Kabuki Syndrome
Comprehensive Guide to Kabuki Syndrome: Diagnosis, Care, and Long-Term Management
What is Kabuki Syndrome?
Kabuki syndrome (KS) is a rare genetic condition that affects multiple body systems. It was first described in 1981 and is named for the resemblance of the characteristic facial features to the stage makeup used in traditional Japanese Kabuki theater.
KS is caused by changes (variants) in genes that control how the body reads and uses its DNA during development. The two known genes are:
- KMT2D — responsible for 55–80% of cases, inherited in an autosomal dominant pattern
- KDM6A — responsible for 2–6% of cases, inherited in an X-linked pattern
Approximately 15–20% of individuals with clinical features of KS have no identified gene variant. Most cases occur as new (de novo) variants, meaning neither parent is affected. However, in rare cases, a variant is inherited from an affected parent.
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What are the Characteristic Features of Kabuki Syndrome?
KS has five cardinal features:
1. Distinctive facial features
2. Skeletal anomalies
3. Persistent fetal fingertip pads (fleshy pads on the tips of the fingers)
4. Intellectual disability (usually mild to moderate)
5. Postnatal growth deficiency (short stature that develops after birth)
Distinctive facial features of KS include:
- Long openings of the eyelids (long palpebral fissures) with the lower eyelids turned outward at the outer edges
- Arched and broad eyebrows, sometimes with thinning or notching of the outer third
- A short bridge between the nose and upper lip (short columella) with a flat or depressed nasal tip
- Large, prominent, or cupped ears
These facial features may become more recognizable with age and can be subtle in infancy.
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What Other Medical Conditions are Associated with Kabuki Syndrome?
Because KS affects many body systems, individuals may experience a wide range of associated conditions. Not every person with KS will have all of these, and severity varies widely.
Heart:
- Congenital heart defects are found in approximately 28–75% of individuals
- Left-sided obstructive lesions (such as aortic coarctation and bicuspid aortic valve) and septal defects are most common
- Annual monitoring for aortic dilatation is recommended
Immune system:
- Increased susceptibility to infections (especially ear infections and sinus infections) affects approximately 44% of individuals
- Low immunoglobulin levels (hypogammaglobulinemia) are found in approximately 58%
- Autoimmune conditions (such as immune thrombocytopenic purpura, hemolytic anemia, and vitiligo) occur in approximately 14%
- KS is now recognized as an inborn error of immunity
Endocrine (hormonal):
- Hyperinsulinism (excess insulin production causing low blood sugar) can occur, especially in the newborn period, and may cause serious neurologic harm if untreated
- Short stature is common and may respond to growth hormone therapy
- Premature breast development (premature thelarche) in girls is the most common endocrine finding (16–41%)
- Hypothyroidism and growth hormone deficiency have also been reported
Kidneys and urinary tract:
- Congenital anomalies of the kidneys and urinary tract are found in up to 62% of individuals in some studies
- These may include hydronephrosis, horseshoe kidney, kidney asymmetry, double collecting systems, or kidney agenesis
- Cryptorchidism (undescended testes) and hypospadias may occur in males
Gastrointestinal:
- Feeding difficulties are very common, especially in infancy
- Gastroesophageal reflux (GERD) is frequent
- Anal atresia and other gastrointestinal malformations may occur
- Chronic diarrhea should prompt evaluation for malabsorption or celiac disease
Skeletal:
- Scoliosis (curvature of the spine)
- Short fifth (pinky) fingers
- Joint laxity (loose joints)
- Hip and knee joint problems
Neurologic:
- Seizures occur in some individuals
- Brain MRI abnormalities have been reported
- Microcephaly (small head size) may occur
Eyes and ears:
- Ptosis (drooping eyelids) and strabismus (crossed eyes)
- Hearing loss (both conductive and sensorineural) is common
- Frequent ear infections (otitis media)
Mouth and teeth:
- Cleft lip and/or cleft palate
- High-arched palate
- Widely spaced teeth, missing teeth (hypodontia), and other dental anomalies
Development and behavior:
- Developmental delay and intellectual disability (usually mild to moderate, but variable)
- Some individuals show features of autism spectrum disorder
- Many individuals with KS are described as sociable and friendly
Growth and weight:
- Failure to thrive is common in infancy
- A tendency toward overweight or obesity may develop in early childhood
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How is Kabuki Syndrome Diagnosed?
Diagnosis is based on the 2019 International Consensus Diagnostic Criteria.
A definitive diagnosis requires a history of infantile hypotonia (low muscle tone) and developmental delay and/or intellectual disability, PLUS one or both of the following:
1. A pathogenic or likely pathogenic variant identified in the KMT2D or KDM6A gene through genetic testing
2. Typical facial features of KS: long palpebral fissures with eversion of the lateral lower eyelid, PLUS two or more of the following: arched/broad eyebrows with lateral notching or sparseness; short columella with depressed nasal tip; large, prominent, or cupped ears; persistent fingertip pads
Probable and possible diagnoses can also be made when some but not all criteria are met.
Genetic testing (gene sequencing and deletion/duplication analysis of KMT2D and KDM6A) is recommended for all individuals with suspected KS. However, approximately 15–20% of clinically diagnosed individuals will not have an identifiable variant in either gene.
A clinical geneticist is best positioned to evaluate for KS, apply the diagnostic criteria, and coordinate genetic testing and counseling.
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What Evaluations are Recommended After Diagnosis?
Once KS is diagnosed, the following evaluations are recommended if not already completed:
- Echocardiography (heart ultrasound) with attention to left-sided obstructive lesions and aortic root
- Renal ultrasound to screen for kidney and urinary tract anomalies
- Hearing evaluation (audiology)
- Vision evaluation (ophthalmology)
- Immunology evaluation including immunoglobulin levels and lymphocyte subsets
- Endocrine evaluation including screening for hyperinsulinism (especially in neonates and young children — a diagnostic fast may be considered), thyroid function, and growth assessment
- Developmental assessment
- Dental evaluation
- Skeletal evaluation if scoliosis or joint problems are suspected
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How is Kabuki Syndrome Managed?
There is no cure for KS, but management focuses on treating specific medical issues, supporting development, and preventing complications. Care is individualized and typically involves multiple specialists.
Heart:
- Standard treatment of congenital heart defects per cardiologist
- Annual monitoring for aortic dilatation
- Prophylactic antibiotics before dental or surgical procedures may be indicated for those with specific heart defects
- If catheterization or angioplasty is being considered, the care team should be informed of a potential increased risk of aortic aneurysm
Immune system:
- Referral to immunologist for recurrent infections
- Intravenous immunoglobulin (IVIG) therapy may be considered for documented immunoglobulin deficiency
- Monitoring for autoimmune conditions
Endocrine:
- Standard treatment for hyperinsulinism per endocrinologist; many individuals with persistent hyperinsulinism respond to diazoxide therapy
- Growth hormone therapy may be considered for short stature, with referral to endocrinologist
- Premature thelarche alone does not require treatment if there are no other signs of premature puberty
Feeding and gastrointestinal:
- Thickened feedings and positioning after meals for reflux
- Gastrostomy tube placement if feeding difficulties are severe or swallowing is poorly coordinated
- Evaluation for malabsorption or celiac disease if chronic diarrhea is present
Hearing and vision:
- Pressure-equalizing tubes for conductive hearing loss; hearing aids for sensorineural hearing loss; cochlear implants may be considered
- Standard treatment for strabismus, ptosis, and refractive errors
Mouth and teeth:
- Craniofacial clinic management for cleft lip/palate (the palate may be shorter, which can lead to velopharyngeal insufficiency after typical cleft repair)
- Orthodontic referral for hypodontia or significant malocclusion
Development and education:
- Psychoeducational testing and special education services tailored to the child's needs
- Evaluation by a developmental pediatrician or psychiatrist if behavior suggests autism spectrum disorder
- Speech therapy, occupational therapy, and physical therapy as needed
Seizures:
- Standard anti-seizure treatment per neurologist
Kidneys and urinary tract:
- Standard treatment per urologist for hypospadias or cryptorchidism
- Nephrology follow-up if structural kidney anomalies are identified
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Important Precautions
Anesthesia and surgery:
- Joint laxity can affect the cervical spine — care must be taken in positioning during intubation
- Structural airway anomalies may make intubation difficult — inform the anesthesia team about the KS diagnosis before any procedure
- Bleeding risk may be increased in individuals with immune thrombocytopenia — check platelet counts before surgery
Vaccinations:
- Individuals with documented immune deficiency should be evaluated by an immunologist before receiving live vaccines
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Recommended Ongoing Surveillance
- Height, weight, and head circumference at each well-child visit (at minimum, yearly)
- Developmental milestones at each well-child visit
- Vision and hearing monitoring on a yearly basis
- Immunoglobulin levels and complete blood count periodically, especially if recurrent infections or signs of autoimmune disease
- Endocrine monitoring (growth, thyroid function, blood sugar) as clinically indicated
- Cardiac follow-up per cardiologist recommendations
- Dental evaluations regularly
- Skeletal monitoring for scoliosis
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Genetic Counseling and Family Planning
- KMT2D-related KS is autosomal dominant: most cases are de novo (new), but if a parent is affected, each child has a 50% chance of inheriting the variant
- KDM6A-related KS is X-linked: if the mother carries the variant, each pregnancy has a 50% chance of transmission; affected males typically have more severe features, while carrier females may have variable features
- Once a causative variant is identified, prenatal testing and preimplantation genetic testing are available for future pregnancies
- Genetic counseling is recommended for all families
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Resources
Kabuki Syndrome:
- GeneReviews: Kabuki Syndrome — www.ncbi.nlm.nih.gov/books/NBK62111
Expert-authored clinical summary including diagnosis, management, and surveillance recommendations
- MedlinePlus: Kabuki Syndrome — medlineplus.gov/genetics/condition/kabuki-syndrome
National Library of Medicine resource with patient-friendly overviews of genetics, features, and inheritance
- NORD (National Organization for Rare Disorders): Kabuki Syndrome — rarediseases.org
Disease-specific information, patient assistance programs, and connections to clinical experts
- Genetic and Rare Diseases Information Center (GARD) — rarediseases.info.nih.gov
NIH-supported resource with detailed information and links to clinical trials
- All Things Kabuki — www.allthingskabuki.org
Family-run support and information network for families affected by Kabuki syndrome
Genetic Testing and Counseling:
- National Society of Genetic Counselors — www.findageneticcounselor.com
Directory to locate a board-certified genetic counselor
- ClinicalTrials.gov — www.clinicaltrials.gov
Search for active clinical trials related to Kabuki syndrome
Immune Deficiency:
- Immune Deficiency Foundation — www.primaryimmune.org
Education and support for patients with primary immunodeficiency, including resources relevant to KS-associated immune dysfunction
General Support:
- Global Genes — www.globalgenes.org
Rare disease patient advocacy organization providing resources, community connections, and support programs
