Kabuki Syndrome

From EyeWiki
Original article contributed by: Samantha Estefania Andrade Leal, MD, MD., Andrea Rangel Padilla, MD.
All contributors: Samantha Estefania Andrade Leal, MD
Assigned editor:
Review: Assigned status Not reviewed on January 5, 2017.



Kabuki Syndrome
Classification and external resources
DiseasesDB 32161


Disease

Kabuki syndrome (KS) also called Kabuki make-up syndrome is a a congenital malformation-mental retardation syndrome first described Niikawa et aland 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’ wascoined(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 arenow 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 KDM6Amutations are de novo mutations found in sporadic cases. In afew cases, an affected person is believed to have inherited themutation from an affected parent. KS caused by mutations in theKMT2D gene is inherited in an autosomal dominant manner,whereas KS caused by mutations in the KDM6A gene is inheritedin an X-linked inheritance manner. The KDM6A gene is locatedon the X chromosome, which is one of the two sex chromosomes.In women, a mutation in one of the two copies of the gene ineach cell is sufficient to cause KS. In men, a mutation in the onlycopy of the gene causes the disorder. A characteristic of X-linkedinheritance is that fathers cannot pass X-linked traits to theirsons.(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 NIKAWA et al. 62 patients SCHRANDER-STUMPEL et al. 29 patients SANLAVILLE et al. 24 patients MICALE et al. 62 patients

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

Cardiopathy

32%

28%

35%

60%

Urogenital

NR

34%

30%

39%

Hearing Loss

(Neurosensory / conductive)

NR

50%

41%

40%

Early telarch

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 NIKAWA et al. 62 patients SCHRANDER-STUMPEL et al. 29 patients SANLAVILLE et al. 24 patients MICALE et al. 62 patients

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

Currently, there are no established consensus diagnostic criteria for KS. Traditionally, five cardinal manifestations have been defined (4):

  1. A ‘peculiar face’: eversion of the lower lateral eyelid, arched long eyebrows with the lateral one-third dispersed or sparse, a depressed nasal tip, and prominent ears; present in all patients.
  2. Skeletal anomalies: deformed spinal column with or without sagittal cleft vertebrae and brachydactyly.
  3. Dermatoglyphic abnormalities: such as the absence of the digital triradius ‘c’ and ‘d’ and the presence of interdigital triradii, as well as hypothenar and interdigital ulnar loop patterns and fingertip pads on all fingers.
  4. Mild to moderate mental retardation.
  5. Postnatal growth deficiency: born with normal growth parameters, but fail to thrive during infancy and show postnatal growth retardation because of feeding problems caused by poorly coordinated sucking and swallowing, as well as gastroesophageal reflux in some patients.


Less frequent findings 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. Irrespectiveof racial differences, the suggested minimal criteria for diagnosis of KS are long palpebral fissures with eversion of the lateral portion of the lower eyelids, broad and arched eyebrows with lateral sparseness, short nasal columella with a depressed nasal tip, prominent or cupped ears, and developmental delay or mental retardation. Most patients with KS have several of these features.

Ophtalmologic characteristics

The authors report ophthalmologic manifestations in 144 of 200 patients with KS(11), in addition to the characteristic external ocular features. Most of the other reported ocular features are serious abnormalities that cause visual impairment. It is not clear why such a significant number of patients with KS have a variety of ocular anomalies.(11)

OCULAR SIGNS REPORTED PATIENTS

Amblyopia

1

Refractive anomalies

6

Ptosis

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

*Kluijt, I. et. al "Kabuki syndrome – Report of six cases and review of the literature with emphasis on ocular features"

Nine of the 200 described cases with KS and microphthalmia, microcornea,and coloboma are interesting, because of the low incidence ofthese features in the general population. Prevalence figures of microphthalmiavary from 0.0092% to 0.15% in defined areas and in anophthalmic outpatient clinic.(12-16)

These eye features have been describedin a large number of many syndromes, including the cat-eye syndrome,CHARGE syndrome, and Lenz’s syndrome.46 This variety of syndromesgives no elucidation for the etiology of these eye anomalies.(11)

Diagnostic test

Detection of KMT2D and KDM6A mutations (92.3%) is expected owing to the strict criteria used to establish a clinical diagnosis6). 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. (18) 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.(17)

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.(17)

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.(11)

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 requirevarious 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 promptfamily 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.

References

1. I. Kluijt, D.B. van Dorp, M.L. Kwee, A. Toutain, K. Keppler-Noreuil, M. Warburg & P. Bitoun (2000) Kabuki syndrome – Report of six cases and review of the literature with emphasis on ocular features, Ophthalmic Genetics, 21:1, 51-61

2. 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. Dentici, M. L., Pede, A. D., Lepri, F. R., Gnazzo, M., Lombardi, M. H., Auriti, C., . . . 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. 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. Adam MP, Hudgins L. Kabuki syndrome: a review. Clin Genet 2005;67:209-19.

6. 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

7. 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. 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. Bogershausen N, Wollnik B. Unmasking Kabuki syndrome. ClinGenet 2013;83:201-11.

10. Matsumoto N, Niikawa N. Kabuki make-up syndrome: a review. Am J Med Genet C Semin Med Genet 2003;117C:57-65.

11. Kluijt, I., Dorp, D. V., Kwee, M., 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

12. Stoll C, Alembik Y, Dott B, Roth MP. Congenital eye malformations in 212,479 consecutive births. Ann Genet 1997;40:122-128.

13. 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.

14. Kallen B, Robert E, Haiirs J. The descriptive epidemiology of anophthalmia and microphthalmia. Int J Epidemiol 1996;25:1009-1016.

15. Warburg M. Genetics of microphthalmos. Int Ophthalmol 1981;4:45-65.

16. Taylor D. Pediatric Ophthalmology. Blackwell Scientific Publications, 1994;136-137.

17. 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

18. 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.

19. 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.

20. 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.

21.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.