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Saethre-Chotzen Syndrome

Synonym: Acrocephalosyndactyly Type III

, MD, MPH, , DDS, PhD, and , MD, PhD.

Author Information

Initial Posting: ; Last Update: January 24, 2019.

Estimated reading time: 19 minutes

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 diagnosis for pregnancies at increased risk and preimplantation diagnosis 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 hand
      Note: 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 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
TWIST1Sequence analysis 372% 4
Gene-targeted deletion/duplication analysis 5, 623% 4
CMA 6, 723% 4, 8
Karyotype5% 9
1.
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.
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.

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)

DisorderGene(s)MOIClinical FeaturesComment
OverlappingDistinguishing
Muenke syndromeFGFR3 1ADUnilateral/bilateral coronal synostosisIn SCS: 2
  • Low-set frontal hairline
  • Downward-sloping palpebral fissures
  • Ptosis
  • Ear abnormalities
  • Interdigital webbing
In Muenke syndrome:
  • Higher prevalence of DD (35% in Muenke syndrome vs 5% in SCS)
  • SNHL (34% in Muenke syndrome vs rare in SCS)
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
ADIf left untreated or incompletely treated, IUCS can → facial asymmetry resembling SCS.By definition, IUCS is not assoc w/other clinical findings of SCS.
  • Coronal synostosis is 2nd most common form of single-suture fusion (after sagittal synostosis).
  • Isolated coronal fusion is ~10x more common than SCS.
Baller-Gerold syndrome
(BGS)
RECQL4ARBilateral coronal craniosynostosis → brachycephaly w/ocular proptosis & flat foreheadIn BGS:
  • Radial ray defect, usually w/oligodactyly (↓ # of digits), aplasia or hypoplasia of the thumb, &/or aplasia or hypoplasia of the radius
  • Growth restriction
  • Poikiloderma
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 SystemEvaluationComment
ConstitutionalMeasure height & growth velocity.If short stature &/or reduced linear growth velocity present, evaluation by an endocrinologist
EyesOphthalmologic evaluationEvaluate for ptosis, strabismus, amblyopia, lacrimal duct stenosis, & papilledema as evidence of increased ICP.
ENT/MouthEvaluate for cleft palate.If present, assess for feeding ability & growth.
Audiologic screening for hearing lossIf present, assess for hearing aid.
CardiovascularRoutine cardiac examRefer if suspicion for cardiac disease.
RespiratoryAssess for sleep apnea.If suspected, refer for polysomnogram.
MusculoskeletalEvaluate for craniosynostosis & facial asymmetry.CT scan if suspected clinically
Screen for vertebral (particularly cervical) anomalies.
  • At age ~2 yrs, ↑ mineralization of vertebrae allows for better interpretation of flexion/extension views of cervical spine in evaluation for functional instability.
  • Such screening is appropriate before initiating activities that put the spine at risk (e.g., surgeries w/long duration, gymnastics, football, soccer).
Examine upper & lower extremities for anomalies.If suspected, follow up w/radiographic & orthopedic evaluations
Miscellaneous/
Other
Developmental assessmentEspecially 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

ManifestationTreatmentConsiderations/Other
Craniofacial
malformation
Ongoing management by an established craniofacial team
  • Typical cranioplasty occurs in the 1st yr of life.
  • In some individuals midfacial surgery is needed during childhood to address dental malocclusion, swallowing difficulties, or respiratory problems.
  • Orthodontic treatment &/or orthognathic surgery may be required at or near completion of facial growth.
Cleft palate
(if present)
Surgical treatmentIn most cases, cranioplasty precedes palatal repair.
Ophthalmologic
abnormalities
Standard treatment as recommended by ophthalmologistPtosis & strabismus should be corrected during early childhood to prevent amblyopia, either w/patching or surgery. If papilledema is detected, consider cranioplasty.
Hearing lossTreated in standard manner
Developmental
delay
Early intervention &/or special education as appropriate

Surveillance

Table 5.

Recommended Surveillance for Individuals with SCS

Medical ConcernEvaluationFrequency
Increased intracranial pressure (ICP)
  • Ophthalmologic evaluation
  • Brian imaging (MRI or CT scan)
  • Annual, if synostosis is not treated
  • If ↑ ICP a concern, perform imaging (preferably MRI) for additional assessment
Craniofacial asymmetry
  • Clinical exam
  • Preoperative CT scan
As needed
Cleft palateSpeech evaluations
  • Annual starting at age 12 mos
  • Frequency after age 6 yrs based on symptoms of palatal dysfunction
Strabismus &/or ptosisOphthalmologic evaluationAs needed if strabismus or ptosis is present
Hearing lossAudiology
  • Annual through age 6 yrs, then as needed
  • Up to every 6 months in patients w/cleft palate or known hearing loss
Sleep-disordered breathingClinical evaluationAnnual (polysomnogram if indicated by history)
Developmental
delay (DD)
Clinical evaluation
  • Annual for preschool-age children, then as indicated
  • If screening suggests DD, comprehensive assessment & referral to early intervention

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 www.ClinicalTrialsRegister.eu 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.

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

Saethre-Chotzen syndrome (SCS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Many individuals diagnosed with SCS have an affected parent.
  • A proband with SCS may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include the following:
    • Complete examination for subtle features (ptosis, mild brachydactyly / 2-3 syndactyly) even in the absence of any calvarial pathology
    • Molecular genetic testing of TWIST1 if a pathogenic variant has been identified in the proband
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of germline mosaicism have been reported.
  • 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 intrafamilial phenotypic variability is observed in SCS) or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

Offspring of a proband. Each child of an individual with SCS has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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 young adults who are affected or at risk.
  • The widely variable phenotypic manifestations of TWIST1 pathogenic variants (intra- and interfamilial) complicate genetic counseling.

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

Once the TWIST1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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.

  • FACES: The National Craniofacial Association
    PO Box 11082
    Chattanooga TN 37401
    Phone: 800-332-2373 (toll-free)
    Email: faces@faces-cranio.org
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free)
    Email: contactCCA@ccakids.com
  • Face Equality International
    United Kingdom
    Email: info@faceequalityinternational.org
  • FACES: The National Craniofacial Association
    PO Box 11082
    Chattanooga TN 37401
    Phone: 800-332-2373 (toll-free)
    Email: faces@faces-cranio.org
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.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 A.

Saethre-Chotzen Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
TWIST17p21​.1Twist-related protein 1TWIST1 databaseTWIST1TWIST1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Saethre-Chotzen Syndrome (View All in OMIM)

101400SAETHRE-CHOTZEN SYNDROME; SCS
601622TWIST FAMILY bHLH TRANSCRIPTION FACTOR 1; TWIST1

Molecular Genetic Pathogenesis

Several genes and gene families including TWIST1, TCF12, ERF, FGFs, FGFRs, MSX2, ALX4, EFNB1, EFNA4, NELL1, RUNX2, BMPs, TGF-βs, SHH, IGFs, IGFRs, and IGFBPs regulate patency of the sutures of the calvarium, likely by interacting with one another. Clinically, Saethre-Chotzen syndrome (SCS) has phenotypic overlap with other craniosynostosis syndromes, particularly Muenke syndrome, caused by the p.Pro250Arg pathogenic variant in FGFR3 [Muenke et al 1997]. While the two genes lead clinically to the same primary malformation –premature fusion of the calvaria – it is not known if they lie in the same, parallel, or independent pathways during calvarial development.

Gene structure. TWIST1 comprises two exons and one intron. The first exon contains an open reading frame encoding a 202-amino acid protein, followed by a 45-bp untranslated portion, a 536-bp intron, and a second untranslated exon (reference sequences NM_000474.3 and NP_000465.1).

Pathogenic variants. To date, more than 209 variants in TWIST1 have been reported to cause SCS, which results from functional haploinsufficiency of Twist-related protein 1, a basic helix-loop-helix (HLH) transcription factor. The majority of reported pathogenic variants are missense, nonsense, or frameshift (i.e., deletions/insertions/duplications/indels); however, a significant number of large deletion or chromosome rearrangements have also been reported [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 (registration required)]. All TWIST1 pathogenic variants cause functional haploinsufficiency.

All of the disease-associated variants are located within the coding region; no splice variants, intronic variants, or changes within the second exon have been reported. No apparent mutational "hot spot" has been identified.

  • Nonsense variants that preclude translation of the DNA binding domain and the HLH domain have been identified from the 5' end of the coding sequence to the end of the HLH motif.
  • Missense variants are clustered within the functional domains.
  • Four persons have been identified with pathogenic variants in the C-terminus, known as the TWIST box, a highly conserved region that binds and inhibits RUNX2 activation [Kress et al 2006, Seto et al 2007, Peña et al 2010]. RUNX2 is considered the "master switch" for osteoblast differentiation and activity.
  • Functional haploinsufficiency of TWIST1, whether due to mutation in the DNA binding, HLH, or TWIST box domains, results in disinhibition of RUNX2 and enhances osteogenesis.

Normal gene product. The Twist-related protein 1 is a member of a large family of basic helix-loop-helix (bHLH) transcriptional regulators. The bHLH motif is identified by the following:

  • The basic domain that mediates specific DNA binding to a consensus hexanucleotide E-box (CANNTG)
  • The HLH domains containing two amphipathic helices that act as dimerization domains (dimerization is required for DNA binding)
  • A loop region that separates the two helices, spacing them appropriately for DNA binding and causing formation of a bipartite DNA-binding groove by the basic domain

Abnormal gene product. TWIST1 pathogenic variants lead to haploinsufficiency [El Ghouzzi et al 2000]. Haploinsufficiency of Twist-related protein 1 changes the ratio of dimers and, therefore, the expression of downstream signaling molecules.

  • Nonsense and frameshift variants have been associated with disease.
  • Missense variants involving the helical domains lead to a loss of heterodimer formation that alters nuclear translocation.
  • In-frame insertion or missense variants within the loop domain alter dimer formation, but not the nuclear location of the protein.

These data suggest that protein degradation and altered subcellular localization account for the loss of functional Twist-related protein 1 from the abnormal allele in individuals with SCS. This model also supports the finding that the coronal sutures are predominantly fused in SCS, since these sutures have a higher level of gene expression of downstream activators, as shown in Twist-null/+ mice models [el Ghouzzi et al 1997, Bourgeois et al 1998, Carver et al 2002, Connerney et al 2008, Miraoui & Marie 2010].

References

Literature Cited

  • Bourgeois P, Bolcato-Bellemin AL, Danse JM, Bloch-Zupan A, Yoshiba K, Stoetzel C, Perrin-Schmitt F. The variable expressivity and incomplete penetrance of the twist-null heterozygous mouse phenotype resemble those of human Saethre-Chotzen syndrome. Hum Mol Genet. 1998;7:945–57. [PubMed: 9580658]
  • Cai J, Goodman BK, Patel AS, Mulliken JB, Van Maldergem L, Hoganson GE, Paznekas WA, Ben-Neriah Z, Sheffer R, Cunningham ML, Daentl DL, Jabs EW. Increased risk for developmental delay in Saethre-Chotzen syndrome is associated with TWIST deletions: an improved strategy for TWIST mutation screening. Hum Genet. 2003a;114:68–76. [PubMed: 14513358]
  • Cai J, Shoo BA, Sorauf T, Jabs EW. A novel mutation in the TWIST gene, implicated in Saethre-Chotzen syndrome, is found in the original case of Robinow-Sorauf syndrome. Clin Genet. 2003b;64:79–82. [PubMed: 12791045]
  • Carver EA, Oram KF, Gridley T. Craniosynostosis in Twist heterozygous mice: a model for Saethre-Chotzen syndrome. Anat Rec. 2002;268:90–2. [PubMed: 12221714]
  • Cohen MM Jr, Kreiborg S. Birth prevalence studies of the Crouzon syndrome: comparison of direct and indirect methods. Clin Genet. 1992;41:12–15. [PubMed: 1633640]
  • Connerney J, Andreeva V, Leshem Y, Mercado MA, Dowell K, Yang X, Linder V, Friesel RE, Spicer DB. Twist1 homodimers enhance FGF responsiveness of the cranial sutures and promote suture closure. Dev Biol. 2008;318:323–34. [PMC free article: PMC2605972] [PubMed: 18471809]
  • de Heer IM, de Klein A, van den Ouweland AM, Vermeij-Keers C, Wouters CH, Vaandrager JM, Hovius SE, Hoogeboom JM. Clinical and genetic analysis of patients with Saethre-Chotzen syndrome. Plast Reconstr Surg. 2005;115:1894–902. [PubMed: 15923834]
  • De Heer IM, Hoogeboom AJ, Eussen HJ, Vaandrager JM, De Klein A. Deletion of the TWIST gene in a large five-generation family. Clin Genet. 2004;65:396–9. [PubMed: 15099347]
  • de Jong T, Bannink N, Bredero-Boelhouwer HH, van Veelen MLC, Bartels MC, Hoeve LJ, Hoogeboom AJM, Wolvius EB, Lequin MH, van der Muelen JJNM, van Adrichem LNA, Vaandrager JM, Ongkosuwito EM, Joosten KFM, Mathijssen IMJ. Long-term functional outcome in 167 patients with syndromic craniosynostosis; defining a syndrome-specific risk profile. J Plast Reconstr Aesthet Surg. 2010;63:1635–41. [PubMed: 19913472]
  • Dollfus H, Biswas P, Kumaramanickavel G, Stoetzel C, Quillet R, Biswas J, Lajeunie E, Renier D, Perrin-Schmitt F. Saethre-Chotzen syndrome: notable intrafamilial phenotypic variability in a large family with Q28X TWIST mutation. Am J Med Genet. 2002;109:218–25. [PubMed: 11977182]
  • el Ghouzzi V, Le Merrer M, Perrin-Schmitt F, Lajeunie E, Benit P, Renier D, Bourgeois P, Bolcato-Bellemin AL, Munnich A, Bonaventure J. Mutations of the TWIST gene in the Saethre-Chotzen syndrome. Nat Genet. 1997;15:42–6. [PubMed: 8988167]
  • El Ghouzzi V, Legeai-Mallet L, Aresta S, Benoist C, Munnich A, de Gunzburg J, Bonaventure J. Saethre-Chotzen mutations cause TWIST protein degradation or impaired nuclear location. Hum Mol Genet. 2000;9:813–9. [PubMed: 10749989]
  • Foo R, Guo Y, McDonald-McGinn DM, Zackai EH, Whitaker LA, Bartlett SP. The natural history of patients treated for TWIST1-confirmed Saethre-Chotzen syndrome. Plast Reconstr Surg. 2009;124:2085–95. [PubMed: 19952666]
  • Fryssira H, Makrythanasis P, Kattamis A, Stokidis K, Menten B, Kosaki K, Willems P, Kanavakis E. Severe developmental delay in a patient with 7p21.1-p14.3 microdeletion spanning the TWIST gene and the HOXA gene cluster. Mol Syndromol. 2011;2:45–9. [PMC free article: PMC3343762] [PubMed: 22570644]
  • Gripp KW, Stolle CA, Celle L, McDonald-McGinn DM, Whitaker LA, Zackai EH. TWIST gene mutation in a patient with radial aplasia and craniosynostosis: further evidence for heterogeneity of Baller-Gerold syndrome. Am J Med Genet. 1999;82:170–6. [PubMed: 9934984]
  • Gripp KW, Zackai EH, Stolle CA. Mutations in the human TWIST gene. Hum Mutat. 2000;15:479. [PubMed: 10790211]
  • Howard TD, Paznekas WA, Green ED, Chiang LC, Ma N, Ortiz de Luna RI, Garcia Delgado C, Gonzalez-Ramos M, Kline AD, Jabs EW. Mutations in TWIST, a basic helix-loop-helix transcription factor, in Saethre-Chotzen syndrome. Nat Genet. 1997;15:36–41. [PubMed: 8988166]
  • Kress W, Schropp C, Lieb G, Petersen B, Busse-Ratzka M, Kunz J, Reinhart E, Schafer WD, Sold J, Hoppe F, Pahnke J, Trusen A, Sorensen N, Krauss J, Collmann H. Saethre-Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome. Eur J Hum Genet. 2006;14:39–48. [PubMed: 16251895]
  • Lee S, Seto M, Sie K, Cunningham M. A child with Saethre-Chotzen syndrome, sensorineural hearing loss, and a TWIST mutation. Cleft Palate Craniofac J. 2002;39:110–4. [PubMed: 11772178]
  • Mefford HC, Shafer N, Antonacci F, Tsai JM, Park SS, Hing AV, Rieder MJ, Smyth MD, Speltz ML, Eichler EE, Cunningham ML. Copy number variation analysis in single-suture craniosynostosis: multiple rare variants Including RUNX2 duplication in two cousins with metopic craniosynostosis. Am J Med Genet Part A. 2010;152A:2203–10. [PMC free article: PMC3104131] [PubMed: 20683987]
  • Miraoui H, Marie PJ. Pivotal role of Twist in skeletal biology and pathology. Gene. 2010;468:1–7. [PubMed: 20696219]
  • Muenke M, Gripp KW, McDonald-McGinn DM, Gaudenz K, Whitaker LA, Bartlett SP, Markowitz RI, Robin NH, Nwokoro N, Mulvihill JJ, Losken HW, Mulliken JB, Guttmacher AE, Wilroy RS, Clarke LA, Hollway G, Ades LC, Haan EA, Mulley JC, Cohen MM Jr, Bellus GA, Francomano CA, Moloney DM, Wall SA, Wilkie AO, et al. A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome. Am J Hum Genet. 1997;60:555–64. [PMC free article: PMC1712518] [PubMed: 9042914]
  • Paumard-Hernández B, Berges-Soria J, Barroso E, Rivera-Pedroza CI, Pérez-Carrizosa V, Benito-Sanz S, López-Messa E, Santos F, García-Recuero II, Romance A, Ballesta-Martínez JM, López-González V, Campos-Barros Á, Cruz J, Guillén-Navarro E, Sánchez Del Pozo J, Lapunzina P, García-Miñaur S, Heath KE. Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants. Eur J Hum Genet. 2015;23:907–14. [PMC free article: PMC4463497] [PubMed: 25271085]
  • Paznekas WA, Cunningham ML, Howard TD, Korf BR, Lipson MH, Grix AW, Feingold M, Goldberg R, Borochowitz Z, Aleck K, Mulliken J, Yin M, Jabs EW. Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations. Am J Hum Genet. 1998;62:1370–80. [PMC free article: PMC1377134] [PubMed: 9585583]
  • Peña WA, Slavotinek A, Oberoi S. Saethre-Chotzen syndrome: a case report. Cleft Palate Craniofac J. 2010;47:318–21. [PubMed: 19860490]
  • Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
  • Roscioli T, Elakis G, Cox TC, Moon DJ, Venselaar H, Turner AM, Le T, Hackett E, Haan E, Colley A, Mowat D, Worgan L, Kirk EP, Sachdev R, Thompson E, Gabbett M, McGaughran J, Gibson K, Gattas M, Freckmann ML, Dixon J, Hoefsloot L, Field M, Hackett A, Kamien B, Edwards M, Adès LC, Collins FA, Wilson MJ, Savarirayan R, Tan TY, Amor DJ, McGillivray G, White SM, Glass IA, David DJ, Anderson PJ, Gianoutsos M, Buckley MF. Genotype and clinical care correlations in craniosynostosis: findings from a cohort of 630 Australian and New Zealand patients. Am J Med Genet C Semin Med Genet. 2013;163C:259–70. [PubMed: 24127277]
  • Seto ML, Hing AV, Chang J, Hu M, Kapp-Simon KA, Patel PK, Burton BK, Kane AA, Smyth MD, Hopper R, Ellenbogen RG, Stevenson K, Speltz ML, Cunningham ML. Isolated sagittal and coronal craniosynostosis associated with TWIST box mutations. Am J Med Genet A. 2007;143A:678–86. [PubMed: 17343269]
  • Seto ML, Lee SJ, Sze RW, Cunningham ML. Another TWIST on Baller-Gerold syndrome. Am J Med Genet. 2001;104:323–30. [PubMed: 11754069]
  • Shetty S, Boycott KM, Gillan TL, Bowser K, Parboosingh JS, McInnes B, Chernos JE, Bernier FP. Cytogenetic and molecular characterization of a de-novo cryptic deletion of 7p21 associated with an apparently balanced translocation and complex craniosynostosis. Clin Dysmorphol. 2007;16:253–6. [PubMed: 17786117]
  • Stoler JM, Rogers GF, Mulliken JB. The frequency of palatal anomalies in Saethre-Chotzen syndrome. Cleft Palate Craniofac J. 2009;46:280–4. [PubMed: 19642760]
  • Tahiri Y, Bastidas N, McDonald-McGinn DM, Birgfeld C, Zackai EH, Taylor J, Bartlett SP. New pattern of sutural synostosis associated with TWIST gene mutation and Saethre-Chotzen syndrome: peace sign synostosis. J Craniofac Surg. 2015;26:1564–7. [PubMed: 26114524]
  • Touliatou V, Mavrou A, Kolialexi A, Kanavakis E, Kitsiou-Tzeli S. Saethre-Chotzen syndrome with severe developmental delay associated with deletion of chromosomic region 7p15→pter. Genet Couns. 2007;18:295–301. [PubMed: 18019370]
  • Trusen A, Beissert M, Collmann H, Darge K. The pattern of skeletal anomalies in the cervical spine, hands and feet in patients with Saethre-Chotzen syndrome and Muenke-type mutation. Pediatr Radiol. 2003;33:168–72. [PubMed: 12612814]

Chapter Notes

Revision History

  • 24 January 2019 (ha) Comprehensive update posted live
  • 14 June 2012 (cd) Revision: mutation scanning no longer available clinically
  • 21 June 2011 (me) Comprehensive update posted live
  • 27 December 2007 (me) Comprehensive update posted live
  • 1 August 2005 (me) Comprehensive update posted live
  • 30 July 2004 (mc) Revision: testing methods
  • 16 May 2003 (me) Review posted live
  • 21 January 2003 (mc) Original submission
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