Kleefstra Syndrome, also known as 9q subtelomeric deletion syndrome, 9q34.3 deletion syndrome, or EHMT1-related neurodevelopmental syndrome, is a rare genetic disorder that causes neurodevelopmental delays, intellectual disability, typical facial presentations (including small skulls, protruding lower jaws, large tongues, and widely spaced eyes), muscle hypotonia and high birth weight. Affected individuals also have congenital cardiac, brain, and genitourinary abnormalities. Children with Kleefstra syndrome may also exhibit autism spectrum disorder (ASD)-like behaviors, sleep disturbances, seizures, and episodes of apathy or regression. Some reports have also described features resembling catatonia in adolescence or adulthood, though this remains rare and not universally observed. Statisticians are unaware of the true prevalence of the genetic abnormality. However, the frequency of kleefstra with mental retardation is estimated to be 1 in 200,000 cases.¹ So, far studies have identified approximately 110 cases with the syndrome.²

The syndrome of abnormalities arises due to a mutation or deletion in the EHMT1 gene on chromosome 9. The EHMT1 gene is present on the q34.3 region of chromosome 9, thus, the multiple names. A wide array of tests including genetic testing is done to reach diagnosis. As it is a genetic mutation disorder there is no treatment available. However, management requires early intervention by a multidisciplinary team (including speech, and occupational therapists, gastroenterologists, orthopedics, etc.) to prevent aggravation of symptoms.

Kleefstra Syndrome Symptoms

The chromosomal microdeletion impacts multiple body parts which leads to the development of widespread symptoms. Presentations range from abnormal facial features to delayed and missing neurological development.

Facial Features:

Microcephaly (Small Head)

Patients usually present with a small head i.e., microcephaly. However, in some cases, there may be wide and short skulls i.e., brachycephaly. Studies show that distinctive facial features of kleefstra include microcephaly, ectropion of lower lips, arched eyebrows, etc.³

Hypertelorism (Widely Spaced Eyes)

Large space between the eyes is another feature of the facial disfigurement caused by kleefstra. Ocular hypertelorism accompanies a flat face and averted nostrils.⁴ In addition to the spaced eyes, the eyebrows vary from normal and meet in the middle (above the nose) i.e., synophrys.

Midface Hypoplasia (Depressed Middle Face)

The middle part of the face grows incompletely. The upper jaw and eyeball sockets are undeveloped, leading to a sunken appearance of the midface. This may be accompanied by protrusion of the lower jaw i.e., mandibular prognathism.

Averted Nares (Front-Opening Nostrils)

Instead of normal downward-opening nostrils, patients have nostrils that open at the front of the face. This feature is almost always present with other facial abnormalities.

Ectropion Of Lips

In addition to the prognathic lower jaw, kleefstra patients often encounter eversion of the lips. The lips are generally rolled out. The vermilion border—especially of the lower lip—can appear thickened or exaggerated, contributing to the characteristic facial appearance seen in this condition.⁵

Macroglossia (Large tongue)

In most patients, people notice a protruding tongue which is attributed to a larger than normal tongue size. Macroglossia, mandibular prognathism, and anterior open bite are major concerns for dentists.⁶

Neuropsychological Complications:

There are significant neuropsychiatric complications that impact the patient’s quality of life. Individuals with kleefstra have a hard time establishing day-to-day social interactions. Learning at school is also a significant challenge.

Speech Delay

Language and speech impairments are salient features of the neurodevelopmental delays entailed with the syndrome. The extent of the speech and communication disturbance can range from moderate to severe. However, early access to professional guidance and communication aid helps improve the quality of life.⁷

Autism

Kleefstra patients have problems interacting and expressing their feelings. This may stem from underlying developmental problems. Such patients exhibit features of autism spectrum disorder which include repetitive activities, nonverbal communication, and minimized social interaction.⁸

Behavioral Issues

In adolescence, individuals start developing awkward behaviors. There is a generalized loss of interest and enthusiasm (apathy) in fun activities and gatherings. Behavioral and emotional scales indicate a strong aspect of autism spectrum disorder in patients which keeps them from interacting normally. ⁹Moreover, there are significant intellectual disabilities as well.
Patients are often seen in an unresponsive state despite being fully awake. Catatonia along with autistic features is a salient diagnostic point of the disease.¹⁰

Epileptic Seizures

The 9q34.3 microdeletion syndrome can induce tonic-clonic seizures in young patients. In most patients there are focal epileptic seizures and the frequency of these seizures depends on the time of the onset. Clinicians note a higher frequency in cases of early-onset epilepsy i.e., before 36 months of age. However, the frequency decreases with time (and age) and anti-epileptic drugs work for most individuals.¹¹

Motor Impairment & Weight Issues:

Children suffering from the disorder usually have high birth weight. Metabolic dysregulation leads to high prevalence of childhood overweight/obesity. This puts the kid at a higher risk of cardiovascular pathologies.¹²

The muscles of individuals with chromosome 9q deletion syndrome are weak and soft due to a loss of muscle tone i.e., hypotonia. Infantile hypotonia is a highlighting feature of the syndrome. The loss of muscle tone is attributed to mutations in the chromosome 9. This makes movement difficult for patients. However, most kids are capable of walking later in life i.e., by 2-3 years of age.

The hypotonia and weight-related issues seen in Kleefstra syndrome may resemble those observed in Prader-Willi syndrome, another genetic disorder known for low muscle tone, and feeding difficulties in infancy, followed by rapid weight gain and developmental delays. However, despite clinical similarities, the underlying genetic mutations and diagnostic criteria for both conditions differ.

Cardiac Problems:

A wide variety of congenital heart defects are seen in the microdeletion syndrome. As per estimates, conotruncal (congenital) heart defects are seen in around 50% of the cases.¹³ You can find the following types of cardiac anomalies:

Atrial/Ventricular septal defect (ASD/VSD)
Bicuspid aortic valve stenosis
Pulmonary stenosis
Tetralogy of Fallot

Respiratory Troubles:

Infants with kleefstra are prone to developing severe respiratory infections. Several patients often present with recurrent respiratory infections. There may also be meconium aspiration along with infection which requires medical attention.¹⁴

Genitourinary Complications:

There is also a wide variety of abnormalities in the urinary/renal system and genitals. Renal complications are present in around 10-30% of cases. Common renal and urinary issues include renal cysts, hydronephrosis (swelling of kidneys due to an abnormal build-up of urine), chronic renal insufficiency, vesicoureteral reflux (backflow of urine from the bladder to the ureters/kidneys), imperforated anus (anus is completely blocked or missing), etc. According to studies imperforated anus, vesicoureteral reflux, hydronephrosis, recurrent UTIs, and chronic kidney disease are the most common urinary symptoms of kleefstra syndrome.¹⁵

Genital anomalies are reported in about 30-40% patients of with the genetic disorder. Common abnormalities of the genitalia include hypospadias (a condition in which the urethral opening is on the underside of the penis and not at the tip), cryptorchidism (when testicles have not properly descended into the scrotum before birth), micropenis.¹⁶

Vision & Hearing Problems:

A noticeable number of kleefstra patients report vision impairments. Hypermetropia (farsightedness) has been diagnosed in infants (just a few months old). Additionally, there may also be accompanying hearing loss (both conductive and sensorineural) at a young age.

Gastrointestinal Issues:

Gastroesophageal reflux distress (GERD) is a common complaint of patients with kleefstra. Changes in the gut microbiota due to insufficiency of the euchromatic histone methyl transferase cause complications like GERD and constipation.¹⁷
Patients may also experience sleep disorders and often seek medical help for the disturbance.

Kleefstra Syndrome Regression

In cases of kleefstra, regression is the condition in which the patient gradually loses developmental skills that he/she previously possessed. Though initially present, patients experience a loss of cognitive, language, and social skills over time. The phenomenon manifests as sleep disturbance, motor skills loss, catatonia, and cognitive decline. However, sleep disturbance can be a precursor of severe regression.¹⁸ Manifestations exacerbate during early childhood.

Kleefstra Syndrome Causes

Based on the underlying gene errors, kleefstra syndrome is divided into two types:

Type 1 (KLEFS1):

In the vast majority of cases, the rare genetic disorder arises when there is a deletion of a sequence of DNA on chromosome 9. There is a deletion of 1 million DNA base pairs on one copy of chromosome 9 in each cell. The deletion takes place at the region q34.3 which contains the EHMT 1 gene. The extent of deletion (size of missing DNA) varies between individuals and so do the symptoms. This specific segment of the DNA is responsible for instructing the enzyme euchromatic histone methyltransferase 1 (EHMT1) to control the normal development and growth of a cell. The absence of the segment leads to cell developmental issues which have widespread manifestations.

Genetic deletion in Kleefstra syndrome - Visual Metaphor showing a DNA puzzle — Visual metaphor: A DNA puzzle with missing pieces represents the EHMT1 gene deletion seen in Kleefstra Syndrome

In about 25% of cases, there is a mutation of the EMHT1 gene instead of a deletion. The mutations lead to the production of an unstable enzyme (histone methyltransferase) that can not function properly.

Type 2 (KLEFS2):

This less common type arises due to mutations in the KMTC2 gene. Unlike the typical widespread presentations seen with the EHMT1 gene mutation, abnormalities in KMTC2 mainly cause mild dysmorphic features and poor/delayed psychomotor development (with language delays and compromised communication skills).

Kleefstra Syndrome Diagnosis

The diagnosis of chromosome 9q deletion syndrome involves multiple steps and diagnostic tests. The syndrome is extremely rare but can be identified based on its typical presentation.

History & Physical Examination:

The first step is a clinical examination that comprises taking a history of all the symptoms present (such as intellectual disability, facial disfigurement, speech delays, etc.) and physically examining features like weight, vision and hearing tests, etc. Family history is also important in cases of genetic disorders.

Diagnostic Tests:

Molecular Genetic Testing

For molecular genetic testing, your healthcare provider will collect a sample of DNA from your blood sample and send it to the laboratory. DNA samples can also be extracted from saliva and tissue.
Different types of genetic testing help doctors reach the diagnosis. Experts frequently adopt the following tests:

Chromosomal Microarray Analysis (CMA):

It detects large deletions in the genome and is used to check chromosomal deletions involving the EHMT1 gene.

Single-Gene Testing:

It is a more precise test that detects smaller deletions of DNA. This test type helps diagnose cases with iatrogenic deletion which is present in 5% of individuals with kleefstra.

Multigene Panel Analysis:

Sometimes, doctors opt for a multigene panel that includes EHMT1 and other genes to diagnose the cause of the intellectual disability.
Other genetic tests that can be employed for the purpose include:

Karyotype testing
Epigenetic signature analysis
Multiplex Ligation-Dependent Probe Amplification (MLPA)

Symptom-Based Tests

To diagnose complications associated with kleefstra, your health professional may order an array of different tests including:

Brain MRI is used to assess brain function and the cause of seizures. This helps rule out any other causes of neurological disabilities.
An electrocardiogram (ECG) helps determine the condition of the heart which is important in saving the patient’s life.
An electroencephalogram (EEG) measures brain activity and can provide details about the abnormalities causing seizures.

Differential Diagnosis:

Kleefstra Syndrome Vs. Down Syndrome

Both syndromes arise due to genetic mutations and have multiple overlapping features but there are several differences that set them apart. As mentioned, kleefstra arises due to the deletion of the EMHT1 gene on chromosome 9 while Down’s syndrome is the outcome of an extra copy of chromosome 21. While developmental, speech delays, and microcephaly are common to both disorders, down’s syndrome patients have some distinguishing features short heights, upward slanting eyes, and excessive skin at the neck.

Kleefstra Syndrome Treatment

Treatment involves a multi-disciplinary approach to managing the myriad of issues associated with the syndrome. The main aim of all therapies is to improve the patient’s quality of life. In developed parts of the world, there are specialized care centers that cater to the needs of children with syndromes (downs, kleefstra, etc.).

Medicinal/Pharmacological Care & Support:

Doctors advise drugs to address different problems. The most commonly prescribed medicines include PPIs/antacids for GERD, anti-epileptic drugs for seizures, anti-psychotic drugs (in cases of mental issues), etc. Orthopedic support devices are advised to counter muscle hypotonia. Hearing aids and cochlear implants are given to improve hearing abilities. Prescription lenses can also be given for visual impairments.

Health professionals also prescribe medications for underlying respiratory, cardiac, and urinary/kidney abnormalities. Antibiotics/antivirals are frequently prescribed for recurrent respiratory and urinary tract infections.

Therapeutic Management:

Generally, doctors use different types of therapies to manage issues arising from genetic microdeletion.

Speech Therapy

Most patients require speech therapy due to communication issues and speech delays. A speech therapist can improve a patient’s communication skills with family. Moreover, patients can learn sign language to express themselves.

Occupational Therapy

This type of therapy teaches the patient how to cope with the condition and focus on daily living skills. The main aim is to improve fine motor skills. Studies show that occupational therapy helps young patients perform better at home and at school.¹⁹

Physical Therapy

Physiotherapy sessions aid in improving muscle tone and prove helpful in enhancing patient’s performance and day-to-day activities.

Behavioral Therapy

It plays a part in addressing the behavioral issues arising from the disorder.

Sensory Integration Therapy

Therapists train the affected children to manage the sensory information and process them accordingly. With play-based approaches, experts stimulate the patient’s senses (touch, movement, hearing, sight, etc.) and integrate sensory input. Examples of adopted activities include brushing and using weighted blankets, etc.

Genetic Counselling:

Genetic counselors are professionals who interact with parents and provide them with insights into the complications that can arise due to the genetic disorder. By accurately informing the parents about the associated issues, counselors allow parents to make informed decisions about their child’s medical condition.

Kleefstra Syndrome Life Expectancy

There is insufficient data to determine the exact life expectancy of kleefstra patients. However, several times death occurs in infancy or early childhood due to cardiac complications and recurrent pulmonary infections. Usually, a team of experts (from different fields) works together to manage kleefstra syndrome.

Conclusion

The chromosome 9q deletion syndrome, now known as kleefstra syndrome is an extremely rare genetic disorder arising from mutation/deletion in chromosome 9 of every cell. The DNA deletion occurs in section q34.3 i.e., EHMT1 gene. The gene is responsible for producing and functioning euchromatic histone methyltransferase (EHMT) enzyme. The missing DNA causes widespread effects including facial disfigurement (small head, sunken midface, large lower jaw/tongue, and widely spaced eyes, etc.), neurodevelopmental issues (speech delays, intellectual disability, autism, seizures, and mental retardation), and muscle hypotonia. Infants are overweight/obese at birth and suffer from cardiac, urinary/renal, and respiratory complications. Patients also develop vision, hearing, gastrointestinal issues, and sleep disturbances over time.

Doctors diagnose kleefstra by physical examination and molecular genetic testing (for the syndrome). Tests like chromosomal microarray analysis (CMA) and single-gene testing/Multigene panel analysis help reach diagnosis. The only treatment available is the management of symptoms via medicines (for GERD, heart problems, antibiotics, etc.) and the use of orthopedic supports (for weak muscle tone). Patient’s quality of life and communication skills can improve with therapies like speech therapy, occupational therapy, behavioral therapy, etc. Genetic counseling of parents allows them to make informed decisions about their child’s condition.

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Kleefstra Syndrome: Causes, Symptoms, and Treatment

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