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Kabuki Syndrome

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Copyright 1992, 2000, 2010

NORD is very grateful to Louanne Hudgins, MD, FAAP, FACMG, Professor of Pediatrics, Chief, Division of Medical Genetics, Stanford University School of Medicine; Director, Perinatal Genetics, Lucile Packard Children's Hospital, for assistance in the preparation of this report.

Synonyms of Kabuki Syndrome

Disorder Subdivisions

General Discussion

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. The exact cause of Kabuki syndrome was recently determined. It is on the basis of a mutation in a gene called MLL2. Clinical testing is not available at the time of this publication.

Symptoms

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 of the features discussed below. Parents of an affected child should talk to their physician and medical team about their child's 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 had 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. Some children with Kabuki syndrome experience speech delays. Palate abnormalities and hearing loss may contribute to speech delays. In some cases, 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.

Children with Kabuki syndrome may also have feeding difficulties including gastroesphogeal 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). Some children may be susceptible to recurring infections including upper respiratory infections and pneumonia. 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 prominences involving the finger tips, known as persistent fetal finger pads.

Skeletal abnormalities may occur in some cases 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 commonly 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 cases, 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 have also been reported. Affected individuals may also experience early onset of breast development (premature thelarche) and rapid weight gain upon puberty. Some males with Kabuki syndrome may have undescended testicles (cryptorchidism).

Causes

In August of 2010, a group of researchers at the University of Washington reported that mutations in the gene MLL2 was responsible for Kabuki syndrome in the majority of affected individuals who were tested. Clinically available testing was not available at the time of this publication.

Most cases of Kabuki syndrome 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 is caused by a dominant mutation in the MLL2 gene that 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 mutation (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 regardless of the sex of the resulting child. Variable expressivity means that the disorder expresses itself in dramatically different ways from one person to another. Most cases of Kabuki syndrome represent new, spontaneous gene mutations that occur with no previous family history.

More research is necessary to determine how mutations in the MLL2 gene result in the development of the disorder and its associated symptoms.

Affected Populations

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 32,000-60,000 individuals in the general population. More than 300 cases 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.

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 "makeup" has since been dropped and the preferred term for the disorder is Kabuki syndrome.

Related Disorders

Features of the following disorders can be similar to those of Kabuki syndrome. Comparisons may be useful for a differential diagnosis.

Turner syndrome is a rare chromosomal disorder of females characterized by short stature and the lack of sexual development at puberty. Other physical features may include a short neck with a webbed appearance, heart defects, kidney abnormalities, and/or various other malformations. Among affected females, there is also a heightened incidence of osteoporosis, type II diabetes, and hypothyroidism. There appears to be great variability in the degree to which girls with Turner syndrome are affected by any of its manifestations. Turner syndrome occurs when one of the two X chromosomes normally found in women is missing or incomplete. Although the exact cause of Turner syndrome is not known, it appears to occur as a result of a random error during the division (meiosis) of sex cells. (For more information on this disorder, choose "Turner" as your search term in the Rare Disease Database.)

IRF6-related disorders include a spectrum of disorders caused by abnormalities in the interferon regulatory factor 6 (IRF6) gene. Van der Woude syndrome (VWS) is at the mild end of the spectrum and popliteal pterygium syndrome (PPS) is at the severe end of the spectrum. Individuals with VWS can have lip pits alone, cleft lip or cleft palate alone, or a combination of these anomalies. The physical features associated with popliteal pterygium syndrome include cleft lip and/or cleft palate, lower lip pits, webbed skin (pterygium) on the backs of both legs (popliteal) and between the legs (intercrural), malformation and/or underdevelopment of the genitals, webbing or fusion of the fingers and/or toes (syndactyly), adhesion of upper and lower jaw and adhesion of upper and lower eyelids. A cone-shaped fold of skin on the nail of the big toe is a very distinctive finding in this condition. (For more information on this disorder, choose "IRF6-related disorders" as your search term in the Rare Disease Database.)

Several additional disorders can have certain symptoms or physical findings that are similar to those found in Kabuki syndrome. However, these disorders usually have other findings that can easily distinguish these disorders form Kabuki syndrome. Such disorders include Fryns syndrome, Rubinstein-Tabyi syndrome, KGB syndrome, Robinow syndrome, FG syndrome and Weaver syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
At the time of this publication, there is no specific diagnostic test for Kabuki syndrome. This is likely to change as mutations in the MLL2 gene have been found to cause the majority of cases of Kabuki syndrome. However, a diagnosis can be made based upon identification of characteristic findings, a detailed patient history, and a thorough clinical evaluation. Physicians look for four of the five characteristic findings - distinctive facial features; skeletal abnormalities; intellectual disability; dermatoglyphic abnormalities such as persistent fetal finger pads; and postnatal short stature. Blood tests and chromosomal studies may be used to rule out other disorders.

Treatment
There is no specific treatment 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, dental specialists, speech pathologists, specialists who asses and treat hearing problems (audiologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment.

Early intervention is important to ensure that children with Kabuki syndrome reach their 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 in order to help regulate a child's 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.

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 may be of benefit for affected individuals and their families.

Investigational Therapies

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: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

Contact for additional information about Kabuki syndrome:

Louanne Hudgins, MD, FAAP, FACMG
Professor of Pediatrics
Chief, Division of Medical Genetics
Stanford University School of Medicine
Director, Perinatal Genetics
Lucile Packard Children's Hospital
300 Pasteur Drive, H315
Stanford, CA 94305-5208
Administrative Associate: Heide Poppenberg
650-498-4937

Kabuki Syndrome Resources

Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder (e.g., heart disease, intellectual disability, etc.)

Organizations:

References

TEXTBOOKS
Jones KL. Ed. Smith's 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
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.

Hoffman JD, ciprero KL, Sullivan KE, et al. Immune abnormalities are a frequent manifestation of Kabuki syndrome. Am J Med Genet A. 2005;135:278-281.

Vaux KK, Jones KL, Jones MC, Schelley S, Hudgins L. Developmental outcome in Kabuki syndrome. Am J Med Genet A. 2005;132A:263-264.

Adam MP, Hudgins L. Kabuki syndrome: a review. Clin Genet. 2004;67:209-219.

Wessels MW, Brooks AS, Hoogeboom J, Niermeijer F, Willems PJ. Kabuki syndrome: a review study of three hundred patients. Clin Dysmorph. 2002;11:95-102.

FROM THE INTERNET
Management of Kabuki Syndrome. A Clinical Guideline. Kabuki Syndrome Guideline Development Group. Dyscerne. March 8, 2010. Available at: http://www.dyscerne.org/dysc/digitalAssets/0/264_Kabuki_Guidelines.pdf Accessed: May 1, 2010.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:147920; Last Update:10/13/2008. Available at: http://www.ncbi.nlm.nih.gov/omim/147920 Accessed: May 1, 2010.

Kabuki Syndrome. Orphanet encyclopedia, April 2003. Available at: www.orpha.net Accessed: May 1, 2010.

Report last updated: 2011/01/11 00:00:00 GMT+0