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.

The characteristic appearance, though less evident in later childhood, of Kabuki syndrome includes:

• palpebral fissures with eversion of the lateral third of the lower eyelid;
• arched and broad eyebrows with sparseness or notching (usually lateral third);
• flat nasal tip and short columella;
• distinct ears which can be large, low set, prominent and/or cupped; and
• persistent fetal finger pads.

Distinctive features can also include:

• growth:
  • early feeding difficulties;
  • postnatal faltering growth; and
  • short stature (may respond to growth hormone therapy, so consider referral to endocrinology);
• skeletal anomalies:
  • joint laxity;
  • fifth finger clinodactyly; and
  • spine abnormalities including spinal dimple, hemivertebrae, butterfly vertebrae and scoliosis;
• functional differences:
  • hearing loss; and
  • increased susceptibility to infections and autoimmune disorders;
• mild-to-moderate intellectual disability; and
• wider structural anomalies such as:
  • eye, including ptosis, strabismus and coloboma;
  • cleft lip and/or palate (in around a third of patients) or high arched palate;
  • dental, including widely spaced teeth and hypodontia;
  • congenital heart defects, including coarctation of the aorta (most common), aortic valve, atrial and/or ventricular septal defects and complex structural rearrangements;
  • gastrointestinal, including anal atresia; and
  • genitourinary, including cryptorchidism in males, horseshoe kidney and renal dysplasia.

Note that individuals with KDM6A-related Kabuki syndrome are less likely to have the typical facial features and have a higher incidence of hypertrichosis and hypoglycaemia secondary to hyperinsulinaemia. As an X-linked condition, affected females tend to have milder features than affected males.

The genes KMT2D and KDM6A have an important role in the function of chromatin – a complex of proteins and DNA which help tightly package 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 of 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.

International consensus diagnostic criteria have been published since 2019.

A definite diagnosis of Kabuki syndrome 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:

• a pathogenic or likely pathogenic variant in KMT2D or KDM6A; and/or
• typical dysmorphic features at some point of life.

Those with a probable or possible diagnosis of Kabuki syndrome on the basis of a history of infantile hypotonia, developmental delay, and/or intellectual disability and typical clinical features should be considered for genomic testing.

For individuals with a variant of uncertain significance in KMT2D or KDM6A, DNA methylation analysis (such as epigenetic signature studies) may be considered.

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:

• Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with apathogenic variant.
• The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).
• Incomplete penetrance can occur when not everyone who has the variant develops the disease.

Kabuki syndrome caused by variants in the KDM6A gene is passed on in an X-linked dominant inheritance pattern (though the gene is known to escape X-inactivation).

Notably, females who carry the KDM6A variant (heterozygous) tend to have milder clinical and developmental features. Males who carry the KDM6A variant (hemizygous) are typically more severely affected, with moderate-to-severe intellectual disability. Each of an affected female’s offspring will have a 50% chance of inheriting the variant. There are no reports in the literature of affected males reproducing, though theoretically all female offspring would inherit the variant (and expect to be more mildly affected than their fathers), whereas all male offspring would be unaffected.

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