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Kabuki syndrome (KS) is a multiple congenital anomaly syndrome characterized by typical facial features, skeletal anomalies, mild to moderate intellectual disability and postnatal growth deficiency.
ORPHA:2322Classification level: Disorder
KS was initially described in Japan, but has now been observed in all ethnic groups. Prevalence estimation is approximately 1:32,000.
KS has a wide and variable clinical spectrum. Cranio-facial features include elongated palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows with the lateral third displaying sparseness or notching; short columella with depressed nasal tip; large, prominent or cupped ears; cleft lip/palate or high-arched palate; and dental anomalies. If the stature is normal at birth, neonates soon present with growth delay and frequent failure to thrive of variable severity. Microcephaly is inconstant. Musculo-skeletal anomalies include brachydactyly V, brachymesophalangy, clinodactyly of fifth digits, spine abnormalities and joint hypermobility and dislocations. Dermatoglyphic abnormalities with persistence of fetal fingertip pads are another cardinal sign of KS. Almost all patients have mild to moderate intellectual deficit and may present with neurological manifestations such as hypotonia or seizures. Global developmental delay is frequent. Autism traits and hyperactivity have been observed but do not seem to be higher than general population rates. Hearing loss is frequent and may have a sensorineural cause or be a consequence of chronic otitis media due to craniofacial malformation or susceptibility to infection. Ocular findings are occasional and include blue sclerae, strabismus, ptosis, coloboma and corneal abnormalities. Congenital heart defects such as left-sided obstructive lesions or septal defects are frequent. Renal and urinary tract anomalies are less common but are present in approximately 25% of KS patients. In girls, premature thelarche can occur but does not require treatment unless there are other signs of premature puberty. Immune dysfunction, leading to autoimmune disorders and increased susceptibility to infection, has also been reported, mostly in adolescents.
KS is associated, in 45 to 80% of cases, with mutations in the MLL2 gene. KDM6Agene deletions have also been reported in a few cases.
Clinical diagnostic criteria for KS have not been established. Diagnosis relies on the clinical observation of 5 cardinal findings which are 1) cranio-facial features, 2) postnatal growth retardation, 3) skeletal anomalies, 4) persistence of fetal fingertips and 5) intellectual deficiency. Molecular analysis may confirm the clinical diagnosis.
Differential diagnosis of KS includes CHARGE, branchiootorenal, Ehlers-Danlos (hypermobile form), Hardikar syndromes, IRF6-related disorders and 22q11 deletion syndrome (see these terms). Various chromosomal anomalies can also induce clinical signs that overlap the KS clinical spectrum.
Antenatal diagnosis is feasible in families with a previous KS child when the causal mutation is already known.
KS occurs sporadically in most cases but may have an autosomal dominant mode of inheritance with a subsequent 50% recurrence risk.
Management and treatment
Management of KS patients focuses on manifestations; for example, treatment for feeding issues in infants may include gastrostomy tube placement. Affected individuals benefit from annual hearing and vision assessment and routine dental evaluation. If immunologic studies are abnormal or if the patient has recurrent infections, assessment by an immunologist should be considered.
Although morbidity is significant, prognosis is quite favorable. Life expectancy is somewhat dependent on cardiac and immunologic complications.