Koolen-de Vries Syndrome

Disease Overview

Summary

Koolen-de Vries syndrome (KdVS) is a rare genetic disorder characterized by intellectual disability and many different signs and symptoms. Frequent features in people affected with KdVS 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 people), 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. Other signs and symptoms may include testes that have not descended (cryptorchidism), hip dysplasia and congenital heart defects (particularly atrial septal defect and ventricular septal defect) as well as abnormalities of the bladder and urinary tract and/or brain.

Koolen-de Vries syndrome is caused by a deletion or change (pathogenic variant) in the KANSL1 gene.

There is no cure yet and treatment is directed to manage the specific symptoms.

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.

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Synonyms

• 17q21. 31 microdeletion syndrome
• KdVS

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Signs & Symptoms

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, but some may not speak at all.

The signs and symptoms that have been reported in people affected with KdVS include:

• Developmental delays (slower progress in learning basic skills like walking, talking and understanding) and/or intellectual disability (challenges with learning and problem-solving) are very common.
  • Speech and language delay in most people:
    • Children typically say their first words between 2.5 and 3.5 years old (much later than usual)
    • Tools like sign language or communication devices (such as tablets with speech apps) can help support communication
    • Speech skills usually improve a lot between the ages of 8 to 12 years
    • Stuttering (repeating sounds or syllables) has been seen in some people, but it is not common
• Distinctive behavior and personality: Most people with KdVS are described as friendly, good-natured and cooperative. However, some people may also have:

• • Attention-deficit/hyperactivity disorder (ADHD) which can make it hard to focus or stay still
  • Autism which affects how a person communicates, interacts with others and experiences the world

• Low muscle tone (hypotonia) meaning muscles feel “floppy” or weak is very common
• Hearing problems
• Distinctive facial features that medical professionals can recognize:
  • High nasal bridge (top part of the nose appears raised)
  • Rounded or pear-shaped nose
  • Broad nasal root (wide area where the nose connects to the forehead)
  • Long columella (the strip of skin between the nostrils)
  • Underdeveloped or thick alae nasi (the outer parts of the nostrils, the nose openings)
  • Droopy eyelids (ptosis)
  • Narrowing of the eye openings (blepharophimosis)
  • Outer corners of the eyes that point upward
  • Epicanthus, a fold of skin that stretches from the upper to the lower eyelid, partially covering the inner canthus
  • Big or protruding ears
    • These features may change as a person ages, for example, as babies, the face often looks more open and softer due to low muscle tone and an open mouth.  As children grow, the face often becomes longer, the chin broader and the nose may look more tubular or pear-shaped.

• Feeding issues and poor sucking caused by low muscle tone in babies
  • Some newborns may need hospital care and/or feeding through a tube
  • As they grow, many children struggle to chew foods with lumpy or solid textures
• Epilepsy (seizures) which are sudden bursts of unusual electrical activity in the brain (present in about one-third of people with KdVS)

• • Seizures usually start in childhood
  • Typical pattern on an EEG (a test that measures brain waves)
  • Sometimes seizures are linked to brain structure differences but not always
  • Seizures usually respond well to anti-epileptic medications

• Vision problems are common and may include:
  • Difficulty seeing things up close (far-sightedness or hypermetropia)
  • Crossed or misaligned eyes (strabismus)
  • Cloudiness in the lens of the eye (cataracts)
• Heart abnormalities:
  • A hole in the wall that separates the lower or upper chambers of the heart (ventricular or atrial septal defects)
  • Widened aorta which is the main blood vessel that carries blood from the heart to the rest of the body

• Spine and skeletal development problems

• Curved spine (scoliosis) which can be very severe

Other less common symptoms may include:

• Dental anomalies (unusual tooth development or placement)
• Slender build (thin body type)
• Fair hair (lighter than expected hair color)
• Multiple birthmarks (spots on the skin that are present from birth) known as pigmented nevus

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Causes

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 genetic information and are important for directing and regulating all processes in the body. The part of the long arm (q) of the 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”.

There is no established relationship between the size of the deletion and the degree of symptoms. Furthermore, there seems to be no clinical difference between people with a 17q21.31 deletion and a KANSL1 pathogenic variant.

The KANSL1 gene helps make a protein that is part of a group of genes responsible for turning other genes on or off when needed. It does this by changing how DNA (genetic material) is packaged inside our cells, which affects how easily certain genes can be used. This protein is active in many parts of the body before birth and continues to work throughout life. Because it helps control the activity of many other genes, it plays an important role in how the body develops and functions.

KdVS follows autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

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Affected populations

KdVS is a rare genetic disorder with an estimated prevalence of approximately 1 in 55,000 individuals. The syndrome affects both males and females equally and has been identified in various ethnic groups. Due to its rarity and the variability of its signs and symptoms, KdVS is often underdiagnosed or misdiagnosed.

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Disorders with Similar Symptoms

There are other conditions with symptoms similar to Koolen-de Vries syndrome (KdVS). Conditions that might be included in a differential diagnosis include:

• 2 deletion syndrome which can cause developmental delays and facial differences
• Prader-Willi syndrome known for low muscle tone, feeding issues in infancy and later-onset obesity
• Fragile X syndrome, a leading cause of inherited intellectual disability and behavioral challenges
• Angelman syndrome which involves severe speech impairment, balance problems and a happy demeanor
• Cardiofaciocutaneous syndrome which includes heart defects, distinctive facial features, skin abnormalities and developmental delay

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Diagnosis

Koolen-de Vries syndrome can be diagnosed in a person with the typical symptoms described above and with genetic testing that identifies either of the following genetic abnormalities:

• A (micro) deletion at chromosome 17 that includes the KANSL1 This is the case for approximately 75% of individuals currently diagnosed with KdVS.
• A pathogenic variant that causes the KANSL1gene to not function normally. This is the case in approximately 25% of individuals currently diagnosed with KdVS.

Genetic testing can be done with chromosomal microarray analysis (CMA) or whole-exome sequencing (WGS). CMA is a genetic test that looks for large deletions and duplications across the entire genome. WES focuses on the protein-coding regions of the genome (exons) and can detect a wide range of variants in many genes.

Early diagnosis is crucial for implementing appropriate interventions and management plans.

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Standard Therapies

Treatment

Currently, no cure for Koolen-de Vries syndrome (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 and hearing problems.

The pediatrician can refer the affected children to specialists as needed. These specialists should work together as a team in a coordinated way. The specialists may include medical geneticists, neurologists, developmental pediatricians, speech and language therapists, occupational and physical therapists, cardiologists, nephrologists or urologists, psychiatrists or psychologists, ophthalmologists, audiologists and education specialists.

Early intervention programs, including physical, occupational and speech therapy can address developmental delays.

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 be followed by a neurologist. People with low muscle tone and obvious language/speech delay should receive intensive supervision by a speech therapist.

Other management may include:

• Individualized education plans (IEPs) to accommodate learning difficulties and promote academic achievement
• Behavioral therapy with strategies to manage behavioral challenges and support social development

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://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: [email protected]

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:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES

Zhang H, Yuan L, Fan M, Liu Z, Yan Y, Liu Q, Zhang K, Li C, Liu D. Clinical and genetic characteristics of a case of Koolen-De Vries syndrome caused by KANSL1 gene mutation and literature review: A case report. Medicine (Baltimore). 2024 Dec 6;103(49):e40923. doi: 10.1097/MD.0000000000040923. PMID: 39654190; PMCID: PMC11631005.

Pfalzer AC, Ivers B, Haynam A, Drake B, Koolen DA, Kasri NN, de Vries BBA, Mefford HC, Morgan A, Bichell TJ, Simon E, Terala A, Myers KA, Point A. Koolen-de Vries Syndrome: a journey from diagnosis to treatments. Ther Adv Rare Dis. 2024 Jul 28;5:26330040241265414. doi: 10.1177/26330040241265414. PMID: 39081270; PMCID: PMC11287726.

INTERNET

Koolen DA, Morgan A, de Vries BBA. Koolen-de Vries Syndrome. 2010 Jan 26 [Updated 2023 Feb 2]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK24676/ Accessed May 22, 2025.

KANSL1. Human Disease Genes Website Series. Last updated:10/1/2025. https://humandiseasegenes.nl/kansl1 Accessed May 22, 2025.

 

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Programs & Resources

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RareCare^® Assistance Programs

NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.

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MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/

Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.

Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/

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Patient Organizations

Koolen-De Vries Syndrome Foundation

NORD Member

Email: [email protected]

Related Rare Diseases: Koolen-de Vries Syndrome

https://rarediseases.org/organizations/koolen-de-vries-syndrome-foundation/

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Learn more about Patient Organization & Membership >

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More Information

The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.

GARD Disease Summary

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).

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Orphanet

Orphanet 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.

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OMIM

Online 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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