What is Kabuki syndrome

Kabuki syndrome is a rare congenital (present from birth) multisystem disorder that affects multiple parts of the body. Specific symptoms and severity can vary. Kabuki syndrome features often include 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; skeletal abnormalities; growth delays; short stature; heart defects; and varying degrees of intellectual disability ¹⁾. Other signs and symptoms may include seizures, small head size (microcephaly), weak muscle tone (hypotonia), eye problems such as rapid, involuntary eye movements (nystagmus) or eyes that do not look in the same direction (strabismus), cleft palate, and roof of the mouth may be high and arched, and dental problems are common in affected individuals ²⁾. 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. 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 variety of other health problems may also occur. Among the most commonly reported are heart abnormalities, frequent ear infections (otitis media), hearing loss, and early puberty.

Kabuki syndrome is most often caused by a mutation in the KMT2D gene, and inherited in an autosomal dominant manner. Some Kabuki syndrome cases are due to a mutation in the KDM6A gene and are inherited in an X-linked dominant manner  ³⁾. Clinical genetic testing is available for both genes. Kabuki syndrome occurs in approximately 1 in 32,000 newborns. More than 300 affected individuals have been reported in the medical literature. Although Kabuki syndrome was first reported in Japan, Kabuki syndrome has since been reported in a wide variety of different ethnic groups.

Kabuki syndrome was first reported in the medical literature in 1981 by Japanese physicians. The disorder was originally called Kabuki-makeup syndrome because the facial features of many affected children resembled the makeup used by actors in kabuki, a form of Japanese theater. The term “makeup” has since been dropped and the preferred term for the disorder is Kabuki syndrome.

Kabuki syndrome treatment is focused on the specific signs and symptoms in each affected person ⁴⁾.

Can people with Kabuki syndrome have children?

Reports of Kabuki syndrome being passed down to children from both males and females imply that in at least some cases, fertility may not be affected ⁵⁾. There have been parents of people with a diagnosis of Kabuki syndrome who have had some features compatible with mild Kabuki syndrome. However, because of the range of intellectual disability present (resulting in reduced possibilities to raise a family), it is not always clear whether fertility is impaired ⁶⁾. It is known that some affected people have endocrine abnormalities which may affect fertility and reproduction ⁷⁾.

People with questions about fertility and pregnancy are encouraged to speak with their health care provider or endocrinologist. A consultation with a genetics professional is also recommended for detailed information about how Kabuki syndrome may be inherited.

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.

What will a child with Kabuki syndrome future look like?

While the effects of Kabuki syndrome vary from individual to individual, many children and adults share similar underlying diagnoses. The impact of each diagnosis varies from person to person, as does their future.

Can an individual with Kabuki syndrome live independently as an adult?

The physical and cognitive effects of Kabuki syndrome affect individuals differently. Some higher functioning adults have gone on to marry and have children.

If I have more children, will they have Kabuki syndrome too?

If the mutation is de novo (new mutation -the parents are not carriers of either KMT2D and KDM6A gene mutations) there is a 1% chance. If either parent is a carrier of KMT2D and KDM6A gene mutations, or has Kabuki syndrome, there is a 50% chance.

Do all children with Kabuki syndrome experience developmental delays?

Most, but not all! Many parents report delays in feeding (eating by mouth vs feeding tube), sitting up, crawling, walking, and talking.

Is Kabuki syndrome contagious?

No! Kabuki syndrome is a genetic disorder, it cannot be spread to others.

Is Kabuki syndrome a progressive disorder?

Kabuki Syndrome is not considered a progressive disorder, however new complications may present over time.

Can a child outgrow Kabuki syndrome?

No. Kabuki Syndrome is a genetic disorder. Early intervention and treatment may lessen complications associated with Kabuki, but it is a lifelong disorder.

Is Kabuki syndrome a fatal disorder?

Kabuki Syndrome does not shorten an individuals life span, however underlying conditions may.

Can children with Kabuki syndrome play sports?

Possibly.! Because Kabuki Syndrome affects each individual differently, it depends on the child. Some children with complex medical needs are not physically able to play sports, while others have successfully kept up with their peers in a variety of sports.

Do all children with Kabuki syndrome require therapeutic intervention?

While Kabuki syndrome affects each individual differently, early intervention has proven to play a vital role in developmental progress for many. Therapy services may include: Occupational, Speech, Physical, Vision and Feeding.

Can children with Kabuki syndrome attend regular classes in school?

Absolutely. Cognitive delays vary with each child so it is important that an IEP (Individualized Education Plan) or 504 Plan be established ahead of time. These plans ensure that a child has the appropriate accommodations in place, to allow them the best possible educational experience. Children with Kabuki syndrome can attend mainstream classes, special education classes or a combination of both. Additionally, some individuals may require one-on-one aides, while others may not.

Kabuki syndrome causes

There are currently two genes identified as the cause for Kabuki syndrome. Mutations on KMT2D, formerly known as MLL2, are believed to affect as many as 75% of those diagnosed. Mutations on KDM6A gene are less common and present in approximately 5% of cases.

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 chromosomes 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.

Kabuki syndrome inheritance pattern

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.

If a father has the mutated X-linked gene:

• all of his daughters will inherit the mutated gene (they will all receive his X chromosome)
• none of his sons will inherit the mutated gene (they only inherit his Y chromosome)

If a mother has the mutated X-linked gene, each of her children (both male and female) has a 50% chance to inherit the mutated gene.

Most cases of Kabuki syndrome are not inherited from a parent and result from a new mutation in one of these genes (in people with no family history of Kabuki syndrome). In a few cases an affected person is believed to have inherited the mutation from an affected parent. In either case, a person with a disease-causing mutation may still pass it on to his/her offspring.

Kabuki syndrome symptoms

Kabuki syndrome is present from birth (congenital). People with Kabuki syndrome have similar, characteristic facial features. These include arched eyebrows; wide eyes that often slant upwards; long and thick eyelashes; a blue tint to the whites of the eyes (blue sclerae); prominent ears; downward slanting corners of the mouth; and a depressed tip of the nose. People with Kabuki syndrome may also have cleft lip; a highly arched or cleft palate; and widely spaced, irregular teeth ⁸⁾.

Most people with Kabuki syndrome have mild to moderate intellectual disability, although this varies considerably. Severe intellectual disability is extremely rare and some children have no intellectual disability. Early speech and language delay is common and some language-related difficulties usually persist ⁹⁾. Palate abnormalities and hearing loss may contribute to speech delays.

Other medical problems may also be present. Congenital heart defects are common. The two most commonly reported heart defects in children with Kabuki syndrome include narrowing of the main artery of the body (coarctation of the aorta) and holes in the membranes (septa) that separate the chambers of the heart (ventricular or atrial septal defects).

Some children may have seizures, diminished muscle tone (hypotonia) and small head size (microcephaly) and seizures. Seizures can develop right after birth (neonatal period) or as late as 12 years of age. Vision and hearing problems may also be present. Some affected children are more susceptible to infections, particularly ear infections ¹⁰⁾.

Growth deficiency is common in individuals with Kabuki syndrome usually becoming apparent during the first year of life (postnatal growth deficiency). Growth deficiency can become more noticeable as affected children grow older. Eventually, affected individuals may be notably below average height for their age (short stature). In rare cases, some children may have had partial growth hormone deficiency.

Children with Kabuki syndrome may also have feeding difficulties including gastroesphogeal reflux, poor sucking ability, and difficulty absorbing or digesting nutrients from food (malabsorption). Consequently, many affected children may fail to gain weight and grow at the rate expected for children of their age and sex (failure to thrive). Some children may be susceptible to recurring infections including upper respiratory infections and pneumonia. Many children have recurrent ear infections (otitis media) which may contribute to hearing loss.

Dental abnormalities such as missing, misaligned or misshaped teeth have been reported. Small and/or thin fingernails and toenails are sometimes seen. In addition, some children will have prominences involving the finger tips, known as persistent fetal finger pads.

Skeletal abnormalities may occur in some patients including abnormally short fingers and toes (brachydactyly), pinkies that are bent (clinodactyly), flat feet, loose (lax) joints, abnormalities of the vertebrae, cranial malformations, and abnormal curvature of the spine (scoliosis or kyphosis). Affected individuals may also be prone to dislocating their hips or kneecaps.

In some patients, additional features involving a variety of organ systems may also be present. Possible kidney (renal) abnormalities include malformation or underdevelopment of the kidneys (renal dysplasia or hypoplasia), obstruction of the normal flow of urine from the kidneys (hydronephrosis) and fusion of the kidneys at the base forming a horseshoe shape (horseshoe kidneys). Gastrointestinal abnormalities include malrotation of the colon and absence or blockage of the anal opening (anal atresia). Immunological deficiencies have also been reported. Affected females may also experience early onset of breast development (premature thelarche), while some males may have undescended testicles (cryptorchidism). Some individuals experience rapid weight gain upon puberty.

Kabuki syndrome behavioral issues

Some children with Kabuki syndrome may develop behavioral abnormalities including anxiousness and a tendency to fixate on objects or activities. They may also dislike certain stimuli including certain noises, smells or textures. Some children with Kabuki syndrome appear to be particularly fond of music.

Many individuals with Kabuki syndrome have sensory processing disorder. This inability to accurately organize sensory information can lead to behavior problems. Some of the more commonly reported sensory issues include need for oral stimulation – including chewing on non-food items, tactile defensiveness towards various sensations and stimuli, panic-like reactions to certain noises, and aversion to textures and/or smells of select foods. Anxiety, obsessive/compulsive traits and autistic-type behaviors are commonly observed. Individuals with Kabuki syndrome often have an obsessive need for routine. Mild depression has been reported in young adults. Parents frequently report an excellent memory for face recognition, song lyrics, dates of events, etc.

Kabuki syndrome diagnosis

Clinical diagnostic criteria for Kabuki syndrome have not been established. Diagnosis relies on the clinical observation of 5 cardinal findings which are 1) cranio-facial features, 2) postnatal growth retardation, 3) skeletal anomalies, 4) persistence of fetal fingertips and 5) intellectual deficiency. Molecular analysis may confirm the clinical diagnosis.

Clinical genetic testing for Kabuki syndrome is available. Sequence analysis followed by deletion/duplication analysis of KMT2D is typically performed first, as a majority of individuals with Kabuki syndrome will have a mutation in this gene. In individuals who are not found to have a mutation in KMT2D, sequence analysis followed by deletion/duplication analysis of KDM6A can be performed next. For those families in which X-linked inheritance is suspected, genetic testing for a mutation in KDM6A may be considered first.

Approximately 30% of individuals with Kabuki syndrome will not be found to have a mutation in either KMT2D or KDM6A. Therefore, a clinical diagnosis can be made based upon identification of characteristic findings, a detailed patient history, and a thorough clinical evaluation. Physicians look for four of the five characteristic findings – distinctive facial features; skeletal abnormalities; intellectual disability; dermatoglyphic abnormalities such as persistent fetal finger pads; and postnatal short stature. Blood tests and chromosomal studies may be used to rule out other disorders.

Kabuki syndrome treatment

There is no specific treatment for Kabuki syndrome. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, dental specialists, speech pathologists, specialists who asses and treat hearing problems (audiologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.

Early intervention is important to ensure that children with Kabuki syndrome reach their potential. Special services that may be beneficial to affected children include special remedial education, physical and occupational therapy, and speech therapy. Sensory integration therapy, in which certain sensory activities are undertaken in order to help regulate a child’s response to sensory stimuli, may be used in some cases.

Some children with Kabuki syndrome who experience severe feeding difficulties may eventually require the placement of a gastronomy tube. In rare cases of partial growth hormone deficiency, affected children may respond to treatment with supplemental growth hormone.

Specific symptoms potentially associated with Kabuki syndrome may require referral to an appropriate specialist. For example, cardiac defects may require a pediatric cardiologist. Various abnormalities associated with Kabuki syndrome may be treated by conventional methods as recommended by a specialist. For example, hearing loss can be treated by surgery or hearing aids. Additional complications such as hip dislocation, scoliosis, cardiac defects, and cleft palate may also be treated surgically. Genetic counseling may be of benefit for affected individuals and their families.

Kabuki syndrome 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 ¹¹⁾.

Kabuki syndrome life expectancy

Kabuki syndrome does not shorten ones life span, however underlying conditions may.  Kabuki syndrome life expectancy is somewhat dependent on cardiac (heart) and immunologic complications ¹²⁾.