Coffin-Siris syndrome
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A toddler has intellectual disability, coarse facial features with a wide nose and full lips, sparse scalp hair with hypertrichosis of the face and back, and hypoplastic or absent nails of the 5th fingers and toes. Brain MRI shows agenesis of the corpus callosum.
AD; pathogenic variants in components of the BAF (mammalian SWI/SNF) chromatin-remodeling complex. Almost all cases are de novo; recurrence in unaffected parents is rare (consider gonadal mosaicism).
| Gene | Approx. frequency | Notes |
|---|---|---|
| ARID1B | ~50% | Most common; haploinsufficiency mechanism; broad allelic spectrum |
| ARID1A | ~5% | Tends to be more severe |
| SMARCB1 | ~10% | Distinctive coarse facial gestalt; cancer surveillance considerations (rhabdoid tumors with biallelic loss) |
| SMARCA4 | ~10% | |
| SMARCE1 | ~5% | |
| ARID2, DPF2, SMARCC2, SOX11 | rare | Expanding spectrum |
Mechanistic theme: all of these genes encode subunits of the BAF complex, which uses ATP hydrolysis to reposition nucleosomes and regulate transcription. Coffin-Siris is the prototypical BAFopathy; the closely related Nicolaides-Baraitser syndrome is caused by SMARCA2 variants (a different BAF subunit).
- Intellectual disability: mild to severe, variable across genes (often more severe with ARID1A, SMARCB1)
- 5th digit anomalies (hallmark): hypoplastic or absent nails and distal phalanges of the 5th fingers/toes
- Craniofacial:
- Coarse facial features
- Wide nasal bridge and tip, broad nasal columella
- Full, everted lower lip
- Long eyelashes, thick/arched eyebrows
- Wide mouth
- Hair: sparse scalp hair with hypertrichosis elsewhere (face, back, limbs)
- Growth: feeding difficulties, growth restriction
- CNS: corpus callosum hypoplasia/agenesis, Dandy-Walker malformation, hydrocephalus
- Other: congenital heart defects (~30-40%), cryptorchidism, scoliosis, recurrent infections, hearing loss, ophthalmologic anomalies
- Clinical recognition (5th digit + facial gestalt) prompts molecular testing
- Multigene panel (BAF/SWI-SNF panel) or exome sequencing: first-tier
- SMARCB1 pathogenic variants warrant discussion of rhabdoid tumor predisposition considerations (biallelic SMARCB1 loss causes rhabdoid tumors; whether single-hit germline SMARCB1 Coffin-Siris variants confer tumor risk is an active area)
- Nicolaides-Baraitser syndrome (SMARCA2): overlapping BAFopathy; sparse hair, prominent IP joints, seizures, more severe ID
- Cornelia de Lange syndrome (cohesinopathy, NIPBL etc.): overlapping coarse facies and limb anomalies but distinguishing eyebrow/eyelash pattern, severe IUGR, gut anomalies
- Mabry syndrome (GPI-anchor disorder): hyperphosphatasia + ID + nail hypoplasia
- Floating-Harbor syndrome (SRCAP): short stature, expressive language delay, broad nose; SRCAP itself is a SWI/SNF-related gene
- Developmental and educational support; early intervention
- Hearing and vision evaluations
- Echocardiogram at diagnosis; renal ultrasound
- Feeding evaluation; G-tube as needed in infancy
- SMARCB1-specific: tumor surveillance discussion case-by-case
BAF = "Barely A Fifth": Coffin-Siris is the prototypical BAFopathy, and its hallmark feature is a hypoplastic or absent 5th digit (nail and distal phalanx of the 5th finger/toe). One phrase ties the molecular complex to the cardinal exam finding.