Kabuki syndrome

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Kabuki syndrome
Synonyms Niikawa-Kuroki syndrome
Child with Kabuki Syndrome 02.jpg
A child with kabuki syndrome displaying the “scrunchy face”
Specialty Medical genetics edit this on wikidata
Symptoms Vary widely among patients but may include: Long eyelashes, depressed nasal tip, atypical fingerprints, ear deformity (macrotia or microtia), hypotonia, joint hyperflexibility, ptosis, blue sclera, cafe au lait spot, GU anomalies (e.g. hypospadias or horseshoe kidney), gi anomalies (e.g. anal atresia or intestinal malformation), hearing loss, immune deficiencies (e.g. hypogammaglobinemia), feeding difficulty (infants), obesity (adulthood), short stature, poor sleep, hyperinsulinemia (hypoglycemia), epilepsy, cardiac defects (e.g. coarctation of the aorta), vertebral anamolies (e.g. butterfly vertebrae), sparse lateral eyelash, finger anomaly (e.g. short 5th finger), cleft palate, dental issues, precocious puberty, scoliosis, hip dysplasia
Usual onset conception
Types type 1 (KMT2D), type 2 (KDM6A); other rare mutations unrecognized for now
Causes loss-of-function mutations in KMT2D or KDM6A genes
Diagnostic method clinical findings; genetic testing
Frequency 1 in 32,000 births

Kabuki syndrome (also previously known as kabuki makeup syndrome, KMS, or Niikawa-Kuroki Syndrome) is a pediatric congenital disorder of genetic origin.[1][2] It affects multiple parts of the body with varying symptoms and severity, although the most common is the characteristic facial appearance.[3] It is quite rare, affecting roughly one in 32,000 births.[4] It was first identified and described in 1981 by two Japanese groups, led by scientists Norio Niikawa and Yoshikazu Kuroki.[5] It is named Kabuki syndrome because of the facial resemblance of affected individuals to stage makeup used in kabuki, a Japanese traditional theatrical form.[4]

Signs and symptoms[edit]

Facial phenotype of en:Kabuki syndrome patient
Child displaying typical facial phenotype of Kabuki syndrome

Specific symptoms for Kabuki syndrome vary, with large differences between affected individuals.[3] Most people with Kabuki syndrome have distinctive facial features that include arched eyebrows, long eyelashes, elongated eyelids with lower lids that turn out, prominent ears, a flat tip of the nose, and a downward slant to the mouth.[3][4]

Child displaying elongated eyelids typical of Kabuki syndrome
Child displaying distinctive facial features of Kabuki syndrome

Other common symptoms are skeletal abnormalities, heart defects, feeding difficulties and a failure to thrive, vision and hearing difficulties, weak muscle tone (hypotonia), small head size (microencephaly), and frequent infections.[3] Mild to moderate intellectual disability and mild to severe developmental delay are often associated with Kabuki syndrome.[3][4][6]


Most cases of Kabuki syndrome are caused by loss-of-function mutations in two different genes: KMT2D and KDM6A.[7] However, about 30% of cases have no mutations that could be identified in either gene where the cause is still unknown.[4]

Genetic Changes[edit]

It is estimated that between 55-80% of cases of Kabuki syndrome are caused by mutations in the KMT2D gene, formerly known as the MLL2 gene.[4] This gene is located on chromosome 12 and is one of the genes involved in the development of this disorder.[4][7] 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.[4]

Another 2-6% of cases are related to mutations in the KDM6A gene.[4] This mutation produces a nonfunctional lysine (K)-specific demethylase 6A. This gene is located on the X chromosome.


Kabuki syndrome can be inherited or caused by a new mutation (called a de novo mutation).[4] Inherited mutations to the KMT2D gene are inherited in an autosomal dominant pattern while those to the KDM6A gene are inherited in an X-linked dominant pattern.[4] The vast majority of mutations occur de novo[3][4] That is, the parents are unaffected and the gene was mutated early in embryological development.

diagram demonstrating autosomal dominant manner
Mutations to the KMT2D gene are inherited in an autosomal dominant manner
Mutations to the KDM6A gene are inherited in an X-linked dominant inheritance pattern


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.[medical citation needed] 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.[medical citation needed]

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.[medical citation needed]


Kabuki syndrome is diagnosed clinically (through identifying symptoms, physical exams, and lab results) or using genetic testing (whole exome or whole genome sequencing).[3]


Due to its rarity, Kabuki Syndrome is not screened for in routine prenatal testing of blood tests, chorionic villus sampling (CVS), or amniocentesis.[medical citation needed] Although not routine for the general population, if Kabuki Syndrome is a specific concern (i.e. expectant mother who has been diagnosed with Kabuki syndrome), it is possible to test for one of the specific mutations.[4] However Kabuki syndome is usually not inherited and therefore most cases do not have a positive family history.[3][4] Kabuki syndrome can have positive screening tests, such as cystic hygroma seen on nuchal translucency ultrasound screening, although these findings are non-specific and have a wide differential diagnosis.[8][9]


There is no specific treatment for Kabuki syndrome.[10] Treatment plans are customized to address the symptoms the individual is experiencing.[10] For example, someone experiencing seizures will be treated with the standard anti-epilepsy therapies.[10]

Additionally, patients with Kabuki syndrome should be evaluated and monitored to address problems that may develop, such as vision or hearing problems, or cognitive difficulties.[10] If congenital heart disease is present, prophylactic antibiotics may be recommended before any procedures such as dental work that might cause infection.[10]


There is no indication that the life expectancy of individuals with Kabuki syndrome is shortened, particularly if cardiac issues and infections are well-managed.[3]


Kabuki syndrome occurs about once in every 32,000 births.[4][11] The disease appears to affect all population groups equally, with no differences based on sex, race, or environment.[12]

Research Directions[edit]


  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. ^ a b c d e f g h i "Kabuki syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2018-04-01. 
  4. ^ a b c d e f g h i j k l m n o "Kabuki syndrome". Genetics Home Reference, U.S. National Library of Medicine. Retrieved 15 April 2018. 
  5. ^ 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. 
  6. ^ Vaux KK, Jones KL, Jones MC, Schelley S, Hudgins L (January 2005). "Developmental outcome in Kabuki syndrome". Am. J. Med. Genet. A. 132A (3): 263–264. doi:10.1002/ajmg.a.30338. PMID 15523636. 
  7. ^ 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. 
  8. ^ Long, Ashleigh; Sinkovskaya, Elena S.; Edmondson, Andrew C.; Zackai, Elaine; Schrier Vergano, Samantha A. (December 2016). "Kabuki syndrome as a cause of non-immune fetal hydrops/ascites". American Journal of Medical Genetics. Part A. 170 (12): 3333–3337. doi:10.1002/ajmg.a.37956. ISSN 1552-4833. PMID 27568880. 
  9. ^ Lajeunesse, C.; Stadler, A.; Trombert, B.; Varlet, M. N.; Patural, H.; Prieur, F.; Chêne, G. (June 2014). "[First-trimester cystic hygroma: prenatal diagnosis and fetal outcome]". Journal De Gynecologie, Obstetrique Et Biologie De La Reproduction. 43 (6): 455–462. doi:10.1016/j.jgyn.2013.04.005. ISSN 1773-0430. PMID 23747217. 
  10. ^ a b c d e Adam, Margaret P.; Hudgins, Louanne; Hannibal, Mark (1993). Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E.; Bean, Lora JH; Stephens, Karen; Amemiya, Anne, eds. GeneReviews®. Seattle (WA): University of Washington, Seattle. PMID 21882399. 
  11. ^ Niikawa, N.; Matsuura, N.; Fukushima, Y.; Ohsawa, T.; Kajii, T. (October 1981). "Kabuki make-up syndrome: a syndrome of mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency". The Journal of Pediatrics. 99 (4): 565–569. ISSN 0022-3476. PMID 7277096. 
  12. ^ "Kabuki Syndrome - NORD (National Organization for Rare Disorders)". NORD (National Organization for Rare Disorders). Retrieved 2018-04-20. 

External links[edit]

V · T · D
External resources

  • All Things Kabuki 501c3 dedicated to raise awareness, incite research, and support individuals and families affected by Kabuki Syndrome.
  • Kabuki Syndrome Network a 501c3 run by volunteer parents of children with Kabuki syndrome. Its goals are to support both families and professionals.