Coffin–Siris syndrome

Overview

Coffin–Siris syndrome (CSS) is a rare genetic disorder characterized by developmental delays, intellectual disability, distinctive facial features, hypoplastic or absent fifth fingernails or toenails, and variable involvement of other organ systems. First described in 1970 by Drs. Coffin and Siris, the syndrome shows wide variability in clinical presentation, even among individuals with the same genetic mutation. CSS belongs to a group of conditions known as “chromatin remodeling disorders” due to mutations affecting genes that regulate gene expression during development.

Causes

Coffin–Siris syndrome is caused by mutations in one of several genes involved in the SWI/SNF chromatin remodeling complex, which regulates DNA accessibility for transcription. Known genes associated with CSS include:

• ARID1B (most common)

• ARID1A

• SMARCB1

• SMARCA4

• SMARCA2

• SMARCE1

The syndrome is typically caused by a de novo (new) mutation and follows an autosomal dominant inheritance pattern. In rare familial cases, it can be inherited from a mildly affected parent.

Symptoms

Symptoms of Coffin–Siris syndrome can vary greatly but commonly include:

• Developmental delay: Particularly in motor and speech milestones

• Intellectual disability: Ranges from mild to severe

• Distinctive facial features:

  • Thick eyebrows or long eyelashes

  • Broad nasal bridge

  • Thick lips

  • Low-set ears

  • Flat midface

• Hypoplastic or absent fifth finger/toenail: A hallmark sign often used for clinical suspicion

• Hypotonia: Low muscle tone, especially in infancy

• Feeding difficulties: In early childhood

• Behavioral issues: Including hyperactivity or autistic-like traits

• Short stature and microcephaly: May be present

• Hearing or vision problems: Less common but possible

• Organ malformations: Such as cardiac, renal, or genital anomalies in some individuals

Diagnosis

Diagnosis of Coffin–Siris syndrome is based on clinical evaluation and confirmed through genetic testing. Diagnostic steps include:

• Physical examination: Assessing for developmental delays, nail hypoplasia, and facial features

• Developmental and neuropsychological assessment: To determine cognitive and motor skill levels

• Genetic testing: Targeted gene panels or whole-exome sequencing to identify pathogenic variants in SWI/SNF complex genes

• Imaging studies: Brain MRI may show structural abnormalities in some cases

• Additional evaluations: Audiology, ophthalmology, cardiology, and renal ultrasound as needed based on symptoms

Treatment

There is no cure for Coffin–Siris syndrome. Management is supportive and tailored to the individual’s specific symptoms. A multidisciplinary team approach is often needed. Key components of treatment include:

• Early intervention programs: Including physical, occupational, and speech therapy

• Special education services: Individualized education plans (IEPs) to support learning

• Behavioral therapy: To address attention deficits, anxiety, or autistic traits

• Medical management: For associated health issues such as heart defects, seizures, or gastrointestinal problems

• Regular monitoring: Growth, hearing, vision, and developmental milestones

• Genetic counseling: For families to understand recurrence risks and inheritance patterns

Prognosis

The prognosis for individuals with Coffin–Siris syndrome varies widely. Some individuals achieve a high level of independence with supportive care, while others may require lifelong assistance due to intellectual and physical disabilities. Early diagnosis and intervention significantly improve developmental outcomes. While the condition is not typically life-threatening, associated organ anomalies or severe complications may impact health. Ongoing research continues to improve understanding and management of this complex syndrome.