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

• 9q Subtelomeric Deletion Syndrome
• 9q34.3 Deletion Syndrome

What is Kleefstra Syndrome? (Definition/Background Information)

• Kleefstra Syndrome is a rare chromosome abnormality that occurs when there is a missing copy of the genetic material located on the long arm (q) of chromosome 9, specifically at band q34.3, and involving the EHMT1 gene. The absence of this gene is believed to mainly cause the associated signs and symptoms of Kleefstra Syndrome
• It can result in abnormal facial features, developmental delays, heart and kidney abnormalities, and learning difficulties. Kleefstra Syndrome may present complications such as connective tissue disorders, delayed achievement of milestones, deafness, behavioral issues, and reduced quality of life
• This chromosomal anomaly may develop from sporadic mutations (vast majority of cases), or it may be inherited from one’s parents (very rarely). Kleefstra Syndrome may be diagnosed through specialized genetic testing. In some children, the condition may be mild and hence can also remain undiagnosed
• Following a diagnosis, the condition may be managed based on the presenting symptoms and extent of involvement of the body systems. The treatment may involve physician experts from several specialties, and can include the use of hearing and visual aids, speech and language therapy, physiotherapy, and surgery for correction of physical defects
• The prognosis is primarily dependent on the severity of the disorder, and it varies from one child to another. Many children with Kleefstra Syndrome are able to cope well through adequate treatment and supportive care. Some of the signs and symptoms associated with the condition are known to improve with time

Who gets Kleefstra Syndrome? (Age and Sex Distribution)

• The incidence of Kleefstra Syndrome is presently unknown, but it is reportedly rare
• In many cases, individuals with mild signs and symptoms may be undiagnosed in their lifetime. Hence, a true incidence of the disorder may be difficult to estimate
• Kleefstra Syndrome is a congenital disorder, and the presentation of symptoms may occur at or following the birth of the child
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Kleefstra Syndrome? (Predisposing Factors)

In a vast majority of individuals, there are no identified risk factors for Kleefstra Syndrome.

• In some individuals, a positive family history may be an important risk factor for Kleefstra Syndrome
• Currently, no environmental and lifestyle (including dietary) factors have been implicated
• The syndrome is not caused by what the expectant mother does or does not do, either prior to or during pregnancy

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 Kleefstra Syndrome? (Etiology)

Kleefstra Syndrome is caused by deletion of genetic material from a region close to the end of the long arm (q) of chromosome 9, specifically at q34.3. Since, the region nearer to the end of the chromosome (or telomere) is deleted/missing, the condition is also known as 9q Subtelomeric Deletion Syndrome.

• The condition particularly results in a loss of the EHMT1 gene, which according to studies, is responsible for a majority of the presentations associated with the disorder
• However, the region at 9q34.3 houses nearly 200 genes and the involvement of other genes in Kleefstra Syndrome is also speculated, besides the involvement of the EHMT1 gene
• Since only a tiny part of the chromosome is lost or missing, it is not visible under a microscope with high magnification. Thus, multiplex ligation-dependent probe amplification (MLPA), cytogenetic fluorescent in situ hybridization (FISH), or array comparative genomic hybridization (array-CGH) studies may be necessary to detect the deletions

The amount of missing chromosome material may vary from one individual to another resulting in a variable set of signs and symptoms.

• In general, there are two chromosomes numbered 9. Children with Kleefstra Syndrome typically will have one (chromosome 9) in normal condition, while the other is abnormal. The abnormality is characterized by a loss of chromosomal material
• Most cases of the disorder develop sporadically (de novo) during embryonic development. This means that no deletion of genetic material at 9q is observed in either of the parents. However, in rare cases, the disorder may be inherited

It is important to note that a child’s development and future is not only influenced by the chromosome material duplicated/deleted and genes involved, but also by other factors such as one’s environment, involvement of other genes, and unique personality.

Additional (general) information on chromosomes, which is helpful in understanding the disorder:

Chromosomes are microscopic thread-like protein structures present in each cell nucleus that carry genetic information in the form of DNA (deoxyribonucleic acid). DNAs are nucleic acids that encodes the genetic information of any organisms; a basic unit of the DNA is termed a gene with a specific set of instructions and a defined function. Each chromosome is “X” shaped with a center, called the centromere, and two short arms (termed p arms) and two long arms (termed q arms).

Humans have 46 chromosomes in the cell nucleus, in 23 pairs, of which one pair is named the sex chromosome. In males, it is designated XY, for chromosome X and chromosome Y; while, in females, it is designated XX, for a pair of chromosome X. The other 22 pairs of chromosomes are numbered chromosome 1 through 22, approximately according to size (with chromosome 1 being the largest; chromosome 21 being the smallest) and are referred to as autosomes or somatic chromosomes. During conception, the embryo inherits one copy of each chromosome from each parent (i.e., mother and father). Any alteration in the chromosome numbers or structure, such as via addition or deletion of chromosomal material, can result in mild to severe genetic abnormalities that may manifest as birth defects, growth delays, and intellectual disabilities.

A chromosome deletion disorder indicates that a certain portion of the chromosomal material is missing, which may be detected through molecular genetic testing. Depending on the nature and amount of material deleted, the manifestation of a set of signs and symptoms are noted.

What are the Signs and Symptoms of Kleefstra Syndrome?

The signs and symptoms of Kleefstra Syndrome may be significantly different from one individual to another. The degree of signs and symptoms are often related to the amount of chromosome material deleted and the number of genes affected. As a general rule, a small loss of chromosome material generally results in milder signs and symptoms. Conversely, larger deletion of the chromosome material generally results in severe signs and symptoms. It is important to note that exceptions may also occur, where individuals with small amount of chromosomal loss, may have disproportionately severe presentations.

The commonly noted signs and symptoms of Kleefstra Syndrome include:

• Abnormal facial features such as broad head with a flat face, widely-spaced eyes with low eyebrows, abnormally-placed and formed ears, upturned nose, an unusually large tongue (in infancy), and high palate
• Developmental delays; delays in milestone achievement such as for rolling, sitting, crawling, and walking
• Hypotonia (low muscle tone) causing floppy babies in infancy
• Intellectual disability
• Speech, language, and communication difficulties
• Genital abnormalities, mostly in boys
• Sleep disturbances, including night-walking
• Seizures may affect some children, especially at a young age
• Structural eye defects causing cortical visual impairment, strabismus, and cataracts
• Heart defects may be seen in about 35% of the cases, and can include atrial septal defect (ASD), ventricular septal defect (VSD), persistent ductus arteriosus (PDA), pulmonary stenosis, and rarely, a condition known as tetralogy of Fallot
• Fine and gross motor skills may be poor and/or delayed
• A range of psychiatric conditions may be seen, including:
  • Autism spectrum disorders - in nearly all the cases
  • Anxiety disorders and major depression in over 40% of the individuals
  • Psychosis in 1 in 3 cases
• Behavioral issues such as mood swings, aggression, and insecurity

Some of the lesser observed signs and symptoms include:

• Feeding difficulties; some children present vomiting and gastroesophageal reflux disease (GERD)
• Constipation
• Minor hand and feet deformities; some children may find standing and walking difficult
• Some children are overweight
• Hearing loss of variable degree; some are temporary
• Hypopigmentation (light-colored skin patches)
• Teeth and dental abnormalities

How is Kleefstra Syndrome Diagnosed?

Children can have varying signs and symptoms. Some children with mild signs and symptoms may go undiagnosed in their lifetimes. Given the rarity of the condition, the healthcare provider should have a high index of suspicion to consider Kleefstra Syndrome in the differential diagnosis. Often, specialized tests are necessary to confirm the disorder.

Kleefstra Syndrome is diagnosed on the basis of the following information:

• Complete physical examination and thorough medical history evaluation, including family medical history
• Assessment of the presenting signs and symptoms, including evaluation of body systems such as vision, hearing, muscles, heart, kidneys, central nervous system, genitalia, and immune system
• Hearing assessment through various tests including:
  • Otoscopy: Examination using an instrument that allows the physician to look inside the ear
  • Weber test: A test in which a vibrating tuning fork is placed on the midline of the head
  • Rinne test: A test in which a vibrating tuning fork is held next to the ear and then in front of the ear, until the individual no longer hears the sound
  • Audiometric test: Hearing tests that involve listening to different tones
• Eye and vision assessment through:
  • General eye exam
  • Visual acuity test using a special and standardized test chart (Snellen chart)
  • Refraction studies using various instruments
  • Fundoscopic (ophthalmoscopic) examination by an eye specialist, who examines the back part of the eye (or the fundus)
  • Slit-lamp examination
• Laboratory tests, as needed, such as electrolyte levels, serum calcium levels, thyroid function test, kidney function test, urine tests, sex hormone studies, etc.
• Radiological studies of the affected regions, as needed
• Assessment of cardiac function
• Neurological examination that involves the central nervous system (brain and spinal cord)
• Behavioral studies
• Prenatal studies including abdominal ultrasonography
• Specialized genetic testing techniques are often required to confirm the diagnosis. This may include:
  • Fluorescence in situ hybridization (FISH) testing
  • Array comparative genomic hybridization (array-CGH)
  • DNA sequencing

Often, karyotyping of the chromosome is not adequate to diagnose the condition, since individuals with this condition can have normal karyotype chromosomal studies.

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 Kleefstra Syndrome?

The complications of Kleefstra Syndrome may include:

• Severe emotional stress for parents and caregivers
• Pregnancy complications have been reported in some cases
• Malfunctioning of sweat glands causing overheating of the body
• Increased risk for ear and upper respiratory tract infections
• Permanent hearing loss
• Connective tissue disorders that may cause hyper-flexible joints or hernias
• Absence of anus
• Kidney and urinary tract defects
• Severe behavioral issues such as self-injury, obsessive-compulsive disorder, or aggressive tendencies
• Developmental abnormalities that can affect day-to-day activities
• Reduced quality of life

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

How is Kleefstra Syndrome Treated?

There is no cure for Kleefstra Syndrome since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops. It also depends on the severity of the signs and symptoms and the body systems affected. Individuals with mild signs and symptoms may require periodic monitoring without significant medical intervention. Often, a multidisciplinary team of specialists including pediatricians, ophthalmologists, otolaryngologists, neurologists, internists, cardiologists, endocrinologists, surgeons, and other healthcare professionals are involved in managing the condition.

The treatment measures for Kleefstra Syndrome may involve:

• Use of hearing aids and cochlear implants, as needed
• Seizure control using anticonvulsant medication, vitamin supplements, and ketogenic diet: Seizure control is important to ensure that the child’s learning ability is not significantly affected
• Special education: Employing suitable learning strategies via music therapy, visual and tactile books, touch screen computers, etc.
• Speech and language therapy; the use of sign language may be beneficial
• Physiotherapy for weakened muscles, including incorporating daily exercise regimen
• Development of motor skills via daily exercises, swimming, and other adapted activities; use of specially-designed toys and daily-used items (such as spoons and cups)
• Use of walking aids including foot orthotics and special footwear
• For feeding difficulties, use of feeding tubes (temporary), medications, feed thickeners, including special diets and nutritional supplements. A surgical procedure named fundoplication may be necessary in some children with severe gastroesophageal reflux disease (GERD)
• Severe constipation may require dietary changes, including increased intake of fiber and wholegrains, along-with the administration of laxatives
• Surgical correction of heart abnormalities and other physical defects, as assessed by a healthcare expert
• Use of suitable glasses for vision defects
• Surgical correction of genital defects
• Sleep disorders may require medication; daytime naps may be advised
• Specialized neurological and psychiatric care including psychotherapy, behavior modification, and establishing discipline techniques, as necessary
• Prescription antipsychotic medication based on evaluation by healthcare experts
• Occupational therapy

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

How can Kleefstra Syndrome be Prevented?

Kleefstra Syndrome may not be preventable since many of these genetic disorders are diagnosed at or following the birth of the child. A majority of cases are sporadic occurrences, which means there is no family history of the condition.

In some rare cases, the condition may be familial, meaning they occur within families. In expecting parents with a familial history:

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy), if available, 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

It is important to note that the chances of both the parents with normal chromosomes having another child with Kleefstra Syndrome is highly unlikely. This may be confirmed via specialized prenatal testing and preimplantation genetic diagnosis (PGD), if needed. Prenatal tests may include chorionic villus sampling (CVS) and amniocentesis.

What is the Prognosis of Kleefstra Syndrome? (Outcomes/Resolutions)

The prognosis of Kleefstra Syndrome is dependent upon the severity of the signs and symptoms and associated complications, if any. It may be assessed on a case-by-case basis, but it is generally difficult to predict the long-term outlook.

• Children with mild conditions are generally able to cope well via appropriate treatment and adaptive behaviors as they get older
• Some children may require extended medical support and care

Additional and Relevant Useful Information for Kleefstra Syndrome:

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

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