Koolen-De Vries Syndrome - Causes, Symptoms, Diagnosis, and Treatment

What Is Koolen-De Vries syndrome?

Koolen-de Vries syndrome is a disorder in which various systems of the body get affected, which leads to developmental delay, moderate intellectual disability, congenital malformations, and behavioral changes in an individual from an early age. This is a genetic condition that occurs due to mutations in multiple genes and can also cause genetic defects in the walls of the heart.

Other Names of Koolen-De Vries Syndrome -

• 17q21.31 deletion syndrome.

• 17q21.31 microdeletion syndrome.

• Chromosome 17q21.31 microdeletion syndrome.

• KANSL1-related intellectual disability syndrome.

• KDVS.

• Koolen syndrome.

• Microdeletion 17q21.31 syndrome.

• Monosomy 17q21.31.

What Are the Causes of Koolen-De Vries Syndrome?

Koolen-de Vries syndrome is caused by a genetic mutation. The clinical features of this condition can be seen at an early age. This usually appears due to a genetic mutation in the KANSL1 gene, which leads to affect the function of this gene. In most of the cases, a small amount of the genetic material is missing including the KANSL1 gene from one copy of chromosome 17. This type of genetic defect is called microdeletion. Therefore, patients with Koolen-de Vries syndrome may have a chromosome 17 microdeletion, and in a small number of individuals, there may be a genetic mutation in gene KANSL1 that may cause one copy of the gene to be nonfunctional.

The microdeletion of a gene usually occurs on the long arm of chromosome 17 and the size of deletion may vary among individuals. However, patients with KANSL1 gene mutations and microdeletion have the same clinical features.

Function of KANSL1 Gene -

The primary function of the KANSL1 gene is to make a protein that helps regulate gene activity by modifying chromatin. Chromatin consists of DNA (deoxyribonucleic acid) and proteins that help pack the DNA into the chromosomes. This protein is produced from the gene KANSL1 and is found in almost every organ and tissue of the body before birth and throughout life. This protein is involved in controlling the activity of multiple genes and plays an important role in the development and functioning of multiple parts of the body. Therefore, the loss of one copy of this gene may cause improper development and function in the body, which leads to the development of the clinical signs of Koolen-de Vries syndrome.

How Is Koolen-De Vries Syndrome Inherited?

Koolen de Vries syndrome (KDVS) is mostly seen in the first child born in a family with a history of this syndrome. Therefore, in the majority of cases, the parents of children with KDVS do not have KDVS and do not have any gene mutation or missing (deleted) copy of the KANSL1 gene. So if a person who does not have KVDS has a child with KDVS has a very low chance of having a second child with the same condition (less than 1 in 100).

In another case, if a person who is affected by KDVS has a child, there is a 50 percent chance that their child may have KDVS. So there is an equal chance of having a child with KDVS or without KDVS. Therefore, KDVS has an autosomal dominant inheritance which has a 50 percent chance of getting the infection from parents.

What Are the Symptoms of Koolen-De Vries Syndrome?

As this condition affects multiple systems of the body, the associated signs and symptoms may vary from person to person. Therefore, the frequency of symptoms in individuals affected with Koolen-De Vries syndrome are as follows -

Symptoms present in more than 75 percent of cases -

• Distinctive facial features such as -

  • High and broad forehead.

  • Ptosis (droopy eyelids).

  • Blepharophimosis (narrowing of the eye openings).

  • Upward-slanting palpebral fissures (outer corners of the eyes that point upward).

  • Prominent ears.

  • Epicanthal folds (skin folds covering the inner corner of the eyes).

  • Bulbous nose.

• Developmental delay or intellectual disability.

• Low muscle tone (hypotonia) in childhood.

• Friendly and cheerful attitude.

Symptoms seen in 50 to 75 percent of the cases -

• Epilepsy.

• Narrow or high palate.

• Dental anomalies.

• Skin and hair problems.

• Nasal speech.

• Long fingers.

• Hypermobility of joints.

• Joint dislocation or deformation.

• Brain anomalies.

• Kidney and genital anomalies.

Less frequent symptoms in 25 to 50 percent of the cases are -

• Farsightedness (hypermetropia).

• Heart defects.

• Small hands.

• Crossed eyes (strabismus).

• Narrow hands.

• Hip dislocation or dysplasia.

• Slender lower limbs.

• Positional deformity of the feet.

• Irregular shape or curvature of the spine (scoliosis or kyphosis).

Symptoms that are very rare and can be seen In some cases 10 to 25 percent of the cases include -

• Loss of hearing due to chronic infection of the ears (otitis media).

• Short height.

• Abnormal shape of the head.

• Low birth weight.

• Sunken chest (pectus excavatum).

Rarely seen symptoms in less than 10 percent of the cases include -

• Small head (microcephaly).

• Cleft lip or palate.

• Vertebras that are joined together (fused vertebrae).

• Clouding of the lens in the eye (cataract).

• Hypothyroidism.

How Is Koolen-De Vries Syndrome Diagnosed?

The symptoms of Koolen-De Vries syndrome are very variable, therefore, multiple tests may be needed to confirm the diagnosis as many of the symptoms will be seen in other conditions also. Initially, the doctor will do a physical examination and observe the clinical features of KDVS. However, the diagnosis can be confirmed through genetic testing which depends upon the type of genetic change present in the patient such as -

• Chromosomal Array - As the majority of the patients affected with KDVS have a missing copy of the KANSL1 gene. Therefore this test will help in identifying whether any pieces of DNA are being added or deleted.

• Gene Sequencing - Only five percent of the cases may have coding errors in the KANSL1 gene. Therefore to detect this gene sequencing is done to identify the specific error in the gene coding.

Additional Tests -

Children with KDVS also have to undergo multiple other tests which may include -

• Echocardiograms can help in detecting abnormalities in the structure of the heart.

• Magnetic resonance imaging (MRI) can help in detecting abnormalities in the structure of the brain.

• An X-ray of the spine may be needed which can help detect scoliosis or other abnormalities.

• Ultrasound can help detect abnormalities of the kidneys and bladder.

What Is the Treatment of Koolen-De Vries Syndrome?

Treatment usually depends upon the type of symptoms experienced by the patient which may include -

• Early intervention with physiotherapy for the motor delay and feeding problems.

• Physical therapy for strengthening the muscles.

• Speech therapy or sign language to improve communication skills.

• Educational programming directed to specific disabilities.

• Antiepileptic drugs to treat epilepsy.

• Orthopedic care such as braces to facilitate movement in case of hip dislocation, positional deformities of the feet, and scoliosis.

• Medicines for treating conditions related to heart or kidneys or other medical issues.

The treatment for KDVS is a multi-specialty approach, including specialties like pediatricians, cardiologists, nephrologists, and urologists, and the affected patient has to go for routine examinations to prevent any complications.

Conclusion

Koolen-De Vries syndrome is a rare genetic disease that may lead to developmental abnormalities or intellectual disability in patients. This syndrome should be included in the differential diagnosis of patients with unexplained developmental problems or intellectual disabilities. Early diagnosis is of key importance, as it may help improve the quality of life and prevent any complications.