All About Kabuki Syndrome

What is Kabuki Syndrome?

Kabuki syndrome is a congenital genetic disorder characterized by distinctive facial features, moderate intellectual disability, growth delays, and abnormalities of vital organs like the heart and kidneys. Although the disease first originated in Japan in the 17th century, Kabuki syndrome finally received its name in 1981 when two scientists noted that the characteristic facial features resemble that of the stage makeup of a traditional Japanese theater known as kabuki.

Considered a rare, orphan disease, Kabuki syndrome occurs in approximately one out of every 32,000 births in Japan. However, the disease is prevalent in numerous populations such as Northern European, Brazilian, Vietnamese, Filipino, East Indian, Arabic, Chinese, Mexican, and African (Cheon et al., 2015). Males and females are affected equally.

Symptoms of Kabuki Syndrome

Kabuki syndrome affects multiple body systems. The symptoms range from mild to severe and not all symptoms are present in someone with the disorder.

Symptoms include:

• Intellectual disability
• Delayed speech 
• Seizures 
• Hypotonia (low muscle tone) 
• Short stature
• Distinctive facial features: widely spaced eyes, high palate or cleft palate, large and low-set ears, flattened nose, misaligned eyes, exaggerated brow arch 
• Skeletal abnormalities: short fingers, lax joints, scoliosis, small skull (microcephaly)  
• Hearing loss
• Misshapen or missing teeth 
• Cardiac defects: coarctation (narrowing of the aorta), ventricular or atrial septal defects (holes in the heart chambers) 
• Kidney problems 
• Immune deficiencies 
• Ptosis (drooping eyelids) 
• Feeding problems 
• Gastrointestinal abnormalities: intestinal malrotation 
• Excessive weight gain post puberty
• Depression and anxiety

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Causes of Kabuki Syndrome

Up to 80 percent of cases of Kabuki syndrome are caused by a mutation in the KMT2D gene. The KMT2D gene is responsible for controlling the production of lysine-specific methyltransferase 2D, an enzyme in organs and tissues throughout the body which modifies a type of protein called histones. Histones shape chromosomes after binding to DNA. When genetic defects interfere with the process of lysine-specific methyltransferase 2D, it impedes normal development.

Rarely, Kabuki syndrome can be the result of a mutation in the KDM6A gene or the causative gene may be unknown.

Inheriting Kabuki Syndrome

Kabuki syndrome follows an autosomal dominant inheritance pattern—meaning an individual must only have one copy of the mutated gene to result in symptoms. There is a 50 percent chance of passing the syndrome on to future generations.

Contrarily, the cases caused by the KDM6A gene are X-linked, which occurs when the mutated gene is on the X-chromosome. Males tend to present more severely than females because they have one X chromosome, while females have two.

Kabuki Syndrome Diagnosis

Being a rare genetic disease, Kabuki syndrome is difficult to diagnose. Although it is congenital, not every patient presents with identical symptoms. An infant with Kabuki syndrome may appear healthy at birth and not experience symptom onset until childhood. That is why many patients are diagnosed too late.

Often, a physician first suspects Kabuki syndrome by the distinctive facial features. After a thorough examination and family history, genetic testing identifies the genetic mutations that cause disease.

Treating Kabuki Syndrome

The treatment for Kabuki syndrome is contingent on the specific symptoms the patient presents with. Upon diagnosis, patients with Kabuki syndrome often have the following tests:

• Echocardiogram (cardiac abnormalities)
• Kidney ultrasound (renal issues) 
• Vision and hearing screening
• Immunoglobulin levels
• X-ray scans 
• Sleep study 
• Neurology evaluation

These tests assist specialists in determining which symptoms require medication or surgical treatment. The most critical treatment entails surgical interventions to correct cardiac and gastrointestinal abnormalities. Surgery can also improve dental and orthopedic symptoms. Physical and occupational therapy teaches patients specific exercises to maintain muscle tone, along with techniques to preserve motor skills and make day-to-day life skills more manageable. Speech therapy reverses significant speech delays.

The Prognosis of Kabuki Syndrome

Those diagnosed with Kabuki syndrome in the 80s when the disease was founded are now at least 40 years of age. If life expectancy is shortened by the disease, it is typically due to cardiac defects or kidney dysfunction. This has proven that many patients with Kabuki syndrome can live well into adulthood. Still, current knowledge prevents experts from knowing the full prognosis.

Probably Genetic spoke at the Kabuki Syndrome Foundation’s 2021 Virtual Research Conference

Lukas Lange, the CEO of Probably Genetic, had the opportunity to speak at the 2021 Virtual  Research Conference hosted by the Kabuki Syndrome Foundation. During the conference he discussed the benefits of increasing access to early diagnostics and the use of telemedicine. With telemedicine comes access to the specialists necessary to diagnose the condition, and the earlier genetic testing is available to patients with Kabuki syndrome, the sooner proper symptom management can be started to improve outcomes. You can find the full program of the conference here.

References

Cheon, C. K., & Ko, J. M. (2015). Kabuki syndrome: clinical and molecular characteristics. Korean journal of pediatrics, 58(9), 317–324. https://doi.org/10.3345/kjp.2015.58.9.317