Kleefstra syndrome (KS) is a rare neurodevelopmental disorder affecting multiple body systems, characterized by a wide spectrum of physical and intellectual challenges. The condition was named after Dutch clinical geneticist Dr. Tjitske Kleefstra, who established the underlying genetic cause. KS was previously known as 9q subtelomeric deletion syndrome, reflecting the initial discovery of the chromosomal abnormality. Individuals with KS experience varying degrees of developmental delay and intellectual disability.
The Genetic Basis of Kleefstra Syndrome
Kleefstra syndrome is caused by a change to the genetic material on chromosome 9. Approximately 50% of cases result from a microdeletion in the 9q34.3 region, located at the end of the long arm of chromosome 9. The remaining cases are caused by a pathogenic variant, or mutation, within the EHMT1 gene (Euchromatic Histone-Lysine N-Methyltransferase 1) located in this area.
The EHMT1 gene provides instructions for creating the histone methyltransferase 1 enzyme. This enzyme plays a role in epigenetic regulation, controlling which genes are turned on or off without changing the underlying DNA sequence. The enzyme adds a methyl group to histone proteins, structural components of chromosomes. This modification suppresses the activity of numerous other genes necessary for normal development.
Disruption of a single copy of the EHMT1 gene, through deletion or mutation, leads to a reduction in the functional enzyme. This haploinsufficiency means the body has only half the required amount of the protein, which causes the syndrome’s effects. Nearly all cases of Kleefstra syndrome occur spontaneously (de novo) in the affected individual and are not inherited.
Key Clinical Features and Variability
Individuals with Kleefstra syndrome present a broad range of manifestations, but intellectual disability is a consistent finding. Cognitive impairment is highly variable, ranging from mild developmental delay to moderate-to-severe intellectual disability. Severe expressive speech delay is common, resulting in limited or absent verbal communication, though nonverbal language capacity may be stronger.
Distinctive physical features provide initial clues for diagnosis. Facial characteristics often include microcephaly (small head size) and brachycephaly (short, wide skull). Other noted features are eyebrows that grow together (synophrys), a sunken appearance of the middle of the face, and a prominent lower lip.
Low muscle tone (hypotonia) is present in childhood and often contributes to delayed motor milestones, such as walking. A significant number of affected individuals also have congenital medical issues involving internal organs. Approximately 50% of people with KS have a congenital heart defect (e.g., ventricular septal defect or tetralogy of Fallot), and 10–30% may have renal or urologic defects, including hydronephrosis.
Behavioral issues frequently appear, particularly in adolescence and adulthood. These include features associated with autism spectrum disorder, such as difficulties with social interaction and communication. Some adolescents and adults may experience periods of behavioral regression, characterized by apathy, loss of interest, or catatonia. Sleep disturbances are also common, often requiring specific management strategies.
Diagnosis and Confirmatory Genetic Testing
Diagnosis begins with a clinical evaluation based on characteristic features, such as developmental delay, hypotonia, and distinctive facial appearance. Suspicion is raised when these clinical findings, especially those involving the heart or kidneys, are observed in a young child. However, a definitive diagnosis relies entirely on confirming the genetic change.
Confirmatory genetic testing identifies the alteration in the 9q34.3 region or the EHMT1 gene. Chromosomal Microarray Analysis (CMA) is commonly used to detect the microdeletion of the 9q34.3 region. CMA efficiently finds the extra or missing segments of the chromosome that include the EHMT1 gene.
If the clinical picture is present but a microdeletion is not detectable, sequencing of the EHMT1 gene is performed. Techniques such as Next-Generation Sequencing (NGS) or whole-exome sequencing identify smaller, intragenic pathogenic variants within the gene. These molecular tests distinguish KS from other syndromes that may share similar features.
Management and Multidisciplinary Supportive Care
Since there is no cure for Kleefstra syndrome, management focuses on comprehensive supportive care tailored to the individual’s specific symptoms and needs. This requires a coordinated, multidisciplinary team approach. The team typically includes pediatricians, neurologists, geneticists, cardiologists, and developmental therapists.
Early intervention programs are highly recommended and significantly influence developmental progress in young children. Specific therapeutic services address the core developmental delays. Physical therapy addresses hypotonia and improves motor skills, while occupational therapy assists with fine motor skills and daily living activities.
Speech-language therapy is important due to severe expressive language delays, often focusing on nonverbal communication methods. Co-occurring medical conditions must be actively monitored and treated; seizures are managed with anticonvulsant medications, and congenital heart defects require regular cardiac evaluation. Behavioral issues, including apathy or regression in older individuals, are managed through intensive behavioral therapy and careful psychiatric monitoring.