Last updated:
3/28/2025
Years published: 1986, 1990, 1994, 1999, 2000, 2002, 2014, 2015, 2018, 2022, 2025
NORD gratefully acknowledges Bianca Fox, NORD Editorial Intern from the University of Notre Dame and Samantha A. Vergano, MD, FAAP, FACMG, Division of Genetic Medicine, Seattle Children’s Hospital, Seattle, WA, for assistance in the preparation of this report.
Coffin-Siris syndrome (CSS) is a rare genetic disorder that is present at birth (congenital). The disorder may be characterized by differences of the head and facial (craniofacial) area resulting in a coarse facial appearance. Craniofacial malformations may include an abnormally small head (microcephaly) or large head (macrocephaly); wide nose with a low nasal bridge; wide mouth with thick, prominent lips; thick eyebrows and eyelashes or excess hair growth in unusual places such as the back (hypertrichosis) and sparse scalp hair. In addition, affected infants and children may have short fifth fingers (“pinkies”) and toes with underdeveloped (hypoplastic) or absent nails, other malformations of the fingers and toes and eye abnormalities. These children may have feeding difficulties and frequent respiratory infections during infancy, tracheo- or laryngomalacia, low muscle tone (hypotonia), abnormal looseness (laxity) of the joints, delayed bone age, learning and developmental differences, hearing loss and other organ system-related abnormalities. The specific symptoms and severity can vary among affected individuals. Treatment is directed towards the symptoms that are present in an individual with CSS.
CSS is caused by changes (pathogenic variants) in twelve different genes: ARID1A, ARID1B, ARID2, SMARCA4, SMARCB1, SMARCE1, DPF2, SOX4, BICRA, SMARCC2, SMARCD1 and SOX11. Researchers think that CSS can be inherited in an autosomal dominant pattern, but most cases appear to be the result of a new gene variant that is not inherited. An individual who has CSS has a 50% chance of passing it down to each child.
Coffin-Siris syndrome (CSS) is a genetic condition that affects development and can involve many parts of the body. Signs and symptoms vary widely from person to person, and not every individual will have all the features described below.
Many individuals with CSS have distinctive differences in the shape and appearance of the face and head, referred to as craniofacial (skull and face) features. These features may be subtle at birth and often become more noticeable over time. Facial differences are seen in approximately 65% of affected individuals overall, but in only about 30% of newborns; and when present, they often prompt consideration of this diagnosis.
Common facial features may include:
Hair differences are also common and may include:
Bone and joint abnormalities are common but vary in type and severity. Historically, CSS was first recognized because of underdeveloped or missing fingernails and/or toenails or end bones of the fingers or toes, most often affecting the fifth finger or toe (“pinkies”). This feature is present in approximately 65-80% of individuals; however, many people with a confirmed diagnosis have little or no involvement of the fifth digits.
Other skeletal findings, reported in about 40-60% of affected individuals, may include:
Feeding difficulties are very common in infants and young children with CSS, affecting up to 90% of individuals. These difficulties may include poor coordination of feeding, oral aversion, vomiting, or poor weight gain (often referred to as failure to thrive). Growth differences may begin before birth.
Rarely, individuals with CSS may also have gastrointestinal (GI) abnormalities, including one portion of the bowel sliding into the next like a telescope (intussusception) or an opening in the diaphragm that allows abdominal organs to move into the chest cavity (diaphragmatic hernia).
Frequent infections, particularly upper respiratory infections, occur in about 60% of individuals. While immune system abnormalities have been reported in a small number of cases, infections are most often related to low muscle tone (hypotonia) and difficulty clearing mucus from the airway.
Low muscle tone (hypotonia) is present in approximately 75% of affected individuals and is often noticeable in infancy. Some children show improvement over time, particularly with physical and occupational therapy.
Developmental delay and intellectual disability are present in nearly all individuals with CSS (about 98%) and are most often in the moderate to severe range, although milder learning differences have been reported. Speech is commonly delayed, with expressive (spoken) language more affected than receptive language (understanding). On average:
Approximately 12% of affected individuals have little or no functional speech by later childhood.
Neurologic and behavioral features may include:
Eye-related (ophthalmologic) findings occur in about 40-50% of affected individuals and may include:
Hearing loss occurs in approximately 15-45% of affected individuals and may be conductive (related to sound transmission through the ear), sensorineural (related to the inner ear or auditory nerve), or mixed. Conductive hearing loss is more common and is often related to frequent ear infections. Only a minority of individuals require hearing aids.
Additional health concerns may include:
Brain imaging (such as MRI scans) may show structural differences in some individuals, meaning parts of the brain may have formed differently before birth. These findings can include:
These brain findings vary widely and do not always predict developmental outcome.
The risk of cancer in CSS is not fully understood. A small number of individuals, particularly those with changes in the ARID1A gene, have developed a childhood liver cancer called hepatoblastoma. Individuals with changes in the SMARCA4 or SMARCB1 genes may have a slightly increased risk for rare tumors, including rhabdoid tumors (rare, fast-growing cancers that most often affect infants and young children). Overall, the risk of cancer appears to be very low. Apart from hepatoblastoma screening in early childhood, routine cancer screening is not currently recommended.
CSS is thus far known to be caused by changes (pathogenic variants) in one of the following genes: ARID1A, ARID1B, ARID2, SMARCA4, SMARCB1, SMARCE1, DPF2, SOX4, BICRA, SMARCC2, SMARCD1 and SOX11. Not all affected individuals have variants in these genes, and it is likely that variants in additional genes cause CSS. Some researchers suggest that isolated (sporadic) and familial cases of CSS may be due to unknown chromosomal abnormalities.
Genes provide instructions for creating proteins that play a critical role in many functions of the body. The ARID and SMARC genes linked to CSS provide the instructions to make several different protein complexes that are known as BRG-1 associated factor (BAF) complex in humans. SOX11 is involved with transcriptional regulation of the BAF complex. These protein complexes regulate gene activity by altering how tightly regions of DNA are packaged, which can affect gene expression. Subsequently, the BAF complex is involved in a variety of processes including cell growth, division and differentiation and the replication and repairing of DNA. It is still unclear how these variants affect the BAF complex, but researchers believe they alter DNA packaging, which can disrupt gene activity and cellular processes and lead to symptoms of CSS.
CSS appears to be inherited as an autosomal dominant condition. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. With CSS, most gene variants appear to be the result of a new (de novo) variant.
In some dominant disorders, including CSS, disease expression may be variable. If individuals inherit a mutated gene for the disease, the characteristics that are expressed may vary greatly and range in severity from person to person.
Variants in the genes associated with CSS have also been linked to other disorders. Variants in the ARID1B gene have been reported in several individuals with isolated intellectual disability and absence of other physical features of CSS. Some genetics professionals diagnose these individuals with ‘ARID1B-related intellectual disability syndrome’ but there are very few differences between the two groups.
CSS occurs worldwide with no ethnic predisposition. Since the disorder was originally described in 1970 by Dr. G.S. Coffin, there are several thousand people who have been diagnosed with CSS. However, it is likely that there are more individuals with CSS who have not yet had molecular testing or who have not come to medical attention. As of February 2025, a clinical registry for individuals with CSS has over 530 people enrolled.
CSS may be suspected in a newborn with underdeveloped nails, short fifth fingers, distinctive facial features, hypotonia, learning and developmental differences, tracheo- or laryngomalacia, or other congenital anomalies. The facial features may become more apparent as the child grows. A diagnosis may be confirmed with molecular genetic testing.
Specialized testing may be done to look for features that may be associated with the disorder. Diagnostic criteria were proposed in 2012 noting that most affected individuals have short fifth fingers with absent or underdeveloped nails, developmental and/or cognitive delays and facial features such as a wide mouth and broad nose. Since the identification of many genes involved in CSS and improved availability of genetic testing, more individuals with CSS are being diagnosed earlier.
It is possible that a diagnosis of CSS may be suspected before birth (prenatally) based upon specialized tests such as ultrasound. Ultrasound studies may reveal findings such as cardiac or kidney malformations and intrauterine growth delay which may be associated with CSS. Diagnosis cannot be made on ultrasound findings alone, however, and molecular testing should be considered.
If a disease-causing gene variant has been identified in an affected family member, molecular testing can be done on the fetus. This involves the removal of fetal cells through chorionic villus sampling (performed at 10 to 12 weeks gestation with cells removed from the placenta) or amniocentesis (performed at 15 to 18 weeks gestation with cells removed from the amniotic fluid). DNA from the fetal cells is then examined to see if the variant is present in the fetus.
Clinical Testing and Workup
Further examinations and specialized imaging techniques may be recommended to determine the extent of the disorder. For example, an MRI (magnetic resonance imaging) may be used to detect structural abnormalities in the brain. X-rays of the hands can be done to confirm the underdevelopment or absence of the end bones in the fifth fingers (but this is not necessary to confirm the diagnosis). An echocardiogram can be used to generate images of the heart to detect cardiac abnormalities. Other examinations can include developmental examinations, dietary evaluations and eye and hearing examinations.
Individuals with CSS should have yearly or more frequent follow-up exams depending on their medical needs. This includes evaluation by a pediatrician to assess developmental progress and to determine the need for any educational or therapeutic interventions and follow-ups with other specialists to track any feeding, gastrointestinal, vision or hearing abnormalities.
There have been reports of liver cancer (hepatoblastoma) in a handful of affected individuals with an ARID1A gene variant. Although the frequency is extremely low, it may be beneficial for young children (birth to 4 years) to receive routine screening for hepatoblastoma (alpha feto-protein levels every 3 months). The risks and benefits of this screening should be discussed between the family and their genetics doctor. There have not been reports of a link between other CSS genes and recurrent cancer.
Treatment
The treatment of CSS is directed toward the specific features of each individual. Such treatment may require the coordinated efforts of a team of medical professionals who may need to systematically and comprehensively plan an affected child’s treatment. These professionals may include pediatricians, physicians who specialize in disorders of the skeleton, joints, muscles, and related tissues (orthopedists), physicians who diagnose and treat heart abnormalities (cardiologists), physicians who specialize in digestive abnormalities, physical therapists, geneticists and/or other health care professionals.
Treatment may include surgical repair of certain craniofacial, skeletal, cardiac or other abnormalities that may be present. The surgical procedures performed will depend upon the severity of the abnormalities, their associated symptoms and other factors.
In children with choanal atresia, surgery or other methods may be required to decrease the airway obstruction or correct the malformation. If Dandy-Walker malformation is present, treatment may include surgical implantation of a specialized device (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed. During infancy, treatment may also be needed to help prevent or aggressively treat respiratory infections. If needed, the placement of a gastrostomy tube (a tube inserted through the abdomen to deliver nutrition directly to the stomach) can help with feeding difficulties.
Early intervention may be important in ensuring that affected children reach their potential. Special services that may be helpful include special education, physical, speech or occupational therapy, or other social and/or vocational services. Additional treatments to assist affected children can include eyeglasses, hearing aids and nutritional supplements.
Genetic counseling is recommended for individuals with CSS and their families. Other treatment is symptomatic and supportive.
Additional research into potential treatments, including drug repurposing, are ongoing.
Dr. Samantha Vergano at Seattle Children’s Hospital in Seattle, WA, has an IRB-approved clinical registry for Coffin-Siris syndrome and related disorders. Physicians and family members can obtain more information about enrollment by emailing [email protected]. Parents who want to enroll their child need to provide the child’s genetic testing results that confirm the diagnosis.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
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Schrier Vergano SA. ARID2, a milder cause of Coffin-Siris Syndrome? Broadening the phenotype with 17 additional individuals. Am J Med Genet A. 2024;194(6):e63540. doi:10.1002/ajmg.a.63540
van der Sluijs PJ, Gösgens M, Dingemans AJM, et al. ARID1B-related disorder in 87 adults: Natural history and self-sustainability. Genet Med Open. 2024;2:101873. Published 2024 Jul 23. doi:10.1016/j.gimo.2024.101873
van der Sluijs PJ, Safai Pour K, Berends CL, Kruizinga MD, Müller AR, van Eeghen AM, Rodríguez-Girondo M, Juachon MJ, Steenbeek D, Cohen AF, Zuiker RGJA, Santen GWE. Clonazepam repurposing in ARID1B patients through conventional RCT and N-of-1 trials: an experimental strategy for orphan disease development. J Med Genet. 2024c:jmg-2024-109951.
Borja NA, Schrier Vergano SA, Tekin M. Coffin-Siris syndrome and cancer susceptibility. Genet Med Open. 2023;1(1):100818. Published 2023 May 16. doi:10.1016/j.gimo.2023.100818
Bosch E, Popp B, Güse E, et al. Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals. Genet Med. 2023;25(11):100950. doi:10.1016/j.gim.2023.100950
van der Sluijs PJ, Vergano SA, Roeder ER, Jongmans MCJ, Santen GWE. Recommending revised hepatoblastoma surveillance in children with a pathogenic ARID1A variant. Reply to “Cancer in ARID1A-Coffin-Siris syndrome: Review and report of a child with hepatoblastoma” by Cárcamo et al. 2022. Eur J Med Genet. 2023;66(2):104694. doi:10.1016/j.ejmg.2022.104694
Cárcamo B, Masotto B, Baquero-Vaquer A, Ceballos-Saenz D, Zapata-Aldana E. “Cancer in ARID1A-Coffin-Siris syndrome: Review and report of a child with hepatoblastoma”. Eur J Med Genet. 2022;65(11):104600. doi:10.1016/j.ejmg.2022.104600
Hanker B, Gillessen-Kaesbach G, Hüning I, Lüdecke HJ, Wieczorek D. Maternal transmission of a mild Coffin-Siris syndrome phenotype caused by a SOX11 missense variant. Eur J Hum Genet. 2022;30(1):126-132. doi:10.1038/s41431-021-00865-2
van der Sluijs PJ, Alders M, Dingemans AJM, et al. A case series of familial ARID1B variants illustrating variable expression and suggestions to update the ACMG criteria. Genes (Basel). 2021;12(8):1275. Published 2021 Aug 20. doi:10.3390/genes12081275
Barish S, Barakat TS, Michel BC, et al. BICRA, a SWI/SNF complex member, Is associated with BAF-disorder related phenotypes in humans and model organisms. Am J Hum Genet. 2020;107(6):1096-1112. doi:10.1016/j.ajhg.2020.11.003
Machol K, Rousseau J, Ehresmann S, et al. Expanding the spectrum of BAF-related disorders: De vovo variants in SMARCC2 cause a syndrome with intellectual disability and developmental delay. Am J Hum Genet. 2019;104(1):164-178. doi:10.1016/j.ajhg.2018.11.007
Milone R, Gnazzo M, Stefanutti E, Serafin D, Novelli A. A new missense mutation in DPF2 gene related to Coffin Siris syndrome 7: Description of a mild phenotype expanding DPF2-related clinical spectrum and differential diagnosis among similar syndromes epigenetically determined. Brain Dev. 2020;42(2):192-198. doi:10.1016/j.braindev.2019.10.007
Nixon KCJ, Rousseau J, Stone MH, Sarikahya M, Ehresmann S, Mizuno S, Matsumoto N, Miyake N, Study DDD, Baralle D, McKee S, Izumi K, Ritter AL, Heide S, Heron D, Depienne C, Titheradge H, Kramer JM, Campeau PM. A syndromic neurodevelopmental disorder caused by mutations in SMARCD1, a core SWI/SNF subunit needed for context-dependent neuronal gene regulation in flies. Am J Hum Genet. 2019;104:596-610.
Zawerton A, Yao B, Yeager JP, et al. De novo SOX4 variants cause a neurodevelopmental disease associated with mild dysmorphism [published correction appears in Am J Hum Genet. 2019 Apr 4;104(4):777. doi: 10.1016/j.ajhg.2019.01.014.]. Am J Hum Genet. 2019;104(2):246-259. doi:10.1016/j.ajhg.2018.12.014
Mannino EA, Miyawaki H, Santen G, Schrier Vergano SA. First data from a parent-reported registry of 81 individuals with Coffin-Siris syndrome: Natural history and management recommendations. Am J Med Genet A. 2018;176(11):2250-2258. doi:10.1002/ajmg.a.40471
Hempel A, Pagnamenta AT, Blyth M, et al. Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome. J Med Genet. 2016;53(3):152-162. doi:10.1136/jmedgenet-2015-103393
Santen GWE, Clayton-Smith J, and the ARID1B-CSS Consortium. The ARID1B Phenotype: What We have Learned so far. Am J Med Genet Part C. 2014;166C:276-289.
Tsurusaki Y, Okamoto N, Ohashi H, et al. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nat Genet. 2012;44(4):376-378. doi: 10.1038/ng.2219
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Richieri-Costa A, et al. Coffin-Siris syndrome in a Brazilian child with consanguineous parents. Rev Brasil Genet.1986;IX:169-177.
Franceschini P, et al. The Coffin-Siris syndrome in two siblings. Pediat Radiol.1986;16:330-333.
Haspeslagh M, et al. The Coffin-Siris syndrome: report of a family and further delineation. Clin Genet.1984;26:374-378.
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INTERNET
Schrier Vergano S, Santen G, Wieczorek D, et al. Coffin-Siris Syndrome. 2013 Apr 4 [Updated 2021 Aug 12]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK131811/ Accessed Feb 25, 2025.
Coffin-Siris syndrome. MedlinePlus. Last updated August 30, 2021. Coffin-Siris syndrome: MedlinePlus Genetics Accessed Feb 25, 2025.
Coffin-Siris syndrome. Genetic and Rare Diseases Information Center. Last updated:11/8/2021. https://rarediseases.info.nih.gov/diseases/6124/coffin-siris-syndrome Accessed Feb 25, 2025.
Coffin-Siris Syndrome Online Mendelian Inheritance in Man, OMIM. John Hopkins University, Baltimore, MD. Entry Number 135900; Last Updated: 05/20/2021. Available at: https://omim.org/entry/135900 Accessed Feb 25, 2025.
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