Coffin-Siris Syndrome

Coffin-Siris syndrome is an autosomal dominant intellectual disability syndrome caused by variants in genes of the BAF (SWI/SNF) chromatin remodelling complex, most commonly ARID1B, with hypoplasia of the fifth digit or nail, coarse facies and sparse scalp hair. Variants are usually de novo.

Pathophysiology. The BAF complex alters nucleosome position to control gene expression in neural development. Haploinsufficiency of ARID1B, or dominant negative variants in ARID1A, SMARCB1, SMARCA4, SMARCE1, SOX11 and ARID2, cause overlapping phenotypes.

ARID1B is the commonest cause of this syndrome and of non-syndromic intellectual disability.

Severity varies, with ARID1B disease often milder than ARID1A or SMARCA4 disease.

• Hypoplastic or absent fifth finger or toe distal phalanx and nail
• Coarse facies: wide mouth, thick lips, broad nasal bridge, thick eyebrows and long eyelashes
• Sparse scalp hair with hypertrichosis of body and face
• Developmental delay and intellectual disability, with markedly delayed speech
• Hypotonia and feeding difficulty
• Agenesis or hypoplasia of the corpus callosum
• Seizures in about half
• Cardiac defects, renal and urological anomalies, and gastrointestinal anomalies
• Recurrent infections, hearing loss and vision problems
• Growth delay and short stature

• Exome sequencing or a gene panel covering ARID1B, ARID1A, SMARCB1, SMARCA4, SMARCE1, SOX11, ARID2 and related genes, with deletion and duplication analysis; chromosomal microarray for 6q25 deletions.
• Hand and foot radiographs for fifth digit hypoplasia.
• Brain MRI for corpus callosum anomalies.
• Echocardiography and renal ultrasound.
• Hearing and vision assessment.
• Parental testing to confirm de novo origin.

• Development and communication: early intervention, speech therapy with augmentative communication, physiotherapy and special education.
• Feeding: feeding therapy and gastrostomy for unsafe swallow, with omeprazole 0.7 to 1 mg/kg daily for reflux.
• Seizures: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily, with valproate or lamotrigine added by seizure type.
• Cardiac, renal and gastrointestinal care: treat anomalies as they arise, and prompt treatment of infection.
• Hearing and vision: audiology and ophthalmology review yearly.
• Endocrine care: monitor growth, and check thyroid function when growth is poor.
• Behaviour and sleep: behavioural support, and melatonin 2 to 5 mg orally 30 to 60 minutes before bed (up to 10 mg if needed).
• Tumour awareness: rare tumours (hepatoblastoma, other cancers) have been reported, so investigate unexplained masses early. Variants in SMARCB1 and SMARCA4 are different from the germline loss-of-function variants of rhabdoid tumour predisposition.
• Genetic counselling: de novo variants carry a low recurrence risk, with a small risk of germline mosaicism.

Special groups.

• Adults: continue epilepsy and behavioural care, and plan transition and supported living.

Monitoring. Development, growth and seizures every 6 months in childhood. Vision and hearing yearly, and echocardiography and renal ultrasound once at diagnosis.

Referral and escalation. Refer to clinical genetics, paediatric neurology and developmental services. Urgent for prolonged seizures, an abdominal mass, or feeding failure.