Kabuki syndrome

Synonyms

3

Overview

Kabuki syndrome (Kabuki makeup syndrome, KMS or Niikawa–Kuroki syndrome), is a pediatric congenital disorder of suspected genetic origin with multiple congenital anomalies and intellectual disabilities. It is quite rare, affecting roughly one in 32,000 births. It was identified and described in 1981 by two Japanese groups, led by the scientists Norio Niikawa and Yoshikazu Kuroki. It is named Kabuki Syndrome because of the facial resemblance of affected individuals to stage makeup used in Kabuki, a Japanese traditional theatrical form.

Symptoms

People with the syndrome have an unusual facial appearance, characterised by long palpebral fissures (openings for the eyes) with eversion, or turning out, of the outer third of the lower eyelids, and arched eyebrows. Affected children also have a broad and depressed nasal tip, large prominent earlobes, abnormalities of the inner ear and a cleft or high-arched palate. Children with Kabuki syndrome may be small at birth and remain small for their age. They may develop scoliosis (curvature of the spine), have a short fifth finger, abnormalities of the vertebrae, hands and hip joints, and suffer from recurrent otitis media (glue ear) in infancy. Some children have congenital heart defects.

People with Kabuki syndrome have developmental delay and intellectual disability that range from mild to severe. Affected individuals may also have seizures, an unusually small head size (microcephaly), or weak muscle tone (hypotonia). Some have eye problems such as rapid, involuntary eye movements (nystagmus) or eyes that do not look in the same direction (strabismus).

A wide variety of other health problems occur in some people with Kabuki syndrome. Among the most commonly reported are heart abnormalities, frequent ear infections (otitis media), hearing loss, and early puberty.

Causes

Kabuki syndrome is considered autosomal dominant disorder and can be caused by a loss-of-function mutation in two different genes. Hundreds of mutations have been identified in diagnosed Kabuki syndrome patients for these genes. Most of these mutations involve a change in amino acid sequence that codes for a premature stop codon, and therefore nonfunctional, short enzymes. KMT2D, formerly known as the MLL2 gene, is located on chromosome 12 and is one of the genes involved in the development of this disorder. A mutation in the KMT2D gene results in a loss of function for the protein this gene codes for, which is a lysine (K)-specific methyltransferase 2D enzyme. KDM6A is another gene, that when mutated, can lead to Kabuki syndrome. This mutation produces a nonfunctional lysine (K)-specific demethylase 6A. This gene is located on the X chromosome. These two genes belong to a family of genes called chromatin-modifying enzymes. Specifically these genes code for a histone methyltransferase (KMT2D) and a histone demethylase (KDM6A), and play a part in the regulation of gene expression. These enzymes transfer methyl groups on and off histones to regulate genes via epigenetic pathways. Epigenetic activation of certain developmental genes is impaired by loss of either enzyme and developmental abnormalities occur, leading to the characteristics of Kabuki syndrome patients. The specific developmental genes have not been fully identified. It is seen that a majority of these cases are due to de novo mutations (those present in the subject but not in the parents). It is important to note that a percentage of patients did not exhibit a mutation in either gene; other causes are currently being researched.

 

Diagnosis

The diagnosis of Kabuki syndrome relies on physical exam by a physician familiar with the condition and by radiographic evaluation, such as the use of x rays or ultrasound to define abnormal or missing structures that are consistent with the criteria for the condition (as described above). A person can be diagnosed with Kabuki syndrome if they possess characteristics consistent with the five different groups of cardinal symptoms: typical face, skin-surface abnormalities, skeletal abnormalities, mild to moderate mental retardation, and short stature. Although a diagnosis may be made as a newborn, most often the features do not become fully evident until early childhood. There is no laboratory blood or genetic test that can be used to identify people with Kabuki syndrome.

Prognosis

The abilities of children with Kabuki syndrome vary greatly. Most children with the condition have a mild to moderate intellectual impairment. Some children will be able to follow a regular education curriculum, while others will require adaptations or modifications to their schoolwork. Many older children may learn to read at a functional level. The prognosis of children with Kabuki syndrome depends on the severity of the symptoms and the extent to which the appropriate treatments are available. Most of the medical issues regarding heart, kidney or intestinal abnormalities arise early in the child's life and are improved with medical treatment. Since Kabuki syndrome was discovered relatively recently, very little is known regarding the average life span of individuals affected with the condition, however, present data on Kabuki syndrome does not point to a shortened life span.

Treatment

The treatments of Kabuki syndrome are still being developed due to its genetic nature. The first step to treatment is diagnosis. After diagnosis, the treatment of medical conditions can often be treated by medical intervention. There are also options in psychotherapy for young children with this disorder, as well as the family of the child. Genetic counseling is available as a preventative treatment for Kabuki syndrome because it can be inherited and expressed by only having one copy of the mutated gene.