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Last updated:
April 02, 2020
Years published: 2003, 2020
NORD gratefully acknowledges Etienne Leveille, MD Candidate, McGill University School of Medicine, Catherine A. Ziats, MD, Clinical Genetics Resident and 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 with hydrocephalus (VACTERL-H) is a rare disorder in which the non-random congenital malformations of VACTERL association co-occur with hydrocephalus. The term VACTERL is an acronym with each letter representing the first letter of the associated malformation:
(V) = vertebral abnormalities
(A) = anal atresia
(C) = cardiac (heart) defects
(T) = tracheoesophageal fistula
(E) = esophageal atresia
(R) = renal (kidney) and radial abnormalities
(L) = limb abnormalities
(H)ydrocephalus is a condition in which accumulation of cerebrospinal fluid (CSF) in and around the brain and spinal cord causes increased pressure on the brain tissue.
VACTERL with hydrocephalus (VACTERL-H) is a rare disorder that affects multiple anatomical systems. Affected children typically present with a variety of congenital anomalies at birth, however, in some children core features of the disorder are not noted until later in life. The combination of congenital anomalies and the related symptoms may vary considerably in different affected individuals.
Hydrocephalus is a condition in which excessive accumulation of cerebrospinal fluid causes increased pressure on the tissues of the brain. In infants and young children this finding may be associated with an abnormally enlarged head size (macrocephaly). Symptoms of acute hydrocephalus typically include vomiting, irritability, seizures, and in severe cases downward deviation of the eyes and eventually, if untreated, coma and death. Other important signs may include developmental delays evidenced by failure to achieve age appropriate developmental milestones and/or declining cognitive performance over time.
VACTERL-H is clinically defined and typically at least three of the eight anatomical components of the disorder are considered necessary for diagnosis. Importantly, there must be no laboratory or clinical evidence of an alternative diagnosis. The defining features of the disorder are discussed individually below.
Vertebral Anomalies
Vertebral anomalies typically include segmentation defects of the bones that comprise the spinal column. They are frequently associated with rib anomalies although this is not always the case. Commonly reported vertebral anomalies include hemivertebrae, “butterfly vertebrae,” and “wedge vertebrae” in which the bones of the spinal column have an abnormal shape or architecture. Additionally, vertebral fusions and supernumerary vertebrae have been described. These changes can result in the spine having an abnormal curvature, or scoliosis, which in some patients is the first sign that an underlying vertebral anomaly may be present.
Anal Atresia
Imperforate anus/anal atresia is a malformation in which the anal opening or the passage that normally connects the anus and the lowest part of the large intestine (rectum) fails to develop. This condition prevents the normal passage of bowel contents and typically results in obstruction of bowel contents. While complete imperforate anus is typically noticed on the initial post-natal examination performed at birth, other less severe forms of stenosis or atresia may present later with signs and symptoms of intestinal obstruction. Signs and symptoms of anal atresia may include persistent nausea and vomiting, intestinal bloating and weight loss due to difficulties with feeding.
Cardiac Defects
A wide range of congenital heart defects have been reported in children with VACTERL-H. 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 ventricular septal defect (VSD) is caused by a hole or small perforation anywhere along the ventricular septum and can present with a variety of symptoms depending on the size and the location of the defect. A small ventricular septal defect may close on its own, however larger defects may affect the ability of the heart to pump blood efficiently to the lungs and the rest of the body and result in congestive heart failure. Signs and symptoms associated with heart failure may include increased respiratory rate (tachypnea), wheezing, increased heartrate (tachycardia), and growth delay in infants (failure to thrive).
Additional congenital heart defects associated with VACTERL-H 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); a complex heart defect referred to as tetralogy of Fallot; transposition of the great arteries (a condition in which the aortic and pulmonary arteries are transposed); 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 these conditions, choose the name of the disease as your search term in the Rare Disease Database.)
Tracheoesophageal Fistula and/or Esophageal Atresia
A tracheoesophageal fistula is an abnormal connection between the trachea and the esophagus. This abnormal connection often leads to feeding problems and respiratory infections as a result of food being passed to the lungs inappropriately.
Esophageal atresia is a condition in which the esophagus, which normally carries food from the mouth to the stomach, is narrowed or incompletely formed. This results in inability of contents of the esophagus such as food to pass to the stomach and intestines to be digested.
Renal/Genitourinary Anomalies
A variety of abnormalities affecting the kidneys and urinary tract have been described in VACTERL-H. These include but are not limited to: lack of development of one or both kidneys (renal aplasia), malformation of one or both kidneys (renal dysplasia), displaced or malpositioned kidneys (renal ectopia), and abnormal backflow (reflux) of urine into the tube (ureter) that carries urine to the bladder (vesicoureteral reflux), and abnormal positioning of the urethral opening at the end of the penis (hypospadias). The presence of a renal or genitourinary anomaly can sometimes result in abnormal accumulation of urine in the kidneys (hydronephrosis) and/or frequent urinary tract infections.
Limb Anomalies
Classically, anomalies of the forearm or thumb side of the forearm (radial side) have been reported in children with VACTERL-H. These 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). However, other anomalies such as presence of extra digits (polydactyly) or missing digits (oligodactyly) of the hands, webbing of the fingers (syndactyly), and/or abnormal fusion of the two forearm bones (radioulnar synostosis) have also been described.
Additionally, while not considered a core feature of VACTERL-H, the presence of a single umbilical artery (which is a vessel important for proper transport of blood and deoxygenated blood away from the fetus) is commonly reported. This finding, if present on prenatal ultrasound is important to identify as it may be the first sign an underlying disorder may be present and should prompt additional imaging testing to search for other anomalies associated with VACTERL-H.
Prognosis
With the improvement of medical and surgical care, the long-term prognosis of patients with VACTERL-H has improved. However, even with early diagnosis and improvements in care, affected individuals often experience a number of medical complications as a result of the presence of specific congenital anomalies. Vertebral malformations often result in chronic back pain, anal atresia often results in incontinence and/or chronic constipation, gastro-esophageal reflux can be a consequence of tracheoesophageal fistulas, and renal anomalies are often associated with increased frequency of urinary tract infections (UTI) and the occurrence of renal stones (nephrolithiasis).
VACTERL-H is generally considered to be a sporadic disorder, not passed down through families, and a consequence of defective differentiation of specific tissue types during early fetal development. However, in a subset of patients there is evidence for a familial or inherited component with some patients reporting multiple affected family members. In patients with a family history of VACTERL-H, the disorder is thought to show autosomal recessive or X-linked inheritance.
Autosomal recessive disorders require that an individual inherits a disease-causing change from each parent. The inherited change results in the gene not to function properly. If an individual receives one working gene and one non-working gene associated with a particular disorder, the individual is said to be a carrier for that disorder, and typically does not have associated symptoms. The risk that two carrier parents will both pass their non-working/faulty gene and, therefore, have a child affected with the disorder is 25% with each pregnancy. There is a 50% risk that carriers will pass their faulty gene to each of their children. In autosomal recessive disorders the risk that a child will inherit a faulty or non-functioning gene is the same for both males and females.
X-linked disorders are caused by inherited changes in genes located on the X chromosome. As males only have one X chromosome, inheriting a non-working copy of an X-linked gene is sufficient to cause disease. Females in contrast have two X chromosomes and so are considered carriers if they inherit one non-working copy of a gene. As would be expected, X-linked disorders are typically more common in males. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
For the majority of children for VACTERL-H a genetic diagnosis is never reached. However, several genes have recently been implicated in this disorder and in patients with a VACTERL-like presentation. The FANCB gene is located on the X chromosome and in addition to being reported in children with VACTERL-H, is a known cause of X-linked Fanconi anemia. Changes in FANCI, FANCL and BRCA2, and other Fanconi anemia-associated genes have also been repeatedly implicated in the disorder. It is important to rule out a diagnosis of Fanconi anemia in these children as Fanconi anemia is associated with increased risk for certain cancers. Additionally, changes in the ZIC3 and PTEN genes have been implicated in isolated cases.
VACTERL with hydrocephalus is an extremely rare disorder that affects males and females in equal numbers. The exact prevalence of the disorder in the general population is unknown.
The diagnosis of VACTERL-H is made clinically. Presence of at least three of the core features or the disorder, including presence of hydrocephalus, is usually typically considered sufficient for diagnosis. Other more common disorders should be ruled out with clinical and/or laboratory studies. Clinical diagnosis is based on the features seen and therefore starts with a complete physical examination. The diagnosis of VACTERL-H is usually made after birth, however, findings seen on prenatal imaging such as a single umbilical artery or radial aplasia may be suggestive of this diagnosis and prompt evaluation for other anomalies. Imaging studies, while not required are typically used to aid in diagnosis as milder anomalies may be difficult to diagnose on clinical examination alone.
Treatment
The treatment of VACTERL with hydrocephalus is directed toward the specific findings in each individual so it usually differs from patient to patient. Many of the structural abnormalities (radial defects, heart defects, anal atresia, etc.) can be surgically corrected. Hydrocephalus may be treated by the insertion of a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body, such as the abdomen where the CSF can be absorbed.
A multidisciplinary approach is essential for optimal treatment given the complexity of anomalies and complications that can be associated with diagnosis. Individuals with VACTERL-H are typically followed by a number of medical and surgical specialists including cardiologists, urologists, neurosurgeons, orthopedists, and ear, nose and throat (ENT) physicians. Specific treatment and follow-up is dictated by the type and severity of the congenital anomaly.
In sporadic and inherited forms of the disorder, genetic counseling is recommended for affected individuals and their families.
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
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder (e.g., heart defects, anal atresia, tracheoesophageal fistula).
TEXTBOOKS
Jones KL, Jones MC, Del Campo M. Smith’s Recognizable Patterns of Human Malformation. 7th ed. Philadelphia, PA: Elsevier Saunders, 2013.
JOURNAL ARTICLES
Alter BP, Giri N. Thinking of VACTERL-H? Rule out Fanconi anemia according to PHENOS. American Journal of Medical Genetics part A 2016;170A: 1520-1524.
McCauley J, et al. X-linked VACTERL with hydrocephalus syndrome: further delineation of the phenotype caused by FANCB mutations. American Journal of Medical Genetics part A 2011;155:2370-2380.
Aliefendioglu D, et al. VACTERL-H associated with central hypothyroidism: a case report. Genetic Counseling 2007;18(3):331-335.
Alter BP, Rosenberg PS, Brody LC. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. Journal of Medical Genetics 2007; 44:1-9.
Holder ST, et al. Fanconi anaemia complementation group B presenting as X linked VACTERL with hydrocephalus syndrome. Journal of Medical Genetics 2006;43: 750-754.
Reardon W, Zhou X-P, and Eng C. A novel germline mutation of the PTEN gene in a patient with macrocephaly, ventricular dilatation, and features of VATER association. Journal of Medical Genetics 2001;38: 820-823.
Grech V, et al. VACTERL with hydrocephalus and isolated tracheo-oesophageal fistula in a first cousin. Clinical Dysmorphology 2000;9:145-6.
Lomas FE, et al. VACTERL with hydrocephalus: family with X-linked VACTERL-H. American Journal of Medical Genetics 1998;76:74-8.
Onyeije CI, et al. Prenatal diagnosis of sirenomelia with bilateral hydrocephalus: report of a previously undocumented form of VACTERL-H association. American Journal of Perinatology 1998;15:193-7.
Froster UG, et al. VACTERL with hydrocephalus and branchial arch defects: prenatal, clinical, and autopsy findings in two brothers. American Journal of Medical Genetics 1996;62:169-72.
Rossbach HC, et al. Fanconi anemia in brothers initially diagnosed with VACTERL association with hydrocephalus, and subsequently with Baller-Gerold syndrome. American Journal of Medical Genetics 1996;61:65-7.
Vandenborre K, et al. VACTERL with hydrocephalus. A distinct entity with a variable spectrum of multiple congenital anomalies. Genetic Counseling 1993;4:199-201.
Wang H, et al. VACTERL with hydrocephalus: spontaneous chromosome breakage and rearrangement in a family showing apparent sex-linked recessive inheritance. American Journal of Medical Genetics 1993;47:114-7.
Iafolla AK, et al. VATER and hydrocephalus: distinct syndrome? American Journal of Medical Genetics 1991;38:46-51.
Evans JA, et al. VACTERL with hydrocephalus: further delineation of the syndrome(s). American Journal of Medical Genetics 1989;34:177-82.
INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:314390; available at https://www.omim.org/entry/314390 Last Update: 05/09/2017; Entry No:276950; available at https://www.omim.org/entry/276950 Last Update: 06/04/2018. Accessed Jan 14, 2020.
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