August 28, 2019
Years published: 1992, 2000, 2010. 2016, 2019
NORD gratefully acknowledges Margaret Adam, MD, FAAP, FACMG, Professor of Pediatrics, Division of Genetic Medicine, University of Washington School of Medicine and Seattle Children’s Hospital for assistance in the preparation of this report.
Kabuki syndrome is a rare, multisystem disorder characterized by multiple abnormalities including distinctive facial features, growth delays, varying degrees of intellectual disability, skeletal abnormalities, and short stature. A wide variety of additional symptoms affecting multiple different organ systems can potentially occur. The specific symptoms associated with Kabuki syndrome can vary greatly from one person to another. To date, changes (mutation) in one of two genes leads to Kabuki syndrome. The first gene is KMT2D (formerly MLL2) and the second gene, which accounts for fewer cases of Kabuki syndrome, is KDM6A. Clinical genetic testing is available for both genes.
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.
Some features of Kabuki syndrome are present at birth (congenital). Other features become apparent as an affected child ages. The specific findings and the severity of those findings can vary from one person to another. A wide variety of findings affecting multiple organ systems of the body can potentially occur. It is important to note that affected individuals may not have all of the features discussed below. Parents of an affected child should talk to their physician and medical team about their child’s specific case, associated features and overall prognosis.
Children with Kabuki syndrome have a distinctive facial appearance, which includes abnormally long openings between the eyelids (palpebral fissures), lower eyelids that are turned outward (everted), prominent eyelashes, arched eyebrows, a broad nose with a flattened or depressed tip, and large, misshaped ears. The distinctive facial appearance associated with Kabuki syndrome develops slowly over several years. Additional facial features include a bluish tinge to the whites of the eyes (blue sclerae), drooping of the upper eyelid (ptosis), misaligned eyes (strabismus), a highly arched roof of the mouth or a cleft palate, depressions involving the inside of the lower lips (lip pits), and an abnormally small jaw (micrognathia).
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.
In addition to growth deficiency, children with Kabuki syndrome may also have mild to moderate intellectual disability. Severe intellectual disability is extremely rare and some children have no intellectual disability. Some children may have seizures, diminished muscle tone (hypotonia) and microcephaly, a condition in which the circumference of the head is abnormally small. Seizures can develop right after birth (neonatal period) or as late as 12 years of age. One rare cause of seizures occurring right after birth is very low blood sugar due to too much insulin (hyperinsulinism). This requires immediate treatment to avoid damage to the brain. All neonates with a known or suspected diagnosis of Kabuki syndrome should undergo routine blood sugar monitoring for the first few days of life.
Some children with Kabuki syndrome experience speech delays. Palate abnormalities and hearing loss may contribute to speech delays. 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. A learning environment that stresses audio-verbal learning over visual learning may be helpful.
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). However, as children enter adolescents, they have a tendency to gain too much weight, which can make other health problems (such as joint dislocations) worse. 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.
Some children with Kabuki syndrome may have certain heart abnormalities that are present from birth (congenital heart defects). 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).
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 and/or a higher chance of developing autoimmune disorders have also been reported. Affected females may also experience early onset of breast development (premature thelarche), while some males may have undescended testicles (cryptorchidism).
In August of 2010, a group of researchers at the University of Washington reported that mutations in the gene KMT2D (formerly MLL2) were responsible for Kabuki syndrome in the majority of affected individuals who were tested. In 2012, a group of researchers from Belgium identified a second gene, termed KDM6A, that causes Kabuki syndrome. Most cases of Kabuki syndrome, particularly those caused by mutation of KMT2D, occur for the first time in the affected individual with no family history of the disorder (de novo). However, familial occurrence of Kabuki syndrome has been reported.
The University of Washington researchers confirmed that Kabuki syndrome caused by a dominant mutation in the KMT2D gene can then be passed on to the offspring of an affected individual. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual (de novo). The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females. Variable expressivity means that the disorder expresses itself in dramatically different ways from one person to another. Most cases of Kabuki syndrome represent new, spontaneous gene mutations that occur with no previous family history.
The gene KDM6A is located on the X chromosome and is subject to X-linked inheritance. Women typically have two X chromosomes and men typically have one X and one Y chromosome. Women who have a mutation in KDM6A on one X chromosome generally have milder features of Kabuki syndrome compared to males who have a mutation in this gene, although exceptions exist. It is also possible for a woman with a mutation in KDM6A to have no symptoms of Kabuki syndrome. Most cases of Kabuki syndrome caused by mutation in KDM6A are the result of a new mutation. However, it is possible for a woman with a mutation in KDM6A to pass on the condition to her children, even if she herself has mild or no symptoms of Kabuki syndrome. For a woman with a KDM6A mutation, the risk of passing the abnormal gene to her offspring is 50 percent for each pregnancy. The risk is the same for males and females, however, female children may have milder or no symptoms of the condition. An affected male will pass on the abnormal gene to all of his daughters but none of his sons.
KMT2D and KDM6A appear to work together to regulate gene expression. However, more research is necessary to determine how mutations in these two genes result in the development of the disorder and its associated symptoms.
Kabuki syndrome affects males and females in equal numbers. The incidence of Kabuki syndrome is unknown, but has been estimated to be somewhere between 1 in 32,000-86,000 individuals in the general population. More than 400 affected individuals who have genetically proven Kabuki syndrome have been reported in the medical literature. Although the disorder was first reported in Japan, Kabuki syndrome has since been reported in a wide variety of different ethnic groups.
International consensus diagnostic criteria for Kabuki syndrome have been published, which allow for a diagnosis to be made when a person has either a positive genetic testing result or a combination of certain clinical features.
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 20% 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 distinctive facial features, persistent fingertip pads, low tone, developmental delay, and intellectual disability. Blood tests and chromosomal studies may be used to rule out other disorders.
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, endocrinologists, 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.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact:
Contact for additional information about Kabuki syndrome:
Margaret Adam, MD
4800 Sand Point Way NE
PO Box 5371/OC.9.850
Seattle, WA 98105
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder (e.g., heart disease, intellectual disability, etc.)
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