What is Kabuki Syndrome?

Kabuki syndrome (KS), also known as Kabuki make-up syndrome and Niikawa-Kuroki syndrome, is a rare genetic condition that was first identified in Japan in 1981. It occurs as a result of changes or mutations in two specific genes – KMT2D or KDM6A. These changes cause a wide range of symptoms and can affect many parts of the body.

The main signs of Kabuki syndrome include unique facial features such as long openings between the eyelids, a slight upward turn of the outer part of the lower eyelids, eyebrows that are arched and may be thinner or have gaps on the edges, a short area between the nose and upper lip, large ears that may stick out or be shaped like a cup, and a cleft lip or palate. It can also lead to abnormalities in the bones, special features in the patterns of skin ridges on the fingers and palms, mild to severe learning difficulties, and slowed growth after birth.

Unfortunately, there’s no specific cure for Kabuki syndrome, but treatment mainly focuses on managing the symptoms and preventing any potential complications. Despite its uniqueness, Kabuki syndrome is not very well known amongst many doctors.

What Causes Kabuki Syndrome?

Kabuki Syndrome (KSK) is caused by alterations in two specific genes: KMT2D and KDM6A. About 75% of people who have Kabuki Syndrome have those changes in the KMT2D gene. These changes can happen spontaneously (de novo) or be passed down from parents to their children (inherited). On the other hand, variations in the KDM6A gene cause about 5% of all cases. This particular gene follows what’s termed as ‘X-linked dominant inheritance,’ meaning a mutation in one of the two copies of the gene in each cell is sufficient to cause the disorder.

However, for around 20% of cases, we don’t know yet what causes Kabuki Syndrome. More research is needed to fully understand these remaining cases.

Risk Factors and Frequency for Kabuki Syndrome

KS, a condition that was first identified in Japan in the 1980s, is estimated to affect between 1 in 32,000 and 1 in 86,000 individuals. While it was initially believed to be more prevalent in the East Asian population, latest research suggests that it does not occur more frequently in any specific ethnic group.

Signs and Symptoms of Kabuki Syndrome

Kabuki Syndrome (KS) is a condition that is named for the distinct facial features resembling traditional Japanese ‘Kabuki’ theatre actors. Two key genes involved in this condition are KMT2D and KDM6A. There are two types of Kabuki Syndrome, based on these genes: KS1, where variants in KMT2D cause more typical features of the syndrome, and KS2, where variants in KDM6A lead to a slightly different version of the syndrome.

Typically, the key HS traits include:

Distinct facial features
Skeletal irregularities
Skin anomalies
Varying degrees of intellectual disability
Problems with growth

However, this syndrome can affect many different body systems, and the signs can vary widely. For example:

Craniofacial: Almost all individuals with Kabuki Syndrome have distinct facial abnormalities such as long palpebral fissures with eversion of the lower eyelids, high arched eyebrows, and a depressed nasal tip. Other attributes include, thick eyelashes, a flattening of the nose, thinning of the upper lip, thickening of the lower lip, and large or prominent ears. There can also be abnormalities to the mouth like a cleft lip, cleft palate, or a high-arched palate. At least one third of patients experience hearing loss, often due to chronic ear infections or inner ear problems.
Cardiovascular: Heart disease is prevalent in individuals with Kabuki Syndrome, particularly in those with mutations in the KMT2D gene. Other heart issues may include pulmonary stenosis, mitral valve anomalies, and conotruncal defects.
Neurologic: Due to the KMT2D gene playing a crucial role in neuronal differentiation, neurological manifestations are common in Kabuki Syndrome. These can include muscle weakness, feeding difficulties, hearing loss, involuntary movements, developmental delay, and neurobehavioral abnormalities. Seizures are also quite common, affecting nearly 40% of those afflicted with this syndrome.
Ocular: Visual issues affect 38% to 72% of patients and may include blue sclerae, ptosis, strabismus, amblyopia, and refractive defect
Musculoskeletal: Half to three quarters of all Kabuki Syndrome patients exhibit musculoskeletal abnormalities such joint dislocations, especially of the hips, shoulders, and knees. There can also be a variety of dental anomalies.

kabuki Syndrome has some differentgs based on the type. For instance, KS1 patients are likelier to display distinctive facial features, feeding issues, palatal problems, renal anomalies, joint dislocation, and premature thelarche in females. Meanwhile, KS2 patients have higher likelihood of displaying hypoglycemia secondary to hyperinsulinism during infancy, short stature in the preadolescent period, hypertrichosis, large central incisors, and large halluces.

Due to the variant and diverse nature of this syndrome, further research is needed to better understand and classify Kabuki Syndrome.

Testing for Kabuki Syndrome

Kabuki syndrome is often hard to diagnose because many of the symptoms don’t appear until later in life. People with the KMT2D mutation (one of the genes associated with the condition) are more likely to show signs of the syndrome during infancy than those with a KDM6A mutation. Some assessment systems can help diagnose people with Kabuki syndrome even if they haven’t had genetic testing, or if the testing doesn’t clearly indicate the cause of their symptoms.

Kabuki syndrome might be suspected in patients who display a mix of five key features, specific structural abnormalities, and particular functional differences. The five key features include certain facial features, skeletal abnormalities (like spine anomalies and finger differences), abnormalities in skin patterns, intellectual disability, and slow growth after birth.

Structural abnormalities can include eye issues, ear pits, cleft lip/palate, dental problems, heart defects, digestive system abnormalities, or genital/urinary system abnormalities. Functional abnormalities may include hearing loss, feeding difficulties, hormonal imbalances, an increased risk of autoimmune disorders and infections, and seizures.

Criteria for diagnosing Kabuki syndrome were established internationally in 2019. The definitive diagnosis can be made if a patient had low muscle tone in infancy, a delay in reaching developmental milestones with or without intellectual disability, and either a confirmed gene mutation or typical physical features. The physical features must include long eyelid openings and at least 2 additional features like high-arched eyebrows, a specific nose shape, abnormal ears, or persistent fingertip pads that are usually only found in fetuses. These physical features only need to have been present at any stage of life to count towards the diagnosis.

Genetic testing can be conducted in two ways, depending on how closely the patient’s symptoms align with Kabuki syndrome. If the symptoms suggest Kabuki syndrome, genetic testing can be done for a single gene or a couple of genes at a time to find any mutations. If Kabuki syndrome isn’t strongly indicated, more comprehensive genomic testing should be carried out, like examining the entire exome (all the parts of the genome that code for proteins) or genome (all of a person’s genes). There have been cases where patients have shown evidence of Kabuki syndrome without a clear gene mutation, and in these cases, the approach to diagnosis might include examining changes in DNA methylation profiles (a process that regulates gene activity) in white blood cells.

Treatment Options for Kabuki Syndrome

Kabuki syndrome is a condition that affects multiple organs and its treatment typically involves dealing with the symptoms, preventing additional complications, and regular check-ups. Because of the multiple organs affected, taking care of individuals with Kabuki syndrome often involves several medical specialists.

While most issues related to Kabuki syndrome are managed with medicine and regular monitoring, heart-related problems and heart birth defects may need surgery. Common heart defects include a smaller left heart and the narrowing of the aorta, the main blood vessel supplying blood to the body. When it comes to eating challenges, doctors might recommend modifying the consistency of the food. If these challenges persist, a feeding tube might be needed and a specialist feeding team might be involved in the patient’s care. Digestive problems like gastroesophageal reflux disease (persistent heartburn) and chronic diarrhea need to be addressed by a digestive system specialist.

Patients with Kabuki syndrome could also experience hearing loss, which might require the use of hearing aids or small tubes placed in the ears to decrease pressure. Mouth and palate irregularities also need to be fixed by a craniofacial team, which specializes in conditions related to the head, face, and jaws. Kidney and urinary tract disorders require special attention from kidney and urinary specialists, and may need surgical intervention. Repeat infections may require monitoring by specialists in immune system disorders who will consider using therapy to boost the body’s defense system in patients showing signs of deficiencies in disease-fighting proteins (immunoglobulin deficiency). Seizures, if present, will be controlled with anti-seizure medicine and guided by a neurologist.

For children who are shorter than average, growth hormones might be given under the guidance of an endocrinologist. While Kabuki Syndrome might not be linked with a growth hormone deficiency, therapy with growth hormones could be considered in those who are deficient. Be aware that data is limited regarding the effect of human growth hormone therapy and the risk of worsening tumor growth.

For children below the age of three, it is recommended they engage in an early intervention program and as they get older, they should be involved in an individualized education program. Physical therapy, occupational therapy, and speech therapy are also recommended for those with Kabuki Syndrome. Anesthesiologists should take special care with these patients should they need to undergo surgery due to potential airway irregularities and loose joint conditions.

Continual monitoring is key in the treatment of Kabuki Syndrome. This includes tracking growth and development, vision, and hearing. If available, growth curves specifically designed for children with Kabuki Syndrome should be used. If abnormal growth rate is observed, patients should be tested for slowed down metabolism (hypothyroidism) and growth hormone deficiencies. Testing thyroid function and blood count every 2-3 years is also necessary.

Baseline tests for vision and heart function should be done for all patients to look for eye and heart-related conditions. Chest X-rays could also be considered for those with respiratory problems. Feeding teams should be involved in monitoring eating difficulties and the mouth area should be checked for issues with the roof of the mouth (palate). Also, kidney ultrasound and genital examinations should be done to check for abnormalities. For those showing signs of spine curvature (scoliosis), X-rays are imperative to detect any spine anomalies. Immunity-based tests are also vital to identify whether patients might have deficiencies in their immune systems’ cells or proteins. In cases of suspected seizures, echoencephalograms (brain electronic activity tests) should be obtained, and brain magnetic resonance imaging might be considered to evaluate for structural abnormalities.

Considering the cognitive, language, and social challenges commonly associated with Kabuki Syndrome, neuropsychiatric and developmental assessments are crucial. These tests aim to identify speech, cognitive, and motor skills as well as behaviors consistent with attention-deficit hyperactivity disorder and autism spectrum disorder. Dental evaluation is advisable for patients aged three and above. Patients may also need to be referred to various specialists according to their specific needs. Talking to a genetic counselor or geneticist is also recommended.

Although still under investigation, histone deacetylase inhibitors (which help regulate genes) and ketogenic diet (typically high in fats and very low in carbohydrates) are some treatment options for Kabuki syndrome. However, these therapies are not yet recommended due to their limited evidence base.

When diagnosing Kabuki syndrome, doctors look at other conditions that may have similar symptoms:

CHARGE syndrome: Shows similar symptoms, like a cleft palate, heart issues, eye abnormalities, and growth issues. However, characteristics like a square face and short/wide ears distinguish it from Kabuki syndrome.
22q11.2 deletion syndrome: It shares symptoms like cleft palate, heart disease, and kidney issues with Kabuki syndrome. But, the eye openings in this syndrome are short and narrow. Also, it features small and C-shaped ears.
IRF6-related disorders: These also have similar features like cleft lip/palate and lip pits, but they don’t generally come with abnormal growth and development, Kabuki syndrome-like facial features, or heart issues.
Brachio-oto-renal syndrome: This can show up with ear pits, cupped ears, hearing loss and kidney issues. But patients typically have normal facial features and normal growth and development.
Hypermobile Ehlers-Danlos syndrome and Larsen syndrome: Both these conditions share features like joint flexibility and blue-colored whites of the eyes with Kabuki Syndrome. However, they don’t typically have issues with other organ systems.
Hardikar syndrome: This may show up similarly to Kabuki syndrome due to prolonged high bilirubin levels and cleft lip/palate. Yet, sclerosing cholangitis (a condition seen in Hardikar syndrome) is not typically seen in people with Kabuki syndrome.

There are also other chromosomal abnormalities that show similar facial features, heart defects, and growth issues as Kabuki syndrome. These can be differentiated through chromosomal microarray or chromosome analysis.

What to expect with Kabuki Syndrome

Kabuki syndrome is a relatively recent condition that was first identified in the early 1980s. Because it’s still quite new, we do not have a lot of information about long-term outcomes. However, most people with Kabuki syndrome are expected to live into adulthood. The outlook for each person with Kabuki syndrome can differ significantly due to the unique combination of symptoms that each person experiences – this is known as the heterogeneity of the syndrome.

Preventing and managing any complications is crucial to help improve the patients’ outlook. This highlights the importance of ongoing medical care and supervision for people with Kabuki syndrome.

Possible Complications When Diagnosed with Kabuki Syndrome

Patients with KS can experience complications that affect multiple body systems. Therefore, it’s crucial to involve a team of medical professionals from different fields in their care. This team can monitor their condition and manage any issues that arise. It’s also essential to identify any problems early on to prevent complications.

Multiple body system complications
Need for a team of diverse medical professionals
Ongoing monitoring necessary
Importance of early issue recognition
Prevention of complications

Preventing Kabuki Syndrome

If a family member has Kabuki syndrome (KS), it’s vital for the whole family to understand what signs to look out for. This will help to spot issues early on, intervene quicker and prevent further problems. Some typical issues that might need management include difficulty eating (which might mean a feeding tube is needed), seizures (which need care and control), and learning and thinking difficulties. These will need assessment and support. If it looks like the person’s joints are too flexible, they should steer clear of activities that could hurt them. Regular check-ins with a pediatrician are important, to keep a close eye on things like growth, hearing, hearing, and vision.

Understanding how KS is passed down in families can make decisions about future pregnancies easier. It’s passed down differently depending on the specific gene mutation involved. The KMT2D gene mutation is usually “autosomal dominant,” which means even getting the mutated gene from just one parent can cause the child to have the condition. The other main mutation is in the KDM6A gene, which is “X-linked.” This means it’s passed down through the mother’s X chromosomes. Genetic counseling can explain this in more detail and is often incredibly useful for people planning families.

In the rare cases when a parent has a mutation, the chances of future children also having Kabuki syndrome is about 50%. For those with the X-linked inheritance, boys with the mutation will show symptoms, girls might have symptoms dependent on whether they inherit the mutation. Once a doctor has discovered the particular gene mutation causing Kabuki syndrome in an individual, they can do prenatal testing in future pregnancies to see if the baby will have Kabuki syndrome.

Care for a person with Kabuki syndrome can continue into adulthood and often requires a significant amount of time and effort. Caregivers may face challenges due to the possible complications associated with Kabuki syndrome like problems with eating, hearing, and sight, as well as other health issues such as infections, seizures, and heart and kidney problems. Regular healthcare visits will become a part of their routine. This commitment can put a strain on caregivers, affecting their mental health, personal life, and even their ability to work outside the home.

Frequently asked questions

Kabuki Syndrome is a rare genetic condition that is caused by changes or mutations in two specific genes - KMT2D or KDM6A. It is characterized by unique facial features, abnormalities in the bones, learning difficulties, and slowed growth after birth. There is no specific cure for Kabuki Syndrome, but treatment focuses on managing symptoms and preventing complications.

Kabuki Syndrome is estimated to affect between 1 in 32,000 and 1 in 86,000 individuals.

The signs and symptoms of Kabuki Syndrome include: - Distinct facial features resembling traditional Japanese 'Kabuki' theatre actors, such as long palpebral fissures with eversion of the lower eyelids, high arched eyebrows, a depressed nasal tip, thick eyelashes, a flattening of the nose, thinning of the upper lip, thickening of the lower lip, and large or prominent ears. - Skeletal irregularities, including joint dislocations (especially of the hips, shoulders, and knees) and musculoskeletal abnormalities. - Skin anomalies, such as blue sclerae. - Varying degrees of intellectual disability. - Problems with growth, including short stature in the preadolescent period for KS2 patients. - Craniofacial abnormalities, such as cleft lip, cleft palate, or a high-arched palate. - Cardiovascular issues, including heart disease, pulmonary stenosis, mitral valve anomalies, and conotruncal defects. - Neurological manifestations, such as muscle weakness, feeding difficulties, hearing loss, involuntary movements, developmental delay, neurobehavioral abnormalities, and seizures. - Ocular problems, including visual issues like ptosis, strabismus, amblyopia, and refractive defect. - Dental anomalies. - Additional signs and symptoms specific to KS1 and KS2 patients, such as feeding issues, palatal problems, renal anomalies, joint dislocation, premature thelarche in females for KS1 patients, and hypoglycemia secondary to hyperinsulinism during infancy, hypertrichosis, large central incisors, and large halluces for KS2 patients. It's important to note that the signs and symptoms can vary widely among individuals with Kabuki Syndrome, and further research is needed to better understand and classify the condition.

Kabuki Syndrome can be caused by alterations in two specific genes: KMT2D and KDM6A. About 75% of cases are caused by changes in the KMT2D gene, while about 5% are caused by variations in the KDM6A gene. For the remaining 20% of cases, the cause is still unknown and further research is needed.

CHARGE syndrome, 22q11.2 deletion syndrome, IRF6-related disorders, Brachio-oto-renal syndrome, Hypermobile Ehlers-Danlos syndrome and Larsen syndrome, Hardikar syndrome, and other chromosomal abnormalities.

The types of tests needed for Kabuki Syndrome include: 1. Genetic testing: This can be done for a single gene or a couple of genes at a time to find any mutations. More comprehensive genomic testing, such as examining the entire exome or genome, may be necessary if Kabuki syndrome is not strongly indicated. 2. DNA methylation profile examination: In cases where patients show evidence of Kabuki syndrome without a clear gene mutation, changes in DNA methylation profiles in white blood cells can be examined. 3. Baseline tests: These include tests for vision, heart function, kidney ultrasound, and genital examinations to check for abnormalities. Chest X-rays may be considered for respiratory problems, and X-rays are necessary to detect spine anomalies in cases of suspected scoliosis. 4. Immunity-based tests: These tests are vital to identify deficiencies in the immune system's cells or proteins. 5. Echoencephalograms and brain magnetic resonance imaging (MRI): These tests may be obtained to evaluate brain activity and structural abnormalities in cases of suspected seizures. 6. Neuropsychiatric and developmental assessments: These tests aim to identify speech, cognitive, motor skills, and behaviors consistent with attention-deficit hyperactivity disorder and autism spectrum disorder. 7. Dental evaluation: Advisable for patients aged three and above. It is important to consult with a genetic counselor or geneticist for further guidance and recommendations.

Kabuki Syndrome is treated by managing the symptoms, preventing complications, and regular check-ups. Treatment often involves multiple medical specialists due to the various organs affected. Medicine and regular monitoring are used for most issues, but heart-related problems and heart birth defects may require surgery. Eating challenges may be addressed by modifying the consistency of food or using a feeding tube. Digestive problems are treated by a digestive system specialist. Hearing loss may require hearing aids or small tubes in the ears. Mouth and palate irregularities are fixed by a craniofacial team. Kidney and urinary tract disorders are managed by kidney and urinary specialists. Repeat infections may require therapy to boost the immune system. Seizures are controlled with anti-seizure medicine and guided by a neurologist. Growth hormones may be given under the guidance of an endocrinologist. Early intervention programs and individualized education programs are recommended. Physical therapy, occupational therapy, and speech therapy are also recommended. Continual monitoring is important, including tracking growth and development, vision, and hearing. Baseline tests for vision and heart function should be done. Feeding teams should monitor eating difficulties. Various tests and evaluations may be done to check for abnormalities and assess cognitive, language, and social challenges. Histone deacetylase inhibitors and ketogenic diet are potential treatment options, but more evidence is needed.

When treating Kabuki Syndrome, there are several potential side effects and considerations to keep in mind. These include: - Multiple body system complications: Kabuki Syndrome can affect multiple organs, so treatment often involves managing symptoms and addressing complications in various areas of the body. - Need for a team of diverse medical professionals: Due to the complexity of Kabuki Syndrome, a team of medical specialists from different fields is often involved in the care of individuals with this condition. - Ongoing monitoring necessary: Continual monitoring of growth, development, vision, hearing, and other aspects of health is crucial in the treatment of Kabuki Syndrome. - Importance of early issue recognition: Early identification of problems is essential to prevent complications and address them promptly. - Prevention of complications: Treatment aims to prevent additional complications and manage existing ones through medication, surgery, therapy, and other interventions.

Most people with Kabuki syndrome are expected to live into adulthood. The outlook for each person with Kabuki syndrome can differ significantly due to the unique combination of symptoms that each person experiences. Preventing and managing any complications is crucial to help improve the patients' outlook. Ongoing medical care and supervision are important for people with Kabuki syndrome.

A team of medical professionals from different fields, including but not limited to: pediatricians, craniofacial specialists, cardiologists, digestive system specialists, kidney and urinary specialists, immune system disorder specialists, neurologists, endocrinologists, physical therapists, occupational therapists, speech therapists, anesthesiologists, genetic counselors, and geneticists.

Genetic Disorders