Search for a rare disease
Other search option(s)
A rare genetic syndromic intellectual disability characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth digit, developmental delay, coarse facial features, and other variable clinical manifestations.
ORPHA:1465Classification level: Disorder
More than 150 cases of genetically confirmed Coffin-Siris syndrome (CSS) have been clinically reported to date. Exact prevalence and incidence are not known but the disorder is probably under-recognized.
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 nine genes have been reported to be causative for CSS (highest to lowest proportion of reported cases): ARID1B (6q25.3), SMARCA4 (19p13.3), SMARCC2 (12q13.2), ARID1A (1p36.11), SOX11 (2p25.2), DPF2 (11q13.1), SMARCB1 (22q11.23),SMARCE1 (17q21.2) , and ARID2 (12q12). These genes encode subunits of the BAF complex, which is involved in regulation of gene expression during development.
To date there have been no consistent clinical criteria to assist in the diagnosis. 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. Microdeletions including ARID1B have been reported.
Differential diagnoses include Nicolaides-Baraitser syndrome, brachymorphism-onychodysplasia-dysphalangism, DOOR syndrome, hyperphosphatasia-intellectual deficiency syndrome, Borjeson-Forssman-Lehmann syndrome, Wiedemann-Steiner syndrome, Rubinstein-Taybi syndrome and Cornelia de Lange syndrome. Fetal hydantoin syndrome may mimick Coffin-Siris syndrome.
As most mutations are de novo, prenatal diagnosis may be difficult to apply.
Autosomal dominant transmission has been reported regarding ARID1B-related disorder, but most cases are related to de novo mutations. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
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. Association of tumor development including schwannomatosis has been reported.