Kabuki syndrome, also known as Niikawa-Kuroki syndrome, is a rare genetic disorder impacting various body systems. It was initially identified in 1981 by two independent Japanese research teams, led by scientists Norio Niikawa and Yoshikazu Kuroki. The syndrome gained its name from the distinct facial features observed in affected individuals, which bear a resemblance to the traditional stage makeup worn by actors in Kabuki, a form of Japanese theater.
This condition is rare, with an estimated occurrence of about one in every 32,000 births. While the defining facial characteristics are often recognized, the severity and combination of other symptoms can vary greatly. Not all individuals with Kabuki syndrome will experience every possible manifestation.
Distinctive Features and Associated Symptoms
Individuals with Kabuki syndrome often present with a recognizable set of facial features. These include long palpebral fissures, which are elongated eye openings, and everted lower eyelids, where the outer part of the lower lid turns outward. Arched eyebrows, sometimes with sparseness or notching on the outer edges, are also common, along with a broad nose that has a flattened or depressed tip. Many individuals also have prominent or unusually shaped ears.
Beyond these facial characteristics, growth delays and short stature are frequently observed. Individuals may also experience varying degrees of intellectual disability, typically ranging from mild to moderate. Poor muscle tone, known as hypotonia, is common in early childhood, contributing to developmental delays.
A wide range of other medical issues can be associated with Kabuki syndrome, affecting multiple body systems. Skeletal abnormalities are frequent, including scoliosis (curvature of the spine), irregularly shaped vertebrae, and short fifth fingers. Joint laxity, where joints are unusually flexible, can also be present.
Heart defects are observed in approximately 50% of individuals, with common examples including coarctation of the aorta (a narrowing of the large artery carrying blood from the heart) and septal defects (holes between the heart’s chambers). Feeding difficulties are nearly always present, sometimes requiring specialized feeding interventions like tube feeding. These difficulties can be compounded by low muscle tone and gastroesophageal reflux.
Other common issues include:
- Hearing impairment, which can be conductive or sensorineural, seen in about 20% of cases.
- Vision problems like strabismus (misaligned eyes) and ptosis (drooping eyelids).
- Increased susceptibility to infections and immune system dysfunction.
- Dental problems, such as missing or unusually shaped teeth.
- A highly arched or cleft palate.
Neurological manifestations include seizures and microcephaly (unusually small head size). Behavioral issues, such as anxiety and sensory processing disorders, are also frequently observed. Endocrine problems like growth hormone deficiency and early puberty have also been noted.
Genetic Origins of Kabuki Syndrome
Kabuki syndrome primarily results from changes in specific genes, with mutations in either the KMT2D or KDM6A genes being the known causes. The KMT2D gene, previously known as MLL2, is responsible for approximately 55% to 80% of Kabuki syndrome cases. This gene provides instructions for creating an enzyme that modifies histones, which are proteins that help organize DNA within cells.
Mutations in the KDM6A gene account for a smaller proportion of cases, around 5%. This gene is located on the X chromosome. Both KMT2D and KDM6A genes play a role in epigenetic modifications, influencing how genes are expressed without altering the underlying DNA sequence. When these genes are disrupted, it can lead to abnormal development.
Most cases result from de novo mutations, meaning the genetic change occurs spontaneously and is not inherited. In such instances, the likelihood of siblings being affected is very low.
Kabuki syndrome can also be inherited. KMT2D-related cases follow an autosomal dominant pattern, meaning one altered gene copy is sufficient, and an affected individual has a 50% chance of passing it on. KDM6A-related cases are X-linked dominant; males with this mutation are often more severely affected than females due to having only one X chromosome. In about 20% of cases, the specific genetic cause remains unknown.
Diagnosis and Comprehensive Management
Diagnosing Kabuki syndrome involves a combination of clinical evaluation and genetic testing. Physicians often suspect Kabuki syndrome based on the presence of its characteristic facial features, along with other associated physical and developmental findings. Confirmation typically relies on genetic testing to identify mutations in the KMT2D or KDM6A genes. Notably, about 30% of individuals with clinical features of Kabuki syndrome may not have a detectable mutation in these two known genes.
There is currently no cure for Kabuki syndrome; therefore, treatment focuses on managing the diverse symptoms experienced by each individual. This requires a coordinated, multidisciplinary approach involving various medical specialists. A team may include pediatricians, geneticists, cardiologists, orthopedists, neurologists, gastroenterologists, audiologists, and ophthalmologists.
Early intervention services are particularly beneficial for individuals with Kabuki syndrome. Physical therapy helps improve motor skill development and address low muscle tone. Occupational therapy assists with fine motor skills and activities of daily living. Speech therapy is valuable for addressing feeding issues and promoting communication development.
The general outlook for individuals with Kabuki syndrome is usually good, with the syndrome itself typically not shortening life expectancy. However, coexisting medical conditions can influence the long-term prognosis, underscoring the importance of ongoing, comprehensive medical care and regular monitoring for potential complications. This continuous management aims to optimize the overall health and quality of life for individuals with Kabuki syndrome.