Kabuki Syndrome

Excerpt

Clinical characteristics: Kabuki syndrome (KS) is characterized by typical facial features (long palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; large, prominent, or cupped ears), minor skeletal anomalies, persistence of fetal fingertip pads, mild-to-moderate intellectual disability, and postnatal growth deficiency. Other findings may include: congenital heart defects, genitourinary anomalies, cleft lip and/or palate, gastrointestinal anomalies including anal atresia, ptosis and strabismus, and widely spaced teeth and hypodontia. Functional differences can include: increased susceptibility to infections and autoimmune disorders, seizures, endocrinologic abnormalities (including isolated premature thelarche in females), feeding problems, and hearing loss.

Diagnosis/testing: The diagnosis of KS is established in a proband of any age with a history of infantile hypotonia, developmental delay, and/or intellectual disability AND one or both of the following:

1. Typical dysmorphic features (long palpebral fissures with eversion of the lateral third of the lower eyelid, and ≥2 of the following: arched and broad eyebrows with the lateral third displaying notching or sparseness; short columella with depressed nasal tip; large, prominent, or cupped ears; persistent fingertip pads)

2. A heterozygous pathogenic variant in KMT2D or a heterozygous or hemizygous pathogenic variant in KDM6A

Management: Treatment of manifestations: Thickened feedings and positioning after meals to treat gastroesophageal reflux; gastrostomy tube placement if feeding difficulties are severe. If cognitive difficulties are evident, psychoeducational testing and special education services to address the individual child's needs. Evaluation by a developmental pediatrician or psychiatrist if behavior suggests autism spectrum disorders. Standard anti-seizure treatment.

Prevention of secondary complications: Prophylactic antibiotic treatment prior to and during any procedure (e.g., dental work) may be indicated for those with specific heart defects.

Surveillance: Monitor height, weight, and head circumference at each well-child visit and, at a minimum, yearly. Developmental milestones should be followed with each well-child visit. Monitor vision and hearing on a yearly basis.

Genetic counseling: KMT2D-related KS is inherited in an autosomal dominant manner; KDM6A-related KS is inherited in an X-linked manner.

Autosomal dominant inheritance: The proportion of KS caused by a de novo KMT2D pathogenic variant is unknown but is likely high based on clinical experience. In the rare case that a parent of the proband is affected, the risk to the sibs is 50%.

X-linked inheritance: If the mother of the proband has a KDM6A pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous and may have features of KS.

Once the causative pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for KS are possible.