Table of Contents

HK J Paediatr (New Series)
Vol 22. No. 1, 2017

HK J Paediatr (New Series) 2017;22:65-67

Clinical Quiz Answer

What is the diagnosis?

HM Tam, JY Leung, IFM Lo, HM Luk

The clinical diagnosis of our patient is Kabuki syndrome (KS). Molecular testing showed there is a heterozygous nonsense mutation (Gln3892*) in exon 39 of KMT2D {NM_003482.3} gene that confirmed clinical diagnosis.

KS was first reported in 1981 by Japanese paediatrician Niikawa and Kuroki.1

There are 5 cardinal features of KS as defined by Niikawa,1 including typical 1) facial features, 2) skeletal anomalies like brachydactyly, 3) persistent finger pads, 4) mild to moderate intellectual disability and 5) postnatal growth deficiency.

Other common manifestations of KS included feeding difficulties (70%), congenital heart defect like septal defect and coarctation of the aorta (40-50%), joint hypermobility (50-75%) and hypotonia (25-89%).2

The typical distinctive facial features of KS had been described in the literature Included long palpebral fissures with eversion of the lateral one third of the lower eyelid, arching eyebrows with lateral part being broad and sparse, dense eyelashes. The columella is short and bulbous nasal tip is depressed resulting in triangular nostrils. Ears are large, prominent and cupped. Ocular hypertelorism may also be observed.1

What is the molecular defect and clinical features in KS?

Currently there are 2 genes being associated with KS. KS type 1, the more common type of KS which accounts for 56-75% of all the Kabuki cases,3 is an autosomal dominant disease caused by mutation of KMT2D gene. KMT2D gene is located at chromosome 12q13.12.4 It encodes MLL2 protein, also named as H3K4 methyltransferase, which regulates the methylation of histone 3 lysine 4. This affects the action of euchromatin which in turn disturbs active transcription.3 The mutation is most frequently due to nonsense (36.5%), deletion/duplication (33.2%) and missense (21.6%) mutations and results in loss of function of MLL2 protein.3

Type 2 KS is the result of KDM6A gene mutation which is located at chromosome Xp11.3.4 The KDM6A gene mutation accounts for 5-8% of all causes of KS.3 The gene codes for H3K27 demethylase which is responsible for the activation of chromatin by erasing repressive polycomb-derived methylation marks and deposition of activating H3K4 methylation mark on chromatin. These allow the recruitment of RNA polymerase II complex.3 Haploinsufficiency of the protein is attributed to the deletion (25%), nonsense (28.5%) or missense (21.9%) mutation of the gene.3

The prevalence of different symptoms in MLL2 ( KMT2D ) and non-MLL2 mutations is demonstrated in Table 1.

Table 1 Compare the prevalence of symptoms between MLL2 and non-MLL2 mutations5-8
Clinical features MLL2 mutation (%) Non-MLL 2 mutation (%)
Flat nasal tip 60.0-85.3 23.3-45.5
Intellectual disability 52.2 29.0
Arched eyebrows 53.8-85.3 24.6-45.5
Broad nasal root 44.6-85.3 15.5-45.5
Thin upper and full lower lips 52.5-85.3 23.7-45.5
Short stature 39.7-44.74 17.5-100.0
Lax joint 32.5-50.8 8.70-24.6
Blue sclera 23.3 6.7
Frequent infection 39.7-64.1 14.3-42.4
Large dysplastic ears 48.5 30.9
Hypotonia 47.5-86.49 0.0-32.2

What is the diagnostic criteria for KS?

There is no universal clinical diagnostic criteria established for KS. The diagnosis is mainly based on clinical features. Scoring system has been proposed to enhance clinical diagnosis and to predict the KMT2D gene mutation (Table 2). Based on 6 different features, the likelihood of having KMT2D gene mutation is assessed. With the maximum score of 10, the higher the score, the greater the chance of getting the gene mutation. The mean score for those patients with KMT2D gene variant is 6.1 while those without the gene variant obtain 4.5 points.5

Table 2 Kabuki syndrome phenotype scoring system (KMT2D gene mutation)5
Phenotypic finding Details Score
Facial features
  • Eye: long palpebral fissures, everted lower eyelids, arched eyebrows with lateral one third being sparse, strabismus, blue sclera, ptosis
  • Ear: prominent unfold cupped ears
  • Nose: flat nasal tip, board nasal root
  • Teeth: abnormal dentition, oligodontia
  • Others: high/cleft palate, micrognathia, thin upper and full lower lips, lip nodules
Limb features
  • Persistent fetal pads - Brachydactyly or clindactyly
  • Lax joints - Hip dislocation
Microcephaly   1
Short stature   1
Heart   1
Kidney   1
Total   0-10
*0-3 features=1 point; 4-6 features=2 points; 7-9 features=3 points; 10-12 features=4 points; 13-15 features=5 points
**0-1 features=0 point; 2-4 features=1 point

What is the management of KS?

The management for KS is mainly supportive and symptomatic (Table 3).

Table 3 The management for KS is mainly supportive and symptomatic4
KS features Investigation and management
Feeding problem 24 pH probe and barium swallow if indicated.
Gastro-esophageal reflux Gastrostomy tube replacement may be necessary
Seizure Electroencephalogram for clinical seizure
Hormone deficiency Endocrine assessment like baseline hormonal level (thyroid function and growth hormone)
Congenital heart problem Baseline cardiac evaluation
Congenital renal problem Baseline renal ultrasound
Eye problem e.g. myopia Annual eye assessment
Hearing Annual hearing assessment
Hearing aid or even tympanostomy tube placement may be required
Immune deficiency T cell count and immunoglobin level
Short stature Monitor growth rate by specific growth chart
Developmental delay Developmental evaluation and appropriate training


We would like to thank the patient and family for their contribution.


1. Niikawa N, Kuroki Y, Kajii T, et al. Kabuki make-up (Niikawa-Kuroki) syndrome: A study of 62 patients. Am J Med Genet 1988;31:565-89.

2. Kawame H, Hannibal MC, Hudgins L, Pagon RA. Phenotypicspectrum and management issues in Kabuki syndrome. J Pediatr 1999;134:480-5.

3. Böershausen N, Gatinois V, Riehmer V, et al. Mutation Update for Kabuki Syndrome Genes KMT2D and KDM6A and Further Delineation of X-Linked Kabuki Syndrome Subtype 2. Hum Mutat 2016;37:847-64.

4. McKusick VA. Kabuki syndrome ©2016. Retrieved July 26, 2016, from

5. Makrythanasis P, van Bon BW, Steehouwer M, et al. MLL2 mutation detection in 86 patients with Kabuki syndrome: A genotype-phenotype study. Clin Genet 2013;84:539-45.

6. Miyake N, Koshimizu E, Okamoto N, et al. MLL2 and KDM6A mutations in patients with Kabuki syndrome. Am J Med Genet A 2013;161A:2234-43.

7. Banka S, Veeramachaneni R, Reardon W, et al. How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum. Eur J Hum Genet 2012;20:381-8.

8. Paulussen AD, Stegmann AP, Blok MJ, et al. MLL2 mutation spectrum in 45 patients with Kabuki syndrome. Hum Mutat 2011;32:E2018-25.


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