Kabuki syndrome 2 (KDM6A)

Overview

Kabuki syndrome is a rare genetic condition that affects many parts of the body, leading to a range of health challenges. It is named after the traditional Japanese Kabuki theatre, as individuals with the condition often have facial features that resemble the stage make-up used by actors [PMID:24078652]. There are two main types of Kabuki syndrome. Type 1 is caused by changes in the KMT2D gene, while type 2 is caused by changes in the KDM6A gene, which is the focus here.

Individuals with Kabuki syndrome type 2 typically experience developmental delay, intellectual disability, and various health problems affecting the heart, kidneys, skeleton, and immune system. The condition is present from birth, and its severity can vary significantly among affected individuals. Early diagnosis and ongoing support are important for managing the diverse symptoms associated with Kabuki syndrome type 2.

Symptoms & clinical features

The symptoms of Kabuki syndrome type 2 are wide-ranging and can affect almost every system in the body. Developmental delay is a common feature, meaning that children may reach milestones like walking and talking later than expected. Intellectual disability, ranging from mild to severe, is also frequently observed [PMID:24078652]. Many individuals have distinctive facial features, which can include long eyelashes, arched eyebrows, widely spaced eyes, and an everted (outward-turned) lower eyelid.

Beyond developmental and facial characteristics, other symptoms can include skeletal abnormalities such as short stature, curvature of the spine (scoliosis), or joint laxity. Heart defects, kidney problems, and hearing loss are also reported in some individuals. Feeding difficulties, often in infancy, and recurrent infections due to immune system dysfunction may also occur. Some individuals may experience seizures or issues with hormone regulation [PMID:32501004].

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Affected organs

Kabuki syndrome type 2 can affect multiple organ systems. The brain is significantly impacted, leading to intellectual disability and developmental delays. Skeletal features are often affected, with common findings including short stature, spinal abnormalities, and joint hypermobility. Heart defects are present in a notable proportion of individuals, ranging from mild to more complex structural issues.

Kidneys can also be affected, sometimes with structural abnormalities or reduced function. The immune system may be compromised, increasing susceptibility to infections. Hearing loss, either conductive or sensorineural, is another common concern. Additionally, issues with the gastrointestinal system, such as feeding difficulties, and endocrine system, leading to hormone imbalances, have been observed in some individuals.

Brain

Central nervous system involvement

Cellular impact

Mechanism at cellular level

Risks & severity

Kabuki syndrome type 2 presents with a variable range of severity, even within the same family. Developmental delay and intellectual disability are common, but their extent can differ significantly between individuals. Some may have mild learning difficulties, while others face more substantial intellectual challenges requiring extensive support.

Life-threatening complications, such as severe heart defects or recurrent infections due to immune dysfunction, can occur in some cases, highlighting the need for careful monitoring. While exact prevalence figures are not well established, the condition is considered rare. The age of onset for symptoms is typically at birth or in early infancy, as developmental delays become apparent during early childhood. The full spectrum of health issues often unfolds over time, necessitating ongoing medical follow-up [PMID:32501004].

Genetic causes

Kabuki syndrome type 2 is caused by pathogenic variants in the KDM6A gene. The KDM6A gene provides instructions for making an enzyme known as lysine-specific demethylase 6A. This enzyme plays a crucial role in epigenetics, specifically in modifying histone proteins. Histones are proteins that act as spools around which DNA is wound; their modifications can influence whether a gene is turned 'on' or 'off'.

The KDM6A enzyme works by removing methyl groups from specific histones. This action helps to regulate gene expression, meaning it controls which genes are active in particular cells and at specific times. When there are pathogenic changes in the KDM6A gene, the enzyme may not function correctly or at all. This disruption leads to widespread errors in gene regulation during development, resulting in the diverse symptoms seen in Kabuki syndrome type 2 [PMID:24078652].

• KDM6A
  lysine demethylase 6A
  KDM6A encodes lysine-specific demethylase 6A, a histone-modifying enzyme essential for regulating gene expression during development and preventing uncontrolled cell growth.

Inheritance pattern

Kabuki syndrome type 2 follows an X-linked recessive (XLR) inheritance pattern. This means the KDM6A gene is located on the X chromosome, one of the two sex chromosomes. Females typically have two X chromosomes (XX), while males have one X and one Y chromosome (XY).

Because males only have one X chromosome, a pathogenic variant in their single KDM6A gene is usually enough to cause the condition. Therefore, males are more frequently and severely affected. Females, with two X chromosomes, generally need pathogenic variants on both X chromosomes to develop severe symptoms. However, if a female carries one pathogenic variant on one X chromosome, she may be a 'carrier' and typically does not show full symptoms, but might have milder features or be at risk of passing the condition to her children. A mother who is a carrier has a 50% chance with each pregnancy of passing the pathogenic variant to her son (who would be affected) or to her daughter (who would be a carrier).

Diagnosis & testing

Diagnosing Kabuki syndrome type 2 typically begins with a clinical evaluation based on the distinctive features and developmental delays observed in an individual. However, because the symptoms can overlap with other conditions, genetic testing is essential to confirm the diagnosis [PMID:32501004].

Genetic testing for Kabuki syndrome type 2 involves looking for pathogenic variants in the KDM6A gene. This is usually performed via a blood test. In the UK, individuals suspected of having Kabuki syndrome type 2 may be referred to a clinical genetics service by their GP or another specialist. The NHS Genomic Medicine Service provides comprehensive genetic testing, and relevant R-codes (e.g., R146 for syndromic intellectual disability) may be used to guide testing pathways. A genetic counsellor can help explain the testing process, interpret results, and discuss implications for the family.

Management & lifestyle

The management of Kabuki syndrome type 2 is highly individualised, focusing on addressing the specific symptoms and needs of each person. A multidisciplinary team of specialists is often involved, which may include paediatricians, geneticists, cardiologists, neurologists, orthopaedic surgeons, and developmental therapists. Regular monitoring for potential complications such as heart defects, kidney issues, and hearing loss is crucial.

Developmental therapies, including physiotherapy, occupational therapy, and speech and language therapy, are often recommended to support developmental progress and address learning difficulties. Educational support tailored to the individual's needs is also important. Some individuals may benefit from interventions for feeding difficulties or immune system support to manage recurrent infections. Genetic counsellors can provide valuable information and support to families throughout the management journey within the NHS framework.

UK care pathway

In the UK, individuals suspected of having Kabuki syndrome type 2 typically enter the NHS Genomic Medicine Service pathway. This journey usually begins with a referral from a GP or paediatrician to a regional clinical genetics service. Genetic testing, guided by NHS R-codes such as R146 for syndromic intellectual disability, is then used to confirm the diagnosis by identifying pathogenic variants in the KDM6A gene. Following diagnosis, patients and their families will have access to genetic counselling services, which provide essential information, support, and guidance on the condition, inheritance patterns, and family planning. Care is then coordinated by a team of specialists to manage the various symptoms and ensure comprehensive support.

Related conditions

When considering Kabuki syndrome type 2, it is helpful to be aware of other conditions that might present with similar features or have shared genetic mechanisms. Kabuki syndrome type 1, caused by variants in the KMT2D gene, has a very similar clinical presentation and is often clinically indistinguishable from type 2, making genetic testing essential for differentiation. Other conditions associated with intellectual disability and distinctive facial features, such as Cornelia de Lange syndrome or Noonan syndrome, might also be considered in a differential diagnosis. These conditions are typically distinguished through detailed clinical assessment and specific genetic testing panels.

• Kabuki syndrome
  Neurogenetics
  Shares 1 gene

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