Saethre-Chotzen Syndrome
Summary
Clinical characteristics.
Classic Saethre-Chotzen syndrome (SCS) is characterized by coronal synostosis (unilateral or bilateral), facial asymmetry (particularly in individuals with unicoronal synostosis), strabismus, ptosis, and characteristic appearance of the ear (small pinna with a prominent superior and/or inferior crus). Syndactyly of digits two and three of the hand is variably present. Cognitive development is usually normal, although those with a large genomic deletion are at an increased risk for intellectual challenges. Less common manifestations of SCS include other skeletal findings (parietal foramina, vertebral segmentation defects, radioulnar synostosis, maxillary hypoplasia, ocular hypertelorism, hallux valgus, duplicated or curved distal hallux), hypertelorism, palatal anomalies, obstructive sleep apnea, increased intracranial pressure, short stature, and congenital heart malformations.
Diagnosis/testing.
The diagnosis of SCS is established in a proband with typical clinical findings and the identification of a heterozygous pathogenic variant in TWIST1 by molecular genetic testing.
Management.
Treatment of manifestations: Ongoing management by an established craniofacial team which may include cranioplasty in the first year of life and midface surgery in childhood as needed for dental malocclusion, swallowing difficulties, and respiratory problems. If a cleft palate is present, surgical repair usually follows cranioplasty. As needed: orthodontic treatment and/or orthognathic surgery at the completion of facial growth; developmental intervention; routine treatment of hearing loss; ophthalmologic evaluation and, if ptosis is present, intervention to prevent amblyopia, with surgical repair during early childhood as needed.
Surveillance: Annual ophthalmologic evaluation for papilledema; brain imaging for additional evaluation when there is evidence of increased intracranial pressure; clinical examination for facial asymmetry as needed; annual speech evaluation starting at age 12 months in those with a cleft palate. Audiology evaluations every 6-12 months; annual clinical evaluation for sleep-disordered breathing and developmental delays.
Agents/circumstances to avoid: If cervical spine abnormality with instability is present in an individual, activities that put the spine at risk should be limited.
Genetic counseling.
SCS is inherited in an autosomal dominant manner. Many individuals diagnosed with SCS have an affected parent; the proportion of cases caused by a de novo pathogenic variant is unknown. The family history of some individuals diagnosed with SCS may appear to be negative because of failure to recognize the disorder in family members (wide phenotypic variability is observed within families with SCS) or reduced penetrance. Each child of an individual with SCS has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible if the pathogenic variant has been identified in the family.
Diagnosis
Suggestive Findings
Saethre-Chotzen syndrome (SCS) should be suspected in individuals with a combination of the following features:
- Craniosynostosis (premature fusion of one or more sutures of the calvarium)
- The coronal suture is the most commonly affected, although any or all sutures can be affected.
- Craniosynostosis often presents with an abnormal skull shape (e.g., brachycephaly [short, broad skull], acrocephaly [tall skull], anterior plagiocephaly [flat skull]).
- Low frontal hairline, ptosis, strabismus, facial asymmetry
- Small ears with a prominent crus, hearing loss
- Parietal foramina
- Vertebral anomalies
- Limb anomalies [Trusen et al 2003] including the following:
- Partial cutaneous syndactyly of the second and third digits of the handNote: Although the degree of syndactyly or its presence is highly variable, it is effectively diagnostic in the presence of the first three features: craniosynostosis, low frontal hairline (...), and small ears (...).
- Radioulnar synostosis
- Brachydactyly
- Hallux valgus
- Duplicated distal phalanx of the hallux
- Triangular epiphyses of the hallux
Establishing the Diagnosis
The diagnosis of SCS is established in a proband with typical clinical findings and a heterozygous pathogenic variant in TWIST1 identified by molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, concurrent or serial single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of SCS is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with craniosynostosis or those in whom the diagnosis of SCS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of SCS, molecular genetic testing approaches can include single-gene testing, chromosomal microarray analysis (CMA), or use of a multigene panel.
- Single-gene testing. Sequence analysis of TWIST1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
- Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including TWIST1) that cannot be detected by sequence analysis.Note: The risk for developmental delay with large deletions involving TWIST1 is approximately 90%, or eight times greater than with intragenic pathogenic variants [Cai et al 2003a, Fryssira et al 2011]; therefore, CMA should be considered in individuals with features of SCS and developmental delay.
- A craniosynostosis multigene panel that includes TWIST1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. 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. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Note: A karyotype should be considered if a diagnosis of SCS is strongly suspected despite normal results on molecular testing, since chromosome rearrangements disrupting TWIST1 (e.g., translocations, inversions, or ring chromosome 7 involving 7p21) have been reported in individuals with SCS with atypical findings, including developmental delay [Shetty et al 2007, Touliatou et al 2007].
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by craniosynostosis, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.
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 Saethre-Chotzen Syndrome
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| TWIST1 | Sequence analysis 3 | 72% 4 |
| Gene-targeted deletion/duplication analysis 5, 6 | 23% 4 | |
| CMA 6, 7 | 23% 4, 8 | |
| Karyotype | 5% 9 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
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.
- 4.
Gripp et al [2000], Cai et al [2003a], de Heer et al [2005], Kress et al [2006], Foo et al [2009], Roscioli et al [2013], Paumard-Hernández et al [2015], The Human Gene Mutation Database
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may 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. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by Cai et al [2003a] or Tahiri et al [2015]) may not be detected by these methods.
- 6.
Note that most reported deletions and duplications are large enough to likely be detected by CMA; however, gene-targeted deletion/duplication analysis does have a higher resolution.
- 7.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including TWIST1) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 7p21 region. CMA designs in current clinical use target the 7p21 region.
- 8.
CMA should be considered in individuals with features of SCS and developmental delay.
- 9.
Cai et al [2003a], Shetty et al [2007], Touliatou et al [2007], The Human Gene Mutation Database
Clinical Characteristics
Clinical Description
With the ability to detect pathogenic variants in TWIST1, the phenotypic spectrum of Saethre-Chotzen syndrome (SCS) is increasingly broad. Both milder and more severe phenotypes are recognized.
Classic Saethre-Chotzen syndrome is characterized by coronal synostosis (unilateral or bilateral), facial asymmetry (particularly in individuals with unicoronal synostosis), strabismus, ptosis, and characteristic appearance of the ear (small pinna with a prominent superior and/or inferior crus). Partial cutaneous syndactyly of digits two and three of the hand is common and may be subtle.
- It is important to note that other cranial sutures (i.e., sagittal, lambdoid, and metopic) can undergo premature fusion in individuals with SCS.
- However, individuals with SCS with no evidence of pathologic suture fusion have been described; thus, craniosynostosis is not an obligatory finding.
- There may be a family history of abnormal skull shape, but affected relatives may not have been diagnosed with a craniosynostosis syndrome.
- Whereas mild-to-moderate developmental delay and intellectual disability have been reported in some individuals with SCS, normal cognitive development is more common. However, those with a large genomic deletion involving TWIST1 are at an increased risk for intellectual challenges. See Genotype-Phenotype Correlations.
Findings variably present include the following:
- Maxillary hypoplasia, ocular hypertelorism, and lacrimal duct stenosis
- Palatal anomalies, including narrow palate, bifid uvula, and cleft palate [Stoler et al 2009]
- Conductive, mixed, and profound sensorineural hearing loss [Lee et al 2002]
- Obstructive sleep apnea (OSA). Mild OSA, defined by changes in nocturnal oxygen saturation, was diagnosed in 5% of individuals with SCS in one recent study [de Jong et al 2010].
- Increased intracranial pressure (ICP). A recent study found that 21% of individuals with SCS had increased ICP based on the finding of papilledema that persisted more than one year after surgery [de Jong et al 2010].
- Skeletal concerns such as segmentation defects of the vertebrae, parietal foramina, radioulnar synostosis, duplication of the distal hallux, and hallux valgus
- Congenital heart malformation
- Short stature
A more severe phenotype, indistinguishable from that of Baller-Gerold syndrome (BGS) (see Differential Diagnosis), has been observed. This phenotype includes severe craniosynostosis, radial ray hypoplasia/agenesis, vertebral segmentation defects, and other anomalies [Gripp et al 1999, Seto et al 2001]. Two individuals with clinical features consistent with BGS were found to have novel TWIST1 pathogenic variants.
Genotype-Phenotype Correlations
Most pathogenic variants causing SCS are intragenic and cause haploinsufficiency of the protein product, Twist-related protein 1. No specific genotype-phenotype correlations have been identified except for the following.
The vast majority of individuals with single-nucleotide variants have normal intelligence. The risk for developmental delay in individuals with deletions involving TWIST1 is approximately 90%, or eightfold greater than in individuals with intragenic pathogenic variants [Cai et al 2003a]; individuals with a TWIST1 deletion and normal development have been reported [de Heer et al 2005, Kress et al 2006].
Penetrance
Precise penetrance data are not available; however, wide phenotypic variability and incomplete penetrance are well described [Dollfus et al 2002, de Heer et al 2005].
Nomenclature
Robinow-Sorauf syndrome is now known to be caused by pathogenic variants in TWIST1 [Cai et al 2003b] and is considered part of the mild end of the phenotypic spectrum of SCS.
Prevalence
SCS is one of the more common forms of syndromic craniosynostosis. Prevalence estimates range from 1:25,000 to 1:50,000 [Howard et al1997, Paznekas et al 1998]. It is generally agreed that SCS has approximately the same prevalence as Crouzon syndrome [Cohen &Kreiborg 1992].
Variability of the SCS phenotype may result in underdiagnosis.
Differential Diagnosis
Table 2.
Disorders to Consider in the Differential Diagnosis of Saethre-Chotzen Syndrome (SCS)
| Disorder | Gene(s) | MOI | Clinical Features | Comment | |
|---|---|---|---|---|---|
| Overlapping | Distinguishing | ||||
| Muenke syndrome | FGFR3 1 | AD | Unilateral/bilateral coronal synostosis | In SCS: 2
| Consider testing for FGFR3 p.Pro250Arg if a TWIST1 pathogenic variant is not identified in an individual w/a presumed diagnosis of SCS. |
| Isolated unilateral coronal synostosis (IUCS) 3, 4 (OMIM PS123100) | ALX4 ERF MSX2 SMAD6 TCF12 TWIST1 ZIC1 | AD | If left untreated or incompletely treated, IUCS can → facial asymmetry resembling SCS. | By definition, IUCS is not assoc w/other clinical findings of SCS. |
|
| Baller-Gerold syndrome (BGS) | RECQL4 | AR | Bilateral coronal craniosynostosis → brachycephaly w/ocular proptosis & flat forehead | In BGS:
| Rothmund-Thomson syndrome & RAPADILINO syndrome (OMIM 266280), also caused by RECQL4 pathogenic variants, have overlapping clinical features w/BGS. |
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; SNHL = sensorineural hearing loss
- 1.
Muenke syndrome is defined by the presence of the specific FGFR3 pathogenic variant c.749C>G, which results in the protein change p.Pro250Arg.
- 2.
In their study of 39 families (71 affected individuals) ascertained on the basis of coronal synostosis, Kress et al [2006] determined that individuals with a TWIST1 pathogenic variant could be distinguished from those with the FGFR3 p.Pro250Arg pathogenic variant based on differences in facial features.
- 3.
Isolated coronal synostosis refers to coronal suture fusion with no evidence of other malformations.
- 4.
In an analysis of 186 individuals with isolated single-suture craniosynostosis, 7.5% had at least one rare deletion or duplication found using CMA [Mefford et al 2010].
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Saethre-Chotzen syndrome (SCS), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with SCS
| Organ System | Evaluation | Comment |
|---|---|---|
| Constitutional | Measure height & growth velocity. | If short stature &/or ↓ linear growth velocity, eval by an endocrinologist |
| Eyes | Ophthalmologic evaluation | Evaluate for ptosis, strabismus, amblyopia, lacrimal duct stenosis, & papilledema as evidence of ↑ ICP. |
| ENT/Mouth | Evaluate for cleft palate. | If present, assess for feeding ability & growth. |
| Audiologic screening for hearing loss | If present, assess for hearing aid. | |
| Cardiovascular | Routine cardiac exam | Refer if suspicion of cardiac disease. |
| Respiratory | Assess for sleep apnea. | If suspected, refer for polysomnogram. |
| Musculoskeletal | Evaluate for craniosynostosis & facial asymmetry. | CT scan if suspected clinically |
| Screen for vertebral (particularly cervical) anomalies. |
| |
| Examine upper & lower extremities for anomalies. | If suspected, follow up w/radiographic & orthopedic evaluations | |
| Miscellaneous/ Other | Developmental assessment | Esp in those w/chromosome deletion involving TWIST1. If delay suspected, refer for early intervention. |
| Consultation w/clinical geneticist &/or genetic counselor |
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with SCS
| Manifestation | Treatment | Considerations/Other |
|---|---|---|
| Craniofacial malformation | Ongoing management by an established craniofacial team |
|
| Cleft palate (if present) | Surgical treatment | In most cases, cranioplasty precedes palatal repair. |
| Ophthalmologic abnormalities | Standard treatment as recommended by ophthalmologist | Ptosis & strabismus should be corrected in early childhood to prevent amblyopia, either w/patching or surgery. If papilledema is detected, consider cranioplasty. |
| Hearing loss | Treated in standard manner | |
| Developmental delay | Early intervention &/or special education as appropriate |
Surveillance
Table 5.
Recommended Surveillance for Individuals with SCS
| Medical Concern | Evaluation | Frequency |
|---|---|---|
| Increased intracranial pressure (ICP) |
|
|
| Craniofacial asymmetry |
| As needed |
| Cleft palate | Speech evaluations |
|
| Strabismus &/or ptosis | Ophthalmologic evaluation | As needed if strabismus or ptosis is present |
| Hearing loss | Audiology |
|
| Sleep-disordered breathing | Clinical evaluation | Annual (polysomnogram if indicated by history) |
| Developmental delay (DD) | Clinical evaluation |
|
Agents/Circumstances to Avoid
If cervical spine abnormality with instability is present in an individual, activities that put the spine at risk should be limited.
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.