Course:MEDG550/Student Activities/Kabuki Syndrome

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File:Child with Kabuki Syndrome 01.jpg
Young boy with Kabuki syndrome
File:Child with Kabuki Syndrome 07.jpg
Young girl with Kabuki Syndrome

Kabuki syndrome is a rare genetic condition that affects many parts of the body. It is characterized by a distinctive appearance to the face, intellectual disability and problems with growth. Individuals with Kabuki syndrome also sometimes have problems with their heart, intestines, kidneys and skeleton.[1] This condition is congenital, meaning a child is born with it, and can be diagnosed either soon after birth or when a child begins to show some developmental problems. There is currently no cure for Kabuki syndrome, but various treatment options are available to reduce the risk of medical problems and improve the quality of life. This condition affects males and females equally and is sometimes also called Niikawa-Kuroki syndrome.[2]

Clinical Features

How exactly Kabuki syndrome presents in a person can vary widely from child to child. This means that affected individuals can have many of the following features, or only a few.

The most common characteristics include:

  • Distinct facial features, such as:[1]
    • The openings of the eyes or eyelids being longer than normal (elongated palpebral fissures)
    • Highly arched eyebrows
    • Long eyelashes
    • Broad, flattened tip of the nose
    • Earlobes that are large and stick out a bit from the head
    • Eyes that are spaced far apart
    • An opening or split in the roof of the mouth that happened because the tissues didn't fuse together during development (cleft palate) or the roof of the mouth is high and narrow (high arched palate)
  • Intellectual disability and developmental delay[2]
    • Can range from moderate to severe
  • Skeletal abnormalities[1]
    • Sideways curving of the spine (scoliosis)
    • Short fingers and toes (brachydactyly)
    • Pinky finger that curves towards the other fingers (clinodactyly of the fifth finger)
  • Below-average height[1]

Kabuki syndrome may be associated with other health problems, including:[1]

  • Being born with a heart defect (congenital heart defect)
  • Kidney and urinary tract abnormalities
  • Frequent infections related to the immune system not working as well as it should (immunoglobulin deficiency)
  • Dental problems (such a missing or misshaped (peg-like) teeth)
  • Seizures
  • Small holes near the ears (ear pits)
  • Hearing loss
  • Behavioural difficulties
  • Feeding difficulties
  • Undescended testicles
    DNA is packaged or condensed into structures called chromosomes.

Genetics

A gene is a segment of DNA that has a specific job or function. The genes involved in Kabuki syndrome are named KMT2D and KDM6A. Nucleosomes consist of a section of DNA that is wrapped around special proteins called histones.

Human bodies are made up of billions of cells, inside each cell is its nucleus, and inside the nucleus we find DNA. DNA can be thought of as the instructions telling our bodies how to function. The DNA in our cells is organized or compacted into chromosomes. We have 23 pairs of chromosomes. A person inherits one set from their dad and one set from their mom, making up 46 chromosomes in total.

We can think of our DNA as being broken up into discrete sections called genes. Each gene has its own job or function. A gene is a piece of genetic information, or DNA, which provides information to our cells to make proteins. Proteins are responsible for different functions within our bodies that help us to grow and develop.[3]

If DNA is the instructions telling our bodies how to function, sometimes there can be changes in those instruction so that the body can no longer make sense of the information and the protein that is made can no longer do its job properly. A word could be misspelled, or there could be missing or extra pieces of genetic information. These changes in our DNA are called variants (less oftenly referred to as mutations). In most cases, Kabuki syndrome is caused by a variant in either the KMT2D or KDM6A genes.

KMT2D

Between 55-85% of cases of Kabuki syndrome are caused by variants in KMT2D. Typically this gene is responsible for the production of an enzyme (a type of protein) called lysine-specific methyltransferase 2D which is found throughout the body.[2] This enzyme's job is to modify a special protein called a histone by adding a methyl group to the histone. In the picture on the right, the histones are the little circular proteins that DNA wraps around to form a nucleosome. Histones help package the DNA into chromosomes and are important for regulating the activity of other genes in our bodies, including those that are involved in development.[2] If there are changes or variants in KMT2D the enzyme can no longer work properly and cannot modify the histones. The downstream effect of this is that the activity of other genes is changed so that they also cannot do their jobs properly.

KDM6A

Autosomal Dominant Inheritance: The father has a variant in one of his genes and is thus affected. For each of his children there is always a 50% chance he will pass down the copy of the gene with the change. [4].

Between 2-6% of cases of Kabuki syndrome are caused by variants in KDM6A. Typically this gene is responsible for the production of an enzyme called lysine-specific demethylase 6A.[2] This enzyme's job is to remove methyl groups from histones.[2] This enzyme also regulates the activity of other genes in our bodies.

The fact that variants in KMT2D and KDM6A affect the expression of other genes helps to explain why so many different parts of the body are affected in Kabuki Syndrome. It is the case though that some people with Kabuki syndrome have no detectable change in either gene, and the cause of their condition is unknown.[5]

Inheritance

Humans have two copies of each genes, we inherit one copy from our mother and the other from our father. The inheritance pattern for Kabuki syndrome is determined by which gene (KMT2D or KDM6A) has the variant.

Autosomal Dominant (KMT2D)

Autosomal dominant conditions occur when there is a variant in only one copy of the gene.[3] 'Autosomal’ means the gene is found on one of our 22 chromosomes that are not involved in our biological sex (numbered 1-22). KMT2D is on chromosome 12[2]. For dominant conditions, we require both copies of the gene to be working properly. The one copy of the gene that is still working is not able to produce enough of the protein needed for proper function[2].

Each child of an individual with Kabuki syndrome, caused by a change in KMT2D, has a 50% chance of also having Kabuki syndrome[1]. This is because there is a 50% chance that person will pass down the working copy of the gene and a 50% chance they pass down the non-working copy of the gene.

X-Linked Dominant (KDM6A)

X-linked Dominant Inheritance: This pattern of inheritance works differently depending on which parent is affected. An affected mother with a variant in one X chromosome would have a 50% chance that she will pass it down to each child
An affected father would have a 50% chance of passing on the variant to a daughter and no chance of passing it on to a son because father's always pass down their Y chromosome to their sons. [4]

KDM6A is located on the X chromosome[2]. Females have two X chromosomes and males have an X chromosome and a Y chromosome[3]. If a female has a variant in one of the two copies of the gene then, like autosomal dominant inheritance, the working copy is not enough for proper function and the female would have Kabuki syndrome[2]. A woman who is affected and carries a mutation on one of her X chromosomes has a 50% chance that she will pass that on to a child. A man who is affected and carries a variant on his only X chromosome will pass down the mutation (and the disorder) to all of his daughters and none of his sons (because males always receive their X chromosome from their mothers and their Y chromosome from their fathers).


Most cases of Kabuki syndrome are the result of a new mutation in one of the genes described above[1]. This means that most of the time Kabuki syndrome occurs in people with no family history of the disorder. In a minority of cases, a person with Kabuki syndrome is believed to have inherited the mutation from an affected parent[1]. It is possible that a child with Kabuki syndrome has inherited this from one of his or her parents even if there appeared to be no family history of the condition[1]. Evaluation of the parents may determine that one is in fact affected but was never diagnosed due to a mild expression of the disorder.

Frequency

Kabuki syndrome is believed to affect 1/32,000 births, and males and females are equally affected.[2]

Management

Evaluation

The symptoms individuals with Kabuki syndrome experience can vary from person to person. The individual needs of the patient need to be evaluated and treatment tailored to their specific situation. Below are the recommendations regarding evaluation[1].

  • Physical exam
  • Standard growth evaluation including height, weight and head circumference
  • Studies to determine if there may be for hormone deficiencies or imbalances
  • Determining if children are reaching their developmental milestones
  • Physical therapy evaluation for children with Kabuki syndrome who experience reduced muscle tone which is the amount of tension or resistance to stretch in a muscle (hypotonia)
  • Brain imaging if if there is an indication of headaches, seizures and/or other neurological problems.
  • Echocardiogram for all individuals with Kabuki syndrome at the time of diagnosis, if a cardiac defect is present, referral to a paediatric cardiologist is recommended
  • A formal eye exam for all individuals with Kabuki syndrome at the time of diagnosis
  • Ultrasound of the kidneys exam at time of diagnosis for all individuals with Kabuki syndrome. Referral to a nephrologist should be made if there is an indication of the kidneys being swollen, a referral to a urologist may be necessary as well
  • Spine radiographs for all individuals with Kabuki syndrome, if scoliosis is indicated, an orthopaedic assessment should be considered
  • Medical genetics consultation
  • Dental assessment when the affected child has reached toddler age
  • Assessment by a developmental pediatrician or psychiatrist to evaluate cognitive difficulties, strengths and weaknesses

Treatment[1]

Treatments recommended for a number of the symptoms a child with Kabuki syndrome might experience are described below [1].

Feeding Difficulties

  • Thickened food and ensuring that children are sitting in such a way after a meal that will improve their reflux symptoms
  • For children with severe feeding difficulties a gastronomy tube (G-tube) may be used. A G-tube is a tube inserted through the belly that brings nutrition directly to the stomach. It's one of the ways doctors can make sure kids who have trouble eating get the fluid and calories they need.

Seizure

  • Standard anti-seizure medication

Hearing Loss

  • Determining if there are any inner ear abnormalities
  • Annual hearing assessments

Immunoglobulin Deficiency

  • Scheduled delivery of is a product made up of antibodies that can be given intravenously (through a vein). Antibodies are proteins that your body makes to help you fight infections

Genetic Counselling

If a child is suspected of having Kabuki syndrome or if there is a family history of Kabuki syndrome the family may benefit from genetic counselling. Genetic counsellors are healthcare professionals trained to provide patients with information regarding genetic disorders and guide them in their process of making informed medical and personal decisions.[6] Genetic counsellors work with the patient to understand complex genetic information along with providing emotional support as the patient makes decisions.[6] Genetic counsellors can assist in providing information about as well as facilitating pre-conception options, prenatal options and genetic testing.[6]

Genetic Testing

There are tests that look for variants in the two genes known to cause Kabuki syndrome. Three possible results can come from this type of genetic test:

  • A positive test results means that a variant was found in one of these genes. This would help confirm the diagnosis of Kabuki syndrome
  • A negative test results means that no changes were found in either gene. This does not rule out the diagnosis of Kabuki syndrome because of the proportion of cases that have unknown causes
  • A variant of uncertain significance (VUS) means that a change was found in one of these genes, but we are not sure at this time whether this is the cause of Kabuki syndrome. This type of result is something that can change over time as we gain more information and insight into the genes that are known to cause Kabuki syndrome. If someone receives a VUS it can be recommended that they recontact their health care provider in a few years time to see if there is new information available.

Resources

Below are resources for information and support regarding Kabuki syndrome, as well as understanding genetics and genetic counselling.

Kabuki Syndrome Network
8060 Struthers Crescent
Regina Saskatchewan S4Y 1J3
Canada
Phone: 306-543-8715
Email: margot@kabukisyndrome.com
http://www.kabukisyndrome.com

All Things Kabuki

5155 E. Capon Circle

Wasilla, AK 99654 USA

Phone: (907) 360-8590

Email: [[1]]

Website: https://www.allthingskabuki.org

Supporting Aussie Kids with Kabuki Syndrome

PO Box 90

South Australia, 5097 Australia

Phone: (042) 260-8858

Email: [[2]]

Website: https://www.sakks.org

Genetics Home Reference
Help Me Understand Genetics
https://ghr.nlm.nih.gov/primer
Kabuki Syndrome

https://ghr.nlm.nih.gov/condition/kabuki-syndrome

To locate a genetics clinic near you, please visit https://www.cagc-accg.ca (Canada) or https://www.nsgc.org (United States).

References

  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 Adam MP, Hudgins L, Hannibal M. Kabuki Syndrome. 2011 Sep 1 [Updated 2013 May 16]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: https://www.ncbi.nlm.nih.gov/books/NBK62111/
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 Kabuki syndrome. Genetics Home Reference. October, 2013; http://ghr.nlm.nih.gov/condition/kabuki-syndrome.
  3. 3.0 3.1 3.2 "Help Me Understand Genetics - Genetics Home Reference." U.S. National Library of Medicine. National Institutes of Health, n.d. Web. 12 Jan. 2017, https://ghr.nlm.nih.gov/primer#
  4. 4.0 4.1 "National Institutes of Health (NIH)." National Institutes of Health. U.S. Department of Health and Human Services, n.d. Web. 12 Jan. 2017, https://www.nih.gov/
  5. Kabuki syndrome. Genetics Home Reference. October, 2013; http://ghr.nlm.nih.gov/condition/kabuki-syndrome.
  6. 6.0 6.1 6.2 How A Genetic Counselor Could Help You or Your Family. (n.d.). Retrieved January 12, 2017, from http://www.nsgc.org/page/patients