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VACTERL Association

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Copyright 1987, 1989, 1992, 2003, 2009, 2012

NORD is very grateful to Marco Castori, MD, Clinical Geneticist, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy, for assistance in the preparation of this report.

Synonyms of VACTERL Association

Disorder Subdivisions

General Discussion

VACTERL association is a nonrandom association of birth defects that affects multiple median and para-median 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) = (non-radial) limb abnormalities
(S) = single umbilical artery

Variability of such associations is wide and the relevance of each component usually varies by the observers. For this reason, from an original nucleus of "VATER" anomalies, the subsequent observation of an increased rate of heart malformations (C), non-radial limb anomalies (L) and single umbilical artery (S) expanded the phenotypic continuum grouping together all these conditions (i.e. VATER, VACTER, VACTERL and VACTERLS associations). At the moment, VACTERL association is the most frequently used term to define this condition. In addition, to the above mentioned features, affected children may also exhibit pre- and/or post-natal growth deficiency with failure to gain weight and grow at the expected rate (failure to thrive). Further low-frequency findings include facial asymmetry (hemifacial microsomia), external ear malformations, lung lobation defects, intestinal malrotation and genital anomalies. VATER/VACTERL features are more common in twinning. In some cases, the acronym VATER association is used. Mental functioning and intelligence is usually unaffected; developmental delay/mental retardation should suggest an alternative diagnosis. The exact cause of VACTERL association is unknown. Most cases occur randomly, for no apparent reason (sporadic).

Symptoms

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. VACTERL association is a diagnosis of exclusion (see Related Disorders) and no set of validated diagnostic criteria has been published to date. 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. Standard karyotyping and exclusion of Fanconi anemia (see below) by DEB test are easily accessible tests which may support the diagnosis. 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. Some studies suggest that the 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.)

Causes

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 (blastogenesis; i.e. first two-four weeks of gestation).

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.

Affected Populations

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, although fetal ultrasound scan may be of some help to exclude recurrence.

Related Disorders

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.)

Fanconi anemia is an inherited anemia that leads to progressive, severe bone marrow failure, also known as aplastic anemia. The disorder is characterized by weakness, severe bleeding due to insufficient blood clotting and susceptibility to infection. Fanconi anemia may also be associated with heart (cardiac), kidney (renal), and/or skeletal abnormalities. Patients are also at increased risk for developing leukemia and other cancers. There are several different subtypes (complementation groups) of Fanconi anemia, each of which is thought to result from an abnormal change (mutation) to a different gene. Fanconi anemia follows autosomal recessive inheritance. (For more information on this disorder, choose "Fanconi" 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.)

Trisomy 18 shows a significant overlap with VACTERL association, especially in the prenatal period and at birth. In fact, the combination of radial ray anomalies, congenital heart defect, renal malformations and growth retardation of prenatal onset is quite common in both conditions. Marked developmental delay easily differentiates the conditions in infancy, but it cannot be of some help at an early age. Differentiation between the hemifacial microsomia associated spectrum (the so-called "oculo-auriculo-vertebral spectrum") and VACTERL association may be difficult in specific cases. Both disorders rise in the blastogenesis period and possibly share a significant proportion of pathogenic processes and etiological factors. Facial asymmetry and ear anomalies are relatively common in VACTERL association, while in approx. 10% of oculo-auriculo-vertebral spectrum cases the resulting phenotype is severe with additional central nervous system malformations, radial ray involvement and/or anomalies of the lower midline structures. Therefore, differentiating between VACTERL association and oculo-auriculo-vertebral spectrum may be difficult in some cases. Consequently, the term hemifacial microsomia-VACTERL association (HM-VACTERL) has been used by some authors to define this overlapping phenotype. . (For more information on this disorder, choose "Trisomy 18" as your search term in the Rare Disease Database.)

Standard Therapies

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 Vertical Expandable Prosthetic Titanium Rib (VEPTR) was approved by the FDA in 2004 as a treatment for thoracic insufficiency syndrome (TIS) in pediatric patients. TIS is a congenital condition where severe deformities of the chest, spine, and ribs prevent normal breathing and lung development. The VEPTR is an implanted, expandable device that helps straighten the spine and separate ribs so that the lungs can grow and fill with enough air to breathe. The length of the device can be adjusted as the patient grows. The titanium rib was developed at the University of Texas Health Science Center in San Antonio. It is manufactured by Synthes Spine Co.: http://www.synthes.com/sites/NA/Products/Spine/Screw_Hook_Rod_and_Clamp_System/Pages/VEPTR_and_VEPTR_II.aspx

For more information, please contact:

Synthes, Inc.
1302 Wrights Lane East
West Chester, PA 19380
800-523-0322

Investigational Therapies

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
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Contact for additional information about VACTERL association:
Marco Castori, MD
Clinical Geneticist (Consultant)
Medical Genetics
Department of Molecular Medicine
Sapienza University
San Camillo-Forlanini Hospital
Circonvallazione Gianicolense 87
I-00152 Rome, Italy
E-mail: mcastori@scamilloforlanini.rm.it

Organizations related to VACTERL Association

References

TEXTBOOKS
Jones KL, ed. Smith's Recognizable Patterns of Human Malformation. 6th ed. Philadelphia, PA: W. B. Saunders Co: 2006:756.

JOURNAL ARTICLES
Tercanli S, et al. Prenatal diagnosis and management in VACTERL association. Z Geburtshilfe Neonatol. 2002;205:65-70.

Kim J, et al. The VACTERL association: lessons from the Sonic hedgehog pathway. Clin Genet. 2001;59:306-15.

Erkan D, et al. VATER association: is it recognized by rheumatologists? Clin Rheumatol. 2001;20:128-31.

Kallen K, et al. VATER non-random association of congenital malformations: study based on data from four malformation registries. Am J Med Genet. 2001;101:26-32. Comment in: Am J Med Genet. 2001;101:33-5.

Kolon TF, et al., Upper urinary tract manifestations of the VACTERL association. J Urol. 2000;163:1949-51.

Tongsong T, et al. Prenatal sonographic diagnosis of VATER association. J Clin Ultrasound. 1999;27:378-84.

Botto LD, et al. The spectrum of congenital anomalies of the VATER association: an international study. Am J Med Genet. 1997;71:8-15.

Rittler M, et al. VACTERL association, epidemiologic definition and delineation. Am J Med Genet. 1996;63:529-36.

Corsello G, et al. VATER/VACTERL association: clinical variability and expanding phenotype including laryngeal stenosis. Am J Med Genet. 1992;44:813-5. Erratum in: Am J Med Genet. 1993;47:118.

Hersh JH, et al. Townes syndrome. A distinct multiple malformation syndrome resembling VACTERL association. Clin Pediatr (Phila). 1986;25:100-2.

Evans JA, et al. Tracheal agenesis and associated malformations: a comparison with tracheoesophageal fistula and the VACTERL association. Am J Med Genet. 1985;21:21-38.

Khoury MJ, et al. A population study of the VACTERL association: evidence for its etiologic heterogeneity. Pediatrics. 1983;71:815-20.

INTERNET
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. VACTER Association. Entry No: 192350. Last Edited September 22, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed March 14, 2012.

Report last updated: 2012/03/16 00:00:00 GMT+0