Kabuki syndrome

Other Names: NKS; Niikawa-Kuroki syndrome; KMS; Kabuki make up syndrome

Kabuki syndrome is a disorder that affects many parts of the body. It is characterized by distinctive facial features including arched eyebrows; long eyelashes; long openings of the eyelids (long palpebral fissures) with the lower lids turned out (everted) at the outside edges; a flat, broadened tip of the nose; and large protruding earlobes.

The name of this disorder comes from the resemblance of its characteristic facial appearance to stage makeup used in traditional Japanese Kabuki theater.

File:13 year old with Kabuki Syndrome.jpg

File:Child with Kabuki Syndrome 08.jpg

Epidemiology

Kabuki syndrome occurs in approximately 1 in 32,000 newborns.

Cause

Kabuki syndrome is caused by mutations in the KMT2D gene (also known as MLL2) or the KDM6A gene.

Between 55 and 80 percent of cases of Kabuki syndrome are caused by mutations in the KMT2D gene. This gene provides instructions for making an enzyme called lysine-specific methyltransferase 2D that is found in many organs and tissues of the body. Lysine-specific methyltransferase 2D functions as a histone methyltransferase. Histone methyltransferases are enzymes that modify proteins called histones. Histones are structural proteins that attach (bind) to DNA and give [[chromosome[[s their shape. By adding a molecule called a methyl group to histones (a process called methylation), histone methyltransferases control (regulate) the activity of certain genes. Lysine-specific methyltransferase 2D appears to activate certain genes that are important for development.

Between 2 and 6 percent of cases of Kabuki syndrome are caused by mutations in the KDM6A gene. This gene provides instructions for making an enzyme called lysine-specific demethylase 6A. This enzyme is a histone demethylase, which means that it helps to remove methyl groups from certain histones. Like lysine-specific methyltransferase 2D, lysine-specific demethylase 6A regulates the activity of certain genes, and research suggests that the two enzymes work together to control certain developmental processes.

The KMT2D and KDM6A gene mutations associated with Kabuki syndrome lead to the absence of the corresponding functional enzyme. A lack of the enzymes produced from these genes disrupts normal histone methylation and impairs proper activation of certain genes in many of the body's organs and tissues, resulting in the abnormalities of development and function characteristic of Kabuki syndrome.

Some people with Kabuki syndrome have no identified KMT2D or KDM6A gene mutation. The cause of the disorder in these individuals is unknown.

Inheritance

When Kabuki syndrome is caused by mutations in the KMT2D gene, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

When Kabuki syndrome is caused by mutations in the KDM6A gene, it is inherited in an X-linked dominant pattern. The KDM6A gene is located on the X chromosome, which is one of the two sex chromosomes. In females (who have two X chromosomes), a mutation in one of the two copies of the gene in each cell is sufficient to cause the disorder. In males (who have only one X chromosome), a mutation in the only copy of the gene in each cell causes the disorder. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Most cases of Kabuki syndrome result from a new mutation in one of these genes and occur in people with no history of the disorder in their family. In a few cases, an affected person is believed to have inherited the mutation from one affected parent.

Signs and symptoms

People with Kabuki syndrome have mild to severe developmental delay and intellectual disability. Affected individuals may also have seizures, an unusually small head size (microcephaly), or weak muscle tone (hypotonia). Some have eye problems such as rapid, involuntary eye movements (nystagmus) or eyes that do not look in the same direction (strabismus).

Other characteristic features of Kabuki syndrome include short stature and skeletal abnormalities such as abnormal side-to-side curvature of the spine (scoliosis), short fifth (pinky) fingers, or problems with the hip and knee joints. The roof of the mouth may have an abnormal opening (cleft palate) or be high and arched, and dental problems are common in affected individuals. People with Kabuki syndrome may also have fingerprints with unusual features and fleshy pads at the tips of the fingers. These prominent finger pads are called fetal finger pads because they normally occur in human fetuses; in most people they disappear before birth.

A wide variety of other health problems occur in some people with Kabuki syndrome. Among the most commonly reported are heart abnormalities, frequent ear infections (otitis media), hearing loss, and early puberty.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormal dermatoglyphics(Abnormal fingerprints)
• Butterfly vertebrae
• Eversion of lateral third of lower eyelids
• Hemivertebrae(Missing part of vertebrae)
• Highly arched eyebrow(Arched eyebrows)
• Long eyelashes(Increased length of eyelashes)
• Macrotia(Large ears)
• Protruding ear(Prominent ear)
• Short 5th finger(Short fifth finger)
• Short columella
• Short middle phalanx of finger(Short middle bone of finger)
• Sparse lateral eyebrow(Limited hair on end of eyebrow)

30%-79% of people have these symptoms

• Abnormal cardiac septum morphology
• Cerebral cortical atrophy(Decrease in size of the outer layer of the brain due to loss of brain cells)
• Cleft palate(Cleft roof of mouth)
• Coarctation of aorta(Narrowing of aorta)
• Conductive hearing impairment(Conductive deafness)
• Failure to thrive(Faltering weight)
• Feeding difficulties(Feeding problems)
• High palate(Elevated palate)
• Hydrocephalus(Too much cerebrospinal fluid in the brain)
• Hypodontia(Failure of development of between one and six teeth)
• Joint hyperflexibility(Joints move beyond expected range of motion)
• Microcephaly(Abnormally small skull)
• Microdontia(Decreased width of tooth)
• Ptosis(Drooping upper eyelid)
• Recurrent infections(Frequent infections)
• Scoliosis
• Sensorineural hearing impairment
• Short stature(Decreased body height)
• Ventriculomegaly
• Widely spaced teeth(Wide-spaced teeth)

Diagnosis

The diagnosis of KS is established in a proband of any age with a history of infantile hypotonia, developmental delay, and/or intellectual disability AND one or both of the following :

• Typical dysmorphic features at some point of life
• A heterozygous pathogenic variant in KMT2D or a heterozygous or hemizygous pathogenic variant in KDM6A.

Typical dysmorphic features include long palpebral fissures (a palpebral fissure measurement ≥2 SD above the mean for age) with eversion of the lateral third of the lower eyelid AND two or more of the following:

• Arched and broad eyebrows with the lateral third displaying notching or sparseness
• Short columella with depressed nasal tip
• Large, prominent, or cupped ears
• Persistent fingertip pads

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, concurrent or serial single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.

Treatment

Thickened feedings and positioning after meals to treat gastroesophageal reflux; gastrostomy tube placement if feeding difficulties are severe. If cognitive difficulties are evident, psychoeducational testing and special education services to address the individual child's needs. Evaluation by a developmental pediatrician or psychiatrist if behavior suggests autism spectrum disorders. Standard antiepileptic treatment for seizures.

Prevention of secondary complications: Prophylactic antibiotic treatment prior to and during any procedure (e.g., dental work) may be indicated for those with specific heart defects.

Prognosis

Information about the long-term outlook (prognosis) for people with Kabuki syndrome is limited. It is thought that the prognosis for living into adulthood is good, particularly if congenital anomalies (such as congenital heart defects), and infections, are properly managed in childhood.Life expectancy is somewhat dependent on cardiac (heart) and immunologic complications.

NIH genetic and rare disease info

• NIH info on Kabuki syndrome

Kabuki syndrome is a rare disease.

Kabuki syndrome Resources
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