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Kabuki Syndrome

What Is It, Causes, Signs, Symptoms, and More

Author:Lahav Constantini

Editors:Alyssa Haag,Józia McGowan, DO,Kelsey LaFayette, DNP, ARNP, FNP-C

Illustrator:Jessica Reynolds, MS

Copyeditor:Stacy Johnson, LMSW


What is Kabuki syndrome?

Kabuki syndrome is a rare genetic syndrome characterized by multiple manifestations affecting several organ systems. Genetic mutations mainly cause it, but in some cases of Kabuki syndrome, the cause remains unknown. Some signs and symptoms of Kabuki syndrome may appear at birth. However, some may only appear later in life. Affected individuals are often referred to specialists to receive specific treatments through a multidisciplinary team. 

Of note, the syndrome's name is based on a form of Japanese theater called ‘kabuki.’ The condition used to be called “Kabuki-makeup syndrome” due to the similarities between the actors' makeup and the affected individuals’ facial features.

Affected child with arched, broad eyebrows; long palpebral fissures; and long eyelashes.

What causes Kabuki syndrome?

A spontaneous mutation in either the KMT2D gene or the KDM6A gene causes most cases of Kabuki syndrome. Most people with Kabuki syndrome have variants of the KMT2D gene (previously known as MLL2), which can occur as de novo mutations and are inherited in an autosomal dominant pattern.

A smaller percentage of affected individuals have pathogenic variants of the KDM6A gene located on the X chromosome. Due to this X-linked dominant inheritance pattern, the syndrome affects males who inherit the mutated gene, as well as females, who are heterozygous, who may also manifest features of the syndrome. 

Both genes activate chromatin, a material that makes up chromosomes. They have a more significant role in epigenetics (i.e., gene expression regulation without altering the genetic sequence).

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What are the signs and symptoms of Kabuki syndrome?

Kabuki syndrome can include various signs and symptoms involving several organ systems. While these manifestations vary from one individual to another, the hallmark characteristics are skeletal abnormalities and distinctive facial features; growth deficiencies; hearing loss; intellectual disability; and behavioral and emotional problems. Other features can include gastrointestinal or genitourinary anomalies, cleft palate or cleft lip, and hypodontia (i.e., one to six missing teeth).

The dysmorphic features of people with Kabuki syndrome commonly include bone abnormalities such as scoliosis, abnormal vertebral shape, and short fingers, particularly the fifth finger; persistent fingertip pads (i.e., the prominent soft tissue at the ventral tips of the fingers); and distinctive facial features, such as arched and broad eyebrows with sparseness in the lateral parts, excessively long palpebral fissures (i.e., the elliptic space between the two canthi in an open eye); eversion of the lateral third of the lower eyelid; ptosis; long eyelashes; depressed nasal tips; and ears that are excessively large, prominent, or cupped. 

Growth deficiencies typically include a growth delay and short stature, which may be due to abnormally low growth hormone levels. 

Hearing loss is likely attributed to repeated ear infections during childhood and other contributing factors, such as the cleft palate and abnormal development of the eustachian tube

Children with Kabuki syndrome are often born with congenital heart disease; hypotonia in infancy, which can lead to difficulties in feeding and motor development; seizures; and mild to moderate intellectual disabilities.

In addition, people with Kabuki syndrome may have an increased susceptibility to infections, a higher risk of autoimmune disorders, and endocrine abnormalities, such as hyperinsulinemia leading to hypoglycemia that could lead to seizures and brain damage, and is thus routinely monitored in the first days of life; or hypermethioninemia, which refers to high levels of the amino acid methionine in the blood.

How is Kabuki syndrome diagnosed?

Diagnosis of Kabuki syndrome can be made through genetic testing or based on the presence of specific clinical features. Genetic testing mainly consists of single-gene testing (i.e., sequencing of the KMT2D gene, and if negative, the KDM6A gene) or a multigene panel that includes several genes of interest, which may also help with the differential diagnosis. 

To establish a diagnosis based on clinical features, the individual must have a history of hypotonia in infancy, a developmental delay, an intellectual disability, and typical dysmorphic features and pathogenic or likely-pathogenic variants of the KMT2D gene or KDM6A gene. 

Typical dysmorphic features are confirmed when palpebral fissures are long and there is an eversion of the lateral third of the eyelid, together with two or more additional representative features, including arched and broad eyebrows with notching or sparseness in the lateral third; short columella (bottom part of the nasal septum separating the nostrils) with depressed nasal tip; large, prominent, or cupped ears; and persistent fingertip pads. 

Following diagnosis, providers may also do specific tests to evaluate the extent of affected systems, such as a developmental assessment to assess speech, language, cognition, and vocational skills; or an echocardiogram to evaluate for heart defects. 

How is Kabuki syndrome treated?

Since Kabuki syndrome involves various organ systems, individuals are consistently monitored and managed by a multidisciplinary team tailored to the affected individual according to their specific signs and symptoms. For example, children with Kabuki syndrome and gastroesophageal reflux disease may be given thickened feedings (i.e., breast milk or formula made thicker to reduce reflux) or be positioned differently after meals. In more complex cases, a gastrostomy tube may be placed. If short stature is present, growth hormone therapy may be considered by an endocrinologist. In cases of recurrent infections, referral to an immunologist and consideration of treatment with intravenous immunoglobulin therapy or prophylactic antibiotic therapy in some instances (e.g., before medical procedures) may be warranted. Psychoeducational evaluations and specialized educational services may be conducted when cognitive difficulties occur. Similarly, other specific manifestations experienced by each individual are managed by their corresponding specialist so that a team of experts in various fields ultimately collaborates to maximize the quality of life.

Families of infants with Kabuki syndrome are recommended to begin early interventions, preferably in designated programs, to undergo specialized physical, occupational, speech, and feeding therapy according to the child’s needs. Early intervention aims to reduce the risk of complications and maximize the physical and psychomotor developmental potential. 

What are the most important facts to know about Kabuki syndrome?

Kabuki syndrome is a rare genetic syndrome that can cause various symptoms affecting various organ systems. The cause is generally related to pathogenic variations in one of two genes, KMT2D and KDM6A. Diagnosis is based on genetic testing and diagnostic criteria. Management is typically aimed toward individual needs and symptoms and requires multispeciality team care.

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Related links

Inheritance patterns
Growth hormone deficiency
Neurodevelopmental disorders: Clinical (2018 edition)

Resources for research and reference

Adam MP, Hudgins L, Hannibal M. Kabuki Syndrome. 2011 Sep 1 [Updated 2022 Sep 15]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK62111/ 

Adam, M. P., Banka, S., Bjornsson, H. T., Bodamer, O., Chudley, A. E., Harris, J., Kawame, H., Lanpher, B. C., Lindsley, A. W., Merla, G., Miyake, N., Okamoto, N., Stumpel, C. T., Niikawa, N., & Kabuki Syndrome Medical Advisory Board (2019). Kabuki syndrome: international consensus diagnostic criteria. Journal of medical genetics, 56(2), 89–95. https://doi.org/10.1136/jmedgenet-2018-105625

Boniel, S., Szymańska, K., Śmigiel, R., & Szczałuba, K. (2021). Kabuki Syndrome-Clinical Review with Molecular Aspects. Genes, 12(4), 468. https://doi.org/10.3390/genes12040468

Kliegman, R. M., & Nelson, W. E. (2020). Nelson Textbook of Pediatrics. Elsevier. 

McIntire, S. C., Nowalk, A. J., & Zitelli, B. J. (2012). Zitelli and Davis' Atlas of Pediatric physical diagnosis. Elsevier Saunders. 

Wang, Y. R., Xu, N. X., Wang, J., & Wang, X. M. (2019). Kabuki syndrome: review of the clinical features, diagnosis, and epigenetic mechanisms. World journal of pediatrics : WJP, 15(6), 528–535. https://doi.org/10.1007/s12519-019-00309-4