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 a heterozygous pathogenic (or likely pathogenic) variant in TWIST1 identified 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.

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 (or likely pathogenic) variant in TWIST1 identified by molecular genetic testing (see Table 1).

Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

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).

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.

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.

Treatment of Manifestations

Surveillance

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.

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:

• If a parent has SCS and/or is known to have the pathogenic variant identified in the proband, the risk to sibs is 50%.
• If the proband has a known TWIST pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the TWIST pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for SCS because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.

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, the parent's 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/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

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

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

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].

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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