Kabuki Syndrome
All content on Eyewiki is protected by copyright law and the Terms of Service. This content may not be reproduced, copied, or put into any artificial intelligence program, including large language and generative AI models, without permission from the Academy.
Disease Entity
Disease
Kabuki syndrome (KS) also called Kabuki make-up syndrome is a a congenital malformation-mental retardation syndrome first described Niikawa et al and Kuroki et al[1],two independent groups in Japan at the Journal of Pediatrics in 1981.
Because its characteristic facial features resembled the make-up of actors in Kabuki, the traditional Japanese theater, the term ‘Kabuki make-up syndrome’ was coined[2].
KS is a rare syndrome characterized by distinct dysmorphic facial features, postnatal growth retardation, intellectual disabilities, skeletal abnormalities, unusual dermatoglyphic patterns[2], and various organ malformations[3].
KS was initially thought to be specific to Japanese individuals. Its estimated prevalence in Japan is 1/32,000)[4]. However, there are now reports of KS in a variety of ethnic groups, including Northern European, Brazilian, Vietnamese, Filipino, East Indian, Arabic, Chinese, Mexican, and African [5]. The global incidence of KS is not known.
Etiology
The genetic etiology of KS was not elucidated until 2010. At this time, Ng SB et al.[6] reported that heterozygous mutations in KMT2D are the major genetic cause of KS. Subsequent mutation screenings in KS cohorts found a KMT2D mutation in 55.8% to 80% of patients[7][8]. Most mutations were private de novo mutations; familial occurrence with an autosomal dominant pattern has also been reported(9). Most identified mutations are truncating, likely leading to haploinsufficiency of the KMT2D protein. Heterozygous deletions in a second gene, KDM6A, are another cause of KS [9]. To date, the genetic basis of KS remains unknown in 20% to 45% of patients[9], and further investigation is therefore needed.[8]
Most reported KMT2D and KDM6A mutations are de novo mutations found in sporadic cases. In a few cases, an affected person is believed to have inherited the mutation from an affected parent. KS caused by mutations in the KMT2D gene is inherited in an autosomal dominant manner, whereas KS caused by mutations in the KDM6A gene is inherited in an X-linked inheritance manner. The KDM6A gene is located on the X chromosome, which is one of the two sex chromosomes. In women, a mutation in one of the two copies of the gene in each cell is sufficient to cause KS. In men, a mutation in the only copy of the gene causes the disorder. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.[2]
Risk Factors
There are no known risk factors.
Diagnosis
Usually KS is identified by a pediatrician after physical examination of the patient and review of his or her medical history. However, clinical diagnosis is challenging because the phenotype tends to evolve over time, and characteristic facial features, such as long palpebral fissures with everted lower lids, become more evident during childhood. [10] Newborns display milder facial anomalies and more organ malformations when compared with older individuals.[3]
Physical examination
| ANOMALIES | NIIKAWA et al. 62 patients[4] | SCHRANDER-STUMPEL et al. 29 patients[11] | SANLAVILLE et al. 24 patients[12] | MICALE et al. 62 patients[13] | |
|---|---|---|---|---|---|
|
Growth |
Low Size |
75% |
62% |
54% |
61% |
|
Microcephaly |
5% |
31% |
48% |
29% | |
|
Extremities |
Finger Pads |
77% |
100% |
96% |
75% |
|
Brachydactyly / clinodactyly |
89% |
75% |
100% |
63% | |
|
Articular hypermobility |
NR |
96% |
75% |
48% | |
|
Visceral |
Cardiovascular anomalies |
32% |
28% |
35% |
60% |
|
Urogenital |
NR |
34% |
30% |
39% | |
|
Hearing Loss (Neurosensory / conductive) |
NR |
50% |
41% |
40% | |
|
Early thelarche |
NR |
50% |
39% |
16% | |
|
Neurologic |
Epilepsy |
NR |
10% |
14% |
21% |
|
Hypotonia |
NR |
83% |
79% |
60% | |
|
Agenesis of the corpus callosum |
NR |
NR |
NR |
5% | |
| Intellectual deficit | LOW - MODERATE |
MODERATE |
100% |
84% | |
| Immunological | Autoimmune disease |
NR |
NR |
NR |
7% |
|
Skeletal |
Dislocation of knee / hip / flat foot /scoliosis |
NR |
81% |
50% |
9.7% |
| FACIAL FINDINGS | NIIKAWA et al. 62 patients[4] | SCHRANDER-STUMPEL et al. 29 patients[11] | SANLAVILLE et al. 24 patients[12] | MICALE et al. 62 patients[13] |
|---|---|---|---|---|
|
Long palpebral fissures |
100% |
100% |
96% |
95% |
|
Eversion of the external third of the lower eyelid |
98% |
83% |
92% |
85% |
|
Arched eyebrows |
88% |
79% |
83% |
82% |
|
Epicanthus |
NR |
NR |
NR |
NR |
|
Strabismus |
NR |
NR |
38% |
42% |
|
Palpebral ptosis |
12% |
NR |
63% |
50% |
|
Long Lashes |
NR |
NR |
NR |
NR |
|
Blue Sclerotic |
NR |
36% |
29% |
17% |
| Thin upper lip and thick lower lip |
NR |
NR |
NR |
71% |
|
High palate with fissure |
79% |
69% |
63% |
50% |
|
Anomalous dentition |
78% |
71% |
80% |
53% |
|
Micrognathia |
NR |
NR |
63% |
32% |
| Broad nasal bridge with depressed nasal tip |
93% |
79% |
83% |
69% |
| Dysplastic ears |
78% |
100% |
83% |
90% |
Diagnosis
The international expert panel in 2019 [14]proposed that a definite diagnosis of KS can be made in a male or female patient of any age with a history of infantile hypotonia, developmental delay and/ or intellectual disability, and one or both of the following major criteria:
1. A pathogenic or likely pathogenic variant in KMT2D or KDM6A.
2. Typical dysmorphic features at some point of life.
(Typical dysmorphic features include long palpebral fissures (a palpebral fissure measurement of greater than or equal to 2 SD above the mean for age) with eversion of the lateral third of the lower eyelid), and two or more of the following:
1. Arched and broad eyebrows with the lateral third displaying notching or sparseness. 2. Short columella with depressed nasal tip. 3. Large, prominent, or cupped ears. 4. Persistent fingertip pads.
A probable diagnosis[14] can be made in an individual with a history of infantile hypotonia, developmental delay, and/or intellectual disability and long palpebral fissures (a palpebral fissure measurement greater than or equal to 2 SD above the mean for age) with eversion of the lateral third of the lower eyelid and at least three supportive clinical features described in table below.[14]
The three supportive clinical features can be in any combination and from any system listed in table below (eg, one feature each from three systems, all three features from one system or any other combination thereof).
A possible diagnosis[14] should be entertained in an individual with a history of developmental delay and/or intellectual disability and at least two supportive clinical features in table below and at least one of the following dysmorphic features at one point of life:
1. Arched and broad eyebrows with the lateral third displaying notching or sparseness. 2. Short columella with depressed nasal tip. 3. Large, prominent or cupped ears. 4. Persistent fingertip pads.
| SUPPORTIVE CLINICAL FEATURES | |
| SYSTEM | CLINICAL FEATURES |
| Constitutional | Short stature |
| Craniofacial | Microcephaly
Cleft palate. Lip pits. Oligodontia and/or abnormal incisors. Progressive sensorineural hearing loss |
| Cardiac | Congenital heart defect, excluding a patent ductus
arteriosus. |
| Gastrointestinal | Feeding difficulties |
| Genitourinary | Mispositioned kidneys.
Hypospadias in males. |
| Musculoskeletal | Brachydactyly
Non-traumatic joint dislocation, including congenital hip dislocation |
| Endocrinological | Hyperinsulinemia hypoglycemia in infancy |
| Immunological | Hypogammaglobulinemia or low serum IgA |
Less frequent findings in Kabuki syndrome include visceral abnormalities, premature breast development in girls, and susceptibility to frequent infections. There is a study that phenotypically characterized 12 Korean patients with KS[2]. All patients showed the characteristic facial dysmorphism, including long palpebral fissures, eversion of the lateral portion of the lower eyelids, and a broad nasal root, and 92% displayed intellectual disabilities.
Ophthalmologic characteristics
The authors Kluijt, I. et. al reported six cases of KS with ocular findings and performed literature review on ophthalmic manifestations of KS. The authors found that a total of 144 of 200 reported patients with KS had significant ocular abnormalities in addition to the characteristic external ocular features, such as eyelids with long S-shaped palpebral fissures and eversion of the lateral third of the lower lid. These latter characteristics constitute one of the cardinal features of KS. Most of the other reported ocular features are serious abnormalities that cause visual impairment. [15], The summary of ocular findings in addition to the characteristic external ocular features are described in table below. It is not clear why such a significant number of patients with KS have a variety of ocular anomalies.[15]
| OCULAR SIGNS | REPORTED PATIENTS |
|---|---|
|
Amblyopia |
1 |
|
Refractive anomalies |
6 |
|
Ptosis, Epicanthus |
20 |
|
Strabismus |
43 |
|
Nystagmus |
1 |
|
Ophthalmoplegia |
3 |
|
Paralysis of VI cranial nerve |
1 |
|
Microphthalmia, microcornea, coloboma |
9 |
|
Megalocornea |
2 |
|
Corneal opacities, Peter’s anomaly |
5 |
|
Phtisis bulbi |
1 |
|
Blue sclerae |
44 |
|
Cataracts |
3 |
|
Retinal pigmentation/hypopigmentation |
1 |
|
ERG and VEP abnormal |
1 |
|
Obstructed nasolacrimal ducts |
1 |
Nine of the 200 described cases with KS and microphthalmia, microcornea, and coloboma are interesting, because of the low incidence of these features in the general population. Prevalence figures of microphthalmia vary from 0.0092% to 0.15% in defined areas and in ophthalmic outpatient clinic.[16][17][18][19][20] Ophthalmologic features such as Marcus Gunn pupil (a type of relative afferent pupil defect that causes a pathologically decreased pupillary light reflex and nocturnal lagophthalmos have also been reported in Kabuki syndrome. [21]
These eye features have been described in a large number of many syndromes, including the cat-eye syndrome, CHARGE syndrome, and Lenz’s syndrome. This variety of syndromes gives no elucidation for the etiology of these eye anomalies.[15]
Diagnostic test
Detection of KMT2D and KDM6A mutations (92.3%) is expected owing to the strict criteria used to establish a clinical diagnosis[6]. Therefore, exhaustive mutation analysis of KMT2D and KDM6A may be a useful first step toward early diagnosis and counseling of patients with KS. About 140 different mutations in the KMT2D gene have been reported in patients with KS (http://www.hgmd.org).
Differential diagnosis
The facial phenotype reported by Poley et al. [22] showed some similarity of Hardikar syndrome(HS) with KS. It was suggested that the absence of mental retardation and fingertip pads, reported in KS and not in HS, and the presence of biliary ductal malformation and retinopathy in HS and not in KS, definitely differentiate the two clinical entities. Mental retardation is considered a typical feature of KS.[23]
Nonetheless, a normal intelligence does not exclude the diagnosis. Congenital hepatic abnormalities were described in KS and therefore should not be considered a distinctive feature of HS [4].
A critical reading of the literature pointed to apparent similarities between the two conditions and underscored that HS was identified as a very rare clinical entity entailing a certain degree of clinical heterogeneity. Ejarque, I. et. al suggest that HS may represent a subgroup within the wide clinical spectrum of KS. Molecular analysis of the MLL2 gene in patients clinically diagnosed as having HS may help to clarify this issue.[23]
Management
The importance of ophthalmological examination in all patients with KS for the early detection of ocular anomalies in order to prevent visual impairment. The generally mild mental handicap of these patients could be worsened by poor vision, which could be prevented in some cases by adequate treatment and follow-up at an early age.[15]
A multidisciplinary management of these patients is crucial because of their multiple systemic findings that could compromise their health and development.
Medical follow up and Treatment
As KS is a multisystem disorder, people with KS may require various diagnostic and screening tests, assessments, referrals, and multidisciplinary interventions at different stages of their lives.[2]
Early diagnosis of the disease is crucial in regard to patient management of his or her associated medical problems and for prompt family and genetic counseling, and serves as a starting point for therapeutic interventions.[2]
Prognosis
KS is a relatively new diagnosis. Children first diagnosed in the 1980s would be in their 40s today, although little long-term follow-up has been performed. It is currently believed that children with this diagnosis are likely to live into adulthood. Heart problems and the potential for infection or renal failure, however, make the prognosis for an average life span uncertain [5][10]. At the time there is not enough information on the long-term prognosis in this syndrome, because it began to investigate in the 80s and the patients studied do not reach the elderly.
Additional Resources
- Kabuki syndrome: National Library of Medicine (US). Genetics Home Reference [Internet]. Bethesda (MD): Health Conditions; 2019 Feb 19. Kabuki syndrome; [reviewed 2017 Jan; cited 2019 Feb 19]; Available from: https://ghr.nlm.nih.gov/condition/kabuki-syndrome Accessed February 25, 2019.
References
- ↑ Kuroki Y, Suzuki Y, Chyo H, Hata A, Matsui I. A new malformation syndrome of long palpebral fissures, large ears, depressed nasal tip, and skeletal anomalies associated with postnatal dwarfism and mental retardation. J Pediatr 1981: 99: 570–573.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Cheon, C., & Ko, J. M. (2015). Kabuki syndrome: clinical and molecular characteristics. Korean Journal of Pediatrics, 58(9), 317. doi:10.3345/kjp.2015.58.9.317
- ↑ 3.0 3.1 Dentici ML, Di Pede A, Lepri FR, Gnazzo M, Lombardi MH, Auriti C, Petrocchi S, Pisaneschi E, Bellacchio E, Capolino R, Braguglia A, Angioni A, Dotta A, Digilio MC, Dallapiccola B. (2014). Kabuki syndrome: clinical and molecular diagnosis in the first year of life. Archives of Disease in Childhood, 100(2), 158-164. doi:10.1136/archdischild-2013-305858
- ↑ 4.0 4.1 4.2 4.3 Niikawa N, Kuroki Y, Kajii T, Matsuura N, Ishikiriyama S, Tonoki H, et al. Kabuki make-up (Niikawa-Kuroki) syndrome: a study of 62 patients. Am J Med Genet 1988;31:565-89.
- ↑ 5.0 5.1 Adam MP, Hudgins L. Kabuki syndrome: a review. Clin Genet 2005;67:209-19.
- ↑ 6.0 6.1 Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet 2010;42:790-3
- ↑ Li Y, Bogershausen N, Alanay Y, Simsek Kiper PO, Plume N, KeuppK, et al. A mutation screen in patients with Kabuki syndrome. HumGenet 2011;130:715-24.
- ↑ 8.0 8.1 Banka S, Veeramachaneni R, Reardon W, Howard E, Bunstone S,Ragge N, et al. How genetically heterogeneous is Kabuki syndrome?:MLL2 testing in 116 patients, review and analyses of mutation andphenotypic spectrum. Eur J Hum Genet 2012;20:381-8.
- ↑ 9.0 9.1 Bogershausen N, Wollnik B. Unmasking Kabuki syndrome. ClinGenet 2013;83:201-11.
- ↑ 10.0 10.1 Matsumoto N, Niikawa N. Kabuki make-up syndrome: a review. Am J Med Genet C Semin Med Genet 2003;117C:57-65.
- ↑ 11.0 11.1 Schrander-Stumpel C, Meinecke P, Wilson G, Gillessen-Kaesbach G, Tinschert S, König R, Philip N, Rizzo R, Schrander J, Pfeiffer L, et al. The Kabuki (Niikawa-Kuroki) syndrome: further delineation of the phenotype in 29 non-Japanese patients. Eur J Pediatr. 1994 Jun;153(6):438-45. PubMed PMID: 8088300.
- ↑ 12.0 12.1 Sanlaville D, Genevieve D, Bernardin C, Amiel J, Baumann C, de Blois MC, Cormier-Daire V, Gerard B, Gerard M, Le Merrer M, Parent P, Prieur F, Prieur M, Raoul O, Toutain A, Verloes A, Viot G, Romana S, Munnich A, Lyonnet S, Vekemans M, Turleau C. Failure to detect an 8p22-8p23.1 duplication in patients with Kabuki (Niikawa-Kuroki) syndrome. Eur J Hum Genet. 2005 May;13(5):690-3. Review. PubMed PMID: 15770228.
- ↑ 13.0 13.1 Micale L, Augello B, Fusco C, Selicorni A, Loviglio MN, Silengo MC, Reymond A, Gumiero B, Zucchetti F, D'Addetta EV, Belligni E, Calcagnì A, Digilio MC, Dallapiccola B, Faravelli F, Forzano F, Accadia M, Bonfante A, Clementi M, Daolio C, Douzgou S, Ferrari P, Fischetto R, Garavelli L, Lapi E, Mattina T, Melis D, Patricelli MG, Priolo M, Prontera P, Renieri A, Mencarelli MA, Scarano G, della Monica M, Toschi B, Turolla L, Vancini A, Zatterale A, Gabrielli O, Zelante L, Merla G. Mutation spectrum of MLL2 in a cohort of Kabuki syndrome patients. Orphanet J Rare Dis. 2011 Jun 9;6:38. doi: 10.1186/1750-1172-6-38. PubMed PMID: 21658225; PubMed Central PMCID: PMC3141365.
- ↑ 14.0 14.1 14.2 14.3 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 Feb;56(2):89-95. doi: 10.1136/jmedgenet-2018-105625.
- ↑ 15.0 15.1 15.2 15.3 Kluijt I, van Dorp DB, Kwee ML, Toutain A, Keppler-Noreuil K, Warburg M, Bitoun P. (2000). Kabuki syndrome ? Report of six cases and review of the literature with emphasis on ocular features. Ophthalmic Genetics, 21(1), 51-61. doi:10.1076/1381-6810(200003)21:1;1-I;FT051
- ↑ Stoll C, Alembik Y, Dott B, Roth MP. Congenital eye malformations in 212,479 consecutive births. Ann Genet 1997;40:122-128.
- ↑ Bermejo E, Martinez-Frias ML. Congenital eye malformations: clinical-epidemiological analysis of 1,124,654 consecutive births in Spain. Am J Med Genet 1998;75:497-504.
- ↑ Kallen B, Robert E, Haiirs J. The descriptive epidemiology of anophthalmia and microphthalmia. Int J Epidemiol 1996;25:1009-1016.
- ↑ Warburg M. Genetics of microphthalmos. Int Ophthalmol 1981;4:45-65.
- ↑ Taylor D. Pediatric Ophthalmology. Blackwell Scientific Publications, 1994;136-137.
- ↑ Boniel S, Szymańska K, Śmigiel R, Szczałuba K. Kabuki Syndrome—Clinical Review with Molecular Aspects. Genes. 2021; 12(4):468. https://doi.org/10.3390/genes12040468
- ↑ Poley JR, Proud VK. Hardikar syndrome: new features. Am J Med Genet A. 2008 Oct 1;146A(19):2473-9. doi: 10.1002/ajmg.a.32266. PubMed PMID: 18792981.
- ↑ 23.0 23.1 Ejarque, I., Uliana, V., Forzano, F., Marciano, C., Merla, G., Zelante, L., . . . Faravelli, F. (2011). Is Hardikar syndrome distinct from Kabuki (Niikawa-Kuroki) syndrome? Clinical Genetics, 80(5), 493-496. doi:10.1111/j.1399-0004.2011.01672.x
- Nobili V, Marcellini M, Devito R, Capolino R, Viola L, Digilio MC. Hepatic fibrosis in Kabuki syndrome. Am J Med Genet A 2004: 124A: 209–212.
- Nydegger A, Van DM, Fisher RA, Jaeken J, Hardikar W. Hardikar syndrome: long term outcome of a rare genetic disorder. Am J Med Genet A 2008: 146A: 2468–2472.
- Verrotti A, Agostinelli S, Cirillo C, D'Egidio C, Mohn A, Boncimino A, et al. Long-term outcome of epilepsy in Kabuki syndrome. Seizure 2011;20:650-4.
