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 solely on clinical findings (although consensus clinical diagnostic criteria have not yet been published). The diagnosis of CSS is established in a proband with suggestive findings by identification of a heterozygous pathogenic variant in one of the genes listed in Table 1.

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 is inherited in an autosomal dominant manner; however, most affected individuals have the disorder as the result of de novo CSS-causing pathogenic variant. If the CSS-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

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.

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 suggestive findings and a heterozygous pathogenic variant in one of the genes listed in Table 1 identified by molecular genetic testing.

Note: Identification of a heterozygous variant of uncertain significance in one of the genes listed in Table 1 does not establish or rule out the diagnosis of this disorder.

Molecular testing approaches typically include use of a multigene panel or more comprehensive genomic testing.

Note: Serial single-gene testing in the order in which pathogenic variants most commonly occur is another option, but given the number of genes associated with this phenotype, such testing is not commonly done. However, because mutation of ARID1B is found in a relatively large number of affected individuals compared to mutation in the other genes listed in Table 1, sequence analysis of ARID1B, followed by gene targeted deletion/duplication analysis, can be considered as a first step. If this is not diagnostic, use of a multigene panel or more comprehensive genomic testing is often performed next.

• A multigene panel that includes the genes listed in Table 1 and other genes of interest (see Differential Diagnosis) may 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 are likely to change 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. (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.
• Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

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 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.

Phenotype Correlations by Gene

Phenotype correlations by gene have been seen in clinically diagnosed individuals with pathogenic variants in ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX4, and SOX11 [Wieczorek et al 2013, Kosho et al 2014b, 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].

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.

ARID2. Affected individuals typically do not have birth defects.

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.

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.

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.

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 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 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.

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 CSS-causing 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 a CSS-causing 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/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular 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].

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 in which most tumors are associated with biallelic loss-of-function variants, and correspondingly, somatic pathogenic variants in the SMARCB1 have been found in atypical teratoid and rhabdoid tumors [Roberts & Biegel 2009, Biegel et al 2014].

Acknowledgments

Dr Schrier Vergano would like to acknowledge Ashley Vasko, BS, and Catherine Nguyen, MS, who assisted with the 2021 revision of this chapter.

Author Notes

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

Revision History

• 12 August 2021 (aa) Revision: added genes: BICRA, DPF2, SMARCC2, SMARCD1, SOX4
• 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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