Koolen de Vries syndrome
Alternate names[edit | edit source]
17q21.31 deletion syndrome; Monosomy 17q21.31; Microdeletion 17q21.31 syndrome; Chromosome 17q21.31 microdeletion syndrome; 17q21.31 microdeletion syndrome; KANSL1-Related Intellectual Disability Syndrome
Definition[edit | edit source]
Koolen de Vries syndrome is a disorder characterized by developmental delay, mild to moderate intellectual disability, congenital malformations, and behavioral features.
Summary[edit | edit source]
- Developmental delay is noted from an early age.
- People with this disorder typically have a disposition that is described as cheerful, sociable, and cooperative.
- They usually have weak muscle tone (hypotonia) in childhood.
- About half have recurrent seizures (epilepsy).
Epidemiology[edit | edit source]
The prevalence of Koolen-de Vries syndrome is estimated to be 1 in 16,000. However, the underlying genetic cause is often not identified in people with intellectual disability, so this condition is likely underdiagnosed.
Cause[edit | edit source]
- Koolen-de Vries syndrome is caused by genetic changes that eliminate the function of one copy of the KANSL1 gene in each cell.
- Most affected individuals are missing a s'mall amount of genetic material, including the KANSL1 gene, from one copy of chromosome 17'.
- This type of genetic abnormality is called a microdeletion.
- A small number of individuals with Koolen-de Vries syndrome do not have a chromosome 17 microdeletion but instead have a mutation within the KANSL1 gene that causes one copy of the gene to be nonfunctional.
- The microdeletion that causes Koolen-de Vries syndrome occurs on the long (q) arm of chromosome 17 at a location designated q21.31.
- While the exact size of the deletion varies among affected individuals, most are missing a sequence of about 500,000 DNA building blocks (base pairs) containing several genes.
- However, because individuals 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 found in most organs and tissues of the body before birth and throughout life.
- By its involvement in controlling the activity of other genes, this protein plays an important role in the development and function of many parts of the body.
- Loss of one copy of this gene impairs normal development and function, but the relationship of KANSL1 gene loss to the specific signs and symptoms of Koolen-de Vries syndrome is unclear.
Inheritance[edit | edit source]
- Koolen-de Vries syndrome is considered an autosomal dominant condition because a deletion or mutation affecting one copy of the KANSL1 gene in each cell is sufficient to cause the disorder.
- In most cases, the disorder is not inherited.
- The genetic change occurs most often as a random event during the formation of reproductive cells (eggs and sperm) or in early fetal development. Affected people typically have no history of the disorder in their family.
- While it is possible for them to pass the condition on to their children, no individuals with Koolen-de Vries syndrome have been known to reproduce.
- Most people with Koolen-de Vries syndrome caused by a deletion have had at least one parent with a common variant of the 17q21.31 region of chromosome 17 called the H2 lineage.
- This variant is found in 20 percent of people of European and Middle Eastern descent, although it is rare in other populations.
- In the H2 lineage, a 900 kb segment of DNA, which includes the region deleted in most cases of Koolen-de Vries syndrome, has undergone an inversion.
- An inversion involves two breaks in a chromosome; the resulting piece of DNA is reversed and reinserted into the chromosome.
- People with the H2 lineage have no health problems related to the inversion.
- However, genetic material can be lost or duplicated when the inversion is passed to the next generation.
- Other, unknown factors are thought to play a role in this process.
- So while the inversion is very common, only an extremely small percentage of parents with the inversion have a child affected by Koolen-de Vries syndrome.
Signs and symptoms[edit | edit source]
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
- Friendly and cheerful attitude
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
Diagnosis[edit | edit source]
The symptoms are very variable. Besides developmental delay and intellectual disability, no single clinical feature is required to establish the diagnosis, although childhood low muscle tone (hypotonia) is a common feature, reported in almost all affected people.
To establish the diagnosis of the syndrome one of the following is needed:
- A 17q21.31 microdeletion involving at least KANSL1
- A mutation in the KANSL1 gene (through an exam known as sequence analysis)
Treatment[edit | edit source]
Treatment 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 is indicated if neurological or other problems are suspected.
NIH genetic and rare disease info[edit source]
Koolen de Vries syndrome is a rare disease.
Koolen de Vries syndrome Resources | |
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