Última actualización:
June 09, 2022
Años publicados: 2022
NORD gratefully acknowledges Bert de Vries, MD, PhD, Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands, and the Koolen-de Vries Syndrome Foundation, for the preparation of this report.
Koolen-de Vries syndrome (KdVS) is a rare genetic disorder with an estimated prevalence of about 1 in 30,000 people. Frequent features in individuals with this condition include feeding problems in infancy, muscle weakness (hypotonia) in young children, developmental problems, language/speech delay, learning disabilities and mild to moderate intellectual disability, epilepsy (in about 1 in 3 persons), characteristic facial features, farsightedness, hearing impairment, flexible joints, flat feet and curvature of the spine and/or congenital abnormalities.
Affected children and adults are often sociable and friendly, but behavior problems such as hyperactivity and compulsive behavior may also be present. Some children with KdVS have birth defects. In a significant portion of boys for instance, the testes have not descended (cryptorchidism). Hip dysplasia is more common as well and some of the children have congenital heart defects (particularly atrial septal defect and ventricular septal defect), abnormalities of the bladder and urinary tract and/or brain. Koolen-de Vries syndrome is caused by deletion or change (pathogenic variant) in the KANSL1 gene.
Introduction
The 17q21.31 microdeletion syndrome was discovered in 2006 by three independent research groups. In 2012, it was established that KANSL1 was the causative gene for KdVS. The syndrome is named after Dutch geneticists David A. Koolen and Bert B. A. de Vries, who helped discover the syndrome in 2006 and the KANSL1 gene in 2012.
KdVS is associated with a broad spectrum of symptoms that vary greatly from person to person. Some individuals are more affected than others and an individual with KdVS will not have all the symptoms mentioned in this section. For instance, most will learn to speak at a later age, while some may not speak at all.
Symptoms like developmental delay and/or intellectual disability are very common and present in almost all of individuals with KdVS. This includes speech and language delay which is present in almost all individuals. Children with KdVS usually do learn to speak, but at a significantly later age. The first words occur between ages 2.5 and 3.5 years on average. Sign language or communication devices can help promote communication development and communication in general. Usually however, speech development improves significantly around age 8 to 12 years. Stuttering has been described in some individuals, but not in most. In most individuals, behavior is described as friendly, amiable and cooperative. However, behavior problems, including attention-deficit/hyperactivity disorder and autism have been reported.
Low muscle tone and specific facial features that can be recognized by a medical expert are very common as well. The nose can have a high nasal bridge, broad nasal root, long columella and underdeveloped and/or thick alae nasi. The facial characteristics change with age. In infancy the facial gestalt is mostly characterized by low muscle tone with an open mouth appearance. With increasing age there is usually elongation of the face and broadening of the chin and the “tubular” or “pear” shape form of the nose may become more apparent.
Low muscle tone can be evident from a very young age, along with poor sucking and feeding problems. Some newborns may require hospitalization and/or tube feeding. When they get older, many children with KdVS have problems chewing lumpy or solid textures.
Epilepsy is a relatively common symptom in individuals with KdVS, affecting about a third of individuals. Seizures usually start in childhood, presenting with a typical pattern when measuring brain activity. The seizures are sometimes related to structural abnormalities of the brain, but not always and generally respond well to anti-epileptic drugs.
Other common symptoms include visual problems including far-sightedness, strabismus or cataracts. Congenital abnormalities in the heart or kidney may also be present. These include, but are not limited to, a heart abnormality in which there is a hole in the wall that separates the lower or upper chambers or a widened aorta (the main and largest artery in the human body). During puberty and thereafter, some individuals develop a curved spine (scoliosis) that requires treatment.
Finally, there is a wide range of symptoms described more frequently in individuals with KdVS than in healthy individuals but are not very common. These include dental anomalies, a slender build, fair hair and multiple birthmarks.
KdVS is caused by a deletion of a small part of chromosome 17 or by a change (pathogenic variant) in the KANSL1 gene. Chromosomes are the carriers of the genetic information and are important for directing and regulating all processes in the body. The part of chromosome 17 that is missing in many people with KdVS is denoted by “q21.31”. The missing portion of the hereditary material is called a “deletion”. Because this small deletion is not visible with older techniques, the syndrome was first known as a “17q21.31 microdeletion”. Until 2012, KdVS was called the 17q21.31 microdeletion syndrome, but in 2012 it was discovered that variants in the KANSL1 gene (one of the genes in the 17q21.31 region) can lead to the KdVS. This is the reason the condition was renamed. There is no relationship between the size of the deletion and the degree of symptoms. Furthermore, there is no clinical difference between persons with a 17q21.31 deletion and a KANSL1 pathogenic variant.
KdVS follows autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. In people with KdVS, the mutated gene is typically a new (de novo) gene variant. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
The prevalence of Koolen-de Vries syndrome is unknown. The estimated prevalence of the 17q21.31 deletion is 1 in 30,000 individuals. Preliminary data suggest that pathogenic variants in the KANSL1 gene may be as frequent as the microdeletions, but more studies are needed to determine an unbiased prevalence. Koolen-de Vries syndrome occurs with equal frequency in males and females.
Koolen-de Vries syndrome can be diagnosed in an individual with the typical symptoms described above and either of the following genetic abnormalities:
A (micro) deletion at chromosome 17 that includes the KANSL1 gene. This is the case for approximately 75% of individuals currently diagnosed with KdVS.
A pathogenic variant that causes the KANSL1 gene to not function normally. This is the case in approximately 25% of individuals currently diagnosed with KdVS.
Treatment
Currently, no treatment for KdVS is available. However, most of the symptoms can be treated, so the quality of life for individuals with KdVS can be improved. First and foremost, it is important that children with KdVS are regularly seen by a pediatrician. The pediatrician can assess the seriousness of the symptoms, such as the degree of developmental delay, nutritional problems, language development and possible visual-hearing problems. Imaging of the heart, bladder and urinary tract is recommended to determine if congenital anomalies are present. The position of the feet and spine should be monitored. Some people with KdVS have been reported with deviations of the feet (particularly flat feet) and a spine that becomes curved, especially lateral curvature (scoliosis). Children with epilepsy should also be followed by a neurologist. Individuals with low muscle tone and obvious language/speech delay should receive intensive supervision by a speech therapist.
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Koolen DA, Morgan A, de Vries BBA. Koolen-de Vries Syndrome. 2010 Jan 26 [Updated 2019 Jun 13]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK24676/ Accessed June 8, 2022.
KANSL1. Human Disease Genes Website Series. Last updated: 29-04-2022. https://humandiseasegenes.nl/kansl1 Accessed June 8, 2022.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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