Kabuki syndrome
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Kabuki syndrome is an inherited multisystem disorder characterised by distinctive facial features, mild-to-moderate intellectual disability and postnatal growth deficiency.
Kabuki syndrome (Niikawa-Kuroki syndrome, Kabuki make-up syndrome) presents in the neonatal period or infancy with hypotonia, feeding difficulties and postnatal growth deficiency, typically evident by age 12 months. Cardinal features include a recognisable facial gestalt with long palpebral fissures and eversion of the lateral lower eyelids, large cupped ears and persistent fetal fingertip pads, accompanied by skeletal anomalies and dermatoglyphic abnormalities. Multisystem involvement is the rule: approximately 70% of affected individuals have a congenital heart defect, with left-sided obstructive lesions, particularly coarctation of the aorta, predominating. Up to 50% develop hearing loss, most often conductive from chronic otitis media, although sensorineural and progressive forms occur. Kidney and urinary tract anomalies, including positional anomalies, renal dysplasia and hydronephrosis, affect more than 25%. Endocrine manifestations include hyperinsulinaemic hypoglycaemia, and humoral immune deficiency together with autoimmune disease has been documented. Intellectual disability lies in the mild-to-moderate range in most individuals, though presentation is highly variable, ranging from near-normal cognition to severe developmental impairment.
The estimated prevalence is 1/32,000 (GeneReviews, 2019). A minimum birth incidence of 1/86,000 has been calculated in Australia and New Zealand.
Kabuki syndrome is caused by germline pathogenic variants in two genes encoding components of the ASCOM chromatin-modifying complex: KMT2D (~75%) at 12q13.12 and KDM6A (~3-5%) at Xp11.3. KMT2D encodes a histone H3 lysine 4 methyltransferase that deposits activating methylation marks, while KDM6A encodes an H3K27 demethylase that removes repressive polycomb-derived marks; together they promote an activated chromatin state, and loss of function of either gene leads to the disorder. KDM6A escapes X-chromosome inactivation. The genetic cause remains unidentified in approximately 30% of individuals with a clinical diagnosis of Kabuki syndrome.
KMT2D-related KS is inherited in an autosomal dominant manner; KDM6A-related KS is inherited in an X-linked manner. Most affected individuals represent simplex cases: the proportion of KMT2D-related Kabuki syndrome caused by a de novo pathogenic variant is likely high, and approximately 80% of males with KDM6A-related disease are simplex. Once the familial pathogenic variant has been identified, prenatal molecular testing is technically possible.
Kabuki syndrome is diagnosed clinically using the international consensus diagnostic criteria (Adam et al., 2019); meeting these criteria establishes the clinical diagnosis. The criteria combine the recognisable facial gestalt, characteristic dermatoglyphic findings (persistent fingertip pads), and a constellation of skeletal, growth and neurodevelopmental features. A disorder-specific genome-wide DNA methylation signature has been identified in peripheral blood leukocytes and can clarify the diagnosis when molecular genetic testing yields no pathogenic variant or a variant of uncertain significance.
Main differential diagnoses include:
- : cleft palate, congenital heart defects, ocular coloboma and growth restriction overlap with Kabuki syndrome, but CHARGE shows a square face, short wide ear with little or no earlobe, prominent columella and broad nasal root rather than the everted long palpebral fissures and persistent fingertip pads of Kabuki syndrome; CHD7
- 22q11.2 deletion syndrome: shares cleft palate, congenital heart defects and urinary-tract anomalies, but features short narrow palpebral fissures, a bulbous nasal tip and small C-shaped ears, contrasting with the long everted palpebral fissures and large cupped ears of Kabuki syndrome; recurrent 22q11.2 deletion (TBX1 region)
- Branchiootorenal syndrome: ear pits, cupped ears, hearing loss and kidney anomalies overlap, but BOR shows otherwise normal craniofacies, growth and development with branchial cleft cysts and renal hypoplasia/agenesis; EYA1, SIX1
- Establishing the diagnosis through identification of a causative pathogenic variant, with confirmation of the clinical suspicion at the molecular level.
- Enabling specific and individualised surveillance – including growth measurements, annual ophthalmology and audiology review, scoliosis assessment until skeletal maturity, periodic thyroid function tests and complete blood count – as the prerequisite for targeted medical care decided by the treating physicians in consultation with the affected individual.
- Family member testing of at-risk relatives once the familial pathogenic variant has been identified, supporting reproductive and clinical decision-making within the family.
- Adam MP, Hannibal M. Kabuki Syndrome. GeneReviews. 2019 Feb 28. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 21882399. Available from:
- Wang Y, Hu F, Xu X, Tan J, Yu T, Li N, et al. Clinical delineation and genotype-phenotype correlation in 104 children with kabuki syndrome: A single-center, cross-sectional and follow-up study in China. European Journal of Pediatrics. 2025;184(4):271. PMID: .
- Boniel S, Szymańska K, Śmigiel R, Szczałuba K. Kabuki Syndrome-Clinical Review with Molecular Aspects. Genes. 2021;12(4):468. PMID: .
- Rosenfeld E, Mitteer LM, Boodhansingh K, Sanders VR, McKnight H, De Leon DD. Clinical and Molecular Characterization of Hyperinsulinism in Kabuki Syndrome. Journal of the Endocrine Society. 2024;8(7):bvae101. PMID: .
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Our editorial team consists of medical specialists and scientists in the field of human genetics. All content is created and reviewed in accordance with current scientific standards.
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