Summary
Clinical characteristics.
Classically, Coffin-Siris syndrome (CSS) was characterized by specific dysmorphic features (coarse facies, sparse scalp hair, thick eyebrows with long lashes, wide nasal bridge with broad nasal tip, anteverted nares with thick ala nasi, wide mouth with thick, everted vermilion of the upper and lower lips, and hypertrichosis), the absence or underdevelopment of the fifth digit finger/toe or nail, learning and developmental differences, and various organ system-related anomalies. As genetic technology has evolved, more individuals with subtle physical exam findings are being diagnosed with CSS. The vast majority of affected individuals have developmental delay / intellectual disability, typically in the moderate-to-severe range, although those with mild cognitive impairment or even normal intelligence have more rarely been described. Most affected individuals have feeding difficulties (with ~25%-50% requiring a feeding tube in childhood, some of whom then outgrow it), hypotonia, and frequent infections. About half of affected individuals have epilepsy. Other findings may include skeletal features (joint laxity, scoliosis), hearing impairment (both conductive and sensorineural), eye issues (ptosis, strabismus), congenital heart defects, genitourinary malformations, and behavioral issues (including hyperactivity and/or aggressiveness).
Diagnosis/testing.
The diagnosis of CSS is established in a proband with suggestive findings and a heterozygous pathogenic variant in one of the following 14 known genes identified by molecular genetic testing: ARID1A, ARID1B, ARID2, BICRA, DPF2, PHF6, SMARCA2, CMARCA4, SMARCB1, SMARCC2, SMARCD1, SMARCE1, SOX4, or SOX11.
Management.
Treatment of manifestations: Feeding therapy with consideration of placement of gastrostomy tube in those with persistent feeding issues. Standard treatment for developmental delay / intellectual disability, epilepsy, tics, sleep disturbance, scoliosis, joint laxity, knee subluxations, obesity, refractive error, strabismus, ptosis, hearing loss, congenital heart defects, undervirilization, inguinal hernia, frequent infections, and hepatoblastoma.
Surveillance: At each visit, measurement of growth parameters; evaluation of nutrition status and safety of oral intake; assessment for new neurologic manifestations, such as seizures or tics; monitoring of developmental progress and educational needs; behavioral assessment for anxiety, ADHD, ASD, aggression, & self-injury; monitoring for signs and symptoms of sleep disturbance; evaluation for mobility and self-help skills; and assessment for signs and symptoms of frequent infections. Annually or as clinically indicated, ophthalmology evaluation and vision assessment; audiology evaluation. At least every six months in those with teeth, dental evaluation. In those with ARID1A-related CSS: serum AFP level (with consideration of liver ultrasound) every three months until age four years.
Clinical Characteristics
Clinical Description
The clinical manifestations of Coffin-Siris syndrome have expanded over the years as greater phenotypic variability has been recognized. Classically, the syndrome was first identified by the absence or underdevelopment of the fifth digit finger/toe or nail. Additional "classic" features have included sparse scalp hair, hypertrichosis, learning and developmental differences, and various organ system-related anomalies. As genetic technology has evolved, more individuals with subtle physical exam findings are being diagnosed with CSS.
To date, at least 550 individuals have been identified with a diagnosis of Coffin-Siris syndrome, including those enrolled in the Coffin-Siris syndrome / BAF complex registry [Wieczorek et al 2013; Kosho et al 2014; Santen et al 2014; Ciliberto et al 2023; Schmetz et al 2024; Schrier Vergano 2024; S Schrier Vergano, unpublished data]. ARID1B has been reported in around 1% of cohorts of individuals with neurodevelopmental disorder [Hoyer et al 2012]. The following description of the phenotypic features associated with this condition is based on these reports.
Table 2.
Select Features of Coffin-Siris Syndrome
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Feature | % of Persons w/Feature | Comment |
---|
Developmental delay / intellectual disability | 98% | Typically in the moderate-to-severe range |
Feeding problems | 90% | |
Hypotonia | 75% | |
Hypoplasia of the fifth digits/nails 1 | 65%-80% | Some individuals with a molecularly confirmed diagnosis of CSS have little or no fifth digit involvement. |
Dysmorphic facial features | 65% | ~30% at birth. Because facial features typically coarsen over time, the characteristic facies may not be apparent until later in childhood. |
Frequent infections | 60% | |
Other skeletal findings | 40%-60% | Including joint laxity and scoliosis |
Epilepsy | 50% | |
Hearing impairment | 45% | Both sensorineural and conductive hearing loss has been reported. |
Eye issues | ~40% | Ptosis, strabismus, myopia |
Congenital heart defects | 35% | |
Genitourinary malformations | 33% | |
Behavioral issues | 25% | May include hyperactivity &/or aggressiveness |
- 1.
Typically, individuals with a clinical diagnosis of CSS have either aplasia or hypoplasia of the distal phalanx or absence of the nail, classically involving the fifth finger, but other digits may also be affected. Toes can also be affected, where the finding tends to involve multiple digits.
Dysmorphic facial features typically prompt consideration of this diagnosis (see Suggestive Findings and , , ).
Developmental delay (DD) and intellectual disability (ID). Intellectual disability is present in most and is typically moderate to severe (IQ range: 40 to 69); however, IQ as high as 97 has been reported [Santen et al 2012]. Ranges of IQ/DQ (developmental quotient) may depend on the gene involved and the degree of other medical challenges (see Phenotype Correlations by Gene).
While formal studies of IQ have not yet been conducted, those who have been tested range from mild to severe depending on the gene (i.e., individuals with ARID2-related CSS tend to range from mild to moderate) [Schrier Vergano 2024].
On average, children with CSS learn to sit at 12 months, walk at 30 months, and speak their first words at 24 months.
Expressive language is more severely affected than receptive language, with no speech in about 12% of individuals (median age: 10 years). A review of language acquisition in registry-enrolled individuals reported by
Vasko & Schrier Vergano [2022] identified that:
26% of individuals had normal speech development (words by 18 months)
<1% had mild development delay (speech by 19-21 months)
13% had moderate speech delay (speech by 22-25 months)
60% had severe speech delay (speech after 25 months)
In a study of 35 adult individuals with CSS, only one presented with absence of ID [
Schmetz et al 2024].
Other neurodevelopmental features
Epilepsy/tics. Both seizures and tics have been described in affected individuals. Seizure frequency may be as high as 38% but has varied depending on the age of the cohort [Ciliberto et al 2023]. A variety of seizure types have been reported. There is no typical age of onset for seizures or tics. Seizures can begin even in the teenage years, and some affected individuals may begin experiencing seizures after puberty. The majority of affected individuals who develop seizures appear to respond to traditional anti-seizure medication [Ciliberto et al 2023] (see Management).
Neurobehavioral/psychiatric manifestations. Autism has been reported in as high as 44% of individuals, although as with many features, the true prevalence may be underestimated depending on the age of the individual and available testing/evaluations [Vasko & Schrier Vergano 2022]. Behavioral abnormalities include hyperactivity (~10%), aggressiveness (~10%), and attention-deficit/hyperactivity disorder (25%).
Sleep disturbances are not uncommon but the prevalence of certain conditions like narcolepsy and restless leg syndrome are unknown. Many families report disrupted sleep, particularly in individuals with a concomitant diagnosis of autism.
Skeletal findings. The most striking clinical feature of CCS is the finding of small nails on the fifth finger or toe, affecting about 40% of individuals. Individuals with a diagnosis of CSS have either aplasia or hypoplasia of the distal phalanx or absence of the nail, typically involving the fifth finger, but other digits may also be affected. Toes can also be affected, where the finding tends to involve multiple digits. As the phenotype expands, more individuals with pathogenic variants in the BAF complex do not have the classic digit findings (see Molecular Pathogenesis).
Other skeletal findings can include the following:
Skin and hair findings
Hypertrichosis (95%) may appear in areas unexpected for an individual's ancestry (i.e., back, shoulders).
A low anterior hairline is common (75%).
Sparse scalp hair (60%), particularly involving the temporal region. Hair may appear at an appropriate age but may be very thin.
Hernias (10%)
Growth issues/dental. Weight and height is below the 50th centile for most, and below the 5th centile for 20%-35% of affected individuals. Nineteen of 35 adult individuals with CSS were reported to have obesity [Schmetz et al 2024].
Hearing impairment (15%-45%) is often associated with recurrent upper respiratory tract infections. Both sensorineural and conductive hearing loss has been reported, although conductive hearing loss occurs more often due to frequent infections or small ear canals. A minority of individuals with hearing loss need hearing aids (see Management).
Ophthalmologic abnormalities can include ptosis (50%), strabismus (50%), and/or myopia (20%). In a cohort of 35 adults, 29 had ophthalmic issues [Schmetz et al 2024].
Frequent infections. These are poorly characterized but are often consistent with upper respiratory viral infections. While some individuals with CSS have undergone immunology testing, there do not appear to be consistent defects in cellular immunity. Much of the frequency of illnesses may be attributed to overall hypotonia and difficult with clearing of secretions.
Other associated features
Cardiac anomalies have been reported in about one third of affected individuals and have included ventricular septal defects, atrial septal defects, tetralogy of Fallot, and patent ductus arteriosus.
Renal and genitourinary malformations can include cryptorchidism (in males) most commonly, but also horseshoe kidney, hypospadias, and other abnormalities.
Neuroimaging. Central nervous system malformations can include Dandy-Walker variant, gyral simplification, and agenesis of the corpus callosum.
Tumor risk. Although pathogenic variants in a subset of the genes causing CSS have been implicated in tumorigenesis, data on tumor risk in CSS are lacking. Tumors have been reported in individuals with CSS, but not all cases are connected to the constitutional CSS genetic change. In a cohort of 35 adults with CSS, no one had a malignancy [Schmetz et al 2024]. Apart from hepatoblastoma screening, routine cancer surveillance is not recommended.
An individual with a 4.2-Mb
deletion that included (among 14 genes)
ARID1B developed papillary thyroid cancer [
Vengoechea et al 2014]. However, given the large number of individuals reported with
ARID1B pathogenic variants with no subsequent reports of thyroid cancer, the authors feel that it is unlikely that there is a strong relationship between the two.
Prognosis. In the absence of long-term studies, information on life span in individuals with CSS is not available. Children have been reported to succumb to aspiration pneumonia and/or seizures, although this is not common [Schrier et al 2012]. As with any rare conditions, individuals with tracheostomies or needing respiratory support may have higher mortality at younger ages.
It is unknown whether life span in CSS is abnormal. One reported individual is alive at age 69 years [Määttänen et al 2018], demonstrating that survival into adulthood is possible. Schmetz et al [2024] reported 35 individuals aged 18 to 37 years, and van der Sluijs et al [2024] reported a large cohort of adults with CSS aged 18-69 years. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.
Phenotype Correlations by Gene
Phenotype correlations by gene have been seen in individuals with pathogenic variants in ARID1A, ARID1B, ARID2, BICRA, DPF2, SMARCA4, SMARCB1, SMARCE1, SOX4, and SOX11 [Wieczorek et al 2013, Kosho et al 2014, Santen et al 2014, Tsurusaki et al 2014a, Hempel et al 2016, Vasileiou et al 2018, Gazdagh et al 2019, Machol et al 2019, Zawerton et al 2019, Bosch et al 2023, Schmetz et al 2024].
ARID1A. Heterozygous pathogenic variants in ARID1A have been associated with a number of cases of hepatoblastoma; the risk is estimated to be about 3.6% (see Clinical Description, Tumor risk).
ARID1B. Individuals with a pathogenic variant in ARID1B are typically at the milder end of the spectrum of CSS and often have normal growth. Moderately severe feeding problems are noted in two thirds, seizures in one third, and hypoplasia of the corpus callosum in one third of affected individuals. Facial gestalt is consistent with CSS, albeit at times milder.
ARID2. Affected individuals typically do not have significant birth defects but may have short stature, mild-to-moderate learning and developmental differences, and hypotonia. Hip dysplasia appears more common in individuals with ARID2-related CCS than in those with CSS due to other genes [Schrier Vergano 2024].
BICRA. A small cohort of individuals with a pathogenic variant in BICRA have been reported; individuals appear to have moderate-to-severe developmental delay / intellectual disability with autism, seizures, and behavioral challenges. However, one affected individual with a heterozygous pathogenic variant in BICRA has been reported with normal intelligence. Classic CSS features, such as digital anomalies, have not been consistently reported.
DPF2. Individuals with a pathogenic variant in DPF2 tend to have mild-to-moderate learning and developmental differences, as well as some classic CSS features including digital anomalies and coarse facial features.
SMARCA4. Individuals with a pathogenic variant in SMARCA4 appear to have growth impairment that is mild prenatally and mild to moderate postnatally; sucking/feeding difficulty is almost always observed. While individuals can sometimes have severe developmental delays, significant behavioral challenges tend to be more characteristic. Facial features have demonstrated less coarseness, while hypoplastic fifth fingers or toes and hypoplastic fifth fingernails or toenails are a near-constant finding (with hypoplasia of other fingernails or toenails being an occasional finding). Prominence of interphalangeal joints and distal phalanges is also noted in some affected individuals.
SMARCB1. Individuals with a pathogenic variant in SMARCB1 typically are more severely affected; all have growth impairment (usually noted as mild prenatally and moderate to severe postnatally) with sucking/feeding difficulties. Structural central nervous system abnormalities with hypotonia and seizures are typical findings, accompanied by severe developmental delay / intellectual disability. Affected individuals are usually nonverbal. Typical skeletal findings include hypoplastic fifth fingers or toes, hypoplastic other fingernails or toenails, prominent distal phalanges, and scoliosis. Some individuals may walk independently. Gastrointestinal complications and hernia as well as cardiovascular and genitourinary complications are common.
SMARCE1. Individuals with pathogenic SMARCE1 variants tend to have severe intellectual disability, typical facial gestalt, and hypoplastic or absent fifth finger- and toenails associated with hypoplasia of other nails. The hands are characterized by long and slender fingers. Individuals are typically small for gestational age and have postnatal short stature and severe microcephaly, complex congenital heart defects, feeding difficulties, and seizures.
SOX4. Severely affected individuals may show neurologic complications including hypotonia, spastic quadriparesis, and epilepsy.
SOX11. Neurodevelopmental abnormalities tend to be more prevalent than organ system or physical complications, but cohort studies have identified idiopathic hypogonadotropic hypogonadism and physical features including microcephaly and short stature, with some researchers suggesting that it may represent a separate neurodevelopmental condition [Al-Jawahiri et al 2022].
Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations have been identified for ARID1A, ARID2, BICRA, DPF2, PHF6, SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCD1, SMARCE1, SOX4, or SOX11.
ARID1B. Affected individuals with a pathogenic variant in exon 1 of ARID1B may have a milder phenotype. Although some individuals with this type of pathogenic variant have features that are indistinguishable from those with pathogenic variants in the other exons of ARID1B, other individuals with pathogenic variants in exon 1 have very mild clinical features. Inheritance from apparently unaffected parents has been occasionally described in individuals who have a pathogenic variant in exon 1, although usually parents who have undergone more thorough phenotyping may be found to also be mildly affected. This has not been described up to now for pathogenic variants in the other exons (see ARID1B-Related Disorder).
Prevalence
More than 530 individuals with molecularly confirmed CSS have been reported (per the CSS registry). Rough estimates suggest a possible frequency of one in 100,000 births based on known cases, indicating that the diagnosis is still rare. True prevalence is likely higher.
In addition, the identification of a pathogenic variant in ARID1B in some members of a large cohort with intellectual disability [Hoyer et al 2012] suggests that the prevalence of pathogenic variants in genes associated with CSS (and possibly of subtle phenotypic features of CSS) may be higher than currently appreciated among those with apparently nonsyndromic intellectual disability.
Management
Several publications have recommended various medical surveillance guidelines for individuals with Coffin-Siris syndrome (CSS) [Mannino et al 2018, Schrier Vergano 2024, van der Sluijs et al 2024]. However, as clinical variability between individuals is high, clinicians are encouraged to use their own clinical judgment when evaluating and managing these individuals.
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with CSS, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to diagnosis) are recommended.
Table 5:
Coffin-Siris Syndrome: Recommended Evaluations Following Initial Diagnosis
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System/Concern | Evaluation | Comment |
---|
Constitutional
| Measurement of growth parameters | To assess for growth restriction or poor growth in younger persons & obesity in adults |
Neurologic
| Neurologic eval to incl assessment for signs & symptoms of seizures/tics |
|
Development
| Developmental assessment | To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education
|
Neurobehavioral/
Psychiatric
| Neuropsychiatric eval | For persons age >12 mos: screening for concerns incl ADHD, aggression, &/or findings suggestive of ASD |
Respiratory
| Assessment for signs & symptoms of sleep disturbance | Consider referral to sleep medicine clinic &/or sleep study. |
Musculoskeletal
| Orthopedics / physical medicine & rehab / PT & OT eval | To incl assessment of:
Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Assessment for signs & symptoms of knee subluxation, joint laxity, & scoliosis
|
Gastrointestinal/
Feeding
| Gastroenterology / nutrition / feeding team eval | To incl eval of aspiration risk, oral aversion, & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
|
Eyes
| Ophthalmologic eval | To assess for ptosis, strabismus, & refractive errors |
Hearing
| Audiologic eval | To assess for hearing loss |
ENT/Mouth
| Dental eval | In those who have teeth |
Cardiovascular
| Echocardiogram | To assess for congenital heart defects |
Genitourinary
| Renal ultrasound | To assess for structural renal anomalies |
Assessment for undervirilization in males & inguinal hernia | Consider referral to urologist or general surgeon, respectively. |
Immunologic
| Assessment for signs & symptoms of recurrent infections | Consider referral to immunologist w/frequent or unusual infections (recurrent pneumonia, skin infections, etc.). |
Oncology
| Consider baseline ultrasound of liver & serum AFP level | To evaluate for hepatoblastoma in those who have a heterozygous pathogenic variant in ARID1A |
Genetic counseling
| By genetics professionals 1 | To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of CSS to facilitate medical & personal decision making |
Family support
& resources
| By clinicians, wider care team, & family support organizations | Assessment of family & social structure to determine need for:
|
ADHD = attention-deficit/hyperactivity disorder; AFP = alpha-fetoprotein; ADL = activities of daily living; ASD = autism spectrum disorder; CSS = Coffin-Siris syndrome; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
- 1.
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Treatment of Manifestations
There is no cure for CSS. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6).
Table 6.
Coffin-Siris Syndrome: Treatment of Manifestations
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Manifestation/Concern | Treatment | Considerations/Other |
---|
Developmental delay /
Intellectual disability /
Neurobehavioral issues
| See Developmental Delay / Intellectual Disability Management Issues. | |
Epilepsy
| Standardized treatment w/ASM by experienced neurologist |
|
Tics
| Standard treatment per neurologist | |
Sleep disturbance
| Standard treatment per sleep medicine specialist | |
Scoliosis, joint laxity, knee subluxation
| Orthopedist / physical medicine & rehab / PT & OT | Consider need for positioning & mobility devices, disability parking placard. |
Poor weight gain / Oral aversion
|
| Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia |
Obesity
| Standard treatment per nutritionist | May develop in adults |
Refractive errors, strabismus, ptosis
| Standard treatment per ophthalmologist | |
Hearing loss
| Standard treatment per otolaryngologist & audiologist | |
Hearing aids may be helpful. | Community hearing services through early intervention or school district |
Congenital heart defects
| Standard treatment per cardiologist | |
Undervirilization & inguinal hernia
| Standard treatment per urologist or general surgeon, respectively | |
Frequent infections
| Standard treatment per primary care physician | Consider referral to immunologist w/frequent or unusual infections (recurrent pneumonia, skin infections, etc.). |
Hepatoblastoma
| Standard treatment per oncologist | This is a rare complication & is assoc specifically w/a pathogenic variant in ARID1A. |
Family/Community
| Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
|
|
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
- 1.
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.
Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Motor Dysfunction
Gross motor dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.
Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.
Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.
Neurobehavioral/Psychiatric Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.
Table 7.
Coffin-Siris Syndrome: Recommended Surveillance
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System/Concern | Evaluation | Frequency |
---|
Feeding
|
| At each visit |
Neurologic
|
|
Development
| Monitoring of developmental progress & educational needs |
Neurobehavioral/
Psychiatric
| Behavioral assessment for anxiety, ADHD, ASD, aggression, & self-injury |
Respiratory
| Monitoring for signs & symptoms of sleep disturbance |
Musculoskeletal
| Physical medicine, OT/PT assessment of mobility, self-help skills |
Immunologic
| Assessment for signs & symptoms of frequent infections |
Family/
Community
| Assessment of family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning) |
Eyes
| Ophthalmology eval & vision assessment | Annually or as clinically indicated |
Hearing
| Audiology evaluation |
Dental
| Dental eval | At least every 6 mos in those w/teeth |
Oncology
| Consider serum AFP level & liver ultrasound in those who have a pathogenic variant in ARID1A1 | Every 3 mos until age 4 yrs |
ADHD = attention-deficit/hyperactivity disorder; AFP = alpha-fetoprotein; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
- 1.
Because of the rarity of tumors in CSS, the utility of tumor surveillance is unclear. There have been several reports of individuals with ARID1A variants who subsequently were diagnosed with hepatoblastoma [Cárcamo et al 2022, van der Sluijs et al 2023]; as the frequency appears to exceed the recommended threshold for cancer screening, consideration of serum AFP levels and liver ultrasound every three months until age four years may be appropriate for individuals with ARID1A-related CSS.
Therapies Under Investigation
Van der Sluijs et al [2025] examined the utility of clonazepam in individuals with CSS based on preliminary data that identified decreased GABA-ergic inhibitory synapses in Arid1b+ mice, with some possible improvement in tone and attention to tasks and decreased anxiety [Jung et al 2017]. This study concluded that clonazepam did not provide any additional benefit to individuals with CCS due to pathogenic variants in ARID1B [van der Sluijs et al 2025].
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Risk to Family Members
Parents of a proband
Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband’s parents:
In the rare circumstance that a parent of the
proband is affected and/or is known to have a CSS-causing
pathogenic variant, the risk to the sibs is 50%.
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a
proband appears to be low but increased over that of the general population because of the possibility of parental
gonadal mosaicism.
Offspring of a proband. Each child of an individual with CSS has a 50% chance of inheriting the CSS-related pathogenic variant.
Other family members. The risk to other family members depends on the status of the proband's parents: in the rare event of an affected parent, other family members may be at risk.
Prenatal Testing and Preimplantation Genetic Testing
Once the Coffin-Siris syndrome-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal t and preimplantation genetic esting. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.