Kleefstra syndrome

 Kleefstra syndrome

Overview

Kleefstra syndrome is a rare genetic condition that affects development and involves many body systems. People with Kleefstra syndrome usually have distinct facial features, developmental delay, intellectual disability, low muscle tone (hypotonia), and communication difficulties. Kleefstra syndrome is caused by a mutation in a gene called EHMT1 or the deletion of a specific region of chromosome 9 that includes EHMT1.

Other names for Kleefstra syndrome include 9q-syndrome, 9q34.3 deletion syndrome, and chromosome 9q deletion syndrome.

Kleefstra syndrome is a rare genetic condition that affects multiple organ systems and has specific developmental and behavioral symptoms. Children with Kleefstra syndrome may have specific facial features including a small head size (microcephaly), a broad forehead, widely spaced eyes (hypertelorism), distinctive eyebrows and large tongue (macroglossia). Low muscle tone (hypotonia) along with a large birth weight and childhood obesity are also common. Additionally, heart (cardiac), kidney (renal), genital and brain abnormalities may be seen. Most people with Kleefstra syndrome will have some form of intellectual disability which may occur with autistic-like features, speech delay and the development of extreme apathy and/or lack of movement and communication (catatonia) after puberty. Additional symptoms that can occur include epilepsy (seizures) and/or febrile seizures (seizures in the setting of a fever), hearing loss, stomach (gastrointestinal) issues, respiratory infections and farsightedness (hyperopia). Fewer than 1,000 people have been diagnosed with Kleefstra syndrome in the U.S.Kleefstra syndrome was initially known as “9q subtelomeric deletion syndrome” because it is caused by changes in a specific region of chromosome 9, known as 9q34.3. It was renamed in honor of Dr. Tjitske Kleefstra, a clinical geneticist who was one of the first to describe the syndrome in scientific publications. This renaming occurred in the early 2000s.

SYMPTOMS

Kleefstra syndrome has a wide range of symptoms that include physical, developmental and behavioral characteristics. While some physical features are apparent from birth (congenital), other symptoms, particularly behavioral, often develop during early childhood.

People with Kleefstra syndrome have distinctive facial features including a small head size (microcephaly), flattening of the back of the skull (brachycephaly), broad forehead, arched or connected eyebrows (synophrys), widely spaced (hypertelorism) and up-slanting eyes, nostrils that open to the front instead of downwards (anteverted nares), a flatter appearance of the midface (midface hypoplasia), large tongue (macroglossia), full bottom lip (everted lower vermilion), protruding jaw (prognathism) and thickened outer-ear (thickened helix). As children get older, their facial characteristics become more defined and noticeable.

Low muscle tone (hypotonia) is a common symptom. About half of babies with Kleefstra syndrome are born with a large birth weight and may develop childhood obesity.

Other physical symptoms include heart (cardiac) defects such as a hole in the wall between the heart’s chambers (atrial septal defect and/or ventral septal defect), narrowing of the heart vessels (aortic coarctation and/or pulmonic stenosis) and a malformed heart valve (bicuspid aortic valve). These symptoms have been seen in about half (50%) of people diagnosed with Kleefstra syndrome.

Kidney (renal) issues, including abnormal flow of urine (vesicoureteral reflux), stretching and swelling of the kidney (hydronephrosis), development of fluid-filled pouches (renal cysts) and chronic renal failure (insufficiency) are found in approximately 10%-30% of people with Kleefstra syndrome.

Genital differences, including the failure of the testicles to descend into the scrotum (cryptorchidism), the opening of the urethra not being located at the tip of the penis (hypospadias) and small penis, are reported in 30% of affected males.

Brain abnormalities can include underdevelopment (hypoplasia) of the connection between the left and right side of the brain (corpus callosum) and outer layer of brain (cortex).

Most people with Kleefstra syndrome will have some form of intellectual disability which is typically moderate to severe. Autism spectrum disorder along with expressive speech delay is also common. People with Kleefstra syndrome may develop a lack of interest/difficulty in communicating or moving (catatonia) and extreme apathy after puberty. Psychiatric and sleep problems are also associated with the condition.

Other symptoms include epilepsy (seizures) and/or febrile seizures (seizures in the setting of a fever), hearing loss, stomach (gastrointestinal) issues, respiratory infection and farsightedness (hyperopia).

CAUSES

Kleefstra syndrome is a genetic condition caused by changes in a specific region of chromosome 9, known as 9q34.3. The genetic changes that lead to Kleefstra syndrome can take different forms, including deletions (missing pieces) of the chromosome or pathogenic variants (previously known as mutations) within a specific gene called EHMT1.

The EHMT1 gene provides the instructions for making an enzyme called euchromatin histone methyl transferase 1, which is involved in a cellular process called histone methylation. This enzyme plays an essential role in controlling how genes work by stopping specific genes from being active, which is crucial for proper growth and body functions. Genetic changes (deletions or pathogenic variants) within the EHMT1 gene result in a loss of function of this enzyme, which can disrupt the normal regulation of other genes and lead to the symptoms of Kleefstra syndrome.

In most people with Kleefstra syndrome, the genetic change that causes the disorder is not inherited from a parent but occurs spontaneously (de novo) in the individual with Kleefstra syndrome. However, in a small number of patients reported in the medical literature, Kleefstra syndrome was inherited (passed down) from a parent with no symptoms to a child. This type of inheritance is called autosomal dominant. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease.

AFFECTED POPULATIONS

Kleefstra Syndrome affects both males and females equally. It occurs in people from all ancestral backgrounds. How often it occurs is not well understood. Many people with Kleefstra syndrome may be undiagnosed, making it challenging to accurately gauge the frequency of the disorder in the general population.

DISORDERS WITH SIMILAR SYMPTOMS

Symptoms of the following disorders can be similar to those of Kleefstra syndrome.

Comparisons may be useful for a differential diagnosis.

Smith-Magenis syndrome (SMS) is a complex developmental disorder that affects multiple organ systems of the body. The disorder is characterized by a pattern of abnormalities that are present at birth (congenital) as well as behavioral and cognitive problems. Common symptoms include distinctive facial features, skeletal malformations, varying degrees of intellectual disability, speech and motor delays, sleep disturbances and self-injurious or attention-seeking behaviors. The specific symptoms present in each patient can vary dramatically from one individual to another. Approximately 90% of cases are caused when a portion of chromosome 17 is missing or deleted (monosomic). This deleted portion within chromosome 17p11.2 includes the RAI1 gene, which is believed to play a major role in the development of the disorder. In the remaining cases, there is no deleted material on chromosome 17; these cases are caused by pathogenic variants in the RAI1 gene. Other genes within the deleted segment may also play a role in variable features in the syndrome, but it is not fully understood how significant a role they play in the development of SMS. Unlike Kleefstra syndrome, people with SMS often have tooth agenesis, which means they are born without certain teeth or have fewer teeth than expected. They are also at a higher risk of developing sinopulmonary infections such as otitis media, pneumonia and sinusitis. Individuals with Smith-Magenis syndrome may exhibit aggression and self-injurious behaviors at a higher rate. (For more information on this disorder, choose “Smith Magenis Syndrome” as your search term in the Rare Disease Database.)

Pitt-Hopkins syndrome (PTHS) is a rare, genetic, neurological disorder. Affected individuals typically have distinctive facial features, intellectual disability, delays in reaching developmental milestones, impaired ability to speak, and can have recurrent seizures and breathing pattern abnormalities. Additional symptoms that can occur include poor coordination (ataxia), repetitive nonfunctional hand movements, constipation, sleep disturbances and severe nearsightedness (myopia). Behavioral abnormalities are common, although children are often described as social and having happy dispositions. Some affected children meet the criteria for autism spectrum disorder. The specific signs and symptoms of the disorder and their severity can vary from one affected individual to another. Pitt-Hopkins syndrome is caused by a pathogenic variant in the TCF4 gene. This variant occurs spontaneously and in almost all patients and does not run in a family. (For more information on this disorder, choose “Pitt-Hopkins Syndrome” as your search term in the Rare Disease Database.)

KMT2C-associated syndrome, also known as “Kleefstra syndrome-2,” is a rare neurodevelopmental disorder inherited in an autosomal dominant pattern. The main symptoms of the syndrome include intellectual disability and developmental delay. In addition, individuals with this syndrome may also have specific facial features such as a flattened midface (midface hypoplasia), prominent eyebrows (synophrys) and everted lower lip. This condition has been observed in individuals with de novo variants in the KMT2C gene.

MBD5 haploinsufficiency is a neurological condition that results in developmental delay, intellectual disability; speech, language, and sleeping difficulties; seizures and autistic-like and self-injurious behaviors. This condition can be diagnosed in individuals who have a deletion in the 2q23.1 region of chromosome 2, which may affect the entire MBD5 gene or only a portion of it, or who have a pathogenic variant in the MBD5 gene.

DIAGNOSIS

Kleefstra Syndrome may first be suspected based on characteristic features of the condition and tests done in a clinical evaluation. Often, a person with Kleefstra syndrome will be the only person with the condition in their family history. Molecular genetic testing that identifies the characteristic deletion in chromosome 9 or identifies a variant in the EHMT1 gene can confirm the diagnosis. Molecular genetic testing for the parents might also be recommended. A genetic counselor can explain what type of testing is most appropriate for the child and family.

Clinical Testing and Work-Up

A clinical work up should include a physical examination including evaluation of the height, weight and head circumference, with particular attention to facial features.

An echocardiogram and electrocardiogram (EKG) may be done to look for any potential heart defects and rhythm disturbances. The echocardiogram provides information about the structure of the heart and the EKG uses electrical currents to evaluate the rhythm of the heart.

A neurology evaluation might be suggested, including an electroencephalogram (EEG) and magnetic resonance imaging (MRI) for the brain, in children who have had recorded or suspected seizures. An EEG measures electrical activity in the brain to detect seizures and a brain MRI creates a cross sectional image of the brain. MRIs can also be utilized in children with movement disorders, regression of psychomotor development or extreme catatonia.

The workup might also include a renal ultrasound to evaluate the kidneys, an assessment for sleep disturbances, hearing evaluation for hearing loss, a psychiatric evaluation and a developmental assessment including motor, speech, cognitive and vocational skills.

STANDARD THERAPIES

 Treatment

An interdisciplinary team should work together to care for these patients under the coordination of a pediatrician or medical geneticist. Members of this team, depending on the specific symptoms unique to the individual, can include a pediatric neurologist (a physician who specializes in the diagnosis and treatment of disorders of the brain, nerves and nervous system in children), an ophthalmologist (a physician who specializes in the diagnosis and treatment of disorders of the eye), an audiologist (a healthcare provider who specializes in the diagnosis and treatment of disorders of the ears), a cardiologist ( a physician who specializes in the diagnosis and treatment of disorders of the heart), a gastroenterologist (a physician who specializes in the diagnosis and treatment of disorders of the gastrointestinal tract), a urologist and/or nephrologist (a physician who specializes in the diagnosis and treatment of disorders of the genitals and/or kidneys), a speech therapist, occupational therapist, physical therapist and a psychiatrist. The addition of a specialist for adults with intellectual disability may be considered in adulthood.

Genetic counseling in encouraged and can be beneficial to both the patient and their family.

A developmental assessment can determine appropriate therapies, such as occupational, speech, physical and feeding therapies to help with the difficulties in motor control. Medical equipment such as wheelchairs and walkers might be considered for some patients. Medications like baclofen, Botox, and anti-parkinsonian prescriptions or orthopedic procedures that can help with symptoms of hypotonia and dystonia should be managed by the appropriate specialist.

To address communication and behavioral concerns, augmentative and alternative communications (AAC) can provide care for those with difficulties in expressive language, and an applied behavior analysis (ABA) can be implemented as treatment for autism spectrum disorder. ABA adapts to the strengths and weaknesses of each child. A developmental pediatrician can provide guidance in behavior management as well as prescriptions when appropriate. Early intervention programs, developmental preschools and individualized education plans (IEPs) are all beneficial for social, cognitive and intellectual development.

Type of Doctor Department :A Pediatrician or Neurologist, Psychiatrist,