VACTERL association occur in addition to hydrocephalus. Hydrocephalus is a condition in which excessive accumulation of cerebrospinal fluid in the skull causes pressure on the tissues of the brain and may result in abnormally enlarged head size (macrocephaly). Additional common symptoms associated with hydrocephalus include vomiting, irritability, seizures, and downward gaze of the eyes (sunsetting). In some cases, affected infants may experience delays in reaching developmental milestones (developmental delays). The specific symptoms that occur in VACTERL with hydrocephalus vary from one child to another. Unlike VACTERL association, VACTERL with hydrocephalus is a genetic disorder and may be inherited as an autosomal recessive or X-linked recessive trait. (For more information on this disorder, choose VACTERL with hydrocephalus as your search term in the Rare Disease Database.)

CHARGE syndrome is a rare pattern of malformations that may affect several organ systems of the body. CHARGE is an acronym that stands for (C)oloboma of the eye; (H)eart defects; (A)tresia of the Choanae, meaning bony or membranous blockage of the passageway between the nose and throat; (R)etardation of growth and development and/or mental deficiency; (G)enital anomalies; and (E)ar anomalies and/or deafness. Four or more of these characteristic features must be present for a diagnosis of CHARGE syndrome. Some affected individuals may also have other, variable symptoms and findings, such as a small head, incomplete closure of the roof of the mouth (cleft palate), an abnormal groove in the upper lip (cleft lip), swallowing difficulties, paralysis of facial nerves (facial palsy), an abnormal connection between the windpipe and the tube that carries food from the throat to the stomach (tracheoesophageal fistula), renal malformations, and/or other features. In most cases, CHARGE syndrome is caused by spontaneous mutations with low recurrence risk for the parental couple. However, some familial cases have been reported. (For more information, choose "CHARGE" as your search term in the Rare Disease Database.)

Holt-Oram syndrome (HOS) is a rare genetic disorder characterized by distinctive malformations of the bones of the thumbs and forearms (upper limbs) and/or abnormalities of the heart. The symptoms and physical findings associated with Holt-Oram syndrome may vary greatly from case to case. In many infants with the disorder, the thumbs may be absent or underdeveloped (hypoplastic) or have an extra bone (triphalangy). Affected infants may also have additional upper limb malformations such as underdevelopment (hypoplasia) of or extra bones in the wrists (e.g., scaphoid bone); malformations of certain bones of the hands (metacarpals); and/or underdevelopment of the bones of the forearms (radius and ulna) and/or the bones of the upper arms (humerus). The shoulder blades (scapulae), the collarbones (clavicles), and/or other bones may also be abnormal. In most cases, infants with Holt-Oram syndrome have heart (cardiac) abnormalities that may include structural (anatomical) malformations of the heart and/or abnormal transmission of electrical impulses (signals) that coordinate the heart's muscular contractions (electrocardiographic conduction defects). In individuals with the disorder, atrial and/or ventricular septal defects (ASDs and/or VSDs) are the most common structural heart defects. ASDs are characterized by an abnormal opening in the fibrous partition (septum) that separates the two upper chambers (atria) of the heart. VSDs are characterized by an abnormal opening in the septum that divides the heart's two lower chambers (ventricles). Holt-Oram syndrome is an autosomal dominant disorder. In approximately 60 percent of cases, Holt-Oram syndrome is inherited from an affected parent. In about 40 percent of cases, the disorder is the result of a spontaneous (i.e., de novo) genetic change (i.e., new mutation). (For more information on this disorder, choose Holt-Oram as your search term in the Rare Disease Database.)

Townes-Brocks Syndrome is a rare inherited disorder that is apparent at birth (congenital). Although symptoms and physical characteristics associated with the disorder may vary greatly in range and severity from case to case, abnormalities tend to involve the face, ears, arms and legs (limbs), gastrointestinal system, and kidneys. In individuals with the disorder, one side of the face may appear smaller than the other (hemifacial microsomia). Ear abnormalities may include malformation of the outer ears, excess tags of skin and/or indentations in front of the ears (preauricular tags and/or pits), and/or hearing impairment due to abnormalities of the internal ear (sensorineural hearing loss). Affected individuals may also have malformations of the thumbs, extra fingers (polydactyly), webbing between two or more fingers and/or toes (syndactyly), and/or other limb irregularities. In addition, individuals with Townes-Brocks Syndrome may exhibit absence of the anal opening (imperforate anus); abnormal passages between the rectum and the genitals (rectovaginal or rectoperineal fistula); underdeveloped kidneys (renal hypoplasia); a condition in which urine flows backwards from the bladder into a ureter (vesicoureteral reflux); and/or other related abnormalities. In addition, in some cases, affected individuals may also have abnormalities of the heart and the reproductive organs. Townes-Brocks Syndrome has autosomal dominant inheritance. (For more information on this disorder, choose "Townes Brocks" as your search term in the Rare Disease Database.)

Diagnosis
Because the cause of VACTERL association is unknown, no laboratory test exists that can diagnose or rule out VACTERL association. The diagnosis is a clinical diagnosis based on the features seen. It may take some time to do all the testing necessary to make a diagnosis of VACTERL association. A diagnosis may be made based upon a complete physical exam and a variety of specialized tests that look for the major and minor features of VACTERL association listed above.

Management
Although children with VACTERL association have many problems, they can survive and become healthy, happy citizens. The treatment of VACTERL association is directed toward the specific symptoms that are apparent in each individual, which often varies greatly. Many of the structural abnormalities (radial defects, heart defects, anal atresia, etc.) can be surgically corrected.

Infants 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 children with VACTERL association include cardiologists, urologists, orthopedists, and ear, nose and throat physicians, clinical geneticist.

Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. A team approach is essential for these complex children.

The Titanium Rib Project is underway to implant expandable ribs in children with disorders involving missing, underdeveloped, or otherwise malformed rib cages and/or chest walls. Birth defects, fused ribs, or hypoplastic chests may be improved using the titanium ribs that can be expanded as the child grows. More research is needed to determine the long-term safety and effectiveness of these artificial ribs. People who are interested may have their physicians contact:

Robert Campbell, M.D.
Santa Rosa Children's Hospital
519 West Houston Street
San Antonio, TX 78207
(210) 704-2988


Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
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Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
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