Kabuki Syndrome

Author: Stefano Bosso
Date: 01/06/2013


Bosso Stefano & Argena Giuseppe


Kabuki syndrome, described by two independent groups of Japanese scientists, is a rare autosomal dominant disorder with an estimated prevalence of 1 in 32 000. KS is characterized by the presence of the distinctive craniofacial anomalies associated with the condition; it is characterized by typical facial features (elongated palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; large, prominent, or cupped ears), minor skeletal anomalies, persistence of fetal fingertip pads, mild to moderate intellectual disability , and postnatal growth deficiency . Other findings may include: congenital heart defects , genitourinary anomalies, cleft lip and/or palate, gastrointestinal anomalies including anal atresia, ptosis and strabismus, and widely spaced teeth and hypodontia. Functional differences can include: increased susceptibility to infections and autoimmune disorders, seizures, endocrinologic abnormalities including isolated premature thelarche in females, feeding problems, and hearing loss.

The Diseases DatabaseURL
OMIM single geneKS
Kegg PathwayMLL2


Initially, the majority of individuals reported with KS were Japanese; the prevalence in Japan is estimated at approximately 1:32,000. White et al ( 2004) calculated a minimum birth incidence of 1:86,000 in Australia and New Zealand. KS has been reported in almost all ethnic groups; its prevalence outside Japan presumably approximates that seen in the Japanese population.

Clinical Signs & Symptom

Hereafter it summarizes findings in more than 350 individuals with Kabuki syndrome:

  • Growth and feeding. ( for ex. postnatal growth retardation 35%-81%).
  • Development and behavior. (intellectual disability, usually in the mild to moderate range)
  • Neurologic.
  • Cardiovascular. ( Approximately 40%-50% of individuals with KS have congenital heart defects. Left-sided obstructive lesions, especially coarctation of the aorta, are common)
  • Endocrine. (premature thelarche in girls)
  • Ophthalmologic. §(blue sclerae, strabismus, ptosis, coloboma, and corneal abnormalities such as Peters anomaly. Optic nerve hypoplasia, cataracts, Duane anomaly, pigmentary retinopathy)
  • Ears and hearing.
  • Craniofacial. (The typical facial features: elongated palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; and large, prominent, or cupped ears)
  • Dental.
  • Gastrointestinal. ( not common)
  • Genitourinary. ( renal and urinary tract anomalies in more than 25%)
  • Musculoskeletal. ( joint hypermobility, variable degrees of scoliosis and kyphosis)
  • Immunologic. ( immune dysfunction mostly in adolescents)

Clinical Diagnosis

Consensus clinical diagnostic criteria for Kabuki syndrome (KS) have not been established. Individuals with this condition have characteristic facial features, in addition to a variety of congenital anomalies, which suggest the diagnosis. Listed below are the five cardinal manifestations:
Typical facial features :
1 Elongated palpebral fissures with eversion of the lateral third of the lower eyelid.
2 Arched and broad eyebrows with the lateral third displaying sparseness or notching.
3 Short columella with depressed nasal tip.
4 Large, prominent, or cupped ears.
Skeletal anomalies :
1 Spinal column abnormalities, including sagittal cleft vertebrae, butterfly vertebrae, narrow intervertebral disc space, and/or scoliosis.
2 Brachydactyly V.
3 Brachymesophalangy.
4 Clinodactyly of fifth digits.
Dermatoglyphic abnormalities : persistence of fetal fingertip pads.
Mild to moderate intellectual disability.
Postnatal growth deficiency.

Structural anomalies in KS can include the following :
1 Congenital heart defects.
2 Genitourinary anomalies, including cryptorchidism in males.
3 Cleft lip and/or palate.
4 Gastrointestinal anomalies, including anal atresia.
5 Ophthalmologic anomalies, including ptosis and strabismus.
6 Dental anomalies, including widely spaced teeth and hypodontia.
7 Ear pits (a potentially helpful diagnostic clue when seen with other typical findings).
Functional differences can include the following:
1 Increased susceptibility to infections and autoimmune disorders.
2 Seizures.
3 Endocrinologic abnormalities, including isolated premature thelarche in females.
4 Feeding problems.
5 Hearing loss.

From Kabuki Syndrome Synonyms: Kabuki Make-Up Syndrome, Niikawa-Kuroki Syndrome.2013

Molecular Genetic Testing

Gene. KMT2D (formerly MLL2) and KDM6A are the only genes in which mutations are known to cause KS.
Evidence for possible locus heterogeneity. No other loci are known to be involved in causing KS. However, for approximately 30% of individuals with a clinical diagnosis of Kabuki syndrome, the genetic cause remains unknown. Therefore locus heterogeneity for one or more as-yet unidentified genes remains a possibility.

Majority of cases of Kabuki syndrome are caused by mutations in mixed lineage leukemia 2 (MLL2; OMIM#602113), also known as either MLL4 or ALR; located on chromosome 5. MLL2 encodes a SET-domain-containing histone methyltransferase important in the epigenetic control of active chromatin states. In a larger validation cohort screened by Sanger sequencing, it found MLL2 mutations in approximately two-thirds of 43 Kabuki cases, suggesting that Kabuki syndrome is genetically heterogeneous. From Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome, 2012

KDM6A (29 exons) is one of the X chromosomal genes that largely escapes X inactivation. It encodes a 1,401 residue protein that contains two functional domains. The catalytic domain is a histone demethylase that specifically catalyzes demethylation of mono-, di-, and trimethylated lysine 27 on histone H3 (H3K27). This demethylation mediates tissue-specific expression of various genes and is mostly involved in developmental processes and the cell cycle. Interestingly, KDM6A and MLL2 act together in the epigenetic control of transcriptionally active chromatin by counteracting Polycomb-group (PcG) proteins. The other functional domain of KDM6A plays a role in chromatin remodeling by interacting with the switch/sucrose nonfermentable (SWI/SNF) remodeling complex that contains the transcription activator Brg1.
From Deletion of KDM6A, a Histone Demethylase Interacting with MLL2, in Three Patients with Kabuki Syndrome,2012


Your Favorite Gene SigmaMLL2KDM6A

Protein Aminoacids Percentage (Width 700 px)


Penetrance for mutations in KMT2D appears to be complete; not enough information is available to make any conclusions regarding penetrance for those with mutations in KDM6A. Variable expressivity may lead to underascertainment of mildly affected individuals.

Genotype-Phenotype Correlations

Comparisons of the clinical features of individuals with clinical diagnoses of Kabuki syndrome in whom a KMT2D mutation has been identified versus those in whom a KMT2D mutation has not been identified have found several differences.

The following ten physical features are present more commonly in those with a KMT2D mutation:
* Arched eyebrows
* Blue sclerae
* Broad nasal root
* Depressed nasal tip
* Large dysplastic ears
* Thin vermilion of the upper lip and thick vermilion of the lower lip
* Short stature
* Joint laxity
* Intellectual disability
* Frequent infections

Those with a KMT2D mutation are more likely to have the distinctive Kabuki facial phenotype, which may reflect the fact that a portion of those without a KMT2D mutation may indeed have been misdiagnosed.
In general, those with a KMT2D mutation are also more likely to have renal anomalies, feeding problems, premature thelarche in females, joint dislocations, and palatal anomalies than are those without a KMT2D mutation.
To date, only six individuals with mutations or deletions in KDM6A have been described, precluding any meaningful genotype - phenotype correlations for those who have KS as a result of mutations in this gene.
From Kabuki Syndrome Synonyms: Kabuki Make-Up Syndrome, Niikawa-Kuroki Syndrome.2013

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