What are the other Names for this Condition? (Also known as/Synonyms)

• 17q21.31 Microdeletion Syndrome
• Kansl1-Related Intellectual Disability Syndrome
• Monosomy 17q21.31 Syndrome

What is Koolen De Vries Syndrome? (Definition/Background Information)

• Koolen de Vries Syndrome (KdVS) is a disorder characterized by developmental delay, mild to moderate intellectual disability, congenital malformations, and behavioral features
• Developmental delay is noted from an early age. Other problems include weak muscle tone (hypotonia) in childhood, recurrent seizures (epilepsy), and distinctive facial features
• Males with Koolen de Vries Syndrome often have undescended testes (cryptorchidism). Other symptoms may include defects in the walls between the chambers of the heart (septal defects) or other heart defects, kidney problems, and skeletal anomalies such as foot deformities
• It is caused by mutations in the KANSL1 gene, or by the loss of a small amount of genetic material in chromosome 17 that includes the KANSL1 gene (chromosome 17 q21.31 microdeletion)
• Inheritance is autosomal dominant
• Treatment may include physiotherapy, speech therapy, and educational programs, as well as medication for epilepsy and surgical treatment for malformations needing to be corrected

(Source: Koolen De Vries Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Koolen De Vries Syndrome? (Age and Sex Distribution)

• Koolen De Vries Syndrome is a rare, congenital disorder occurring at a prevalence of 1 in 16,000 individuals
• The presentation of symptoms may occur at birth
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Koolen De Vries Syndrome? (Predisposing Factors)

• A positive family history may be an important risk factor, since Koolen De Vries Syndrome is an inherited condition
• Currently, no other risk factors have been clearly identified for this disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Koolen De Vries Syndrome? (Etiology)

• Koolen de Vries Syndrome is caused by:
  • Either mutations in the KANSL1 gene, resulting in the loss of function of this gene, or,
  • By the loss (deletions) of a small amount of genetic material (microdeletion) from chromosome 17, that includes the KANSL1 gene
• Most of the cases are due to the microdeletion. The microdeletion occurs on the long (q) arm of chromosome 17 at a location q21.31. While the exact size of the deletion varies among individuals, most are missing several genes. However, because people with KANSL1 gene mutations have the same signs and symptoms as those with the microdeletion, researchers have concluded that the loss of this gene accounts for the features of this disorder
• The KANSL1 gene provides instructions for making a protein that helps regulate gene activity (expression) by modifying chromatin. Chromatin is the complex of DNA and protein that packages DNA into chromosomes. The protein produced from the KANSL1 gene is involved in controlling the activity of other genes, and in the development and function of many parts of the body. The relationship of KANSL1 gene loss to the specific signs and symptoms of Koolen de Vries syndrome is unclear
• Most people with Koolen de Vries syndrome (KdVS) are the first person born in their family with the syndrome. However, the condition can run in families, and in those cases, it is inherited in an autosomal dominant manner

(Source: Koolen De Vries Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

What are the Signs and Symptoms of Koolen De Vries Syndrome?

The signs and symptoms of Koolen de Vries Syndrome may vary in type and severity among the affected individuals.

The most frequent symptoms (present in more than 75% of the cases) may include:

• Distinctive facial features (including a high, broad forehead; droopy eyelids (ptosis); a narrowing of the eye openings (blepharophimosis); outer corners of the eyes that point upward (upward-slanting palpebral fissures); skin folds covering the inner corner of the eyes (epicanthal folds); a bulbous nose; and prominent ears)
• Developmental delay/ intellectual disability
• Low muscle tone (hypotonia) in childhood

In about 50% to 75% of the cases the following symptoms may be present:

• Epilepsy
• Skin and hair problems
• Nasal speech
• Narrow/high palate
• Dental anomalies
• Slender/long fingers
• Joints that are too flexible (hypermobility) and/or joint dislocation or deformation
• Brain anomalies
• Kidney and genital anomalies

Less frequent symptoms (25%-50%) are:

• Far-sightedness (hypermetropia)
• Crossed eyes (strabismus)
• Narrow hands
• Small hands
• Heart defects
• Hip dislocation/dysplasia
• Persistence of fingertip pads
• Slender lower limbs
• Positional deformity of the feet
• Abnormal curvature of the spine (scoliosis/kyphosis)

In some cases (10% to 25% of the cases) the following symptoms may be present:

• Hearing loss due to chronic infection of the ears (otitis media)
• Low birth weight
• Short stature
• Abnormal head shape
• Sunken chest (pectus excavatum)

Uncommon symptoms (in less than 10% of the cases) include:

• Cleft lip/palate
• Very small head (microcephaly)
• Clouding of the lens in the eye (cataract)
• Narrowing of the muscular opening at the lower end of the stomach that connects to the intestines (pyloric stenosis)
• Vertebras that are joined together (fused vertebrae)
• A condition in which a bone (vertebra) in the spine moves forward out of the proper position onto the bone below it (spondylolisthesis)
• Hypothyroidism

(Source: Koolen De Vries Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Koolen De Vries Syndrome Diagnosed?

Koolen de Vries Syndrome is diagnosed on the basis of:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Laboratory tests
• Imaging studies
• Biopsy studies, if necessary
• Chromosome analysis or molecular genetic testing to check for or confirm 17q21.31 microdeletion involving the KANSL gene, or causative KANSL gene mutation(s)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Koolen De Vries Syndrome?

The complications of Koolen De Vries Syndrome may include:

• Risks of falls and injury due to epilepsy
• Severe pain due to dislocation of joints, and movement difficulties
• Severe intellectual deficiency
• Abnormal heart functions due to structural defects in the organ
• Reduced quality of life

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Koolen De Vries Syndrome Treated?

The treatment for Koolen De Vries Syndrome depends on the symptoms, and may include:

• Early intervention with physiotherapy for feeding problems and motor delay
• Physical therapy aimed at strengthening the muscles
• Therapy to improve development of the child's fine and gross motor skills
• Speech therapy, sign language, pictures and computer touch screens aiming to improve communication skills
• Educational programming directed to the specific disabilities identified
• Routine antiepileptic drugs
• Orthopedic care for scoliosis, hip dislocation, and positional deformities of the feet
• Standard treatment for cardiac, renal, urologic, and other medical issues
• Surgery cryptorchidism if indicated

Affected people should have routine examinations by a primary care physician and pediatrician, cardiologist, nephrologist, and/or urologist. Referrals to other specialists are indicated if neurological or other problems are suspected.

(Source: Koolen De Vries Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How can Koolen De Vries Syndrome be Prevented?

Currently, Koolen De Vries Syndrome may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Koolen De Vries Syndrome? (Outcomes/Resolutions)

• The prognosis of Koolen De Vries Syndrome is dependent upon the severity of the signs and symptoms and associated complications, if any
• Individuals with mild conditions have better prognosis than those with severe symptoms and complications
• Individuals with severe signs and symptoms may require lifelong supportive care from caregivers
• Typically, the prognosis may be assessed on a case-by-case basis

Additional and Relevant Useful Information for Koolen De Vries Syndrome:

Koolen de Vries Syndrome may be known by the following additional synonyms:

• 17q21.31 Deletion Syndrome
• Chromosome 17q21.31 Microdeletion Syndrome

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/