Kabuki syndrome

Kabuki syndrome (also previously known as kabuki makeup syndrome, KMS, or Niikawa-Kuroki Syndrome) is a pediatric congenital disorder of genetic origin. It affects multiple parts of the body with varying symptoms and severity, although the most common is the characteristic facial appearance. It is quite rare, affecting roughly one in 32,000 births. It was first identified and described in 1981 by two Japanese groups, led by 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. Kabuki syndrome (also previously known as kabuki makeup syndrome, KMS, or Niikawa-Kuroki Syndrome) is a pediatric congenital disorder of genetic origin. It affects multiple parts of the body with varying symptoms and severity, although the most common is the characteristic facial appearance. It is quite rare, affecting roughly one in 32,000 births. It was first identified and described in 1981 by two Japanese groups, led by 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. Specific symptoms for Kabuki syndrome vary, with large differences between affected individuals. Most people with Kabuki syndrome have distinctive facial features that include arched eyebrows, long eyelashes, elongated eyelids with lower lids that turn out, prominent ears, a flat tip of the nose, and a downward slant to the mouth. Other common symptoms are skeletal abnormalities, short stature, heart defects, feeding difficulties and a failure to thrive, vision and hearing difficulties, weak muscle tone (hypotonia), small head size (microencephaly), and frequent infections. Mild to moderate intellectual disability and mild to severe developmental delay are often associated with Kabuki syndrome. Infants and young children often experience difficulties relating to hypotonia, feeding issues/failure to thrive, infections, surgical repair of heart and palate defects and developmental delays. Young children with Kabuki syndrome benefit from early intervention services. School age children tend to have less medical issues requiring hospitalization, though frequent infections, hearing loss and feeding issues occur. In addition, intellectual impairment, difficulty with visuospatial tasks and maintaining attention usually require an IEP (individualized education plan) if the child attends public school. Older children and adults report difficulties with anxiety. Endocrine abnormalities and immune system abnormalities such as ITP (idiopathic thrombocytopenia) and CVID (common variable immune deficiency) are medical issues that tend to present in older children, adolescents and adults. Kabuki syndrome is one of the mendelian disorders of epigenetic machinery. Most cases of Kabuki syndrome occur de novo, that is, the parents are unaffected and the gene was mutated early in embryological development. It is classified as a Mendelian disorder because individuals who have a de novo mutation in a specific gene pass the mutation to offspring according to the laws of Mendelian inheritance. There are two known genes that cause Kabuki syndrome: KMT2D and KDM6A. However, about 30% of cases have no identifiable causative mutation. It is estimated that between 55-80% of cases of Kabuki syndrome are caused by mutations in the KMT2D gene, formerly known as the MLL2 gene. This gene is located on chromosome 12. A mutation in the KMT2D gene results in a non functional lysine (K)-specific methyltransferase 2D enzymeand demonstrates an autosomal dominant pattern of inheritance. Another 2-6% of cases are related to mutations in the KDM6A gene, located on the X chromosome. This mutation produces a nonfunctional lysine (K)-specific demethylase 6A enzyme and demonstrates an X-linked dominant pattern of inheritance. The KMT2D and KDM6A 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. Under normal circumstances, these enzymes transfer methyl groups on and off histones to regulate genes via epigenetic pathways. When the genes that encode these enzymes are mutated, epigenetic activation of certain developmental genes is impaired and developmental abnormalities occur, leading to the characteristics of Kabuki syndrome patients. The specific developmental genes that are affected by the impaired epigenetic mechanisms in Kabuki syndrome are not yet fully known. There are hundreds of different mutations that have been identified in Kabuki syndrome patients. Most of these mutations are in the KMT2D gene and involve a change in amino acid sequence that creates a shortened and nonfunctional chromatin-modifying enzyme. A consensus on clinical diagnostic criteria for Kabuki syndrome (KS) was defined in December 2018 by an international group of experts. The authors propose that a definitive diagnosis can be made in an individual of any age with a history of infantile hypotonia, developmental delay and/or intellectual disability, and one or both of the following major criteria: (1) a pathogenic or likely pathogenic variant in KMT2D or KDM6A; and (2) typical dysmorphic features (defined below) at some point of life. Typical dysmorphic features include long palpebral fissures with eversion of the lateral third of the lower eyelid and two or more of the following: (1) arched and broad eyebrows with the lateral third displaying notching or sparseness; (2) short columella with depressed nasal tip; (3) large, prominent or cupped ears; and (4) persistent fingertip pads. Further criteria for a probable and possible diagnosis, including a table of suggestive clinical features, were included in the publication. The original description of Kabuki syndrome by Niikawa et al defined five cardinal manifestations, although some of these “cardinal manifestations” may or may not be present in a patient with Kabuki syndrome.