Kabuki syndrome

The diagnosis of Kabuki syndrome is made by identification of a combination of typical clinical features, in addition to the presence of a heterozygous pathogenic variant in either the KMT2D or KDM6A gene. Consensus guidelines outlining diagnostic criteria are available.

Distinctive features include:

• long palpebral fissures with eversion of the lateral third of the lower eyelid;
• arched, sparse or notched eyebrows;
• flat nasal tip and a short columella;
• distinct ears: large, low set, prominent, cupped;
• ptosis and strabismus;
• persistent fetal finger pads;
• oligodontia or hypodontia;
• cleft lip and/or palate (present in about a third of affected individuals (those without this feature may have a high-arched palate));
• short stature and other skeletal anomalies:
  • early feeding difficulties and faltering growth (growth deficiency tends to present postnatally;
  • joint laxity, scoliosis, kyphosis, clinodactyly;
• developmental delay/intellectual disability:
  • delayed early milestones;
  • intellectual disability, typically mild to moderate;
• congenital cardiac and renal anomalies:
  • coarctation of the aorta (this is the most common cardiac anomaly);
  • aortic valve anomalies;
  • atrial and/or ventricular septal defects; and
  • complex structural rearrangements.

Individuals with Kabuki syndrome may also exhibit structural renal and urinary tract anomalies. Hydronephrosis is a common finding, with horseshoe kidney, renal dysplasia and hypospadias also described.

Note that, in those with short stature, studies have demonstrated a positive response to growth hormone therapy. A referral to endocrinology should therefore be considered.

The genes KMT2D and KDM6A have an important role in the function of chromatin, a complex of protein and DNA that packages the DNA into the nucleus of the cell. In addition to packaging the DNA, chromatin affects the way in which transcription is regulated. Along with other factors, open or closed chromatin structures dictate whether transcription can occur, effectively turning genes on or off. Pathogenic variants in KMT2D or KDM6A disrupt this process via a loss-of-function mechanism.

For information about testing, see Presentation: Infant with congenital malformation and dysmorphism syndrome.

In many individuals with Kabuki syndrome, the causative pathogenic variant occurs de novo, and the majority of cases are simplex. If neither parent is found to carry their affected child’s variant, the chance of recurrence for future pregnancies will be less than 1%.

Kabuki syndrome caused by variants in the KMT2D gene is inherited in an autosomal dominant pattern. This means that the offspring of an affected individual will each have a 50% (1-in-2) chance of also being affected.

Kabuki syndrome caused by variants in the KDM6A gene is inherited in an x-linked recessive manner. Females who carry the variant (heterozygous) are unaffected, and males who carry the variant (hemizygous) are affected. Each of a carrier female’s offspring will have a 50% chance of inheriting the variant; male offspring have a 50% chance of developing Kabuki syndrome, and female offspring have a 50% chance of being a carrier. For affected males, female offspring have a 50% chance of being a carrier and male offspring will not inherit the condition.

Management of children with Kabuki syndrome is complex and should be delivered via a multidisciplinary team. Detailed suggested approaches have been published by several authors. Individuals with Kabuki syndrome are likely to require input from clinical genetics, community paediatrics, ophthalmology, audiology, endocrinology and cardiology teams.

For clinicians

• GeneReviews: Kabuki syndrome
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• Kabuki UK: Common medical issues
• NHS England: National Genomic Test Directory
• U.S. National Library of Medicine: ClinicalTrials.gov database

References:

• Adam MP, Banka S, Bjornsson HT and others. ‘Kabuki syndrome: International consensus diagnostic criteria‘. Journal of Medical Genetics 2019: volume 56, issue 2, pages 89–95. DOI: 10.1136/jmedgenet-2018-105625

For patients

• Kabuki Syndrome Foundation: What is Kabuki syndrome?
• Kabuki UK