Kleefstra Syndrome (KS) is a rare genetic neurodevelopmental disorder impacting multiple organ systems and developmental milestones. It is characterized by intellectual disability, recognizable physical attributes, and a range of associated medical and behavioral challenges. As a condition resulting from a change in a single gene, KS has complex and wide-ranging effects on development and function. Kleefstra Syndrome is considered extremely rare, with only a few hundred individuals diagnosed worldwide since its formal recognition.
The Genetic Basis
The underlying cause of Kleefstra Syndrome is the functional loss of one copy of the EHMT1 gene, located on chromosome 9 (9q34.3). This gene codes for the enzyme Euchromatic Histone Methyltransferase 1, which plays a significant role in gene regulation. Approximately half of all cases result from a microdeletion of this chromosomal region that includes the EHMT1 gene. The remaining cases are typically caused by a small, pathogenic variant or mutation within the gene itself.
The mechanism leading to the syndrome is haploinsufficiency, meaning one functional copy of the gene is insufficient for normal development. The EHMT1 enzyme performs epigenetic modification by adding methyl groups to histone proteins, which represses the expression of certain genes. Epigenetics refers to changes in gene activity that affect how DNA is read without altering the underlying sequence.
When the EHMT1 gene is non-functional, this epigenetic regulation is disrupted, preventing the proper silencing of genes essential for normal brain development and tissue formation. This disruption drives the wide spectrum of symptoms observed in Kleefstra Syndrome. Most cases arise spontaneously as new, or de novo, genetic changes in the affected individual, meaning they are not inherited.
Key Clinical Manifestations
The effects of Kleefstra Syndrome include physical, neurological, and developmental characteristics. Nearly all affected individuals experience global developmental delay and intellectual disability, typically ranging from moderate to severe. Motor skill development is often delayed due to low muscle tone (hypotonia), which is frequently present from infancy. Speech is profoundly affected, resulting in severe expressive speech delay and little verbal communication, although language comprehension is generally higher.
Distinctive facial features are common and often lead to the initial clinical suspicion. These features can include microcephaly (unusually small head size) and a broad, short skull shape. Individuals often have synophrys (eyebrows that meet in the middle) and prognathism (a prominent lower jaw). Other characteristics include a short, upturned nose, widely spaced eyes, and an everted or full lower lip.
A range of associated medical issues requires attention throughout life. Congenital heart defects are present in a significant number of individuals, often involving structural issues like atrial or ventricular septal defects. Renal and urologic abnormalities, such as hydronephrosis or vesico-ureteral reflux, are also frequently observed. Additionally, affected individuals are prone to severe and recurrent respiratory infections, sometimes linked to gastroesophageal reflux.
Behavioral and psychiatric issues emerge and evolve over time. Autistic-like features, including difficulties with social interaction and communication, are common during childhood. In adolescence and adulthood, a subset of individuals may experience a regression in skills, accompanied by psychiatric symptoms such as extreme apathy, catatonic-like features, or mood disorders. Monitoring these neurological and behavioral changes is an ongoing part of comprehensive care.
Diagnosis and Confirmation
Diagnosis begins when a physician notes the characteristic clinical findings, such as intellectual disability, hypotonia, and distinctive facial features. Definitive confirmation relies on advanced genetic testing to identify the underlying change in the EHMT1 gene. The testing strategy must detect the two primary types of genetic alterations that account for the syndrome.
Chromosomal Microarray Analysis (CMA) is used to detect large-scale genetic imbalances. CMA effectively identifies the deletion of the 9q34.3 chromosomal region containing the EHMT1 gene, accounting for about half of all cases. For the remaining cases caused by smaller, intragenic mutations, gene sequencing of EHMT1 is necessary to pinpoint the exact pathogenic variant.
Once the diagnosis is confirmed, genetic counseling is provided to the family. Counseling explains the genetic findings and discusses the autosomal dominant inheritance pattern. This step ensures the family understands the long-term implications of the diagnosis and connects them with appropriate resources and support networks.
Ongoing Care and Management
Management of Kleefstra Syndrome requires a multidisciplinary approach focusing on supportive care to maximize developmental outcomes and address medical issues. A team of specialists, including developmental pediatricians, cardiologists, neurologists, and geneticists, coordinates care due to the syndrome affecting numerous body systems.
Early intervention services address developmental delays as soon as possible. Physical Therapy (PT) is employed to improve gross motor skills and manage low muscle tone. Occupational Therapy (OT) assists with fine motor skills and adaptive techniques for daily living activities, such as feeding and dressing. Speech and Language Therapy (SLT) is particularly important, often focusing on alternative and augmentative communication methods, such as sign language or communication devices, given the severe expressive speech delay.
Routine medical monitoring is an ongoing component of care. This includes regular cardiology evaluations to detect and manage congenital heart defects. Frequent renal assessments are necessary for kidney or urologic abnormalities. Neurological surveillance is also required for individuals who experience seizures, which may necessitate anticonvulsant medication management. Educational support requires implementing an Individualized Education Program (IEP) to tailor the learning environment to the student’s unique cognitive and developmental needs.