Kabuki+Syndrome

=KABUKI SYNDROME=

Name of Condition
toc Kabuki Syndrome or Niikawa-Kuroki Syndrome

 Kabuki Syndrome, also less commonly known as Niikawa-Kuroki Syndrome, is a genetic disorder that is characterized by abnormal facial features, mental retardation, and other physical abnormalities ("Kabuki syndrome," 2011). . The facial features associated with Kabuki Syndrome are broad, arched eyebrows, elongated eyelids with the lower eyelid being upturned, a cleft palate, a flat, broad nose, and unnaturally large earlobes (Adam et al 2011 ). The cause of this genetic disorder was recently discovered to be a mutation on the MLL2 gene (Hannibal et al 2011 ). Kabuki syndrome is named for the facial features that resemble that of the traditional makeup worn in Kabuki theater in Japan. This disease is diagnosed in children and affects only a very small percent of the world population, with the highest occurrence rate in Japan (Niikawa et al 1981 ).

History of the Disease
Kabuki Syndrome was first documented by Japanese researchers in 1981 in two separate case studies. Both researchers, Niikawa and Kuroki, were doing observations on unrelated children that were reported as having facial and skeletal abnormalities and were mentally retarded. The study conducted by Niikawa reported on five unrelated Japanese children who displayed similar physical traits as well as varying degrees mental retardation. Niikawa also reported many other characteristics that occurred less frequently, such as scoliosis and widely spaced teeth. All of the children observed by Niikawa appeared to be probands; the disease did not appear anywhere else in their family tree. ( Niikawa et al 1981 ). <span style="font-family: 'Arial','sans-serif'; font-size: 16px;"> <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">The research done by Kuroki also showed similar results; many of the children exhibited the same characteristics observed by Niikawa. Kuroki hypothesized that the disorder was brought on by environmental factors or was possible the result of an X-linked method of inheritance ( <span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">Kuroki et al 1981 <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">).

<span style="font-family: 'Arial','sans-serif'; font-size: 16px;"> <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">A follow-up study conducted by Niikawa in 1988 examined 62 patients that had been diagnosed with Kabuki Syndrome. This study primarily focused on determining the pattern of inheritance. The subjects that took part in the study were a mixture of male and female and were of Japanese and non-Japanese ethnicity. Among the subjects in the study the disorder was found to be distributed evenly between males and females, but the occurrence rate was higher in those of Japanese descent with 58 of the 62 participants being Japanese. Nearly all subjects in the study were probands, having no history of the disease in their pedigree. No environmental factors were found to be the cause of the disorder. Based upon these findings, Niikawa concluded that the most likely mechanism of inheritance was an autosomal dominant disorder and each person expressing the trait represented a new mutation. The study also proposed the possibility of a pseudoautosomal mechanism of inheritance. ( <span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">Niikawa et al 1988 <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">).

<span style="font-family: 'Arial','sans-serif'; font-size: 16px;"> <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">In 1995 a study of ten Kabuki Syndrome patients, all of European descent, showed evidence of an autosomal dominant inheritance mechanism. All subjects displayed the typical facial features associated with Kabuki Syndrome, as well as delayed physical development and varying degrees of mental retardation. Three of the subjects in the study were reported as having a familial history of Kabuki Syndrome. In these subjects, either a parent or close relative also displayed some physical characteristics of the disorder. The results of the study led researchers to favor autosomal dominance, with varied expressivity amongst those affected ( <span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">Ilyina et al 1995 <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">). A case study conducted in 2000 identified evidence of a familial link Kabuki Syndrome. The subjects of the study were an 18-month old girl who exhibited all the classic symptoms of Kabuki Syndrome, and her mother who exhibited many of the same characteristics to a lesser extent. The hallmark facial features of Kabuki Syndrome and low intelligence levels were observed in both individuals. Further investigation into their family tree showed evidence of the disorder, which indicated a dominant pattern of inheritance (<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">Courtens et al 2000 <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">). <span style="font-family: 'Arial','sans-serif'; font-size: 16px;"> <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">A case study of 18 children diagnosed with Kabuki Syndrome was conducted in 1998. The objective of the study was to determine the phenotypic displays that are common among patients with the disease, and to determine how the effects of the disorder can be managed. The study followed 18 children (10 girls and 8 boys) who were distributed amongst several ethnic groups, and were all probands for the disease. The characteristics observed extended from facial characteristics to physical growth, intelligence and cognitive development, immune system complications, and several other traits. The research results indicated that patients with Kabuki Syndrome all exhibit the hallmark facial features associated with the disease, most develop both physically and mentally at slower rates, have anomalies present in their fingerprints, and are prone to many health issues. ( <span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">Kawame et al 1999 <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">).

<span style="font-family: 'Arial','sans-serif'; font-size: 16px;"> <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">In 2010 the autosomal dominant pattern of inheritance was confirmed by a group of researchers that used exome sequencing to pinpoint the gene responsible for Kabuki Syndrome. Researchers sequenced the exomes of ten subjects that had been diagnosed with Kabuki Syndrome. The subjects were of varied ethnic backgrounds. The results of the sequencing found in seven of the patients, a frame shift mutation had occurred in the MLL2 gene. ( <span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">Ng et al 2010 <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">).

<span style="font-family: 'Arial','sans-serif'; font-size: 16px;">Symptoms
<span style="font-family: 'Arial','sans-serif'; font-size: 16px;"><span style="font-family: 'Arial','sans-serif'; font-size: 16px;">There are five hallmark symptoms of Kabuki Syndrome. It is characterized by unusual facial characteristics that resemble the traditional makeup worn by actors in Japanese Kabuki theatre. These facial features include arched eyebrows, elongated eyelids with an inverted lower lid, long eyelashes, a broad nose with a depressed tip, and large, cupped ears. These facial characteristics occur in 100% of people with Kabuki Syndrome ( <span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">Niikawa et al 1981 <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">). Other facial features that occur in some Kabuki Syndrome patients are cleft palates, widely spaced teeth, low hairlines, and an epicanthal fold of the eyelid ("Kabuki syndrome," 2011). <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">. Other hallmarks of Kabuki Syndrome are skeletal anomalies, mild to moderate levels of mental retardation, and dwarfed stature. (<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">Niikawa et al 1981 <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">).

<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;"> There are a multitude of other symptoms that are often exhibited by patients with Kabuki Syndrome. Some dental problems include cleft palates or high palates, hypodontia, widely spaced teeth, conical or screwdriver-shaped incisors, and a prominent lower lip (Matsune et al 2001; Kawame et al 1999; Armstrong et al 2005). Another common feature associated with the disorder is dermatoglyphic anomalies, or unusual fingerprint patterns. In patients with Kabuki Syndrome, abnormalities in the fingerprints are usually an excessive number of ulnar loop patterns and hypothenar loop patterns, and the finger pads are very prominent (Kuroki et al 1981; Kawame et al 1999). Other common problems that can occur alongside Kabuki Syndrome are scoliosis, finger deformities, epilepsy, and heart deformities amongst other things (Armstrong et al 2005; Kawame et al 1999; Lodi et al 2009; Cuesta et al 2011).

<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">Diagnosis
<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">The 1988 study by Niikawa et al names five diagnostic criteria: abnormal facial characteristics (100% occurrence), skeletal anomalies (92% occurrence), dermatoglyphic abnormalities (93% occurrence), mild to moderate mental retardation (92% occurrence), and dwarfed stature (83% occurrence) (Niikawa et al 1988). Kabuki syndrome is clinically diagnosed based upon the presence of the hallmark facial characteristics. These features are common in all patients with KS. Other symptoms that are commonly found in individuals with KS can also be used to help in the diagnosis (Kashiwagi et al 2004; Kawame et al 1998). The diagnosis is rarely made in newborns because the facial features become more pronounced as the individual ages. The definitive diagnosis is typically not made until about two years of age (Vaux et al 2005).

<span style="font-family: 'Arial','sans-serif'; font-size: 16px;">Treatment
<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">In Kabuki Syndrome the facial deformities are not typically treated, unless the patient has cleft lip and or palate reconstruction. However, the intracranial deformities associated with KS can lead to other problems such as seizures, which can be easily controlled with normal epilepsy treatments (Ogawa et al 2003).

<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;"> Children with Kabuki Syndrome often have a high affinity for vocal and instrumental music and some have musical talents, even when this ability does not occur in siblings or other family members. It has been found that music is an effective tool for teaching those affected by the disorder (White et al 2004).

<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">Management
<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">People with Kabuki Syndrome typically have weakened immune systems and are more prone to infectious disease. It is recommended to have regular evaluations of the individual’s health (Hoffman et al 2005). Those with KS are also more prone to heart defects, so it is recommended to have heart evaluations to check for congenital heart defects (Digilio et al 2001).

<span style="font-family: 'Arial','sans-serif'; font-size: 16px;">Inheritance
<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;"><span style="font-family: 'Arial','sans-serif'; font-size: 16px;">Kabuki syndrome is a rare genetic disorder that is caused by a mutation on the MLL2 gene. Most reported cases of Kabuki Syndrome appear to be sporadic, the affected individual being the only person in the family that has the disorder. Some reports though have shown families in which the disease is inherited via autosomal dominance. In these families the trait is typically shown to have variable expressivity. ( <span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">Courtens et al 2000 <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">). <span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;"> <span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;"> <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">In a case study of a Romanian family, Kabuki Syndrome appeared in three generations. The lineage of the disorder was from the maternal grandfather to the mother to her son. All three subjects had the classic facial features of Kabuki Syndrome, but none of them displayed any other physical deformities or developmental and mental problems. Researchers concluded that the trait had been inherited via an autosomal dominant mechanism, and the subjects represented a mild variation of the disorder. ( <span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">Belengeanu et al 2005 <span style="font-family: 'Arial','sans-serif'; font-size: 16px;"> ).

<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;"> <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">A case study of a Taiwanese family in which the father and 3 children displayed Kabuki Syndrome further supports the mechanism of autosomal dominant inheritance. The parents in the study were a 29 year old normal mother and a 30 year old Kabuki father. The father had the characteristic facial features and a lower-than-average level of intelligence. He also displayed some other traits associated with Kabuki Syndrome, but all were mild in level of expression. The physical development of the eldest son was normal, but he had moderate mental retardation, with an IQ of 57. He also possessed the facial features of KS. The second son had similar characteristics, but his physical development was delayed by two years. He also had moderate mental retardation and various other traits. The daughter was by far the most severe case of Kabuki Syndrome. Her facial features were the most pronounced and she had severe mental retardation, with an IQ of 31. She also displayed many other problems associated with KS ( <span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">Hou 2003 <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">). The pattern of inheritance observed in the family was autosomal dominant, with the second generation having much more severe phenotypes.

<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;"> <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">Studies of the inheritance of Kabuki Syndrome in twins have shown that the gene mutation can occur at different times in development. A case study conducted by Hannibal et al observed the characteristics of two monozygotic (identical) twins that had been diagnosed with KS. Both twins exhibited developmental delay, heart disease, and certain dental abnormalities. However the twins were discordant for hearing loss and for a malformation in the central nervous system ( <span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">Hannibal et al 2011 <span style="font-family: 'Arial','sans-serif'; font-size: 16px;"> ). A similar study of identical twins showed concordance in some traits but discordance in others. In this study both twins carried a mutation on chromosome 13, as did their mother who was phenotypically normal. This led researchers to believe that other chromosomes may play a role in the inheritance of Kabuki Syndrome (<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">Lynch et al 1995). In a 2002 study of a different set of monozygotic twins only one was positive for Kabuki Syndrome. In this twin, all five hallmark of the disorder were observed, but the other twin exhibited none of the symptoms. Accounting for other studies of identical twins, the researchers concluded that, in the case of identical twins, the mutation causing Kabuki Syndrome can occur either before or after the zygote divides (Shotelersuk et al 2002).

<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;"> Those with Kabuki Syndrome have a much greater probability of having offspring affected by KS. If the parent is affected with KS, then their children have a 50% chance of also inheriting the disorder. In subjects that are the only family member affected by Kabuki Syndrome it is speculated that the disorder is caused by a de novo mutation or possibly by the Non-Mendelian mechanism of germline mosaicism. However, to date no reports of a germline mosaic method of inheritance have been made (Adam et al 2011).

<span style="font-family: 'Arial','sans-serif'; font-size: 16px;">Molecular Basis/Pathology
<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">The search for the molecular basis of Kabuki Syndrome began in the early 2000’s. However, these early attempts led to inconclusive or in some cases false results. Early research focused on congenital heart defects in KS patients and included brief chromosomal analysis (Digilio et al 2001). The results of the analysis appeared normal in all cases and results of fluorescence in situ hybridization (FISH) ruled out microdeletion of 22q11. By 2005 several research teams published papers refuting earlier claims to the cause of KS (Sanlaville et al 2005; Miyake et al 2005; Kuniba et al 2008; Cusco et al 2008). Sanlaville’s team focused on trying to replicate the studies of Milunsky and Huang, which indicated an 8p22-8p23.1 duplication. Sanlaville’s team failed to find any duplication in 24 Caucasian KS patients (Sanlaville et al 2005). The research done by Miyake et al also attempted to replicate the findings of Milunsky and Huang in Asian patients and their parents. The findings did not exhibit any duplications and asserts that said duplications are not the likely pathology of the disease (Miyake et al 2005). <span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;"> Research done by Kuniba et al tried to evaluate patients for mutations in genes involved in the RASMAPK pathways, reason being that other diseases with congenital deformities involve these pathways. The findings of this study indicated that mutations in the genes in the pathway were not likely causes of KS (Kuniba et al 2008). The study conducted by Cusco et al tested Spanish patients for genomic imbalances using FISH and microarrays. The results confirmed that 8p22-8p23.1 duplications were not the cause of KS. They were unable to identify possible pathways <span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;"> (Cusco et al 2008).

<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;"> <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">Through extensive exome sequencing the gene for Kabuki Syndrome has been pinpointed. Kabuki Syndrome is caused by a mutation on the MLL2 gene. Two types of mutations that can occur on this gene are nonsense mutations and frame shift mutations. In the study, the exomes of ten unrelated of were sequenced. Seven of the individuals were of European descent, two of Hispanic descent, and one of mixed Haitian and European descent. An initial attempt to locate the suspected gene was carried out via enrichment by hybridization (as an alternative to PCR). This generated for each sample 40 x coverage of the exome. To analyze the data they searched only for nonsynonymous variants, coding indels, and splice acceptor and donor site mutations. These parameters lead to only one potential gene which was shared in all ten exomes. This was the MUC16 gene; however, researchers ruled this as a false positive because of the gene’s immense size. A second attempt at locating the gene was carried out by looking for genes that were shared by the individuals and contained previously unidentified variants. The results of this yielded the MLL2 gene. Confirmation of the MLL2 gene was done through Sanger sequencing and array comparative genomic hybridization (aCGH). A loss-of-function mutation was identified in nine of the ten samples. To confirm these results the researchers then sequenced the exomes of 43 additional Kabuki patients. In 26 of the 43, there appeared to be nonsense or frame shift mutations on the MLL2 gene. They also tested the chromosomes of 190 non-Kabuki patients and the results were negative for the mutations. ( <span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">Ng et al 2010 <span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">). The findings of this research indicate that the MLL2 gene is the location of the mutations that cause Kabuki Syndrome.

<span style="font-family: 'Arial','sans-serif'; font-size: 16px;">Recent Advancements in Research
<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;"><span style="font-family: 'Arial','sans-serif'; font-size: 16px;">A recent study conducted on 45 Kabuki patients from the Netherlands and Belgium aimed to determine the type of mutations in the MLL2 gene. DNA was extracted from the patients and their parents from peripheral blood samples. Mutation screening was then conducted on the entire MLL2 gene via direct sequence analysis in both directions. The primers used for all 54 exons were tagged with M13 extensions to customize the analysis. PCR was then carried out on all samples and the results were compared to a known MLL2 sequence. Parents of the individuals were also tested for mutations on the gene through sequence analysis. Of the 45 patients, 34 had heterozygous mutations, most of which were nonsense or frameshift mutations. The results also indicated a new type of mutation: splice-site mutations which skip exons. In the future, Paulussen’s team of researchers intends to revisit the case study patients to look for exon deletions through higher resolution microarrays ( <span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">Paulussen et al 2010 <span style="font-family: 'Arial','sans-serif'; font-size: 16px;"> ).

<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;"> <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">A 2011 study continued on the research conducted by Ng et al. In this study, all 54 exons of the MLL2 gene were sequenced for 34 Kabuki patients. DNA was extracted from blood lymphocytes of both the patients and their parents. The primers used in this experiment were created to amplify the exons and adjacent splice sites. PCR was conducted and its products were sequenced. The results found that 19 of the 34 patients had heterozygous mutations at the MLL2 gene. Nonsense, frameshift, missense, and splice-site mutations were all identified in this experiment. Of the 12 families that were tested, 11 appeared to have a de novo mutation. Fifteen of the patients tested negative for the MLL2 gene mutation. The researchers speculate that further analysis of the exome sequencing will reveal heterogeneity in Kabuki Syndrome ( <span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">Yun et al 2011).

<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;"> <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">A screening of 110 families with Kabuki Syndrome found that 74% were positive for MLL2 mutations. The MLL2 positive and MLL2 negative cases did not differ clinically, except that there were more renal anomalies in MLL2 positive patients. The purpose behind this study was to: determine the range of MLL2 mutations that cause KS, determine if the genotype would predict the phenotype, whether MLL2 positive and negative cases differed clinically, and to identify MLL2 negative cases for future gene discovery research. The study was carried out by amplifying DNA with TAQ DNA polymerase and then sequencing it. MLL2 negative samples were analyzed using arrays ( <span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">Hannibal et al 2011 <span style="font-family: 'Arial','sans-serif'; font-size: 16px;">).

<span style="font-family: 'Arial','sans-serif'; font-size: 16px;">Population Genetics
<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">Kabuki Syndrome is most prevalent in the Japanese with an occurrence rate of 1/32,000 live births (Niikawa et al 1988). It is estimated that the occurrence rate in Australia and New Zealand is 1/86,000 births. This difference in rate was attributed to under-diagnosis of the disease (<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">White et al 2004). There are reports of patients with Kabuki Syndrome of European, Asian, and Hispanic descent. Kabuki Syndrome affects men and women in equal rates (Niikawa et al 1988).

<span style="font-family: 'Arial','sans-serif'; font-size: 16px;">Additional Resources
<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">[|www.kabukisyndrome.com]

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<span style="color: #000000; font-family: 'Arial','sans-serif'; font-size: 16px;">References
<span style="color: #000000; display: block; font-family: 'Arial','sans-serif'; font-size: 16px; height: 1px; left: -40px; overflow: hidden; position: absolute; top: -25px; width: 1px;"> They were unable to identify possible pathways