VACTERL Association

Epidemiology and Etiology

Epidemiology

• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 1 in 10,000–40,000 live births
• Recurrence risk in a sibling or child: < 1%

Etiology

• VACTERL cases are often sporadic Sporadic Selective IgA Deficiency.
• Often no family history Family History Adult Health Maintenance of the condition
• No clear inheritance pattern
• Multiple genetic and environmental factors likely contribute
• Associated with:
  • Genetic variants affecting Shh and Wnt signaling pathways
  • Genetic alterations in ciliary genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure (e.g., DNAH gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics family, IFT complex)

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 Atresia Hypoplastic Left Heart Syndrome (HLHS) (imperforate anus)
  • Complete or partial/ stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS)
  • Bowel obstruction Bowel obstruction Any impairment, arrest, or reversal of the normal flow of intestinal contents toward the anal canal. Ascaris/Ascariasis/inability to pass meconium Meconium The thick green-to-black mucilaginous material found in the intestines of a full-term fetus. It consists of secretions of the intestinal glands; bile pigments; fatty acids; amniotic fluid; and intrauterine debris. It constitutes the first stools passed by a newborn. Prenatal and Postnatal Physiology of the Neonate
• C for Cardiac defects
  • Ventricular septal defect Ventricular Septal Defect Tetralogy of Fallot (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) ( ASD ASD Autism spectrum disorder (ASD) is a neurodevelopmental disorder marked by poor social skills, restricted interests/social interactions, and repetitive/stereotyped behaviors. The condition is termed a “spectrum” because of the wide variability in the severity of symptoms exhibited. Autism Spectrum Disorder) 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 Fistula Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. Anal 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: Anatomy 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: Anatomy
  • Causes breathing and feeding difficulties 
• E for Esophageal atresia Atresia Hypoplastic Left Heart Syndrome (HLHS) (duodenal atresia Atresia Hypoplastic Left Heart Syndrome (HLHS) may also be seen)
• R for Renal anomalies
  • Horseshoe kidney Horseshoe Kidney Congenital Renal Abnormalities, unilateral/bilateral renal agenesis Agenesis Teratogenic Birth Defects (missing kidney), cystic Cystic Fibrocystic Change/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: Anatomy
  • May affect kidney function
• L for Limb abnormalities
  • Thumb aplasia Aplasia Cranial Nerve Palsies/ hypoplasia Hypoplasia Hypoplastic Left Heart Syndrome (HLHS) (underdeveloped or missing thumbs) 
  • Radial dysplasia (underdeveloped or missing radius Radius The outer shorter of the two bones of the forearm, lying parallel to the ulna and partially revolving around it. Forearm: Anatomy in forearms Forearms Part of the upper extremity in humans and primates extending from the elbow to the wrist. Bowen Disease and Erythroplasia of Queyrat)
  • Polydactyly Polydactyly A congenital anomaly of the hand or foot, marked by the presence of supernumerary digits. Physical Examination of the Newborn, syndactyly Syndactyly A congenital anomaly of the hand or foot, marked by the webbing between adjacent fingers or toes. Syndactylies are classified as complete or incomplete by the degree of joining. Syndactylies can also be simple or complex. Simple syndactyly indicates joining of only skin or soft tissue; complex syndactyly marks joining of bony elements. Development of the Limbs

Associated conditions

• Single umbilical artery Umbilical artery Specialized arterial vessels in the umbilical cord. They carry waste and deoxygenated blood from the fetus to the mother via the placenta. In humans, there are usually two umbilical arteries but sometimes one. Prenatal and Postnatal Physiology of the Neonate (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 and Types
• 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: Anatomy 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 Genetic Screening Physical Examination of the Newborn 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 and Types.
• 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 Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies not done for diagnosis of VACTERL association, but to evaluate for conditions in the differential diagnosis

Management

• Medical management:
  • Oxygen 
  • Nasogastric intubation Intubation Peritonsillar Abscess (feeding tube)
• Surgical management:
  • Certain malformations (e.g., anal atresia Atresia Hypoplastic Left Heart Syndrome (HLHS), tracheoesophageal fistula Fistula Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. Anal 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 Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies, can help differentiate most of these syndromes. The following is a selection Selection Lymphocyte activation by a specific antigen thus triggering clonal expansion of lymphocytes already capable of mounting an immune response to the antigen. B cells: Types and Functions 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 inheritance Autosomal dominant inheritance Autosomal Recessive and Autosomal Dominant 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 Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies confirms the diagnosis. Treatment is symptomatic, with management of the airway Airway ABCDE Assessment, heart defects, and feeding ability as the priorities in early life. 
• Townes-Brocks syndrome: a rare genetic condition with autosomal dominant inheritance Autosomal dominant inheritance Autosomal Recessive and Autosomal Dominant Inheritance. Also affects multiple body systems with similar clinical features as VACTERL association, with the most common features being anal atresia Atresia Hypoplastic Left Heart Syndrome (HLHS), 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 Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies 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 inheritance Autosomal dominant inheritance Autosomal Recessive and Autosomal Dominant Inheritance. Affects multiple body systems with similar features to VACTERL association. However, a hypothalamic hamartoma Hamartoma A focal malformation resembling a neoplasm, composed of an overgrowth of mature cells and tissues that normally occur in the affected area. Colorectal Cancer is pathognomonic. Additional features include bifid epiglottis Epiglottis A thin leaf-shaped cartilage that is covered with laryngeal mucosa and situated posterior to the root of the tongue and hyoid bone. During swallowing, the epiglottis folds back over the larynx inlet thus prevents foods from entering the airway. Larynx: Anatomy, nail hypoplasia Hypoplasia Hypoplastic Left Heart Syndrome (HLHS), and polydactyly Polydactyly A congenital anomaly of the hand or foot, marked by the presence of supernumerary digits. Physical Examination of the Newborn. Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies 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 and Types: 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 Inheritance or X-linked inheritance X-linked inheritance Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Alport Syndrome. A multitude of congenital defects similar to that in VACTERL association is present. Renal and characteristic limb anomalies (missing thumb/ radius Radius The outer shorter of the two bones of the forearm, lying parallel to the ulna and partially revolving around it. Forearm: Anatomy) 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 and Types is associated with bone marrow failure Bone marrow failure Inherited or acquired diseases characterized by insufficient and/or dysplastic blood cells. Paroxysmal Nocturnal Hemoglobinuria, 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 transplant Bone marrow transplant Transfer of hematopoietic stem cells from bone marrow or blood between individuals within the same species (homologous transplantation) or transfer within the same individual (autologous transplantation). Hematopoietic stem cell transplantation has been used as an alternative to bone marrow transplantation in the treatment of a variety of neoplasms. Organ Transplantation, blood transfusions Blood transfusions The introduction of whole blood or blood component directly into the bloodstream. Transfusion Products, 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 Hydrocephalus Excessive accumulation of cerebrospinal fluid within the cranium which may be associated with dilation of cerebral ventricles, intracranial. Subarachnoid Hemorrhage. 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 Inheritance or X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) pattern of inheritance. Diagnosis is clinical and one of exclusion. A shunt may be needed to help drain excess cerebrospinal fluid Cerebrospinal Fluid A watery fluid that is continuously produced in the choroid plexus and circulates around the surface of the brain; spinal cord; and in the cerebral ventricles. Ventricular System: Anatomy for treatment of the hydrocephalus Hydrocephalus Excessive accumulation of cerebrospinal fluid within the cranium which may be associated with dilation of cerebral ventricles, intracranial. Subarachnoid Hemorrhage. Additional treatments are based on clinical manifestations.