Kabuki syndrome (ORPHA:2322)
A rare multiple congenital anomalies/neurodevelopmental disorder characterized by five major features: intellectual disability (typically mild to moderate), visceral malformations (frequently congenital heart defects), persistence of fetal fingertip pads, post-natal short stature, skeletal anomalies (brachymesophalangy, brachydactyly V, spinal column abnormalities and fifth digit clinodactyly) and specific facial features (arched and broad eyebrows, long palpebral fissures, eversion of the lower eyelid, large prominent, cupped ears, depressed nasal tip and short columella). Various additional features are frequently observed.
Epidemiology
The prevalence of Kabuki syndrome (KS) is estimated at 1/32000 birth and seems a frequent etiology in malformed fetus.
Clinical description
Presentation is typically with neonatal/infantile hypotonia and feeding difficulties (affecting more than 70%). KS associates developmental delay and intellectual disability in 90% of patients. Intellectual disability is frequently mild to moderate; however, the spectrum ranges from normal intellect to severe disability. Verbal language acquisition and memory are usually better than visuospatial or processing speed. Individuals with KS usually achieve walking and language milestones. Heart malformations are observed in around 50% of patients. Kidney malformations, deafness, and seizures of different types are observed in 20%. Immune deficiency and recurrent infection are frequent. Autoimmune features increase with age affecting around 20% of the adults with KS. Scoliosis and patellar luxation require frequent screening and should be monitored carefully at puberty. Missing teeth are frequently observed. Obesity could arise from the age of 5 and requires monitoring. Growth hormone deficiency is observed in 25-30%. Premature thelarche occurs in 30% of females.
Etiology
KS is usually due to de novo pathogenic variants in about 70% of patients fulfilling the diagnostic criteria. For the majority of patients (56% to 75%), KS is due to mutations in KMT2D (12q13.12) and for the minority of patients (5%), KS is due to mutations in KDM6A (xp11.2).
Diagnostic methods
Diagnosis is evoked on clinical examination, and confirmed using genetic studies.
Differential diagnosis
Differential diagnosis includes CHARGE, 3MC, and Hardikar syndromes, KAT6B-related disorders, and other genetic disorders involving chromatin regulation.
Antenatal diagnosis
For parents of an index individual, detection of KS by amniocentesis in subsequent pregnancies should be discussed. KS could be identified using exome sequencing during pregnancy screening for malformative syndromes.
Genetic counseling
Transmission of KMT2D-related KS is autosomal dominant; however, in most situations, the pathogenic variants arise de novo and thus the risk of sibling recurrence is low. The estimated recurrence risk to siblings is 1% based on the possibility of parental germline mosaicism. Transmission of KDM6A-related KS is X-linked with males slightly more affected than females.
Management and treatment
Management requires a lifelong multidisciplinary approach. Regular follow-up by a clinical geneticist, pediatrician, psychologist/psychiatrist, speech therapist, physiotherapist and ophthalmologist will have a major impact. Feeding difficulties may require tube feeding (nasogastric or gastrostomy). Developmental assessments are required in order to tailor medical services to each individual's needs. Other specialists can be required, such as a cardiologist, gastroenterologist, nephrologist, immunologist, ENT (ear, nose and throat) or stomatologist. Special attention is need for fine graphomotor and visuals difficulties.
Prognosis
The prognosis is usually good. A specific survey is required for autoimmune and kidney problems. Autonomy may be limited and affected individuals will sometimes require life-long support from caregivers.

                            Last update: 
                            September 2020


                            - Expert reviewer(s): 
                            Pr David GENEVIEVE | ITHACA*


                                * European Reference Network