KBG Syndrome

KBG syndrome is an autosomal dominant neurodevelopmental disorder caused by loss-of-function variants or deletions of ANKRD11 (16q24.3), with macrodontia of the upper central incisors, short stature, characteristic facies and intellectual disability. Many cases are de novo, and parents with mild features are sometimes found on testing.

Pathophysiology. ANKRD11 regulates chromatin through histone deacetylase recruitment, and haploinsufficiency disturbs neural and skeletal development. The same gene is involved in the 16q24.3 microdeletion syndrome.

Severity varies from learning difficulty to moderate intellectual disability.

Diagnosis is often delayed until school age, when behaviour and learning problems lead to testing.

• Macrodontia of the upper central incisors, other dental crowding and malocclusion
• Short stature, delayed bone age
• Broad eyebrows, long philtrum, thin upper lip, triangular face, prominent ears
• Brachydactyly, clinodactyly of the fifth finger, short fingers
• Intellectual disability, speech delay, ADHD, autism spectrum disorder, anxiety
• Seizures and EEG abnormalities in some
• Conductive or sensorineural hearing loss, recurrent otitis media
• Cardiac defects, cryptorchidism, palatal anomalies and feeding difficulty
• Skeletal anomalies: costovertebral anomalies, scoliosis, delayed closure of fontanelle

• ANKRD11 sequencing with deletion and duplication analysis, or chromosomal microarray for the 16q24.3 deletion.
• Clinical assessment: dental examination (macrodontia), height and growth chart, and hand and facial features.
• Hand and spine radiographs for bone age and skeletal anomalies.
• Echocardiography, hearing assessment and renal ultrasound.
• EEG if seizures or staring spells occur.
• Developmental and behavioural assessment.
• Parental testing because mildly affected carriers occur.

• Dental care: orthodontic review from early childhood, and treatment of crowding and malocclusion.
• Hearing: audiology every 12 months, treatment of otitis media with grommets for persistent effusion, and hearing aids when needed.
• ADHD: methylphenidate 5 mg orally once or twice daily increasing weekly by 5 to 10 mg to a usual maximum of 60 mg daily, with growth and blood pressure monitoring, after cardiac assessment.
• Anxiety: cognitive behavioural therapy, and sertraline 25 to 50 mg daily increasing to a maximum of 200 mg daily when needed.
• Seizures: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily, or other agents by seizure type.
• Growth: monitor height; growth hormone is not routine, and benefit is uncertain.
• Development: early intervention, speech therapy and an education plan.
• Orthopaedic care: scoliosis surveillance, and correction of cryptorchidism by orchidopexy.
• Genetic counselling: 50% chance of transmission from an affected parent.

Special groups.

• Parents with mild features: offer clinical assessment and testing, because recurrence risk is then 50%.

Monitoring. Growth, development and behaviour every 6 to 12 months. Hearing yearly, dental review every 6 months, and cardiac review as advised.

Referral and escalation. Refer to clinical genetics, developmental paediatrics and an orthodontic service. Urgent for seizures, regression or severe behavioural change.