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Kabuki syndrome
Kabuki syndrome is a rare inherited condition that can impact a person's physical development, intellectual abilities, and overall health. It typically manifests from birth and affects individuals differently, requiring tailored medical support.
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Overview
Kabuki syndrome is a rare genetic condition that affects multiple parts of the body. It is named after the traditional Japanese Kabuki theatre, due to some individuals with the syndrome having facial features that can resemble the make-up used by actors [PMID:33671239]. People with Kabuki syndrome often experience developmental delays, intellectual disability, and a range of other health concerns that can vary significantly from person to person.
The condition is present from birth, although diagnosis might not occur immediately. The specific health challenges and their severity can differ widely, even among family members with the same genetic change. Effective management focuses on addressing individual symptoms and supporting development.
Symptoms & clinical features
Individuals with Kabuki syndrome often present with a combination of distinctive physical features. These can include long eyelashes, arched eyebrows, eyelid abnormalities, and prominent ears. Many also have a short stature, skeletal abnormalities such as spinal problems, and joint laxity, meaning their joints are more flexible than usual [PMID:27083091].
Beyond physical characteristics, developmental delays are common, particularly affecting speech and motor skills. Intellectual disability, ranging from mild to moderate, is also frequently observed. Other health issues can include heart defects, kidney problems, feeding difficulties in infancy, and immune system dysfunction, which may lead to recurrent infections [PMID:33671239]. Hearing loss and dental anomalies are also often reported.
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Affected organs
Kabuki syndrome can affect many different organ systems. The brain is impacted, leading to developmental delays and intellectual disability. Skeletal anomalies are common, affecting bones and joints throughout the body, including the spine and fingers. The heart may have structural defects, and the kidneys can also be affected.
The immune system can be compromised, increasing susceptibility to infections. Feeding difficulties often point to issues with the gastrointestinal system in infancy. Hearing and vision can also be impaired, requiring regular monitoring and intervention. Endocrine issues, such as growth hormone deficiency, may also be present.
Risks & severity
The severity of Kabuki syndrome is highly variable, even within the same family. Some individuals may experience mild developmental delays and fewer health complications, while others may have more significant intellectual disability and require extensive medical support for complex health issues. The exact prevalence of Kabuki syndrome is estimated to be around 1 in 32,000 live births, though this might be an underestimate due to its varied presentation [PMID:33671239].
Developmental delays and intellectual disability are common, with a range of cognitive abilities observed. The risk of certain medical conditions, such as heart defects or immune dysfunction, is elevated compared to the general population. While Kabuki syndrome is a lifelong condition, proactive management and supportive therapies can significantly improve quality of life. There is no specific age of onset, as the condition is congenital (present from birth).
Genetic causes
Kabuki syndrome is caused by pathogenic variants in one of two genes: KMT2D or KDM6A. The KMT2D gene provides instructions for making a protein that modifies histone proteins. Histones are crucial for packaging DNA into chromosomes and influencing which genes are turned on or off. The KMT2D protein's role in gene regulation is vital for normal embryonic development.
Similarly, the KDM6A gene also codes for an enzyme involved in modifying histone proteins. This enzyme helps to remove chemical tags from histones, which also affects how genes are expressed. Pathogenic variants in either KMT2D or KDM6A disrupt these essential gene regulation processes, leading to the wide range of developmental and health issues observed in Kabuki syndrome [PMID:27083091]. These genetic changes typically result in a loss of function of the respective proteins.
- KDM6A lysine demethylase 6AKDM6A encodes lysine-specific demethylase 6A, a histone-modifying enzyme essential for regulating gene expression during development and preventing uncontrolled cell growth.
- KMT2D lysine methyltransferase 2DThe KMT2D gene provides instructions for an enzyme crucial in regulating gene activity through histone methylation, essential for proper development and linked to Kabuki syndrome.
Inheritance pattern
Kabuki syndrome is inherited in an autosomal dominant pattern. This means that a person only needs one copy of an altered gene (either KMT2D or KDM6A) to develop the condition. In most cases, the genetic change occurs spontaneously (de novo) in the affected individual and is not inherited from either parent. This means neither parent carries the pathogenic variant.
However, in a small number of instances, an affected individual may inherit the altered gene from a parent who also has Kabuki syndrome, or from a parent who has a very mild form of the condition or is a mosaic carrier. If a parent has the pathogenic variant, there is a 50% chance with each pregnancy that their child will inherit the condition. Genetic counselling is important for families to understand these inheritance patterns and recurrence risks.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of Kabuki syndrome is typically suspected based on a combination of characteristic clinical features. However, a definitive diagnosis requires genetic testing. This testing usually involves analysing the KMT2D and KDM6A genes to identify specific pathogenic variants [PMID:27083091].
In the UK, genetic testing for Kabuki syndrome can be accessed through the NHS Genomic Medicine Service (GMS). A GP or specialist paediatrician may refer individuals with suspected Kabuki syndrome to a clinical genetics service. These services can arrange for appropriate genetic tests, which may fall under specific R-codes for syndromic intellectual disability or specific gene panels, such as R253 Intellectual disability (early onset) or R285 Multiple congenital anomalies and/or learning disability. Genetic counsellors within these services provide support and explain the implications of a diagnosis.
Management & lifestyle
Management of Kabuki syndrome is multidisciplinary and focuses on addressing the individual's specific symptoms and developmental needs. This often involves a team of specialists, including paediatricians, geneticists, cardiologists, neurologists, orthopaedists, and speech and language therapists. Regular monitoring for potential complications, such as heart defects, kidney problems, or hearing loss, is a key part of ongoing care.
Therapeutic interventions may include physiotherapy, occupational therapy, and speech and language therapy to support developmental progress. Educational support tailored to the individual's learning style is also crucial. Surveillance for immune system dysfunction and appropriate management of infections are important. While there is no cure, comprehensive and coordinated care can significantly improve outcomes and quality of life for individuals with Kabuki syndrome. Families should work closely with their NHS care team to develop an individualised management plan.
UK care pathway
In the UK, individuals suspected of having Kabuki syndrome are typically referred by their GP or another specialist to a clinical genetics service. This service is part of the NHS Genomic Medicine Service (GMS). Genetic counsellors play a vital role within these services, providing information and support to families regarding diagnosis, inheritance, and management options.
Genetic testing for Kabuki syndrome is available through the GMS and is usually requested by a clinical geneticist. This testing helps to confirm the diagnosis and can also inform family planning. Depending on the clinical presentation, the relevant NHS National Genomic Test Directory R-codes might include R253 (Intellectual disability, early onset) or R285 (Multiple congenital anomalies and/or learning disability).
Frequently asked questions
Is Kabuki syndrome always inherited from a parent?
No, in most cases, the genetic change causing Kabuki syndrome happens spontaneously (de novo) in the affected child and is not inherited from either parent. However, in a small number of families, it can be inherited in an autosomal dominant pattern.
What are the main challenges for individuals with Kabuki syndrome?
Individuals with Kabuki syndrome often face developmental delays, intellectual disability, and a range of physical health issues such as heart defects, kidney problems, and immune system dysfunction. The specific challenges vary greatly from person to person.
Can Kabuki syndrome be cured?
Currently, there is no cure for Kabuki syndrome. However, management focuses on treating the specific symptoms and providing supportive therapies to help individuals achieve their best possible development and quality of life.
How is Kabuki syndrome diagnosed in the UK?
Diagnosis in the UK is confirmed through genetic testing, typically arranged by a clinical genetics service within the NHS Genomic Medicine Service. This testing looks for pathogenic variants in the KMT2D or KDM6A genes after a clinical suspicion is raised.
What support is available for families affected by Kabuki syndrome?
Families can access support through NHS clinical genetics services, genetic counsellors, and various specialist healthcare professionals. Patient support groups and charities also provide valuable information, resources, and community connections.
References
- Boniel S, Szymańska K, Śmigiel R. Kabuki Syndrome-Clinical Review with Molecular Aspects. Genes. 2021. PMID: 33805950
- Adam MP, Banka S, Bjornsson HT. Kabuki syndrome: international consensus diagnostic criteria. Journal of medical genetics. 2019. PMID: 30514738
- Adam MP, Bick S, Mirzaa GM. Kabuki Syndrome. 1993. PMID: 21882399
- Barry KK, Tsaparlis M, Hoffman D. From Genotype to Phenotype-A Review of Kabuki Syndrome. Genes. 2022. PMID: 36292647
- Neumann D, Karnik R. Kabuki Syndrome. 2024. PMID: 38917269
- Bokinni Y. Kabuki syndrome revisited. Journal of human genetics. 2012. PMID: 22437206
- Bögershausen N, Gatinois V, Riehmer V. Mutation Update for Kabuki Syndrome Genes KMT2D and KDM6A and Further Delineation of X-Linked Kabuki Syndrome Subtype 2. Human mutation. 2016. PMID: 27302555
- Bögershausen N, Wollnik B. Unmasking Kabuki syndrome. Clinical genetics. 2013. PMID: 23131014