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Last updated: 7/6/2023
Years published: 1992, 2000, 2010. 2016, 2019, 2023
NORD gratefully acknowledges Margaret Adam, MD, FAAP, FACMG, Professor of Pediatrics, Division of Genetic Medicine, University of Washington School of Medicine and Seattle Childrenโs Hospital for assistance in the preparation of this report.
Summary
Kabuki syndrome is a rare, multisystem disorder characterized by multiple abnormalities including distinctive facial features, growth delays, varying degrees of intellectual disability, skeletal abnormalities and short stature. A wide variety of additional symptoms affecting multiple different organ systems can potentially occur. The specific symptoms associated with Kabuki syndrome can vary greatly from one person to another. To date, changes (pathogenic variants or mutations) in one of two genes lead to Kabuki syndrome. The first gene is KMT2D (formerly MLL2) and the second gene, which accounts for fewer cases of Kabuki syndrome, is KDM6A. Clinical genetic testing is available for both genes.
Introduction
Kabuki syndrome was first reported in the medical literature in 1981 by Japanese physicians. The disorder was originally called Kabuki-makeup syndrome because the facial features of many affected children resembled the makeup used by actors in kabuki, a form of Japanese theater. The term โmakeupโ has since been dropped and the preferred term for the disorder is Kabuki syndrome.
Some features of Kabuki syndrome are present at birth (congenital). Other features become apparent as an affected child ages. The specific findings and the severity of those findings can vary from one person to another. A wide variety of findings affecting multiple organ systems of the body can potentially occur. It is important to note that affected individuals may not have all the features discussed below. Parents of an affected child should talk to their physician and medical team about their childโs specific case, associated features and overall prognosis.
Children with Kabuki syndrome have a distinctive facial appearance, which includes abnormally long openings between the eyelids (palpebral fissures), lower eyelids that are turned outward (everted), prominent eyelashes, arched eyebrows, a broad nose with a flattened or depressed tip, and large, misshaped ears. The distinctive facial appearance associated with Kabuki syndrome develops slowly over several years. Additional facial features include a bluish tinge to the whites of the eyes (blue sclerae), drooping of the upper eyelid (ptosis), misaligned eyes (strabismus), a highly arched roof of the mouth or a cleft palate, depressions involving the inside of the lower lips (lip pits) and an abnormally small jaw (micrognathia).
Growth deficiency is common in individuals with Kabuki syndrome, usually becoming apparent during the first year of life (postnatal growth deficiency). Growth deficiency can become more noticeable as affected children grow older. Eventually, affected individuals may be notably below average height for their age (short stature). In rare cases, some children may have partial growth hormone deficiency.
In addition to growth deficiency, children with Kabuki syndrome may also have mild to moderate intellectual disability. Severe intellectual disability is extremely rare, and some children have no intellectual disability. Some children may have seizures, diminished muscle tone (hypotonia) and microcephaly, a condition in which the circumference of the head is abnormally small. Seizures can develop right after birth (neonatal period) or as late as 12 years of age. One rare cause of seizures occurring right after birth is very low blood sugar due to too much insulin (hyperinsulinism). This requires immediate treatment to avoid damage to the brain. All neonates with a known or suspected diagnosis of Kabuki syndrome should undergo routine blood sugar monitoring for the first few days of life. If an infant has low blood sugar after birth, further blood studies should be completed to evaluate for hyperinsulinism. This evaluation is typically done in consultation with a hormone specialist (endocrinologist).
Some children with Kabuki syndrome experience speech delays. Palate abnormalities and hearing loss may contribute to speech delays. Some children with Kabuki syndrome may develop behavioral abnormalities including anxiousness and a tendency to fixate on objects or activities. They may also dislike certain stimuli including certain noises, smells or textures. Some children with Kabuki syndrome appear to be particularly fond of music. A learning environment that stresses audio-verbal learning over visual learning may be helpful.
Children with Kabuki syndrome may also have feeding difficulties including gastroesophageal reflux, poor sucking ability, and difficulty absorbing or digesting nutrients from food (malabsorption). Consequently, many affected children may fail to gain weight and grow at the rate expected for children of their age and sex (failure to thrive). However, as children enter adolescents, they tend to gain too much weight, which can make other health problems (such as joint dislocations) worse. Some children may be susceptible to recurring infections including upper respiratory infections and pneumonia. Therefore, all children should undergo a baseline evaluation for an abnormality of how the immune system works (an immunodeficiency). Many children have recurrent ear infections (otitis media) which may contribute to hearing loss.
Dental abnormalities such as missing, misaligned or misshaped teeth have been reported. Small and/or thin fingernails and toenails are sometimes seen. In addition, some children will have a feature of the fingertips, known as persistent fetal fingertip pads.
Skeletal abnormalities may occur in some patients including abnormally short fingers and toes (brachydactyly), pinkies that are bent (clinodactyly), flat feet, loose (lax) joints, abnormalities of the vertebrae, cranial malformations and abnormal curvature of the spine (scoliosis or kyphosis). Affected individuals may also be prone to dislocating their hips or kneecaps.
Some children with Kabuki syndrome may have certain heart abnormalities that are present from birth (congenital heart defects). The two most reported heart defects in children with Kabuki syndrome include narrowing of the main artery of the body (coarctation of the aorta) and holes in the membranes (septa) that separate the chambers of the heart (ventricular or atrial septal defects).
In some patients, additional features involving a variety of organ systems may also be present. Possible kidney (renal) abnormalities include malformation or underdevelopment of the kidneys (renal dysplasia or hypoplasia), obstruction of the normal flow of urine from the kidneys (hydronephrosis) and fusion of the kidneys at the base forming a horseshoe shape (horseshoe kidneys). Gastrointestinal abnormalities include malrotation of the colon and absence or blockage of the anal opening (anal atresia). Immunological deficiencies and/or a higher chance of developing autoimmune disorders have also been reported. Affected females may also experience early onset of breast development (premature thelarche), although this typically does not require treatment., Some males may have undescended testicles (cryptorchidism), which frequently requires treatment.
In August of 2010, a group of researchers at the University of Washington reported that pathogenic variants in the gene KMT2D (formerly MLL2) were responsible for Kabuki syndrome in most affected individuals who were tested. In 2012, a group of researchers from Belgium identified a second gene, termed KDM6A, that causes Kabuki syndrome. Most cases of Kabuki syndrome, particularly those caused by variants of KMT2D, occur for the first time in the affected individual with no family history of the disorder (de novo). However, familial occurrence of Kabuki syndrome has been reported.
The University of Washington researchers confirmed that Kabuki syndrome caused by a dominant pathogenic variant in the KMT2D gene can then be passed on to the offspring of an affected individual. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new gene change in the affected individual (de novo). The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females. Variable expressivity means that the disorder is expressed in dramatically different ways from one person to another, even within affected individuals from the same family.
Kabuki syndrome caused by KDM6A gene variants follows X-linked inheritance. Females typically have two X chromosomes and males typically have one X and one Y chromosome. Females who have a pathogenic variant in KDM6A on one X chromosome generally have milder features of Kabuki syndrome compared to males who have a pathogenic variant in this gene, although exceptions exist. It is also possible for a female with a variant in KDM6A to have no symptoms of Kabuki syndrome. Most cases of Kabuki syndrome caused by variants in KDM6A are the result of a new gene change. However, it is possible for a female with a variant in KDM6A to pass on the condition to her children, even if she herself has mild or no symptoms of Kabuki syndrome. For a female with a KDM6A variant, the risk of passing the abnormal gene to her offspring is 50 percent for each pregnancy. The risk is the same for males and females, however, female children may have milder or no symptoms of the condition. An affected male will pass on the abnormal gene to all his daughters but none of his sons.
KMT2D and KDM6A appear to work together to regulate gene expression. They are part of a newer class of conditions that impact the โepigenetic machineryโ, sometimes called Mendelian disorders of the epigenetic machinery (MDEMs). For a gene to be expressed (or read), the DNA must be in an โopenโ configuration. Proteins called histones are involved in keeping DNA โopenedโ (able to be read) or โclosedโ (unable to be read). Modifications to histones help determine if DNA will be read or not. KMT2D places activating marks on histones, so DNA can be read. It can โwriteโ that DNA should be opened and to read these marks as well. KDM6A erases marks that keep DNA closed, so that DNA can be opened and read. However, more research is necessary to determine the specifics of how abnormal histone modification results in the development of the disorder and its associated symptoms.
Kabuki syndrome affects males and females in equal numbers. The incidence of Kabuki syndrome is unknown but has been estimated to be somewhere between 1 in 32,000-86,000 individuals in the general population. More than 400 affected individuals who have genetically proven Kabuki syndrome have been reported in the medical literature. Although the disorder was first reported in Japan, Kabuki syndrome has since been reported in a wide variety of different ethnic groups.
International consensus diagnostic criteria for Kabuki syndrome have been published, which allow for a diagnosis to be made when a person has either a positive genetic testing result or a combination of certain clinical features.
Clinical genetic testing for Kabuki syndrome is available. While genetic testing of one gene at a time is possible, more commonly a small panel of genes is evaluated at the same time (multigene panel). Most multigene panels include sequencing and evaluation of small copy number variants (CNV) of both KMT2D and KDM6A (among other genes) in one test. If molecular genetic testing (sequencing and CNV analysis) does not identify a genetic change in either KMT2D or KDM6A, or if there is a variant of unknown clinical significance (a nondiagnostic genetic testing result) in either KMT2D or KDM6A, a further test termed an โepigenetic signatureโ can be used to determine if the person has Kabuki syndrome. Since Kabuki syndrome is part of the MDEM class of disorders, a unique pattern of epigenetic markings can be assessed to see if it is consistent with Kabuki syndrome, or possibly another condition within the MDEM group.
Approximately 20% of individuals with Kabuki syndrome will not be found to have a variant in either KMT2D or KDM6A. It is unknown how many of these individuals will have the epigenetic signature consistent with Kabuki syndrome. In this scenario, a clinical diagnosis can be made based upon identification of characteristic findings, a detailed patient history and a thorough clinical evaluation. Physicians look for distinctive facial features, persistent fingertip pads, low tone, developmental delay and intellectual disability. Blood tests and chromosomal studies may be used to rule out other disorders.
Treatment
There is no cure for Kabuki syndrome. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, endocrinologists, dental specialists, speech pathologists, specialists who assess and treat hearing problems (audiologists) and other healthcare professionals may need to plan an affect childโs treatment systematically and comprehensively.
Early intervention is important to ensure that children with Kabuki syndrome reach their developmental potential. Special services that may be beneficial to affected children include special remedial education, physical and occupational therapy and speech therapy. Sensory integration therapy, in which certain sensory activities are undertaken to help regulate a childโs response to sensory stimuli, may be used in some cases.
Some children with Kabuki syndrome who experience severe feeding difficulties may eventually require the placement of a gastronomy tube. In rare cases of partial growth hormone deficiency, affected children may respond to treatment with supplemental growth hormone therapy. Growth hormone therapy may also be considered in those who have short stature without documented growth hormone deficiency.
Specific symptoms potentially associated with Kabuki syndrome may require referral to an appropriate specialist. For example, cardiac defects may require a pediatric cardiologist. Various abnormalities associated with Kabuki syndrome may be treated by conventional methods as recommended by a specialist. For example, hearing loss can be treated by surgery or hearing aids. Additional complications such as hip dislocation, scoliosis, cardiac defects and cleft palate may also be treated surgically.
Genetic counseling is recommended for affected individuals and their families.
There has been significant interest from both researchers and pharmaceutical companies in developing possible targeted therapies (drugs) that can change (or correct) the epigenetic markings in people with Kabuki syndrome. For example, it has been hypothesized that histone deacetylase inhibitors (HDACi) could have a beneficial effect on individuals with KS. However, there is no currently available FDA targeted treatment for Kabuki syndrome.
Similarly, some researchers have hypothesized that placing an affected individual on a ketogenic diet could also change the epigenetic marks and lead to improvement in cognitive functioning. This has not yet been explored in a formal clinical trial and is not currently recommended as a treatment for individuals with Kabuki syndrome.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Contact for additional information about Kabuki syndrome:
Margaret Adam, MD
4800 Sand Point Way NE
PO Box 5371/OC.9.850
Seattle, WA 98105
Phone 206-987-1248
Fax 206-987-2495
TEXTBOOKS
Jones KL. Ed. Smithโs Recognizable Patterns of Human Malformation. 6th ed. Elsevier Saunders, Philadelphia, PA; 2006:118.
Lo IFM, Tam STS. Kabuki Make-Up Syndrome. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:209-210.
Gorlin RJ, Cohen MMJr, Hennekam RCM. Eds. Syndromes of the Head and Neck. 4th ed. Oxford University Press, New York, NY; 2001:938.
JOURNAL ARTICLES
Adam MP, Banka S, Bjornsson HT, Bodamer O, Chudley AE, Harris J, Kawame H, Lanpher BC, Lindsley AW, Merla G, Miyake N, Okamoto N, Stumpel CT, Niikawa N., Kabuki Syndrome Medical Advisory Board. Kabuki syndrome: international consensus diagnostic criteria. J Med Genet. 2019;56:89โ95.
Fahrner JA, Bjornsson H. Mendelian disorders of the epigenetic machinery: postnatal malleability and therapeutic prospects. Hum Mol Genet. 2019;38:R254-R264.
Caciolo C, Alfieri P, Piccini G, Digilio MC, Lepri FR, Tartaglia M, Menghini D, Vicari S. Neurobehavioral features in individuals with Kabuki syndrome. Mol Genet Genomic Med. 2018;6:322โ331.
Lehman N, Mazery AC, Visier A, Baumann C, Lachesnais D, Capri Y, Toutain A, Odent S, Mikaty M, Goizet C, Taupiac E, Jacquemont ML, Sanchez E, Schaefer E, Gatinois V, Faivre L, Minot D, Kayirangwa H, Sang KLQ, Boddaert N, Bayard S, Lacombe D, Moutton S, Touitou I, Rio M, Amiel J, Lyonnet S, Sanlaville D, Picot MC, Geneviรจve D. Molecular, clinical and neuropsychological study in 31 patients with Kabuki syndrome and KMT2D mutations. Clin Genet. 2017;92:298โ305.
Lepri FR, Cocciadiferro D, Augello B, Alfieri P, Pes V, Vancini A, Caciolo C, Squeo GM, Malerba N, Adipietro I, Novelli A, Sotgiu S, Gherardi R, Digilio MC, Dallapiccola B, Merla G. Clinical and neurobehavioral features of three novel Kabuki syndrome patient with mosaic KMT2D mutations and a review of the literature. Int J Mol Sci. 2017;19:E82.
Bogershausen N, Gatinois V, Riehmer V, et al. Mutation update for Kabuki syndrome genes KMT2D and KDM6A and further delineation of X-lined Kabuki syndrome subtype 2. Hum Mutat. 2016;37:847-64.
Lindsley AW, Saal HM, Burrow TA, Hopkin RJ, Shchelochkov O, Khandelwal P, Xie C, Bleesing J, Filipovich L, Risma K, Assaโad AH, Roehrs PA, Bernstein JA. Defects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome. J Allergy Clin Immunol. 2016;137:179โ87.e10.
Schott DA, Blok MJ, Gerver WJ, Devriendt K, Zimmermann LJ, Stumpel CT. Growth pattern in Kabuki syndrome with a KMT2D mutation. Am J Med Genet A. 2016;170:3172โ9.
Lin JL, Lee WI, Huang JL, Chen PK, Chan KC, Lo LJ, You YJ, Shih YF, Tseng TY, Wu MC. Immunologic assessment and KMT2D mutation detection in Kabuki syndrome. Clin Genet. 2015;88:255โ60.
Lederer D, Shears D, Benoit V, Verellen-Dumoulin C, Maystadt I. A three generation X-linked family with Kabuki syndrome phenotype and a frameshift mutation in KDM6A. Am J Med Genet A. 2014;164A(5):1298-1292.
Miyake N, Mizuno S, Okamoto N, et al. KDM6A point mutations cause Kabuki syndrome. Hum Mutat. 2013;34(1):108-110.
Lederer D, Grisart B, Digilio MC, et al. Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am J Hum Genet. 2012;90(1):119-124.
Ng SB et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nature Genet. 2010; Advanced Online Publication 15 August 2010.
Barozzi S, Di Berardino F, Atzeri F, et al. Audiological and vestibular findings in the Kabuki syndrome. Am J Med Genet A. 2009;149A:171-176.
Ramachandran M, Kay RM, Skaggs DL. Treatment of hip dislocation in Kabuki syndrome: a report of three hips in two patients. J Pediatr Orthop. 2007;27:37-40.
INTERNET
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:147920; Last Update: 01/13/2023. Available at: https://www.omim.org/entry/147920 Accessed July 5, 2023.
Kabuki Syndrome. Orphanet. Sept 2020. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=2322 Accessed July 5, 2023.
Adam MP, Hudgins L, Hannibal M. Kabuki Syndrome. 2011 Sep 1 [Updated 2022 Sep 15]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK62111/ Accessed July 5, 2023.
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