By: Helga Toriello, PhD, FACMG

Kabuki syndrome was first described in 1981 by two different groups in Japan (1,2).  Since then, several individuals with Kabuki syndrome have been described, and currently the frequency is estimated at 1/32,000 (3).   This condition is easily recognizable by clinicians familiar with this condition.  The face is distinctive, with long palpebral fissures, arched eyebrows with disruption or lateral sparseness, depressed nasal tip, and large, prominent ears common.  The tips of the fingers and toes have prominent pads.  Children with Kabuki syndrome often have postnatal growth delay as well as developmental delay and learning disabilities.   Major malformations also occur with some frequency, with most common including cardiac, renal, anal, and diaphragmatic malformations (4).  Other distinctive diagnostic manifestations include premature thelarche in girls with Kabuki syndrome, and reports of most children with Kabuki syndrome sleeping with their eyes open (lagophthalmos).  This latter manifestation is often present during infancy. 

In 2010, researchers identified what is likely the major causative gene for this condition.  Ng et al. (5) found mutations in MLL2 in approximately 70% of individuals with the clinical diagnosis of Kabuki syndrome.  Recently, I had the honor of asking some of our families to provide DNA samples to the University of Chicago for validation of their test for Kabuki syndrome.  I am pleased to say that all four of our patients were found to have mutations in this gene.   One of these patients was a little girl referred to the genetics clinic because of premature thelarche (breast development).  In addition, she had cleft lip/palate, chronic otitis media, and swallowing dysfunction.  On physical evaluation, she was noted to have long palpebral fissures, blue sclera, disrupted lateral eyebrows, small fingertip pads, and a history of sleeping with her eyes open (present in approximately 2/3 of individuals with Kabuki syndrome).    

However, the fact that not all children with Kabuki syndrome have mutations in this gene suggests that either individuals who in fact do NOT have Kabuki syndrome are being tested (and thus would be expected to be negative for the test [although a group recently did testing for MLL2 in children with confident diagnoses of Kabuki syndrome, ref. 6] or that other genes are involved in causing this syndrome.  Clearly, with the technology available today, an answer to this dilemma should be available soon. 


1. Kuroki Y et al., J Pediatr 99:570, 1981

2. Niikawa N et al., J Pediatr 99:565, 1981

3. Niikawa N et al., Am J Med Genet 31:565, 1988

4. Adam M and Hudgins L; Clin Genet 67:209, 2005

5. Ng SB et al.; Nat Genet 42:790, 2010

6. Paulussen AD et al.; 32:E2018, 2011