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A characteristic face that resembles the makeup of traditional Japanese Kabuki theater actors, long eyelid gaps that optically enlarge the eyes, arched, wide eyebrows thinned on the sides – these are some of the external features of people suffering from a rare genetic disease called Kabuki syndrome or Niikawa-Kuroki syndrome.
This disease was first described by Japanese doctors, but its occurrence, although very rare, is recorded all over the world. According to medical statistics, it develops 1 in 32-80 thousand births.
Three-quarters of the cases of Kabuki syndrome are caused by a mutation in the MLL2 gene, which is located on chromosome 12q13.2. But not all patients have this mutation, which, according to experts, shows that no other gene mutations have been known that are responsible for the development of the disease. Kabuki syndrome is called a disease of full penetration and variable expression. In other words, sick people have all the characteristic features (full penetration), but with varying severity (variable expression). This is what causes the most problems with the correct diagnosis of the disease. Until recently, no genetic tests in this area were performed in Poland, and concerned parents went to Germany, Belgium, the Netherlands, England or France to get the diagnosis. Currently, they can be performed in the country and in a growing network of laboratories. In the first stage, the study consists in sequencing the entire coding region of exon 39 of the MLL2 gene (the current name KMT2D), in which the most common mutations occur.
The disease is inherited in an autosomal dominant fashion, which means that one defective MLL2 gene is enough to develop Kabuki syndrome. Most mutations arise sporadically. The risk of having a second child with Kabuki syndrome is slight but not excluded. This is because either parent may have cells with the mutated gene. If it is known that the mutation in MLL2 comes from a parent, the risk of having an affected child is 50 percent.
Mysterious gene and Kabuki syndrome
The MLL2 gene is called myeloid / lymphoid or mixed-lineage leukemia 2 and contains information (instructions) on how to make a protein found in almost all tissues of the body. For example, the MLL2 protein is responsible for the synthesis of an enzyme such as histone methyltransferase, whose task is to modify proteins called histones that bind to DNA and shape chromosomes. By adding a molecule known as the methyl group to histone, it regulates the activity of genes that are essential for the proper development and functioning of the body. This enzyme probably also activates other genes responsible for the proper development of the human body. A mutation in the MLL2 gene can also result in breast and colorectal cancers, but this does not affect the development of cancer in patients with Kabuki syndrome.
Children are born healthy, but …
Most babies who develop Kabuki syndrome over time are born healthy babies. Although sometimes muscle weakness is evident right after childbirth. Problems arise when the mother wants to feed the baby. Then it turns out that the child sucks poorly, pours food or even vomits. It makes the child develop poorly and does not gain weight. As a child grows, five basic groups of symptoms can be distinguished.
1. Face dysmorphic features – patients have large eyelid fissures, which make their eyes appear unnaturally large, eyebrows are arched, wide and a bit thinner on the sides. There is a skin fold (diagonal wrinkle) at the corner of the eye near the nose. The baby’s nose is usually short, wide, with a slightly sunken tip. The raised mouth is also characteristic, usually open and protruding or so-called. cup-shaped (flat and round, like an ear against a cup).
2. Abnormal skeleton structure – children have numerous back problems. Scoliosis, kyphosis, deformity of the vertebrae or ribs may occur. Another prominent feature is the short fingers. There is also excessive mobility in the joints, and over time, hip dysplasia occurs.
3. Fingerprints on the fingers the hands are abnormal, the fingertips are raised, and they are called the fetal pads.
4. There is an intellectual disability in moderate or mild form.
5. Little weight gain and poor growth are also characteristic of the syndrome.
Organ disorders in Kabuki syndrome
Children suffering from Kabuki syndrome may also have numerous organ and systemic defects. Often there are heart defects (e.g. aortic stenosis, defects in the interatrial septum), diseases of the genitourinary system (kidney defects, connection between the vagina and the end of the colon in girls, micropenis in boys), digestive system (rectal or duodenal atresia), ophthalmic (strabismus, ptosis, blue sclera) and dental abnormalities (widely spaced teeth, severe malocclusion). Sometimes teeth do not develop at all. The abnormalities also affect the brain.
Mental disorders and functional problems are a separate problem. Sick children are often delayed in psychomotor development, they have problems with moving, speaking and acquiring new skills. Troublesome for caregivers and dangerous for children is the increased susceptibility to infections, which results from the reduced immunity of the organism. Children with the syndrome more often than their healthy peers suffer from autoimmune diseases, such as vitiligo or idopathic thrombocytopenic purpura.
There are also endocrine disorders, such as premature puberty in girls or hypothyroidism. In old age, the characteristic features of the face soften, so that the face does not differ from the appearance of a healthy person. Unfortunately, there is abdominal obesity, which is more visible when the patient is short than in a tall person.
Diagnostics to rule out Kabuki syndrome
Kabuki syndrome is diagnosed based on the exclusion of other conditions that may have similar symptoms.
Prenatal diagnosis, although technically feasible, is usually performed when one of the child’s parents has previously confirmed the presence of a mutation in the MLL2 gene. Diagnostics in a conceived child is considered invasive because it involves taking the fetal cells and examining whether the child has inherited the defective gene.
Caring for a patient with Kabuki syndrome
From the first days of life, children with suspected or already diagnosed Kabuki syndrome must be provided with interdisciplinary medical care. Already at the first feeding problems, it is necessary to consult a gastroenterologist, who will be able to assess whether the child has an open digestive tract, whether he sucks properly, whether he has problems swallowing food and whether he is suffering from gastro-oesophageal reflux. It is also necessary, especially when the child is downpouring, to use proper nutrition, i.e. to introduce thickened mixtures of modified milk marked with the symbol AR.
Since children often have heart defects, care is also needed from a pediatric cardiologist who will be able to make a decision about the need for surgery. Another specialist a child should see is an orthopedic surgeon who will instruct parents on how to handle their child when he or she starts to sit or walk. It is worth remembering about regular hip joints examinations in order to prevent their deformation. Older children must be carefully supervised by their guardians to prevent injuries. The care of an endocrinologist and a neurologist is also a necessity.
When a child starts going to school, learning difficulties arise. A psychologist or a psychiatrist can help to solve them, at least partially. The teacher must be informed about the child’s illness. And when you need to see a dentist, you need to inform the doctor about the syndrome so that he can use drugs to protect the child from another infection.
These are just a few examples of how specialist patient care must be developed. As with most rare diseases, the burden of childcare falls largely on the shoulders of the parents.