An Overview of Kabuki Syndrome

A Rare Genetic Disorder That Affects Many Body Systems.

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Kabuki syndrome is a rare genetic disorder that affects multiple body systems. It’s characterized by distinctive facial features, delayed growth, intellectual disability, and lower than average height. The effects of this condition can be far-ranging, and specific symptoms can vary a great deal from case to case. Present in approximately one in every 32,000 newborns, it arises due to mutations of one of two genes: KMT2D (for most cases) and KDM6A. As such, it can be identified using genetic testing.

Symptoms

There’s a great deal of individual variation when it comes to Kabuki syndrome, and while some symptoms are present at birth, others appear later in life or not at all. The most common of these include:

  • Distinctive facial features: Distinctive facial appearance in Kabuki cases tend to arise over time. Those with this condition tend to have abnormally long eyelid openings, outward-facing lower eyelids, unusually long eyelashes, arched eyebrows, a broad, flat nose, and larger, sometimes malformed ears. In some cases, this disorder is characterized by a bluish tint in the whites of the eyes, drooping upper eyelid, misaligned eyes, cleft palate, abnormally small jaw, or depressions in the inside of the lower lip. 
  • Growth deficiency: This is usually seen within the first year of life of a person with this condition, and it becomes more prominent as they age. This can eventually lead to lower than average height, and, in rare cases, children will display partial hormone growth deficiency. 
  • Intellectual disability: It is not always a hallmark of the condition, but many with it will have mild to moderate intellectual disability and learning problems. In rare cases, this disability is more severe.
  • Microcephaly: In some cases, “microcephaly,” or smaller than average size of the head results from the condition. These cases may also lead to seizures.
  • Speech delay: Occurring either due to palate abnormalities or hearing loss, which often accompany Kabuki syndrome, children with the condition may experience delays in learning speech.
  • Behavioral abnormalities: Children and adults with the condition have a higher rate of anxiety and a tendency to fixate on specific objects or stimuli. This may mean aversion to certain noises, smells, or textures, or attraction to music.
  • Feeding difficulty: In infants and younger children, Kabuki syndrome can lead to difficulty feeding due to gastric reflux, poor sucking ability, and difficulty absorbing nutrients from food.
  • Excessive weight gain in adolescence: While initial feeding and growth can be hindered, in many cases, when children with the condition reach adolescence, they may gain excessive amounts of weight.
  • Infections: Respiratory and ear infections are more common in those with this condition, with many being prone to pneumonia and hearing loss.
  • Dental abnormalities: In some cases, Kabuki syndrome leads to missing or misaligned teeth.
  • Finger tip pads: The persistent presence of prominent pads coming from finger tips called fetal finger pads is a hallmark of the condition.
  • Skeletal abnormalities: A range of skeletal abnormalities can accompany this condition, including shorter than usual fingers and toes, bent pinkies, flat feet, abnormally loose joints, irregular skull shape, as well as scoliosis (lateral bending) and kyphosis (deep curvature) of the spine.
  • Heart defects: Some of the most pressing effects of this condition are the heart defects associated with it, which are usually seen at birth. These include an abnormal narrowing of the body’s largest artery (the aorta), and holes in the walls separating chambers of the heart. 
  • Effects on other organs: Other organs that can be affected by this condition are the kidneys, which can be underdeveloped, be fused together at their base, or experience blockages in the flow of urine from them. In addition, the colon may develop in the wrong position (malrotation), and there may be blockages of the anal opening.  

Causes

Kabuki syndrome is a congenital disorder (present at birth) that is inherited from the parents of the person affected. In approximately 55% to 80% of cases it arises due to a mutation of the KMT2D gene, which regulates enzyme production for various organ systems. These enzymes are associated with the production of “histones,” which are proteins that bind to DNA to provide structure to chromosomes and help activate genes associated with growth and development.

In a much smaller proportion of cases—between 2% and 6%—the syndrome arises due to mutations of KDM6A, another gene associated with histone production. Affected activity here certainly impacts organ growth and development and can lead to Kabuki syndrome symptoms. Notably, a significant proportion of these cases have no identified genetic origin.   

Given that this is a congenital disorder, Kabuki syndrome follows two specific inheritance patterns. Cases linked to KMT2D mutations follow an X-linked, dominant pattern. This means that in women, who have two X chromosomes, a mutation in only one of them will transmit the disease. In men, the one X chromosome they have must be the one with the mutation. As such, fathers do not transmit this syndrome to their male children. Interestingly, a majority of these cases arise due to a new mutation, meaning family history is not a great predictor of the condition.    

Diagnosis

There are two primary ways that Kabuki syndrome is diagnosed: through genetic testing and when a set of specific clinical features and symptoms are identified. For genetic testing, doctors look for deletions or duplications of the relevant genes: KMT2D and KDM6A. Testing the former of these is done first in cases where there is a family history of the condition.

That said, since about 1 in 5 cases don’t involve mutations of these genes, other clinical factors must be considered. Doctors will assess medical history and provide a thorough evaluation looking for other characteristic signs, including distinctive facial appearance, finger pads, developmental delays, and others. In addition, they rule out similar cases through blood tests and analysis. 

Treatment

There’s no singular treatment approach to Kabuki syndrome, and management of the condition often involves coordination between different specialties and modalities of care. Depending on the symptoms that arise, a person with this condition may work with pediatricians, surgeons, speech pathologists, and other specialists. What’s essential for taking this issue on is early intervention; approaches like speech-therapy, physical therapy, and others need to be applied in a timely manner.

For infants who have feeding difficulties, doctors may need to place a feeding tube to ensure proper growth and nutrition. In addition, for cases in which there are significant developmental delays, growth hormone treatment may be indicated. Hearing loss, a common attribute of the condition, is often taken on with hearing aids. Finally, congenital heart defects associated with this condition requires specific attention from a pediatric cardiologist.

Notably, genetic counseling, in which tests are performed and consultations provided, should be considered for Kabuki syndrome cases. 

Coping

As with all conditions that affect development and function, Kabuki syndrome can be difficult to take on both on the part of the affected person and their family. The burden of the condition is quite heavy and requires dedicated management of health and living spaces. Beyond purely medical intervention, those with the condition—and their loved ones—may want to consider therapy or support groups.

Luckily, there are a number of non-profit organizations that offer resources and support for those affected by Kabuki syndrome, including All Things Kabuki, as well as the Genetic and Rare Diseases (GARD) Information Center. Beyond that, it’s important for there to be solid communication within families and among friends to ensure caregivers and those with the condition are supported.  

A Word From Verywell  

Kabuki syndrome can be extremely difficult and challenging; there’s no simple or direct cure for it, so management of the condition does require lifelong effort and care. That said, it’s important to note that the tools and therapies available today are better than they’ve ever been in taking on the physical and psychological impact of this disorder. Certainly, as we learn more about the causes and effects of this rare disease, outcomes will become even better. Hard as it may be to appreciate for those directly impacted, the picture is getting rosier. 

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Article Sources

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  1. Adam M. Kabuki syndrome. National Organization for Rare Disorders. Updated 2019.

  2. National Institutes of Health Genetic Home Reference. Kabuki syndrome. Updated 2020.