VACTERL Association

VACTERL association is a rare disorder that affects multiple body systems in fetal development. There is no clear genetic cause or inheritance pattern for the development of this disorder. The acronym VACTERL stands for the anomalies by which this condition is characterized: Vertebral abnormalities, Anal atresia, Cardiac defects, Tracheoesophageal abnormalities, Renal anomalies, and Limb abnormalities. Cognition is not affected. The diagnosis is one of exclusion in the setting of the presence of at least 3 of the above clinical features. Treatment is based on symptoms and abnormalities present.

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Epidemiology and Genetics

Epidemiology

  • Incidence: 1 in 10,000–40,000 live births
  • Recurrence risk in a sibling or child: < 1%

Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics

  • VACTERL cases are often sporadic.
  • Often no family history of condition
  • No clear inheritance pattern
  • Multiple genetic and environmental factors likely contribute, but specifics are unknown.

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Clinical Presentation

Characteristic features

The acronym VACTERL describes the clinical manifestations of the condition.

  • V for Vertebral abnormalities
    • Misshapen, fused, missing, or extra vertebrae present
    • Scoliosis Scoliosis Scoliosis is a structural alteration of the vertebral column characterized by a lateral spinal curvature of greater than 10 degrees in the coronal plane. Scoliosis can be classified as idiopathic (in most cases) or secondary to underlying conditions. Scoliosis secondary to underlying vertebral anomalies
  • A for Anal atresia (imperforate anus)
    • Complete or partial/stenosis
    • Bowel obstruction/inability to pass meconium
  • C for Cardiac defects 
    • Ventricular septal defect (VSD) is the most common
    • Less commonly, atrial septal defect Atrial Septal Defect Atrial septal defects (ASDs) are benign acyanotic congenital heart defects characterized by an opening in the interatrial septum that causes blood to flow from the left atrium (LA) to the right atrium (RA) (left-to-right shunt). Atrial Septal Defect (ASD) or tetralogy of Fallot Tetralogy of Fallot Tetralogy of Fallot is the most common cyanotic congenital heart disease. The disease is the confluence of 4 pathologic cardiac features: overriding aorta, ventricular septal defect, right ventricular outflow obstruction, and right ventricular hypertrophy. Tetralogy of Fallot
  • T for Tracheoesophageal fistula
    • Abnormal connection between the trachea Trachea The trachea is a tubular structure that forms part of the lower respiratory tract. The trachea is continuous superiorly with the larynx and inferiorly becomes the bronchial tree within the lungs. The trachea consists of a support frame of semicircular, or C-shaped, rings made out of hyaline cartilage and reinforced by collagenous connective tissue. Trachea and esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus
    • Causes breathing and feeding difficulties 
  • E for Esophageal atresia (duodenal atresia may also be seen)
  • R for Renal anomalies
    • Horseshoe kidney, unilateral/bilateral renal agenesis (missing kidney), cystic/dysplastic kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys
    • May affect kidney function
  • L for Limb abnormalities
    • Thumb aplasia/hypoplasia (underdeveloped or missing thumbs) 
    • Radial dysplasia (underdeveloped or missing radius in forearms)
    • Polydactyly, syndactyly

Associated conditions

  • Single umbilical artery (normally 2)
  • Fanconi’s anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
  • Genital and urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract abnormalities
  • Rib anomalies
  • Pulmonary anomalies
  • Ear malformations

Diagnosis and Management

Diagnosis

VACTERL is a diagnosis of exclusion. All other possible conditions should be evaluated and ruled out.

  • History and clinical examination:
    • At least three of the defining characteristics needed for diagnosis
    • Finding one abnormality in this association should prompt evaluation for others. 
    • Those with renal or characteristic limb anomalies should undergo genetic screening for Fanconi’s anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview.
  • Imaging:
    • Chest radiograph to evaluate for vertebral, rib, and possible pulmonary anomalies 
    • Echo to evaluate for cardiac defects
    • Renal ultrasound to evaluate for renal anomalies
    • Abdominal ultrasound to evaluate for genitourinary anomalies
    • Spinal ultrasound and spinal radiographs to evaluate for spinal anomalies
    • Limb radiographs to evaluate for radial dysplasia
  • Labs/genetic testing not done for diagnosis of VACTERL association, but to evaluate for conditions in the differential diagnosis

Management

  • Medical management: 
    • Oxygen 
    • Nasogastric intubation (feeding tube)
  • Surgical management:
    • Certain malformations (e.g., anal atresia, tracheoesophageal fistula Tracheoesophageal fistula Tracheoesophageal fistula is an abnormal connection between the trachea and esophagus. Esophageal Atresia and Tracheoesophageal Fistula, and certain cardiac defects) may require surgery in the 1st few days or years of life.
    • Additional surgeries may be required later depending on malformations present.

Differential Diagnosis

Multiple syndromes have clinical features overlapping with VACTERL association. The presence of anomalies not characteristic of VACTERL association, in combination with genetic testing, can help differentiate most of these syndromes. The following is a selection of the most important differential diagnoses:

  • CHARGE syndrome CHARGE Syndrome CHARGE syndrome is a rare genetic condition with autosomal dominant inheritance in which almost all body systems are affected. The acronym CHARGE stands for the constellation of clinical features seen with this condition: Coloboma, Heart defects, Atresia choanae, Growth retardation, Genetic Abnormalities, and Ear abnormalities. CHARGE Syndrome: a rare genetic condition with autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance inheritance in which almost all body systems are affected. The term CHARGE is an acronym for the clinical features seen with this condition: Coloboma, Heart defects, Atresia choanae, Growth retardation and Genetic abnormalities, and E ar AR Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation abnormalities. Genetic testing confirms the diagnosis. Treatment is symptomatic, with management of the airway, heart defects, and feeding ability as the priorities in early life. 
  • Townes-Brocks syndrome: a rare genetic condition with autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance inheritance. Also affects multiple body systems with similar clinical features as VACTERL association, with the most common features being anal atresia, ear anomalies, and thumb abnormalities. Unlike VACTERL, hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss is common with this condition. Tracheoesophageal fistulas and vertebral anomalies are not typically seen. Genetic testing confirms the diagnosis. Early intervention with hearing aids is needed for hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss. Additional treatments are based on clinical manifestations.
  • Pallister-Hall syndrome: a rare genetic condition with autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance inheritance. Affects multiple body systems with similar features to VACTERL association. However, a hypothalamic hamartoma is pathognomonic. Additional features include bifid epiglottis, nail hypoplasia, and polydactyly. Genetic testing confirms the diagnosis. Treatment is based on the clinical manifestations present.
  • Fanconi’s anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview: genetic condition with autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritanceor X-linked inheritance. A multitude of congenital defects similar to that in VACTERL association is present. Renal and characteristic limb anomalies (missing thumb/radius) are particularly seen. Fanconi’s anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview is associated with bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow failure, acute myeloid leukemia Acute Myeloid Leukemia Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia ( AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia), and other types of neoplasia. Chromosomal breakage studies help confirm the diagnosis. Treatment involves bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow transplant, blood transfusions, medication, and possibly surgery depending on clinical manifestations. 
  • VACTERL-H: a genetic condition involving all the clinical features of VACTERL association, with the additional finding of hydrocephalus. The condition may have an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritanceor X-linked pattern of inheritance. Diagnosis is clinical and one of exclusion. A shunt may be needed to help drain excess cerebrospinal fluid for treatment of the hydrocephalus. Additional treatments are based on clinical manifestations.

References

  1. Solomon B. D. (2011). VACTERL/VATER Association. Orphanet journal of rare diseases, 6, 56. https://doi.org/10.1186/1750-1172-6-56
  2. VACTERL association. MedlinePlus. Retrieved December 8, 2020. URL: https://medlineplus.gov/genetics/condition/vacterl-association/#causes
  3. Altera, B. P. & Rosenberg, P.S. (2013). VACTERL-H Association and Fanconi Anemia. Mol Syndromol. 4(1–2): 87–93. doi: 10.1159/000346035
  4. Bacino, C.A. (2019). Birth defects: Epidemiology, types, and patterns. UpToDate. Retrieved December 8, 2020.  URL: https://www.uptodate.com/contents/birth-defects-epidemiology-types-and-patterns?sectionName=Association&search=vacterl&topicRef=6377&anchor=H3788531324&source=see_link#H3282666919
  5. Yang, L., Li, S., Zhong, L., Qiu, L., Xie, L., & Chen, L. (2019). VACTERL association complicated with multiple airway abnormalities: A case report. Medicine, 98(42), e17413. https://doi.org/10.1097/MD.0000000000017413

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