What are the symptoms and management of Coffin-Siris syndrome?

Coffin-Siris Syndrome: Clinical Features

Coffin-Siris syndrome (CSS) is a rare genetic disorder characterized by distinctive facial features, fifth digit/nail hypoplasia, intellectual disability, speech impairment, and multiple congenital anomalies affecting cardiac, gastrointestinal, and neurological systems. 1

Core Diagnostic Features

Craniofacial Characteristics

• Coarse facial features with two recognized subtypes: "classic" coarse features and "variant" less striking features 1
• Dysmorphic facial features consistently present across all cases 2
• Sparse scalp hair with generalized hypertrichosis elsewhere on the body 2, 1

Digital Abnormalities (Pathognomonic)

• Hypoplastic or aplastic fifth digit nails and distal phalanges - the hallmark feature 2, 1
• Can affect digits beyond the fifth finger, particularly in SMARCE1-related cases 2

Neurodevelopmental Manifestations

• Intellectual disability present in the vast majority of cases, ranging from borderline (IQ ~75) to moderate severity 3, 1
• Developmental delay affecting multiple domains 2, 4
• Muscular hypotonia 4
• Speech and language impairment, with verbal abilities typically stronger than performance skills 3

Neurological Complications

• Epilepsy occurs in a subset of patients with mean seizure onset around 5.5 years 5
• Seizures are typically brief, focal onset with secondary generalization 5
• EEG shows unilateral or bilateral paroxysmal activity in temporal, parietal, and occipital regions 5
• Seizures generally respond well to anticonvulsant therapy with low recurrence rates 5

Behavioral and Psychiatric Features

• Significant attention difficulties are common 3
• Autism Spectrum Disorder features may be present (mild severity profile documented) 3
• Social and thought subdomain concerns 3
• Socio-adaptive deficits (adaptive scores around 64) 3

Academic Challenges

• Scholastic difficulties particularly in reading and mathematical skills 3
• Virtually all children require special education services 3

Multisystem Involvement

Cardiovascular Anomalies

• Cardiac disease variably present 2
• Severe cases can include hypoplastic right ventricle with VSD, truncus arteriosus type III, and persistent left superior/inferior caval veins 4

Gastrointestinal Issues

• Feeding difficulties 2
• Poor growth and failure to thrive 2

Genitourinary Abnormalities

• Various genitourinary malformations reported 2

Other Organ Systems

• Vision abnormalities 2
• Bilateral olfactory nerve aplasia (rare prenatal finding) 4
• Hypoplastic thymus (rare prenatal finding) 4

Genetic Basis

CSS is caused by pathogenic variants in genes encoding BAF (SWI/SNF) chromatin remodeling complex subunits, including SMARCB1, ARID1A, ARID1B, SMARCE1, SMARCA4, and SMARCA2 2, 4, 1. The inheritance pattern is autosomal dominant, typically occurring as de novo mutations 5, 3.

Gene-Specific Considerations

• ARID1B mutations are among the most common causes 5, 3
• SMARCB1 variants cause Coffin-Siris syndrome type 3 4
• ARID1A variants cause Coffin-Siris syndrome type 2 4
• SMARCE1 mutations are the rarest, with distinct phenotype including digital abnormalities beyond the fifth digit 2

Prenatal Manifestations

When detected prenatally, CSS may present with severe congenital heart defects, vascular anomalies, cranial nerve aplasia, and thymic hypoplasia 4. These prenatal findings expand the recognized phenotypic spectrum beyond postnatal presentations 4.

Management Approach

Neurological Management

• Anticonvulsant therapy for epilepsy shows good clinical response 5
• Regular neurological monitoring for seizure control 5

Comprehensive Developmental Support

• Physical therapy for hypotonia and gross motor delays 3
• Occupational therapy addressing hypotonia and sensory integration 3
• Speech and language therapy with oral-motor assessment 3
• Special education services universally required 3

Holistic Assessment Requirements

• Complete neurocognitive evaluation including IQ testing (verbal and performance subtests) 3
• Behavioral assessment screening for ADHD and autism spectrum features 3
• Socio-adaptive functioning evaluation using standardized adaptive scales 3
• Academic skills assessment for reading and mathematics 3

Multisystem Surveillance

• Cardiac evaluation for congenital heart disease 2, 4
• Growth monitoring and nutritional support for feeding difficulties 2
• Vision screening 2
• Genitourinary assessment as indicated 2