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Coffin-Siris syndrome

Synonym(s) CSS
Prevalence <1 / 1 000 000
Inheritance Autosomal dominant
Age of onset Neonatal
  • Q87.1
  • C0265338
  • C536436
MedDRA -


Disease definition

Coffin-Siris syndrome (CSS) is a rare congenital multi-systemic genetic disorder characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth digit, developmental delay, intellectual disability, coarse facial features, and other variable clinical manifestations.


More than 100 cases of confirmed CSS have been clinically reported to date. Exact prevalence and incidence are not known but the disorder is probably under-recognized.

Clinical description

Coffin-Siris syndrome is a clinically and genetically heterogeneous disorder. It involves a wide range of major and minor clinical findings. Characteristic major features include mild to severe developmental or cognitive delay (in all patients), fifth finger nail/distal phalanx hypoplasia or aplasia (almost all patients at birth), and coarse facial features (commonly observed over time). Distinctive facial features include thick eyebrows and long eyelashes, broad nasal bridge, wide mouth with thick, everted upper and lower lips, and abnormal ear position or shape. Common minor findings include short stature, failure to thrive, feeding difficulties, microcephaly, ophthalmological manifestations (cataracts, ptosis, strabismus), cardiac anomalies (ventricular septal/atrial septal defects, tetralogy of Fallot, patent ductus arteriosus), hypertrichosis (arms, face, back) and sparse scalp hair. Minor findings include neurologic involvement (Dandy-Walker malformation, gyral simplification, agenesis of the corpus callosum, seizures, and hypotonia), hearing loss, joint laxity, genito-urinary and renal malformations and frequent infections. Developmental delay and scoliosis appear in infancy and childhood.


Heterozygous mutation or genomic rearrangement in the following five genes have been reported to be causative for CSS (highest to lowest proportion of reported cases): ARID1B (6q25.3), SMARCA4 (19p13.3), SMARCB1 (22q11.23), ARID1A (1p36.1-p35), and SMARCE1 (17q21.2). These genes encode subunits of the BAF complex, which is involved in regulation of gene expression during development. Coffin-Siris syndrome and brachymorphism-onychodysplasia-dysphalangism syndrome (see this term) have been suggested to possibly be allelic variants.

Diagnostic methods

The diagnosis is generally based on the presence of major and at least one minor clinical sign and can be confirmed by molecular genetic testing of the causative genes. Recent studies revealed that fifth finger nail/distal phalanx hypoplasia or aplasia is not a mandatory finding.

Differential diagnosis

Differential diagnoses include Nicolaides-Baraitser syndrome, brachymorphism-onychodysplasia-dysphalangism, DOOR syndrome, hyperphosphatasia-intellectual deficiency syndrome, Rubinstein-Taybi syndrome and Cornelia de Lange syndrome (see these terms).

Antenatal diagnosis

As most mutations are de novo, prenatal diagnosis may be difficult to apply.

Genetic counseling

Autosomal dominant transmission has been reported but most cases are related to de novo mutations. Genetic counseling should be offered to affected families.

Management and treatment

Treatment is essentially supportive and symptomatic. Occupational, physical and speech therapy are recommended. Development and feeding should be monitored closely and patients should undergo regular ophthalmological and audiological testing.


The prognosis is poor in severely affected individuals, with aspiration pneumonia and seizures reported in childhood.

Expert reviewer(s)

  • Pr Naomichi MATSUMOTO
  • Dr Nobuhiko OKAMOTO

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