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Coffin-Siris Syndrome

Synonym: Fifth Digit Syndrome

, MD, , MD, PhD, , MD, , MD, , MD, PhD, and , MD, PhD.

Author Information

Initial Posting: ; Last Revision: February 8, 2018.

Summary

Clinical characteristics.

Coffin-Siris syndrome (CSS) is classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, distinctive facial features, hypotonia, hirsutism/hypertrichosis, and sparse scalp hair. Congenital anomalies can include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Other findings commonly include feeding difficulties, slow growth, ophthalmologic abnormalities, and hearing impairment.

Diagnosis/testing.

Before the molecular basis was known, the diagnosis of CSS was based on clinical findings. With the recent detection of heterozygous pathogenic variants in ARID1A, ARID1B, SMARCA4, SMARCB1, SMARCE1, or SOX11 in some (but not all) individuals with CSS, the diagnostic features have become more clearly described for classic cases. A few individuals diagnosed with CSS on a clinical basis have been found to have pathogenic variants in SMARCA2 or PHF6; on reevaluation, the phenotype of these individuals was most consistent with Nicolaides-Baraitser syndrome or Borjeson-Forssman-Lehmann syndrome, respectively.

Management.

Treatment of manifestations: Occupational, physical, and/or speech therapies to optimize developmental outcomes. Feeding therapy, nutritional supplementation and/or gastrostomy tube placement as needed to meet nutritional needs. Routine management of ophthalmologic abnormalities and hearing loss.

Surveillance: Yearly evaluation by a developmental pediatrician to assess developmental progress and therapeutic and educational interventions; follow up with a gastroenterologist and feeding specialists as needed to monitor feeding and weight gain. Routine follow up of ophthalmologic and/or audiologic abnormalities.

Genetic counseling.

CSS caused by a heterozygous pathogenic variant in one of six genes (ARID1A, ARID1B, SMARCA4, SMARCB1, SMARCE1, and SOX11) is inherited in an autosomal dominant manner, but most commonly results from a de novo pathogenic variant. If the pathogenic variant has been identified in a family member, prenatal testing for pregnancies at increased risk is possible.

Diagnosis

Formal diagnostic criteria for Coffin-Siris syndrome (CSS) have not been established; however, several key features are useful in making a clinical diagnosis.

Suggestive Findings

Coffin-Siris syndrome (CSS) should be suspected in individuals with the following findings [Fleck et al 2001, Schrier et al 2012, Kosho et al 2014b, Santen et al 2014]:

  • Fifth-digit nail / distal phalanx hypoplasia/aplasia. Typically, individuals with a clinical 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 (Figure 1C, D, E, F). Toes can also be affected, where the finding tends to involve multiple digits.
  • Developmental or cognitive delay of variable degree
  • Facial features [Schrier et al 2012]. Individuals with typical features demonstrate a wide mouth with thick, everted upper and lower lips, broad nasal bridge with broad nasal tip, thick eyebrows, and long eyelashes. Together, these features can give a suggestion of coarseness in individuals with CSS (Figure 1A, B).
  • Hypotonia that is central in origin
  • Hirsutism/hypertrichosis. Hair growth in atypical areas (e.g., the back) or excessive hair growth on the arms or face
  • Sparse scalp hair, especially in infancy, particularly in the temporal regions
Figure 1.

Figure 1.

Coffin-Siris syndrome classic features Facial features (i.e., bushy eyebrows, coarse facies, and thick, everted lips) in (A) a clinically diagnosed boy age five years and (B) a clinically diagnosed man age 29 years

Establishing the Diagnosis

The diagnosis of CSS is established in a proband with identification of a heterozygous pathogenic variant in one of the genes listed in Table 1.

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

  • Serial single-gene testing in the order in which pathogenic variants most commonly occur may be considered:
    1.

    Sequence analysis for ARID1B is performed first, followed by deletion/duplication testing if no pathogenic variant is found.

    2.

    If no ARID1B pathogenic variant is identified, sequence analysis followed by deletion/duplication testing should be performed on the other genes (in order of the likelihood of identifying a pathogenic variant: SMARCA4, SMARCB1, ARID1A, PHF6, SMARCE1, SOX11, SMARCA2).

    Note: Evidence indicates that pathogenic variants in SMARCA4, SMARCB1, and SMARCE1 act through a gain-of-function mechanism, suggesting that large pathogenic deletions or duplications are unlikely to occur; however, in-frame deletions or duplications of relevant domains may be pathogenic; one such deletion in SMARCA4 has been reported (see Table 1 and Molecular Genetics).

  • A multigene panel that includes ARID1B, SMARCA4, SMARCB1, ARID1A, PHF6, SMARCE1, SOX11, SMARCA2 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel; see A multigene panel) fails to confirm a diagnosis in an individual with features of CSS. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Coffin-Siris Syndrome

Gene 1Proportion of CSS Attributed to Pathogenic Variants in This Gene 2Proportion of Pathogenic Variants 3 Detected by Test Method 4
Sequence analysis 5Gene-targeted deletion/duplication analysis 6
ARID1A8/172 (5%)8/80/8
ARID1B64/172 (37%)59/643/60 7
SMARCA2 85/172 (2%)4/51/5
SMARCA412/172 (7%)12/120/12
SMARCB112/171 (7%)12/120/13
SMARCE13/171 (2%)3/30/3
SOX112/92 (2%) 95/12 10Unknown 11; 7 individuals w/deletions & a CSS phenotype have been reported 12
PHF6 132/37 (5%) 142/20/2
Unknown 1569/172 (40%)NA
1.
2.

Numbers represent a compilation of unique cases in reports of cohorts of clinically ascertained patients with CSS [Tsurusaki et al 2012, Santen et al 2013, Wieczorek et al 2013, Tsurusaki et al 2014b] except as indicated with a footnote.

3.

See Molecular Genetics for information on allelic variants detected in these genes.

4.

Number of individuals with an identified pathogenic variant / number of individuals tested

5.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Mosaic pathogenic variants have been noted for ARID1A [Santen et al 2013, Wieczorek et al 2013].

7.

Microdeletions of chromosome 6q25.3 that include ARID1B have been reported in: (a) children with CSS ascertained prior to the understanding of the molecular basis of CSS [Tsurusaki et al 2012]; (b) children ascertained with a microdeletion containing ARID1B and secondarily noted to have features similar to CSS [Santen et al 2012]; and (c) individuals with mildly or variably syndromic intellectual disability [Nagamani et al 2009, Halgren et al 2012, Hoyer et al 2012, Michelson et al 2012] for whom available clinical information is insufficient to determine the similarity to CSS. Of note, these individuals may have complex clinical findings due to the involvement of additional genes surrounding the ARID1B locus.

8.

Reevaluation of an individual initially thought to have CSS concluded that findings were more consistent with Nicolaides-Baraitser syndrome [Tsurusaki et al 2012, Van Houdt et al 2012]; however, since a number of individuals with SMARCA2 pathogenic variants were initially ascertained as CSS, the authors have included these numbers for comparison purposes. See Differential Diagnosis.

9.
10.
11.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

12.
13.

Individuals initially ascertained as CSS when younger have been found to have pathogenic variants in PHF6. Most of these have acquired facial features more consistent with Borjeson-Forssman-Lehmann syndrome as they age [Wieczorek et al 2013]. See Differential Diagnosis.

14.
15.

In these studies, approximately 40% (69/172) of individuals with CSS did not have a pathogenic variant in one of the known genes [Tsurusaki et al 2012, Santen et al 2013, Wieczorek et al 2013, Tsurusaki et al 2014b].

Karyotype and chromosomal microarray (CMA). Many individuals who present with congenital anomalies and developmental delay have their chromosomes evaluated through karyotype and/or CMA as part of the initial evaluation. If an individual presenting with features of CSS does not have a pathogenic variant identified by the testing described, a karyotype and/or CMA should be considered based on the occurrence of rare rearrangements that have been reported to cause CSS [Backx et al 2011, Halgren et al 2012, Malli et al 2014].

Clinical Characteristics

Clinical Description

The following information has been compiled from data included in two reports by the Coffin-Siris Syndrome International Collaborators [Kosho et al 2014b, Santen et al 2014]. This section focuses on features common to the molecular subtypes; the findings that vary in frequency or severity between genetic etiologies are noted in Genotype-Phenotype Correlations.

Early Characteristics

Prenatal findings are typically unremarkable, with growth within normal limits. Rarely, CNS or cardiac anomalies, IUGR, and microcephaly have been noted.

Infancy. Although many individuals with Coffin-Siris syndrome (CSS) may not be clinically distinguishable at birth, several of the congenital anomalies may be noted:

  • Hypoplasia of the fifth digits/nails. Most individuals have at a minimum brachydactyly of the fifth digit (seen in 65% of affected infants) and hypoplasia of one or more nails (80%). It should be noted that some individuals with a molecularly confirmed diagnosis of CSS have little or no fifth digit involvement.
  • Dysmorphic facial features (~30% at birth). Because facial features typically coarsen over time, the characteristic facies may not be apparent until later in childhood.
  • Hirsutism often noted
  • Malformations affecting the CNS and cardiac and genitourinary systems (see Findings in Childhood)
  • Other findings appearing in infancy that may be the first indication of CSS:
    • Feeding problems (90%) and slow growth
    • Hypotonia (75%)
    • Seizures (50%)
    • Hearing impairment (45%)
    • Visual impairment (~40%)

Findings in Childhood

Developmental delays. The developmental/cognitive delay is typically apparent when delayed developmental milestones are noted and/or formal cognitive testing is performed.

  • 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 a significant subset of individuals.
  • Intellectual disability is present in most and typically moderate to severe (IQ range: 40 to 69); however, IQ as high as 97 has been reported [Santen et al 2012].
  • Behavioral abnormalities include hyperactivity (~10%), aggressiveness (~10%), and occasionally autistic features.

Brain/CNS issues

  • CNS malformations include Dandy-Walker variant, gyral simplification, and agenesis of the corpus callosum.
  • Seizures and tics. A variety of types of seizures are reported. There is no typical age of onset for seizures or tics.
  • Hypotonia (75%), noted in infancy, is typically persistent.

Facial features (see Figure 1)

  • Coarse facies (95%)
  • Thick eyebrows (90%)
  • Prominent eyelashes (85%)
  • Flat nasal bridge (50%)
  • Short nose (50%)
  • Anteverted nares (50%)
  • Broad nasal tip (75%)
  • Wide nasal base (50%)
  • Thick alae nasi (70%)
  • Broad philtrum (70%)
  • Wide mouth (80%)
  • Thin vermilion of the upper lip (50%)
  • Thick vermilion of the lower lip (80%)

Musculoskeletal findings

  • Small nails on 5th finger or toe (80%)
  • Clinodactyly (40%)
  • Delayed bone age (40%)
  • Joint laxity (66%)
  • Scoliosis (30%)
  • Hernias (10%)

Skin and hair findings

  • Hypertrichosis (95%) may appear in areas unexpected for an individual’s ethnicity (i.e., back, shoulders).
  • A low anterior hairline is common (75%).
  • Sparse scalp hair (60%); hair may appear at an appropriate age but may be very thin.

Feeding difficulties. Children may have oral aversion or difficulty feeding in the absence of any evident intestinal malformations.

Growth issues

  • Weight and height is below the 50th percentile for most, and below the 5th percentile for 20%.
  • Bone age typically lags about two to three years behind chronologic age.
  • Dentition is delayed (40%).

Hearing impairment (45%) is often associated with recurrent upper respiratory tract infections.

Ophthalmologic abnormalities

  • Ptosis (50%)
  • Strabismus (50%)
  • Myopia (20%)

Frequent infections (60%). These are poorly characterized, but often are consistent with upper respiratory viral infections.

Malformations

  • Cardiac anomalies (35%) including ventricular septal defects, atrial septal defects, tetralogy of Fallot, and patent ductus arteriosus
  • Renal and genitourinary malformations (~35%) including cryptorchidism most commonly, but also horseshoe kidney, hypospadias, and other abnormalities

Tumor risk. Although pathogenic variants in a subset of the genes causing CSS have been implicated in tumorigenesis (see Cancer and Benign Tumors), data on tumor risk in CSS are lacking. Tumors have been reported in three individuals with CSS:

Prognosis

In the absence of long-term studies, information on life span in individuals with Coffin-Siris syndrome is not available. Children have been reported to die of aspiration pneumonia and/or seizures, although this is not common [Schrier et al 2012]. Efforts are in progress by the Coffin-Siris Syndrome International Consortium [Kosho et al 2014a] to better understand prognosis in individuals with CSS.

Genotype-Phenotype Correlations

Genotype-phenotype correlations have been seen in clinically diagnosed individuals with pathogenic variants in ARID1A, ARID1B, SMARCA4, SMARCB1, SMARCE1, and SOX11 [Wieczorek et al 2013, Kosho et al 2014b, Santen et al 2014, Tsurusaki et al 2014a, Hempel et al 2016].

ARID1A. Individuals with a pathogenic variant in ARID1A displayed a wide spectrum of severity; some exhibited only mild intellectual disability while others had severe intellectual disability. Some individuals also had serious medical complications (e.g., aspiration pneumonia, seizures) leading to death.

ARID1B. Individuals with pathogenic ARID1B variants 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. Facial gestalt is consistent with CSS, albeit at times milder, with hypertelorism and anteverted nares more commonly noted. Distal digital hypoplasia is usually limited to the fifth digit.

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 (and hypoplasia of other fingernails or toenails an occasional finding). Prominence of interphalangeal joints and distal phalanges is also noted in some.

SMARCB1. Individuals with a pathogenic variant in SMARCB1 typically have a more severely affected phenotype and all have growth impairment, usually mild prenatally and moderate to severe postnatally, with sucking/feeding difficulty. Structural CNS abnormalities with hypotonia and seizures are typical findings accompanied by severe developmental delay/intellectual disability; individuals are typically 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.

SOX11. Individuals display mild to severe intellectual and developmental delay, along with fifth-digit nail and distal phalangeal hypoplasia. Neurodevelopmental abnormalities tend to be more prevalent than organ-system or physical complications.

Penetrance

Penetrance for Coffin-Siris syndrome appears to be complete.

More females than males with CSS were reported in the literature prior to 2001 [Fleck et al 2001]; however, in cases of molecularly confirmed CSS, male:female ratios are similar [Kosho et al 2014b, Santen et al 2014]. No evidence exists for X-linked dominant, sex-limited, or mitochondrial inheritance.

Prevalence

Fewer than 200 individuals with molecularly confirmed Coffin-Siris syndrome have been reported, indicating that the diagnosis is rare. However, this is likely an underestimate, as not all individuals may have come to medical attention.

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 intellectual disability.

Differential Diagnosis

Nicolaides-Baraitser syndrome (NCBRS) is characterized by sparse scalp hair, prominence of the interphalangeal joints and distal phalanges due to decreased subcutaneous fat, characteristic coarse facial features, microcephaly, seizures, and developmental delay/intellectual disability. Developmental delay / intellectual disability is severe in nearly half of individuals with NCBRS, moderate in a third, and mild in the remainder. Nearly a third never develop speech. Of note, after heterozygous SMARCA2 pathogenic variants were identified in NCBRS [Van Houdt et al 2012], reevaluation of an individual initially thought to have CSS determined that findings were more consistent with NCBRS [Tsurusaki et al 2012]. Inheritance is autosomal dominant; to date, all affected individuals have had a de novo SMARCA2 pathogenic variant.

Borjeson-Forssman-Lehmann syndrome (BFLS) (OMIM 301900) is typically characterized by males with severe intellectual disability, epilepsy, hypogonadism, hypometabolism, marked obesity, swelling of subcutaneous tissue of face, narrow palpebral fissure, and large but not deformed ears. Females with pathogenic variants in PHF6, which causes BFLS, demonstrate some phenotypic overlap with individuals with CSS [Wieczorek et al 2013]. The two syndromes, however, are still considered distinctly separate entities [Zweier et al 2013].

ARID2-related intellectual disability (OMIM 617808). Pathogenic variants in ARID2 have been identified in several individuals with a Coffin-Siris-like phenotype. Shang et al identified four individuals with de novo loss-of-function ARID2 variants in a cohort of 970 individuals with neurodevelopmental disorders and previously nondiagnostic testing [Shang et al 2015]. An additional three individuals with syndromic intellectual disability have been reported [Bramswig et al 2017, Van Paemel et al 2017]. An ARID2 de novo missense variant has also been reported in an individual with autism [Iossifov et al 2014]

Most individuals with ARID2 pathogenic variants demonstrate intellectual disability, hypotonia, and behavioral anomalies. Birth defects are not common. Several individuals have demonstrated very mild hypoplasia of the fifth fingernails and hypoplasia of the fifth toenails. Individuals with ARID2 pathogenic variants share some facial features with each other: coarse features, frontal bossing and high forehead, narrow palpebral fissures, flat nasal bridge, slightly broad nose with upturned nasal tip and thick, anteverted alae nasi, prominent philtrum, and a large mouth with a thick lower vermilion. While some of these features demonstrate overlap with Coffin-Siris syndrome, an assessment of a larger cohort of individuals with ARID2 pathogenic variants will be needed to determine whether it is clinically similar to or distinct from Coffin-Siris syndrome.

Mosaic trisomy 9. An individual with mosaic trisomy 9 had features similar to those of CSS, including facial features (wide, bulbous nose), hirsutism, and hypoplasia of the fifth digits [Kushnick & Adessa 1976].

Brachymorphism-onychodysplasia-dysphalangism (BOD) syndrome (OMIM 113477) is characterized by short stature, tiny dysplastic nails, short fifth fingers, a wide mouth with broad nose, and mild intellectual deficits [Verloes et al 1993, Elliott & Teebi 2000]. This latter characteristic is most likely to distinguish individuals with BOD syndrome from those with CSS, as the cognitive disability in CSS is nearly always moderate to severe. Inheritance appears to be autosomal dominant.

DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures) syndrome. Features in common with CSS include hypoplastic terminal phalanges and/or nail anomalies, deafness, and neurologic abnormalities. DOORS syndrome is inherited in an autosomal recessive manner and is caused by biallelic pathogenic variants in TBC1D24. (See TBC1D24-Related Disorders.)

Fetal alcohol spectrum (FAS). Small nails, prenatal and postnatal growth retardation, dysmorphic facial features, and cognitive disabilities may be seen in FAS.

Fetal hydantoin/phenytoin embryopathy. Small nails with hypoplasia of distal phalanges, dysmorphic facial features, digitalized thumbs, low hairline, short or webbed neck, growth retardation, and cognitive disabilities have been described in this syndrome, caused by prenatal exposure to phenytoin.

Mabry syndrome (hyperphosphatasia with mental retardation syndrome 1; OMIM 239300). Mabry syndrome is characterized by delayed development, seizures, coarse facial features, hypoplastic fifth digits, and elevated serum concentrations of alkaline phosphatase [Gomes & Hunter 1970, Kruse et al 1988, Thompson et al 2010]. It is inherited in an autosomal recessive manner and caused by biallelic pathogenic variants in PIGV [Krawitz et al 2010].

Cornelia de Lange syndrome (CdLS). Classic CdLS is characterized by distinctive craniofacial features (arched eyebrows, synophrys, upturned nose, small teeth, microcephaly); growth retardation; and limb anomalies, which can at times include fifth finger hypoplasia similar to CSS. Other findings may include cardiac defects, gastrointestinal anomalies, and genitourinary malformations. Pathogenic variants in NIPBL, SMC1A, SMC3, HDAC8, or RAD21 are causative. CdLS is inherited in an autosomal dominant (NIPBL, SMC3, and RAD21) or X-linked (SMC1A and HDAC8) manner.

4q deletion syndrome. This chromosome deletion syndrome results in a characteristic curved, volar, fifth-digit nail, which may resemble a hypoplastic distal phalanx.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with Coffin-Siris syndrome (CSS), the following evaluations are recommended:

  • Consultation with a clinical geneticist and/or genetic counselor
  • Neurologic and/or developmental examination to record developmental milestones and identify neurologic symptoms or deficits
  • Evaluation for occupational, speech, or physical therapy as needed
  • Gastrointestinal evaluation for feeding difficulties or poor growth
  • Dietary evaluation by a nutritionist as needed
  • Ophthalmologic examination, including a dilated fundus examination and visual acuity
  • Audiology evaluation with auditory brain stem response testing and otoacoustic emission testing to assess for hearing loss
  • Echocardiogram to evaluate for structural cardiac defects
  • Renal ultrasonography to evaluate for structural kidney or genitourinary (GU) anomalies

Treatment of Manifestations

The following are appropriate:

  • Occupational, physical, and/or speech therapies to optimize developmental outcomes
  • Feeding therapy, nutritional supplementation, and/or gastrostomy tube placement as needed to meet nutritional needs
  • Spectacles as needed to correct refractive errors and surgery as needed for strabismus and/or ptosis
  • Hearing aids as needed

Prevention of Secondary Complications

Therapies and interventions which can prevent secondary complications mirror the recommended treatments for an individual’s particular needs. This may include developmental therapies, appropriate cardiac, gastrointestinal, and neurologic evaluations and treatments, and ophthalmologic and audiologic surveillance.

Surveillance

Surveillance includes the following:

  • Yearly evaluation by a developmental pediatrician to assess developmental progress and therapeutic and educational interventions
  • Annual follow up with a gastroenterologist and feeding specialists as needed to monitor feeding and weight gain
  • Regular follow up of ophthalmologic and/or audiologic abnormalities

Because of the rarity of tumors in CSS, the utility of tumor surveillance has not been determined.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

As no females with CSS have been reported to reproduce, potential complications of pregnancy are unknown.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu 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, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Coffin-Siris syndrome (CSS) is inherited in an autosomal dominant manner. Most affected individuals reported to date have had a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

  • Most probands reported to date have the disorder as the result of a de novo ARID1A, ARID1B, SMARCA4, SMARCB1, SMARCE1, or SOX11 pathogenic variant.
  • The proportion of cases caused by a de novo pathogenic variant is unknown, but likely approaches 100%, given the paucity of reports of affected parents in the literature.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include testing of the parents for the pathogenic variant identified in the proband.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, the proband most likely has a de novo pathogenic variant. In rare cases, a parent may have germline mosaicism [Ben-Salem et al 2016].
  • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotype. Therefore, an apparently negative family history cannot be fully confirmed until appropriate evaluations have been performed.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • In the rare circumstance that a parent of the proband is affected and is heterozygous for an ARID1A, ARID1B, SMARCA4, SMARCB1, SMARCE1, or SOX11 pathogenic variant, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism.
  • One report of CSS in two sisters and partial expression in their father has been published [Haspeslagh et al 1984], suggesting parental somatic (and germline) mosaicism. However, there has been no molecular confirmation of the diagnosis, and the affected family members may have a disorder other than CSS.

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.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to couples who have had an affected child.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Risk to future pregnancies is presumed to be low as the familial proband most likely has a de novo ARID1A, ARID1B, SMARCA4, SMARCB1, SMARCE1, or SOX11 pathogenic variant. However, prenatal testing or preimplantation genetic diagnosis are options to consider, as the risk may be greater than in the general population because of the possibility of parental germline mosaicism.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Genetic and Rare Diseases Information Center (GARD)
    P.O. Box 8126
    Gaithersburg MD 20898-8126
    Phone: 888-205-2311; 888-205-3223 (TTY); 301-251-4925
    Fax: 301-251-4911
    Email: GARDinfo@nih.gov
  • American Association on Intellectual and Developmental Disabilities (AAIDD)
    501 3rd Street Northwest
    Suite 200
    Washington DC 20001
    Phone: 202-387-1968
    Fax: 202-387-2193
    Email: sis@aaidd.org
  • Medline Plus
  • National Center on Birth Defects and Developmental Disabilities
    1600 Clifton Road
    MS E-87
    Atlanta GA 30333
    Phone: 800-232-4636 (toll-free); 888-232-6348 (TTY)
    Email: cdcinfo@cdc.gov
  • Clinical Registry of Individuals with Coffin-Siris Syndrome and Other BAF-Related Phenotypes
    Email: Samantha.vergano@chkd.org
  • CoRDS Registry
    Sanford Research
    2301 East 60th Street North
    Sioux Falls SD 57104
    Phone: 605-312-6423
    Email: sanfordresearch@sanfordhealth.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table B.

OMIM Entries for Coffin-Siris Syndrome (View All in OMIM)

135900COFFIN-SIRIS SYNDROME 1; CSS1
600898SRY-BOX 11; SOX11
601607SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY B, MEMBER 1; SMARCB1
603024AT-RICH INTERACTION DOMAIN-CONTAINING PROTEIN 1A; ARID1A
603111SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY E, MEMBER 1; SMARCE1
603254SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY A, MEMBER 4; SMARCA4
614556AT-RICH INTERACTION DOMAIN-CONTAINING PROTEIN 1B; ARID1B

Molecular Genetic Pathogenesis

Many of the proteins identified in CSS to date encode human homologs of proteins first identified in yeast and drosophila in the BRG1- and BRM-associated factor (BAF) complex, originally called the mammalian switch/sucrose non-fermentable (mSWI/SNF)-like nucleosome remodeling complex. This complex contains a DNA-stimulated ATPase activity capable of destabilizing histone-DNA interactions in an ATP-dependent manner [Ronan et al 2013]. SOX11 is predicted to act downstream of the BAF complex in neurogenesis and conversion of postnatal glia into neurons [Ninkovic et al 2013].

There is evidence that pathogenic variants in ARID1A, ARID1B, and SOX11 have a loss-of-function effect, whereas pathogenic variants in SMARCA4, SMARCB1, and SMARCE1 have a dominant-negative or gain-of-function effect.

ARID1A

Gene structure. ARID1A (NM_006015.4) comprises 20 exons and produces an 8585-bp transcript. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Frameshift and nonsense variants have been noted throughout the length of the gene, suggesting haploinsufficiency as the pathogenic mechanism. Many pathogenic variants appear to be mosaic, a finding that should be taken into account when analyzing sequence data.

Normal gene product. The ARID1A protein contains 2285 amino acids (NP_006006.3) and is part of the large ATP-dependent chromatin remodeling SWI/SNF complex, which is required for transcriptional activation of genes normally repressed by chromatin. It is thought that the protein encoded by this gene confers specificity to the SWI/SNF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.

Abnormal gene product. Pathogenic variants in ARID1A may result in aberrant chromatin remodeling, causing downstream dysregulation of further genes and resulting in the CSS phenotype.

ARID1B

Gene structure. ARID1B comprises 20 exons and produces a transcript of 9648 bp (NM_020732.3). Alternatively spliced transcript variants encoding different isoforms have been described. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Microdeletions, nonsense variants, and frameshifts in ARID1B have been seen in individuals with CSS [Santen et al 2012, Shain et al 2012, Tsurusaki et al 2012, Kosho et al 2013, Santen et al 2013, Wieczorek et al 2013, Kosho et al 2014a, Kosho et al 2014b, Miyake et al 2014, Santen et al 2014, Sim et al 2014, Tsurusaki et al 2014b]. No clearly pathogenic missense variants have been identified. Microdeletions and nonsense variants have been reported in several patients with nonspecific intellectual disability [Hoyer et al 2012, Santen et al 2014]. However, evaluation of several of these subjects revealed some mild overlap with CSS features suggesting a range of clinical features for individuals with haploinsufficiency of ARID1B. Other than subjects with large microdeletions including additional genes having additional phenotypes, there is currently no clear genotype-phenotype correlation, suggesting the involvement of other phenotypic modifiers.

Normal gene product. The ARID1B protein contains 2249 amino acids (NP_065783.3) and is a component of the SWI/SNF chromatin remodeling complex, possibly playing a role in cell-cycle activation. ARID1B is similar to ARID1A, and the two proteins function as alternative, mutually exclusive ARID subunits of the SWI/SNF complex. The associated complexes play opposing roles in some contexts.

Abnormal gene product. Loss of ARID1B expression may result in aberrant chromatin remodeling, causing downstream dysregulation of further genes and resulting in the CSS phenotype.

SMARCA4

Gene structure. SMARCA4 comprises 35 exons and produces a 5703-bp transcript (NM_003072.3). Multiple transcript variants encoding different isoforms have been found for this gene. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Pathogenic missense and in-frame deletion variants have been identified in individuals diagnosed with CSS. All pathogenic variants to date are localized in the middle of the gene (including HAS, DEXDc, and HELICc helicase domains) and are expected to exert a dominant-negative or gain-of-function effect [Tsurusaki et al 2012, Santen et al 2013, Kosho et al 2014b, Bramswig et al 2015].

Normal gene product. The SMARCA4 protein contains 1647 amino acids (NP_003063.2) and is part of the large ATP-dependent SWI/SNF chromatin remodeling complex, which is required for transcriptional activation of genes normally repressed by chromatin.

Abnormal gene product. SMARCA4 is involved in chromatin remodeling and transcriptional activation. Pathogenic variants may result in abnormal gene expression, although the exact role of SMARCA4 in the development of a CSS phenotype is not known at this time.

SMARCB1

Gene structure. SMARCB1 comprises nine exons and produces a 1717-bp transcript (NM_003073.3). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Pathogenic variants that cause CSS are localized at the C-terminal end of the highly conserved sucrose / non-fermenting domain 5 (SNF5) toward the C-terminus of the protein (amino acids 363-377). These variants are expected to exert dominant-negative or gain-of-function effects. The pathogenic variant p.Lys364del represents a recurrent de novo pathogenic variant found in nine patients from various ethnic backgrounds; the patients had strikingly similar clinical manifestations [Kosho et al 2014b].

Table 2.

SMARCB1 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.1091_1093delAGAp.Lys364delNM_003073​.3
NP_003064​.2

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The SMARCB1 protein contains 385 amino acids (NP_003064.2) and is a core component of the BAF (hSWI/SNF) complex. This ATP-dependent chromatin-remodeling complex plays important roles in cell proliferation and differentiation, cellular antiviral activities, and inhibition of tumor formation.

Abnormal gene product. SMARCB1 is involved in chromatin remodeling and plays a role in tumor development in the rhabdoid tumor predisposition syndrome, in which most tumors are associated with biallelic loss-of-function variants. The exact mechanism of SMARCB1 in the development of a CSS phenotype is not known at this time.

SMARCE1

Gene structure. SMARCE1 comprises 11 exons and produces a 2425-bp transcript (NM_003079.4). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Rare pathogenic missense variants in SMARCE1, located within HMG domain, are expected to exert a dominant-negative or gain-of-function effect [Tsurusaki et al 2012, Santen et al 2013, Wieczorek et al 2013, Tsurusaki et al 2014b].

Normal gene product. The SMARCE1 protein contains 411 amino acids (NP_003070.3) and is part of the large ATP-dependent SWI/SNF chromatin remodeling complex, which is required for transcriptional activation of genes normally repressed by chromatin.

Abnormal gene product. The exact role of SMARCE1 in the development of the CSS phenotype is not known at this time.

SOX11

Gene structure. SOX11 comprises one exon and produces an 8718-bp transcript (NM_003108.3). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Pathogenic variants in SOX11 include partial- or whole-gene deletions or de novo missense variants in the HMG-box DNA-binding domain [Tsurusaki et al 2014a, Hempel et al 2016].

Normal gene product. The SOX11 protein contains 441 amino acids and comprises a member of the SOX (SRY-related HMG-box) family of transcription factors. It contains a single DNA-binding domain that binds to DNA in a sequence-specific manner. This family of proteins is involved in the regulation of embryonic development and in the determination of the cell fate.

Abnormal gene product. The presence of pathogenic variants in the HMG-box DNA-binding domain, along with the presence of overlapping clinical phenotypes caused by microdeletions, suggests that the mechanism of pathogenesis is haploinsufficiency of the SOX11 protein.

Cancer and Benign Tumors

SMARCA4. Heterozygous germline pathogenic variants in SMARCA4 have been reported to cause rhabdoid tumor predisposition; likewise, somatic pathogenic variants in SMARCA4 have been found in atypical teratoid and rhabdoid tumors [Schneppenheim et al 2010, Hasselblatt et al 2011, Biegel et al 2014].

SMARCB1. Heterozygous germline pathogenic variants in SMARCB1 have been reported to cause the rhabdoid tumor predisposition syndrome via the classic two-hit model of tumorigenesis, and correspondingly, somatic pathogenic variants in the SMARCB1 have been found in atypical teratoid and rhabdoid tumors [Roberts & Biegel 2009, Biegel et al 2014].

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Chapter Notes

Author Notes

All of the authors of this review study the clinical features and molecular basis of the Coffin-Siris syndrome.

Revision History

  • 8 February 2018 (aa) Revision: ARID2- related intellectual disability added to Differential Diagnosis
  • 12 May 2016 (ha) Comprehensive update posted live
  • 11 July 2013 (aa) Revision: ARID1B deletion/duplication analysis available on a clinical basis
  • 4 April 2013 (me) Review posted live
  • 19 July 2012 (md) Original submission
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