Clinical Diagnosis

With the ability to detect mutations in TWIST1, the phenotypic spectrum of Saethre-Chotzen syndrome (SCS) is becoming increasingly broad: phenotypes that are both milder and more severe than classic SCS are recognized.

The clinical diagnosis of SCS is made primarily on the following clinical findings:

• 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] and acrocephaly [tall skull]).
• Low frontal hairline, ptosis, strabismus, facial asymmetry
• Small ears with a prominent crus
• Limb anomalies including brachydactyly, partial cutaneous syndactyly of the second and third digits of the hand, hallux valgus, duplicated distal phalanx of the hallux, triangular epiphyses of the hallux [Trusen et al 2003]
  
  Note: Although the degree of syndactyly or its presence is highly variable, it is effectively diagnostic in the presence of the first three features.

Testing

Cytogenetic testing. 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].

Molecular Genetic Testing

Gene. TWIST1 is the only gene in which mutations are known to cause SCS. (See Table A for information on chromosomal locus and protein name.)

Clinical testing

Sequence analysis of coding region. The mutation detection frequency of sequence analysis of exon 1 (the only translated exon in the gene) varies, most likely by the experience of the ordering clinician.

• In 37 unrelated individuals with a clinical diagnosis of SCS, 46% had an identifiable mutation in TWIST1 [Paznekas et al 1998].
• In other series, a TWIST1 mutation was identified in 64%-80% of individuals [Johnson et al 1998, de Heer et al 2005, Kress et al 2006].

Deletion/duplication analysis can detect exonic or whole-gene deletions not identified by sequence analysis.

• An early study suggested that up to 28.5% of SCS is caused by deletions detectable by Southern blot analysis [Gripp et al 2001].
• A more recent study revealed 11% of persons with deletions detected by copy number analysis [Cai et al 2003a].
• Whole-genome chromosomal microarray analysis (CMA) detected a 690 kb deletion associated with a chromosomal translocation t(2;7) detected on cytogenetic analysis [Schluth-Bolard et al 2008].

Cytogenetic studies/FISH analysis. Cai et al [2003a] identified 3.6% with inversions or translocations identified by marker typing and FISH: two individuals had a translocation or inversion at least 260 kb 3’ of the gene that were position-effect mutations; at least two had other translocations that likely disrupted the gene, but have not been proven to do so.

Table 1. Summary of Molecular Genetic Testing Used in Saethre-Chotzen Syndrome

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1		Test Availability
TWIST1	Sequence analysis of coding region	Sequence variants 2 in exon 1 3	>50%	68% 4	Clinical
	Deletion/ duplication analysis 5	Exonic or whole-gene deletions	11% 6 – 28% 7
	Cytogenetic/FISH	Translocations / inversions involving 7p21	3.6% 6

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. All intragenic mutations identified to date are in exon 1, which contains the entire coding region.

4. In 37 individuals with classic features of SCS (test method not specified) [Cai et al 2003a]

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. See CMA.

6. Cai et al [2003a]

7. Gripp et al [2001]

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. Confirmation of the diagnosis in a proband requires identification of a disease-causing TWIST1 mutation using the following approach:

• Molecular genetic testing of TWIST1 by sequence analysis; if no mutation is identified, deletion/duplication analysis
• If no TWIST1 mutation can be identified by sequence analysis and deletion/duplication analysis AND other disorders such as Muenke syndrome, caused by the p.Pro250Arg mutation in FGFR3 [Muenke et al 1997] have been excluded OR if the phenotype and/or family history suggest a complex chromosome abnormality, consider cytogenetic/FISH analysis

Prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Mutations in the TWIST box, the highly conserved C-terminus that binds and inhibits RUNX2 transactivation, are associated with isolated sagittal or unilateral coronal synostosis, not SCS [Seto et al 2007].

Natural History

With the ability to detect mutations in TWIST1, the phenotypic spectrum of Saethre-Chotzen syndrome (SCS) is becoming 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). It is important to note that other sutures (i.e., sagittal, lambdoid, and metopic) can undergo premature fusion in individuals with SCS and that individuals with SCS with no evidence of pathologic suture fusion have been described.

Partial cutaneous syndactyly of digits two and three of the hand and duplication of the distal hallux are variably present. Less common (but clinically significant) findings include both conductive and sensorineural hearing loss and segmentation defects of the vertebrae. Whereas mild-to-moderate developmental delay and intellectual disability have been reported, normal intelligence is more common.

Less common manifestations of SCS include short stature, parietal foramina, radioulnar synostosis, cleft palate, maxillary hypoplasia, ocular hypertelorism, hallux valgus, and congenital heart malformations.

Other findings variably present:

• Lacrimal duct stenosis, vertebral fusion, and short stature [Anderson et al 1997, Trusen et al 2003]
• Family history of abnormal skull shape and/or a combination of other physical findings. Although usually present in SCS, craniosynostosis is not an obligatory finding; therefore, affected relatives may not have been diagnosed with a craniosynostosis syndrome.
• Intellectual disability. Although learning differences may be noted in persons with intragenic mutations, severe delay or intellectual disability is not typical. In contrast, individuals with a microdeletion in 7p21 usually show significant learning deficits.
• Conductive, mixed, and profound sensorineural hearing loss [Lee et al 2002]
• Palatal anomalies, including narrow palate, bifid uvula, and cleft palate, [Stoler et al 2009]
• 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].
• Obstructive sleep apnea (OSA). Mild obstructive sleep apnea (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].

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 mutations.

Milder phenotypes associated with TWIST1 mutations include the following:

• Blepharophimosis or ptosis with or without craniosynostosis resembling blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) [De Heer et al 2004].
• Robinow-Sorauf syndrome characterized by mild midfacial hypoplasia, shallow orbits, ocular hypertelorism, orbital asymmetry, and broad or duplicated great toes [Kunz et al 1999, Cai et al 2003b].

One case series suggested an increased risk for breast cancer in women with SCS [Sahlin et al 2007]; however, a subsequent study failed to support this claim [James et al 2009].

Genotype-Phenotype Correlations

Most mutations causing SCS are intragenic and cause haploinsufficiency of the protein product, Twist-related protein 1.

With the exception of mutations identified in the TWIST box, no conclusive evidence of genotype-phenotype correlations exists despite the identification of mutations in each of the functional domains of the Twist-related protein 1 (5' DNA binding, DNA binding, helix 1, loop, and helix 2 domains). Mutations in the TWIST box, the highly conserved C-terminus that binds and inhibits RUNX2 transactivation, have been shown to be associated with a milder phenotype of isolated sagittal or unilateral coronal synostosis (see Genetically Related Disorders).

Although insertions, deletions, and nonsense and missense mutations have been described, no genotype-phenotype correlation has been found, suggesting that sequence alterations lead to a loss of functional TWIST1 protein irrespective of the mutation type.

The vast majority of individuals with point mutations 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 mutations [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 mutations 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. It is generally agreed that SCS has approximately the same prevalence as Crouzon syndrome.

Variability of the SCS phenotype may result in underdiagnosis.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Saethre-Chotzen syndrome (SCS), the following evaluations are recommended:

• Determination of the degree of facial asymmetry to establish a baseline for future recognition of progressive facial asymmetry
• Ophthalmologic examination for evaluation of ptosis, strabismus, amblyopia, lacrimal duct stenosis, and increased ICP [Woods et al 2009]
• Screening for vertebral (particularly cervical) anomalies using routine radiographs (At age ~2 years, increased mineralization of the vertebrae allows for better interpretation of flexion/extension views of the cervical spine in evaluation for functional instability.)
• Audiologic screening for hearing loss
• Examination for cleft palate; if cleft palate is present, assessment of feeding ability and growth
• Examination of upper and lower extremities for anomalies; if anomalies are present, x-ray and/or orthopedic evaluation for radial ray or hallux anomalies
• Measurement of height and growth velocity; if short stature and/or reduced linear growth velocity is present, evaluation by an endocrinologist
• Screening developmental assessment on any child demonstrating developmental delays and all children found to have a 7p microdeletion, if developmental delay is identified, comprehensive developmental assessment

Treatment of Manifestations

As with all children with functional craniofacial malformations, management through an established craniofacial team is recommended.

While management protocols are likely to differ among craniofacial teams, it is generally accepted that individuals with SCS should undergo cranioplasty in the first year of life.

Cranioplasty involves extensive surgery to release fused sutures including repositioning and reconstruction of the malformed calvaria. It prevents the following:

• Progressive facial asymmetry that can develop in individuals with unilateral or asymmetric coronal fusion
• Increased intracranial pressure (ICP) that can develop in individuals with multiple sutural synostosis (bicoronal or other sutures)
• Progressive hypertropia resulting from overaction of the ipsilateral inferior oblique muscle in cases of unilateral coronal synostosis [Weiss & Phillips 2006].

In some circumstances, midfacial surgery is necessary during childhood to address dental malocclusion, swallowing difficulties, or respiratory problems.

If cleft palate is present, it is treated as in other disorders, including surgical closure, assurance of adequate feeding and weight gain, and speech therapy. In most cases, cranioplasty precedes palatal repair.

Orthodontic treatment and/or orthognathic surgery may be required at or near the completion of facial growth.

If developmental delay is identified, early intervention and/or special education are appropriate.

Hearing loss, if present, should be treated in a standard manner (see Deafness and Hereditary Hearing Loss Overview).

Ophthalmologic abnormalities are treated in a standard fashion. Ptosis and strabismus should be corrected during early childhood to prevent amblyopia, either with patching or surgery.

Prevention of Secondary Complications

Early referral to a craniofacial center with expertise in the management of SCS can minimize the secondary effects of craniosynostosis and other functional deficits. Referral to early intervention services if there are concerns for developmental delay is appropriate to improve outcome.

Tympanostomy tubes are appropriate for children with cleft palate or other causes of persistent middle ear effusion and/or otitis media.

Cervical spine radiograph to evaluate for segmentation defects is appropriate before initiating activities that put the spine at risk (e.g., gymnastics, football, soccer).

Surveillance

Because increased intracranial pressure (ICP) can develop even after successful treatment of craniosynostosis, brain imaging or ophthalmologic evaluation for chronic papilledema should be obtained periodically until age 15 years, or at any time symptoms (e.g., headache, reduced school performance) are identified.

Examination for progression of facial asymmetry particularly in individuals with untreated unilateral coronal synostosis should continue until the completion of facial growth (age ~16 years).

Audiologic screening throughout childhood is indicated.

Regular ophthalmologic evaluations (frequency determined on the basis of symptoms) should begin before age two years or earlier if strabismus or severe ptosis is identified.

If cleft palate is present, monitor for ear infections and hearing loss.

Screen for sleep-disordered breathing at all visits.

At least annual assessment of developmental status of preschool-aged children is appropriate. If findings suggest developmental delay, comprehensive developmental assessment and referral to early intervention is indicated.

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 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

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 gene mutation. The proportion of cases caused by de novo mutations is unknown.
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation 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 mutation has been identified in the proband

Note: Although many individuals diagnosed with SCS have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members as a result of the wide phenotypic variability of SCS.

Sibs of a proband

• The risk to sibs depends on the genetic status of the parents.
• If a parent has SCS, the risk to each sib of a proband is 50%.
• When the parents are clinically unaffected and do not have a TWIST1 mutation, the risk to the sibs of a proband appears to be low.
• If a TWIST1 mutation cannot be detected in DNA extracted from the leukocytes of either parent of the proband, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. The risk to the sibs of the proband depends on the probability of germline mosaicism in a parent of the proband and the spontaneous mutation rate of TWIST1. No instances of germline mosaicism have been reported, although it remains a possibility.

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

Other family members of a proband. 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 are at risk.

Related Genetic Counseling Issues

The widely variable phenotypic manifestations of TWIST1 mutations (intra- and interfamilial) complicate genetic counseling.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder or the disease-causing mutation, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or 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.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The TWIST1 disease-causing mutation of an affected family member must be identified before molecular genetic testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as SCS are not common. 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. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Little is known about the mechanism by which alteration in Twist-related protein 1 signaling pathways leads to craniosynostosis.

Clinically, Saethre-Chotzen syndrome (SCS) has phenotypic overlap with other craniosynostosis syndromes, particularly Muenke syndrome, caused by the p.Pro250Arg mutation in FGFR3 [Muenke et al 1997]. Although clinically leading to the same primary malformation, premature fusion of the calvaria, it is not known if the two genes lie in the same, parallel, or independent pathways during calvarial development.

Several genes and gene families, including TWIST1, FGFs, FGFRs, MSX2, ALX4, EFNB1, EFNA4, NELL1, RUNX2, BMPs, TGF-ßs, SHH, IGFs, IGFRs, and IGFBPs regulate suture patency, likely by interacting with one another. One model proposes that Twist-related protein 1 functions by forming either homodimers or heterodimers that have distinct regulatory interactions with other genes, such as FGFRs and BMPs. Haploinsufficiency of Twist-related protein 1 changes the ratio of dimers and, therefore, the expression of downstream signaling molecules. 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 mice models [Connerney et al 2008, Miraoui & Marie 2010].

Normal allelic variants. 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).

At least 50 normal allelic variants have been identified within TWIST1 [Fredman et al 2002]. Of these, eight intragenic normal allelic variants have been identified within the coding region [Kasparcova et al 1998, Gripp et al 2000, SNP Database]. In addition, Elanko et al [2001] described a variation in the polyglycine tract length of TWIST1 in individuals with craniosynostosis. None of these rearrangements was consistently associated with clinical disease; thus, they were considered normal variants or at most weakly pathologic variants.

Pathologic allelic variants. To date, 126 mutations in TWIST1 have been determined to cause SCS, which results from functional haploinsufficiency of Twist-related protein 1, a basic helix-loop-helix (HLH) transcription factor. These include 73 distinct nucleotide substitutions (missense and nonsense), 53 deletions/insertions/duplications/indels, and complex rearrangements [Johnson et al 1998, Zackai & Stolle 1998, Gripp et al 2000, Chun et al 2002, Seto et al 2007, Human Gene Mutation Database 2011 (registration required)].

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

• Nonsense mutations 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 mutations are clustered within the functional domains.
• Four persons have been identified with mutations in the C-terminus, known as the TWIST box, a highly conserved region which binds and inhibits RUNX2 activation [Kress et al 2006, Seto et al 2007, Pena et al 2010]. RUNX2 is considered the “master switch” for osteoblast differentiation and activity. The individuals with TWIST box mutations had single suture synostosis (one sagittal and one unilateral coronal) and no additional features of SCS.

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 basic domain that mediates specific DNA binding, the HLH domains containing two amphipathic helices that act as dimerization domains [Murre et al 1994], and a loop region that separates the two helices. A motif of mainly basic residues permits HLH protein to bind to a consensus hexanucleotide E-box (CANNTG) [Voronova & Baltimore 1990]. Dimerization is a prerequisite for DNA binding; it depends on the spacing between the helices and leads to the formation of a bipartite DNA-binding groove by the basic domain.

Abnormal gene product. Germline TWIST1 mutations of lead to haploinsufficiency [el Ghouzzi et al 2000].

• Nonsense mutations predict the synthesis of truncated proteins or nonsense-mediated mRNA decay and result in a lack of abnormal protein, thereby leading to functional haploinsufficiency.
• Missense mutations involving the helical domains lead to a loss of heterodimer formation that alters nuclear translocation.
• In-frame insertion or missense mutations 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 mutant allele in individuals with SCS. The suggestion is further supported by the finding of premature fusion of sutures in twist-null/+ heterozygous mice [el Ghouzzi et al 1997, Bourgeois et al 1998, Carver et al 2002].

Click here for information on animal models (pdf).

Literature Cited

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Suggested Reading

1. Couly GF, Coltey PM, Le Douarin NM. The developmental fate of the cephalic mesoderm in quail-chick chimeras. Development. 1992;114:1–15. [PubMed: 1576952]
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Revision History

• 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 to live Web site
• 1 August 2005 (me) Comprehensive update posted to live Web site
• 30 July 2004 (mc) Revision: testing methods
• 16 May 2003 (me) Review posted to live Web site
• 21 January 2003 (mc) Original submission