BLEPHAROPHIMOSIS, EPICANTHUS INVERSUS, AND PTOSIS 3, FORMERLY, INCLUDED
ACROCEPHALOSYNDACTYLY, TYPE III
BPES3, FORMERLY, INCLUDED
ACS III
ACROCEPHALY, SKULL ASYMMETRY, AND MILD SYNDACTYLY SAETHRE-CHOTZEN SYNDROME WITH EYELID ANOMALIES, INCLUDED
CHOTZEN SYNDROME
SCS
ACS3
Acrocephalosyndactyly type 3
Johnson et al. (1998) found facial asymmetry, low frontal hairline, and ptosis to be the most helpful for identifying patients with Saethre-Chotzen syndrome in the absence of pathognomonic features such as 2,3 syndactyly of fingers and duplicated halluces. ... Johnson et al. (1998) found facial asymmetry, low frontal hairline, and ptosis to be the most helpful for identifying patients with Saethre-Chotzen syndrome in the absence of pathognomonic features such as 2,3 syndactyly of fingers and duplicated halluces. Craniosynostosis and Saethre-Chotzen syndrome may be unicoronal or bicoronal; metopic suture fusion is found in some cases, but sagittal suture fusion is rare. Zackai and Stolle (1998) suggested that it is useful to perform analysis for the P250R mutation in the FGFR3 gene in cases of unicoronal synostosis in which other findings of Saethre-Chotzen syndrome are absent.
In the family described by Saethre (1931), a mother, 2 daughters, and probably other maternal relatives showed mild acrocephaly, asymmetry of the skull, and partial soft tissue syndactyly of fingers 2 and 3 and toes 3 and 4. ... In the family described by Saethre (1931), a mother, 2 daughters, and probably other maternal relatives showed mild acrocephaly, asymmetry of the skull, and partial soft tissue syndactyly of fingers 2 and 3 and toes 3 and 4. Chotzen (1932) found identical malformations in a father and 2 sons. Bartsocas et al. (1970) described a Lithuanian kindred living in the United States in which 10 persons in 3 generations were affected, with several instances of male-to-male transmission. Waardenburg et al. (1961) reported asymmetry of the skull and orbits (plagiocephaly), strabismus, and a thin, long, pointed nose in 6 generations of a kindred. Some affected persons had bifid terminal phalanges of digits 2 and 3 and absence of the first metatarsal. Cleft palate, hydrophthalmos, cardiac malformation, and contractures of elbows and knees were present in some. Aase and Smith (1970) described a syndrome comprising asymmetry of the face (hypoplasia of the left side), unusually shaped ear with prominent crus (see their Figure 2), and simian crease in 5 members of 3 generations (with 1 instance of male-to-male transmission). They pointed out similarities to and differences from the asymmetry of the face and skull with abnormalities of the digits described by Waardenburg et al. (1961). Gorlin (1971) thought the syndrome described by Aase and Smith (1970) was Chotzen syndrome. Carter et al. (1982) recognized 9 patients, including familial cases. Like Aase and Smith (1970), they recognized a long and prominent ear crus as a valuable sign. Kurczynski and Casperson (1988) described mother and daughter with craniosynostosis and symmetrical syndactyly involving the fourth and fifth toes. In addition, both had a short columella and small pinnae. Kurczynski and Casperson (1988) concluded that this represented a new form of acrocephalosyndactyly and suggested the designation auralcephalosyndactyly (109050). Legius et al. (1989) described mother and son with bilateral symmetrical syndactyly of the third, fourth and fifth toes, mild craniosynostosis, and small pinnae. In addition, the mother had fusion of 2 cervical vertebrae and partial duplication of the first metatarsal. Furthermore, the distal phalanges of both great toes were bifid. These skeletal changes in combination with cutaneous syndactyly of the toes, abnormal auricles, and acrocephaly have been described in the Saethre-Chotzen syndrome (Kopysc et al., 1980) and also in the Robinow-Sorauf syndrome (180750) (Carter et al., 1982). Legius et al. (1989) concluded that the Saethre-Chotzen, aurolcephalosyndactyly, and Robinow-Sorauf syndromes may be somewhat different expressions of the same dominant gene. Marini et al. (1991) presented a family illustrating the mild and easily missed expression of the gene in a parent. Niemann-Seyde et al. (1991) observed ACS III in 9 members of 4 generations of a family; 5 of them were severely affected. Russo et al. (1991) described a case of renotubular dysgenesis (267430) in an infant who had widely patent cranial fontanels and whose father and sister showed acrocephalosyndactyly of the Saethre-Chotzen type. This was probably a coincidental association between a recessive disorder and a dominant disorder. Chun et al. (2002) found that 3 patients clinically identified as having the Saethre-Chotzen phenotype, 2 with a TWIST mutation and 1 with a TWIST deletion, had the unusual feature of anal malposition/stenosis. Kress et al. (2006) identified mutations in the TWIST1 gene in 71 patients from 39 of 124 pedigrees with coronal suture synostosis. Fourteen novel mutations were identified. By comparison of clinical features with 42 patients from 24 kindreds with Muenke syndrome and the FGFR3 P250R mutation, classic SCS could be distinguished from the Muenke phenotype by presence of low-set frontal hairline, gross ptosis of the eyelids, subnormal ear length, dilated parietal foramina, interdigital webbing, and broad great toe with bifid distal phalanx. Patients with SCS also tended to have intracranial hypertension as a consequence of early progressive multisutural fusion and normal mental development; those with Muenke syndrome tended to have mental delay and sensorineural hearing loss. Kress et al. (2006) concluded that SCS and Muenke should be considered separate syndromes.
Howard et al. (1997) and El Ghouzzi et al. (1997) demonstrated that the Saethre-Chotzen syndrome results from mutations in the TWIST1 gene (601622). They were prompted to evaluate the TWIST gene, which encodes a basic helix-loop-helix transcription factor, ... Howard et al. (1997) and El Ghouzzi et al. (1997) demonstrated that the Saethre-Chotzen syndrome results from mutations in the TWIST1 gene (601622). They were prompted to evaluate the TWIST gene, which encodes a basic helix-loop-helix transcription factor, because its expression pattern and mutant phenotypes in Drosophila and mouse are consistent with the SCS phenotype in humans. Howard et al. (1997) mapped the human TWIST gene by PCR analysis of somatic cell hybrids to 7p22-p21 in a region homologous to the region of mouse chromosome 12 where the murine TWIST gene had been mapped. They assigned it to a specific YAC which was known to contain the breakpoint of a chromosome translocation in 1 Saethre-Chotzen syndrome case. Bourgeois et al. (1996) had previously cloned human TWIST and mapped it to 7p21. Howard et al. (1997) identified nonsense, missense, insertion, and deletion mutations in TWIST in patients with Saethre-Chotzen syndrome. El Ghouzzi et al. (1997) reported 21-bp insertions and nonsense mutations in the TWIST gene in 7 probands with SCS. Paznekas et al. (1998) screened 32 unrelated patients with features of Saethre-Chotzen syndrome for mutations in the TWIST, FGFR2 (176943), and FGFR3 (134934) genes. Nine novel and 3 recurrent TWIST mutations were found in 12 families. Seven families were found to have the FGFR3 P250R mutation (134934.0014), and 1 individual was found to have a VV269-270 deletion of the FGFR2 gene (176943.0023). The detection rate for TWIST or FGFR mutations, including 5 previously reported patients with TWIST mutations, was 68% in Saethre-Chotzen syndrome patients. More than 35 different TWIST mutations had been reported. The most common phenotypic features, present in more than one-third of Saethre-Chotzen patients with TWIST mutations, were coronal synostosis, brachycephaly, low frontal hairline, facial asymmetry, ptosis, hypertelorism, broad great toes, and clinodactyly. Significant intra- and interfamilial phenotypic variability was present for either TWIST or FGFR mutations. Chun et al. (2002) investigated 11 patients clinically identified as having the Saethre-Chotzen phenotype. Four were found to carry the FGFR3 P250R mutation, 3 were found to be heterozygous for 3 different novel mutations of TWIST, and 2 were found to have a deletion of 1 copy of the entire TWIST gene. Developmental delay was a distinguishing feature of the patients with deletions of TWIST; see CYTOGENETICS section.
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....
DiagnosisClinical DiagnosisWith 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.TestingCytogenetic 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 TestingGene. 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 SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityTWIST1Sequence analysis of coding regionSequence variants 2 in exon 1 3>50%68% 4Clinical Deletion/ duplication analysis 5Exonic or whole-gene deletions11% 6 – 28% 7Cytogenetic/FISHTranslocations / inversions involving 7p213.6% 61. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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.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 StrategyTo 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, perform 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. Genetically Related (Allelic) DisordersMutations 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].
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....
Natural HistoryWith 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].
Most mutations causing SCS are intragenic and cause haploinsufficiency of the protein product, Twist-related protein 1. ...
Genotype-Phenotype CorrelationsMost 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].
Muenke syndrome is a distinct condition caused by the specific point mutation p.Pro250Arg in FGFR3 (encoding fibroblast growth factor receptor 3) [Muenke et al 1997]. Penetrance is reduced [Paznekas et al 1998]....
Differential DiagnosisMuenke syndrome is a distinct condition caused by the specific point mutation p.Pro250Arg in FGFR3 (encoding fibroblast growth factor receptor 3) [Muenke et al 1997]. Penetrance is reduced [Paznekas et al 1998].Both Muenke syndrome and Saethre-Chotzen syndrome (SCS) share the features of unilateral or bilateral coronal synostosis. Individuals with Muenke syndrome do not have the following features of SCS: distinctive facial features, including low-set frontal hairline, downward sloping palpebral fissures; ptosis; ear abnormalities; interdigital webbing. In their study of 39 pedigrees (71 affected individuals) ascertained on the basis of coronal synostosis, Kress et al [2006] determined that individuals with a TWIST1 mutation could be distinguished from those with the FGFR3 p.Pro250Arg mutation based on differences in facial features.Compared to persons with SCS, individuals with Muenke syndrome may have a higher prevalence of developmental delay (35% vs 5%) and sensorineural hearing loss (34% vs 0%). Because clinical findings of Muenke syndrome and Saethre-Chotzen syndrome overlap, testing for the FGFR3 p.Pro250Arg mutation should be considered if no TWIST1 mutation is identified in an individual with a presumed diagnosis of Saethre-Chotzen syndrome (see Muenke Syndrome). Isolated unilateral coronal synostosis. Coronal synostosis is the second most common form of single-suture fusion after sagittal synostosis. Isolated coronal synostosis refers to coronal suture fusion with no evidence of other malformations. Isolated coronal fusion is approximately ten times more common than SCS; if left untreated or incompletely treated, it can result in facial asymmetry resembling SCS. Baller-Gerold syndrome (BGS) is characterized by bilateral coronal craniosynostosis that results in brachycephaly with ocular proptosis and flat forehead; radial ray defect, usually with oligodactyly (reduction in number of digits), aplasia or hypoplasia of the thumb, and/or aplasia or hypoplasia of the radius; growth retardation; and poikiloderma. Findings in individuals with BGS overlap with those of Rothmund-Thomson syndrome (RTS) and RAPADILINO syndrome, all of which are caused by mutations in RECQL4. Inheritance is autosomal recessive.In an analysis of 186 individuals with isolated single-suture craniosynostosis, 7.5% had at least one rare deletion or duplication found using aCGH [Mefford et al 2010]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Saethre-Chotzen syndrome (SCS), the following evaluations are recommended: ...
ManagementEvaluations Following Initial DiagnosisTo 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 ManifestationsAs 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 ComplicationsEarly 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).SurveillanceBecause 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 RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTWIST17p21.1Twist-related protein 1TWIST1 homepage - Mendelian genesTWIST1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Saethre-Chotzen Syndrome (View All in OMIM) View in own window 101400SAETHRE-CHOTZEN SYNDROME; SCS 601622TWIST, DROSOPHILA, HOMOLOG OF, 1; TWIST1Molecular Genetic PathogenesisLittle 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).