Kabuki syndrome

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Kabuki syndrome
Synonyms Niikawa-Kuroki syndrome
A child with kabuki syndrome displaying the typical facial features
Specialty medical genetics

Kabuki syndrome (also previously known as kabuki makeup syndrome, KMS or Niikawa–Kuroki Syndrome) is an autosomal dominant pediatric congenital disorder of suspected genetic origin[1][2] with multiple congenital anomalies and intellectual disabilities. It is quite rare, affecting roughly one in 32,000 births.[3] It was identified and described in 1981 by two Japanese groups, led by scientists Norio Niikawa and Yoshikazu Kuroki.[4] It is named kabuki syndrome because of the facial resemblance of affected individuals to stage makeup used in kabuki, a Japanese traditional theatrical form.

Signs and symptoms[edit]

There is a wide range of congenital problems associated with kabuki syndrome with large differences between affected individuals. Some of the common problems are heart defects, urinary tract anomalies, hearing loss, hypotonia, recurrent ear infections and postnatal growth deficiency. Other characteristics include skeletal abnormality, joint laxity, short stature, and unusual dermatoglyphic patterns.[5]

In terms of development, mild to moderate intellectual disability is a common feature.[6] Also, children with kabuki syndrome often have distinctive behavioral features. A few have normal intelligence, most of whom have learning difficulties such as struggling with fine motor, speech skills, and memory.

There is no indication that the life expectancy of individuals with kabuki syndrome is shortened. Most medical issues are resolved with medical intervention. The fact that there are relatively few adults known with this syndrome is probably related to its recent discovery in 1980 in Japan and around 1990 in Europe and America.


A young patient displaying the facial phenotype typical of kabuki syndrome

The facial appearance of individuals with this syndrome include long eyelids with turning up of the lateral third of the lower eyelid, a broad and depressed nasal tip, large prominent earlobes, and a cleft or high-arched palate.[7]

Other clinical features often include scoliosis, short fifth finger, persistence of fingerpads, and X-ray abnormalities of the vertebrae, hands, and hip joints.


Kabuki syndrome is an autosomal dominant disorder and can be caused by loss-of-function mutations in two different genes.[8] Hundreds of mutations have been identified in diagnosed kabuki syndrome patients for these genes. Most of these mutations involve a change in amino acid sequence that codes for a premature stop codon, and therefore nonfunctional, short enzymes. KMT2D, formerly known as the MLL2 gene, is located on chromosome 12 and is one of the genes involved in the development of this disorder.[8][9] A mutation in the KMT2D gene results in a loss of function for the protein this gene codes for, which is a lysine (K)-specific methyltransferase 2D enzyme.[10] KDM6A is another gene, that when mutated, can lead to kabuki syndrome.[11] This mutation produces a nonfunctional lysine (K)-specific demethylase 6A. This gene is located on the X chromosome. These two genes belong to a family of genes called chromatin-modifying enzymes. Specifically these genes code for a histone methyltransferase (KMT2D) and a histone demethylase (KDM6A), and play a part in the regulation of gene expression. These enzymes transfer methyl groups on and off histones to regulate genes via epigenetic pathways. Epigenetic activation of certain developmental genes is impaired by loss of either enzyme and developmental abnormalities occur, leading to the characteristics of kabuki syndrome patients. The specific developmental genes have not been fully identified. It is seen that a majority of these cases are due to de novo mutations (those present in the subject but not in the parents).[9] It is important to note that a percentage of patients did not exhibit a mutation in either gene; other causes are currently being researched.


Kabuki syndrome can be diagnosed using whole exome or whole genome sequencing. Some patients who were initially clinically diagnosed with Kabuki syndrome were actually found to have Wiedemann-Steiner syndrome.[12]


The treatments of kabuki syndrome are still being developed due to its genetic nature. The first step to treatment is diagnosis. After diagnosis, the treatment of medical conditions can often be treated by medical intervention. There are also options in psychotherapy for young children with this disorder, as well as the family of the child.[13] Genetic counseling is available as a preventative treatment for kabuki syndrome because it can be inherited and expressed by only having one copy of the mutated gene.[13]


  1. ^ "Kabuki Syndrome Gene Identified". National Institutes of Health (NIH). 2015-05-20. Retrieved 2017-10-26. 
  2. ^ Ng, Sarah B.; Bigham, Abigail W.; Buckingham, Kati J.; Hannibal, Mark C.; McMillin, Margaret J.; Gildersleeve, Heidi I.; Beck, Anita E.; Tabor, Holly K.; Cooper, Gregory M. (September 2010). "Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome". Nature Genetics. 42 (9): 790–793. doi:10.1038/ng.646. ISSN 1061-4036. PMC 2930028Freely accessible. PMID 20711175. 
  3. ^ "Kabuki syndrome". Genetics Home Reference. Retrieved 11 February 2013. 
  4. ^ Yoshikazu Kuroki; Yasuyuki Suzuki; Hiroyuki Chyo; Akira Hata; Ichiro Matsui (October 1981). "A new malformation syndrome of long palpebralfissures, large ears, depressed nasal tip, and skeletal anomalies associated with postnatal dwarfism and mental retardation". The Journal of Pediatrics. 99 (4): 570–573. doi:10.1016/S0022-3476(81)80256-9. PMID 7277097. 
  5. ^ den Biggelaar, AM; Kuijpers-Jagtman, AM; Bergé, SJ; Katsaros, C (December 2006). ""Kabuki-syndroom, een congenitaal syndroom met multipele anomalieën (kabuki syndrome, a congenital syndrome with multiple anomalies)". Nederlands Tijdschrift Voor Tandheelkunde". Ned Tijdschr Tandheelkd. 113 (12): 516–19. PMID 17193989. 
  6. ^ Vaux, KK; Jones, KL; Jones, MC; Schelley, S; Hudgins, L (2005). "Developmental outcome in Kabuki syndrome". Am J Med Genet A. 132: 263–4. 
  7. ^ Suarez Guerrero JL, Ordonez Suarez AA, Contreras Garcia GA (2012). "Kabuki Syndrome". Anales de Pediatría. 77 (1): 51–56. doi:10.1016/j.anpedi.2012.01.016. PMID 22387331. 
  8. ^ a b Cheon, CK; Sohn, YB; Ko, JM; Lee, YJ; Song, JS; Moon, JW; Yang, BK; Ha, IS; Bae, EJ; Jin, HS; Jeong, SY (June 2014). ". Identification of KMT2D and KDM6A mutations by exome sequencing in Korean patients with kabuki syndrome". J Hum Genet. 59 (6): 321–5. doi:10.1038/jhg.2014.25. 
  9. ^ a b Ng, SB; Bigham, AW; Buckingham, KJ; Hannibal, MC; McMillin, MJ; Gildersleeve, HI (2010). "Exome sequencing identifies MLL2 mutations as a cause of kabuki syndrome". Nat Genet. 42 (9): 790–3. doi:10.1038/ng.646. PMC 2930028Freely accessible. PMID 20711175. 
  10. ^ "KMT2D". Genetics Home Reference. 
  11. ^ "Kabuki syndrome". Genetic and Rare Diseases Information Center. National Center for Advancing Translational Sciences. Retrieved 15 March 2018. 
  12. ^ Miyake, N., Tsurusaki, Y., Koshimizu, E., Okamoto, N., Kosho, T., Brown, N.J., Tan, T.Y., Yap, P.J.J., Suzumura, H., Tanaka, T., Nagai, T., Nakashima, M., Saitsu, H., Niikawa, N. and Matsumoto, N. (January 2016). "Delineation of clinical features in Wiedemann–Steiner syndrome caused by KMT2A mutations". Clinical Genetics. 89 (1): 115–119. doi:10.1111/cge.12586. 
  13. ^ a b Adam, MP; Hudgins, L; Hannibal, M. "Kabuki Syndrome". 

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