Kabuki syndrome

Key Points at a Glance

Highlights of This Disease

• Kabuki syndrome (KS) is a rare congenital disorder first reported in Japan in 1981, with a prevalence of 1 in 32,000 in Japan.
• Causative genes are KMT2D (KS1, 56–80%) and KDM6A (KS2, 5–8%), both encoding chromatin-modifying enzymes.
• The five main features are characteristic facial appearance, postnatal growth deficiency, intellectual disability, skeletal abnormalities, and dermatoglyphic abnormalities.
• Ophthalmic abnormalities include long palpebral fissures, eversion of the lower eyelid, strabismus, ptosis, and blue sclera, observed at high frequency.
• Hyperinsulinemic hypoglycemia (45.5% in KDM6A mutation cases) is primarily managed with diazoxide, but attention must be paid to side effects such as pulmonary hypertension and hyperglycemic hyperosmolar state.
• In 20–45% of cases, no genetic mutation is identified, but diagnosis is possible based on international clinical criteria.
• Long-term multidisciplinary management is required, and a comprehensive systemic evaluation including ophthalmologic examination should be performed at diagnosis.

1. What is Kabuki syndrome?

Kabuki syndrome (KS) is a rare congenital disorder independently reported in 1981 by Niikawa and Kuroki in Japan. It is named after the characteristic facial features resembling the makeup of Kabuki actors.

The prevalence of KS is estimated at 1 in 32,000 in Japan and 1 in 86,000 in Australia and New Zealand. The incidence is 1 in 68,000 to 1 in 32,000, with no sex or racial differences⁴⁾. Cases have been reported in all ethnic groups worldwide.

It is characterized by five main features.

• Characteristic facial features: long palpebral fissures, eversion of the lower eyelid, arched eyebrows, etc.
• Postnatal growth deficiency: short stature, feeding difficulties
• Intellectual disability: present in 84–100% of cases
• Skeletal abnormalities: brachydactyly, spinal anomalies, etc.
• Dermatoglyphic abnormalities: fetal finger pads, etc.

Q How rare is Kabuki syndrome?

A

The prevalence in Japan is 1 in 32,000 people, and it has been reported in all ethnic groups worldwide. The incidence ranges from 1/68,000 to 1/32,000, with no differences by sex or race⁴⁾.

2. Main symptoms and clinical findings

Subjective symptoms (symptoms noticed by caregivers)

The following symptoms and findings are observed from infancy.

• Feeding difficulties: A characteristic symptom observed in newborns and infants
• Hypotonia: observed in 60–83%
• Failure to thrive/short stature: observed in 54–75%
• Intellectual disability: observed in 84–100%, mostly mild to moderate

Clinical Findings (Findings Confirmed by a Physician)

Characteristic Facial Features

This is the most important finding for diagnosing KS. It is present from infancy and becomes most distinct between 3 and 12 years of age.

• Long palpebral fissures: The most frequent facial finding, observed in 95–100% of cases.
• Eversion of the lateral third of the lower eyelid: Observed in 83–98% of cases. Important for differential diagnosis of congenital anomalies suggested by periorbital findings.
• Arched eyebrows: Observed in 79–88% of cases.
• Short nasal septum: Observed in 69–93% of cases.
• Ear malformations: Observed in 78–100% of cases.
• High palate/cleft palate: Observed in 50–79% of cases.

Ophthalmic Findings

Ophthalmic abnormalities are diverse, and ophthalmologic examination is recommended for all patients.

The main ophthalmic findings reported in Kabuki syndrome are shown below.

Finding	Frequency (out of 200 cases)
Strabismus	43 cases
Blue sclera	44 cases
Ptosis	12–63%
Microphthalmia/coloboma	9 cases
Corneal opacity / Peters anomaly	5 cases
Cataract	3 cases
Refractive error	6 cases

In cases with Xp11.3 microdeletion (1.9 Mb), Norrie disease and Kabuki syndrome overlap, and bilateral retinal detachment may be observed from the neonatal period ¹⁰⁾.

Diseases with similar findings include Cat eye syndrome, CHARGE syndrome, and Lenz syndrome, requiring differentiation.

Limb, skeletal, and visceral findings

• Finger pad pads: present in 75–100%
• Brachydactyly: present in 63–100%
• Cardiovascular abnormalities: present in 28–80%, with left-sided obstructive lesions in about half ⁸⁾. Pectus excavatum has also been reported ⁵⁾.
• Hearing loss: observed in 40–50%
• Oral findings: observed in over 60%⁵⁾

Q What eye abnormalities are seen in Kabuki syndrome?

A

Long palpebral fissures (95–100%) and eversion of the lateral third of the lower eyelid (83–98%) are the most characteristic findings. Various ophthalmic abnormalities such as strabismus, blue sclera, ptosis, microphthalmia, and coloboma are observed, and ophthalmologic examination is recommended at diagnosis.

3. Causes and Risk Factors

Causative Genes

Two major causative genes have been identified, both encoding enzymes involved in chromatin modification.

A comparison of the two genotypes is shown below.

	KS1 (KMT2D)	KS2 (KDM6A)
Gene locus	12q13.12	Xp11.3
Frequency	56–80%	5–8%
Inheritance pattern	Autosomal dominant	X-linked dominant
Mutant type	Predominantly truncating mutations	Loss-of-function

KMT2D encodes H3K4 methyltransferase, and de novo mutations are predominant ⁶⁾. KDM6A encodes H3K27 demethylase, and because it partially escapes X-chromosome inactivation, it follows an X-linked dominant inheritance pattern ⁶⁾. The Y chromosome contains a KDM6C paralog, which may be related to the reason why KS2 is less likely to occur in males ⁶⁾.

RAP1A and RAP1B have been reported as rare causative genes ¹⁾.

Cases without identified gene mutations

In 20–45% of cases, no genetic cause is identified. There are no known environmental risk factors.

Mosaic KS has also been reported, with allele frequencies of 10–37% (minimum 11.2%) ⁸⁾. Mosaic cases may have milder symptoms than typical cases, but can also present with severe complications such as cardiovascular abnormalities ⁸⁾.

Genetic counseling

Most cases of Kabuki syndrome are due to de novo mutations, but some are inherited. If the diagnosis is confirmed, consultation with a genetic specialist is recommended.

Q Can Kabuki syndrome be diagnosed even if no genetic mutation is found?

A

In 20–45% of cases, no causative genetic mutation is identified. The 2019 international diagnostic criteria allow a diagnosis (possible/probable KS) based on clinical features even if no genetic mutation is identified.

4. Diagnosis and Testing Methods

International Diagnostic Criteria (2019)

The international diagnostic criteria established in 2019 classify cases into three categories: definite, probable, and possible.

Definite Diagnosis

Pathogenic KMT2D mutation present: Definite diagnosis even if the five major features are not met.

Pathogenic KDM6A mutation present: Same as above.

Probable KS

No gene mutation: Applies when multiple major features including typical facial features are present among the 5 major features.

Facial features are most distinct at ages 3–12: Diagnosis may be difficult in infancy or adulthood.

Possible KS

No gene mutation: Applies when only some of the 5 major features are present.

Further evaluation recommended: Findings may become clearer with growth.

Genetic Testing

• Whole exome sequencing (WES): Recommended as the first-choice genetic test⁴⁾⁶⁾. Mutation detection rate is 92.3%.
• Episignature analysis (EpiSign): Useful for confirming mosaic KS through DNA methylation profiling⁸⁾

Recommended Systemic Evaluation

The following evaluations should be performed at diagnosis:

• Ophthalmologic examination: Recommended for all patients
• Echocardiography: Evaluation of cardiovascular abnormalities
• Hearing test: Screening for hearing loss
• Endocrine evaluation: Screening for hypoglycemia and short stature

5. Standard Treatment

Overview: Multidisciplinary Management

There is no curative treatment for KS; long-term symptom-based management by a multidisciplinary team is essential. Departments such as pediatrics, ophthalmology, cardiac surgery, endocrinology, otorhinolaryngology, dentistry, and rehabilitation medicine collaborate.

Ophthalmic Management

• Ophthalmic screening: Performed regularly from the time of diagnosis
• Refractive correction and amblyopia treatment: Early intervention for refractive errors and strabismus
• Ptosis surgery: Consider surgery for ptosis that obstructs the visual axis

Management of Hyperinsulinemic Hypoglycemia

The frequency in KMT2D-related KS is approximately 0.3%, while in KDM6A mutation cases it is as high as 45.5%⁷⁾⁹⁾.

• Diazoxide: First-line treatment. Administered at 3–15 mg/kg/day⁷⁾. May need to be continued until age 5.
• Maltodextrin: Used at 0.2–0.5 gm/kg for management after Diazoxide discontinuation²⁾.

Management of Other Complications

• Heart disease: Some cases require surgical repair⁸⁾.
• Short stature: Growth hormone (GH) therapy may be considered⁴⁾.
• Cleft palate: Surgical repair and orthodontic treatment⁴⁾⁵⁾.

Precautions and side effects in treatment

Diazoxide has been reported to have serious side effects. If pulmonary hypertension (PH) develops, discontinuation is required ²⁾. In addition, infections such as influenza can trigger hyperglycemic hyperosmolar state (HHS) (5 pediatric cases reported in the literature) ³⁾. Regular cardiopulmonary function evaluation is necessary during diazoxide administration.

Q How is hypoglycemia in Kabuki syndrome treated?

A

First-line treatment is diazoxide (3–15 mg/kg/day), which may be needed until age 5 ⁷⁾. After diazoxide discontinuation, management with maltodextrin (0.2–0.5 g/kg) has been reported ²⁾. Management should be continued while monitoring for side effects such as pulmonary hypertension and hyperglycemic hyperosmolar state.

6. Pathophysiology and detailed pathogenesis

The pathology of KS is caused by abnormalities in chromatin modification. Both causative genes encode histone modification enzymes.

• KMT2D (KS1): Functions as an H3K4 methyltransferase (H3K4 “writer” enzyme)⁶⁾. Loss-of-function mutations reduce H3K4 methylation and impair enhancer activity
• KDM6A (KS2): Functions as an H3K27 demethylase (H3K27 “eraser” enzyme)⁶⁾. Loss of function leads to excessive accumulation of H3K27me3 and suppression of gene expression

These loss-of-function mutations cause changes in chromatin structure, leading to developmental abnormalities (facial, skeletal, neurological, and visceral) in multiple organs⁸⁾.

Regarding the mechanism of hypoglycemia, it has been suggested that KMT2D and KDM6A may be involved in the development and differentiation of beta cells, and that mutations causing beta cell hyperfunction lead to excessive insulin secretion²⁾⁷⁾.

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7. Latest Research and Future Perspectives (Reports at Research Stage)

For patients: Please read this

The following content is currently at the research stage or under clinical trial and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Pulmonary Hypertension: A New Phenotype of KS

Deng et al. (2023) reported a case of a 3-year-old girl with a KMT2D exon39 mutation (c.12209_12210del) who presented with severe PH with mPAP 71 mmHg and PVR 27 WU¹⁾. Even with triple therapy of Ambrisentan 2.5 mg/day, Tadalafil 10 mg/day, and Remodulin (treprostinil), the estimated mPAP remained 96 mmHg, indicating insufficient efficacy. KMT2D mutation is noted as a potential new phenotype causing PH.

Episignature Diagnosis

Montano et al. (2022) confirmed a diagnosis of low-level mosaic KS1 with an allele frequency of 11.2% using whole-genome DNA methylation profiling (EpiSign)⁸⁾. This approach is expected to be applicable to low-level mosaicism that is difficult to detect with conventional genetic analysis.

Expanding the phenotype: pectus excavatum

Owlia et al. (2026) reported the first case of pectus excavatum in a 6-year-old girl with KS ⁵⁾. Ptosis, strabismus, and sinus hypoplasia were also present, indicating that the KS phenotype is even broader.

Overlap with Norrie disease

Mansoor et al. (2023) reported a 3-day-old male infant with an Xp11.3 microdeletion (1.9 Mb) affecting both the Norrie disease gene and KDM6A ¹⁰⁾. He presented with bilateral retinal detachment, VSD, and ASD; his mother was also diagnosed with KS+FEVR (familial exudative vitreoretinopathy). Ophthalmic complications can be particularly severe in Xp11.3 deletion KS2.

Diagnosis in extremely low birth weight infants

Li et al. (2024) reported a case of KS1 (KMT2D c.4267C>T) diagnosed in an extremely low birth weight infant born at 29 weeks weighing 850 g, along with a review of 10 preterm infants with KS ⁴⁾. All had characteristic facial features, and 7/10 had cardiovascular abnormalities. This demonstrates that diagnosis is possible early after birth even in preterm infants.

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8. References

1. Deng X, Jin B, Li S, Zhou H, Shen Q, Li Y. Pulmonary hypertension: a novel phenotypic hypothesis of Kabuki syndrome: a case report and literature review. BMC Pediatrics. 2023;23:429.
2. Nunez Stosic M, Gomez P. Persistent Hypoglycemia and Hyperinsulinism in a Patient With KMT2D-Associated Kabuki Syndrome. JCEM Case Reports. 2023;1(2):luad032.
3. Kahlon H, Stanley JR, Lineen C, Lam C. Diazoxide-related Hyperglycemic Hyperosmolar State in a Child With Kabuki Syndrome. JCEM Case Reports. 2024;2(7):luae108.
4. Li Q, Zheng Y, Guo X, Xue J. Extremely Low Birth Weight Infant (Gestational Age of 29 Weeks) With Kabuki Syndrome Type I: Case Report and Literature Review. Mol Genet Genomic Med. 2024;12:e70025.
5. Owlia F, Irannezhad M, Bahrololoomi Z, Mosallaeipour S. A certain set of signs that could be compatible with Kabuki syndrome: a case report of an Iranian girl and review of literature. J Med Case Reports. 2026;20:47.
6. Khodaeian M, Jafarinia E, Bitarafan F, Shafeii S, Almadani N, Daneshmand MA, Garshasbi M. Kabuki Syndrome: Identification of Two Novel Variants in KMT2D and KDM6A. Mol Syndromol. 2021;12:118-126.
7. Misirligil M, Yildiz Y, Akin O, Odabasi Gunes S, Arslan M, Unay B. A Rare Cause of Hyperinsulinemic Hypoglycemia: Kabuki Syndrome. J Clin Res Pediatr Endocrinol. 2021;13(4):452-455.
8. Montano C, Britton JF, Harris JR, Kerkhof J, Barnes BT, Lee JA, Sadikovic B, Sobreira N, Fahrner JA. Genome-wide DNA methylation profiling confirms a case of low-level mosaic Kabuki syndrome 1. Am J Med Genet A. 2022;188A:2217-2225.
9. Benina AR, Melikyan MA. Congenital hyperinsulinism as a part of Kabuki syndrome. Problems of Endocrinology. 2022;68(5):91-96.
10. Mansoor M, Coussa RG, Strampe MR, Larson SA, Russell JF. Xp11.3 microdeletion causing Norrie disease and X-linked Kabuki syndrome. Am J Ophthalmol Case Reports. 2023;29:101798.