Kleefstra Syndrome is a rare neurodevelopmental disorder characterized by global developmental delay and intellectual disability, affecting multiple bodily systems. It was previously known as 9q34.3 deletion syndrome, reflecting one of its primary genetic causes. The disorder arises from changes in the genetic material involving a specific gene or a small section of chromosome 9.
The Genetic Basis of Kleefstra Syndrome
The root cause of Kleefstra Syndrome lies in the disruption of the EHMT1 gene (Euchromatic Histone Methyltransferase 1), located on chromosome 9 at position 9q34.3. This gene is sometimes referred to in the same functional class as KMT2C.
The protein produced by EHMT1 is an enzyme called histone methyltransferase, which regulates other genes. This enzyme adds a methyl group to histones—the structural proteins around which DNA is wound—to suppress the activity of certain genes. This process, known as epigenetic regulation, is necessary for the correct development and function of many organs and tissues.
Kleefstra Syndrome results when one copy of the EHMT1 gene is either missing or non-functional, causing a deficiency of the working enzyme. The genetic change typically happens in one of two ways, with each accounting for roughly half of reported cases. The first mechanism is a microdeletion, where a small segment of chromosome 9, including the EHMT1 gene, is lost.
The second mechanism involves a point mutation, where the EHMT1 gene contains a change that renders the protein product unstable or non-functional. In most cases, this genetic alteration is a de novo event, meaning it is a spontaneous change that occurs during the formation of reproductive cells or in early fetal development. The resulting lack of proper gene regulation leads to the characteristic features of the syndrome.
Common Physical and Developmental Features
The clinical presentation includes a spectrum of physical and neurological features. Virtually all individuals present with global developmental delay and intellectual disability, often in the moderate to severe range. Affected individuals frequently experience severely delayed or absent expressive speech, though their general language comprehension may be higher, suggesting non-verbal communication methods are helpful.
Distinctive facial features are a common hallmark of the syndrome and often contribute to the initial clinical suspicion. These may include a wide, short skull (brachycephaly) and a smaller head size (microcephaly). Other specific facial characteristics include:
- Eyebrows that grow together (synophrys)
- Widely spaced eyes (hypertelorism)
- A sunken midface
- A prominent jaw with everted or rolled-out lips
Associated medical issues require careful monitoring across the lifespan. Congenital heart defects, such as atrial or ventricular septal defects, are present in a significant number of individuals. About half of affected individuals may also have kidney or genitourinary abnormalities.
Neurological concerns are prominent, with childhood hypotonia (low muscle tone) contributing to motor delays. Seizures or epilepsy are also a recurring feature of the syndrome. Behavioral issues are common and can include features of autism spectrum disorder. In adolescence and adulthood, some individuals may experience a progressive loss of interest (apathy) or periods of unresponsiveness (catatonia).
Diagnostic Procedures and Confirmation
Diagnosis begins with clinical suspicion based on the characteristic developmental and physical features. Genetic testing is required to confirm the diagnosis by identifying the change in the EHMT1 gene or the deletion on chromosome 9. Approximately 50% of confirmed cases are due to a microdeletion at the 9q34.3 location, and the remaining 50% are caused by an intragenic pathogenic variant in the EHMT1 gene itself.
One of the primary diagnostic tools utilized to detect the microdeletion is a Chromosomal Microarray (CMA). This test is effective at identifying missing or duplicated segments of chromosomes, and a CMA covering the 9q34.3 region can confirm the deletion. However, CMA is less effective at detecting the smaller, intragenic point mutations within the gene.
For cases where the CMA is negative but Kleefstra Syndrome is suspected, Sequence Analysis of the EHMT1 gene is performed to find the point mutation. This technique reads the specific DNA sequence, allowing for the detection of small deletions, insertions, or single-letter changes. A gene-targeted deletion/duplication analysis may also be used to find smaller deletions or duplications within the gene that a standard CMA missed.
Ongoing Management and Support Strategies
Management focuses on a multidisciplinary approach to address the various symptoms and associated medical conditions. Early intervention is important and should be initiated as soon as the diagnosis is made or developmental delays are noted. This includes specialized therapeutic interventions tailored to the individual’s needs.
Speech-language therapy is a primary support, given the severity of expressive language delay. Occupational therapy and physical therapy are routinely employed to address developmental delays, low muscle tone, and improve gross and fine motor skills. Specialized educational programs support intellectual disability and cognitive development.
Routine medical monitoring is required to manage potential complications affecting multiple organ systems. This includes regular cardiac evaluations and echocardiography to monitor for congenital heart defects. Renal and urologic abnormalities also require periodic assessment, often involving specialists like a urologist or nephrologist.
Neurological and behavioral concerns are managed by specialists who may prescribe anticonvulsant medications for seizures or use behavioral therapy for autistic features and other psychiatric issues. As individuals with Kleefstra Syndrome age, they may require support for regressive behaviors or apathy, which can be addressed with intensive behavioral therapy and careful psychiatric assessment.