Paula and Bobby
Parents of Lillie
Saethre-Chotzen syndrome (SCS)
What is Saethre-Chotzen syndrome (SCS)?
Saethre-Chotzen is a rare disease (craniosynostosis) which causes the premature fusing of the bones in the skull.
This premature fusion in turn affects the shape of the head and face. It does not, however, affect brain development and intellectual ability.
Acrocephalosyndactyly - type III Acrocephalosyndactyly type III Acrocephalosyndactyly, Type Iii; Acs3 Acrocephaly, Skull Asymmetry, And Mild Syndactyly Acs Iii ACSIII Chotzen Syndrome SCS
What gene changes cause Saethre-Chotzen syndrome (SCS)?
The syndrome is inherited and the result of mutations to the TWIST 1 gene. It is inherited in an autosomal dominant pattern.
In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.
What are the main symptoms of Saethre-Chotzen syndrome (SCS)?
Physical features of the syndrome include finger and toe webbing, small and unusually shaped ears, a short stature, abnormalities of bones in the spine, curving of the pinky finger, short fingers and toes and a flat head.
Unique facial features of the syndrome include a high forehead, asymmetry of the face, a beaked nose, wide-set eyes and a depressed bridge of the nose.
Possible clinical traits/features:
Narrow nose, Narrow palate, Lambdoidal craniosynostosis, Long nose, Low-set, posteriorly rotated ears, Low-set ears, Low anterior hairline, Microtia, Migraine, Increased intracranial pressure, Abnormal form of the vertebral bodies, Intellectual disability, moderate, Hypertelorism, Cognitive impairment, Hallux valgus, High forehead, Hearing impairment, Short stature, Visual impairment, Hypoplasia of the maxilla, Clinodactyly of the 5th finger, Cleft palate, Malformation of the heart and great vessels, Cryptorchidism, Craniosynostosis, Coronal craniosynostosis, Delayed cranial suture closure, Conductive hearing impairment, Facial asymmetry, Finger syndactyly, Flat forehead, External ear malformation, Atresia of the external auditory canal, Malar flattening, Brachydactyly, Absent first metatarsal, Apnea, Breast carcinoma, Brachycephaly, Buphthalmos, Convex nasal ridge, Cleft of chin, Abnormality of pelvic girdle bone morphology, Abnormal nasolacrimal system morphology, Autosomal dominant inheritance, Plagiocepha
How does someone get tested for Saethre-Chotzen syndrome (SCS)?
The initial testing for Saethre-Chotzen syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical information on Saethre-Chotzen Syndrome
This form of acrocephalosyndactyly was well reviewed by Pantke et al., (1975). It is characterised by asymmetric facies, brachycephaly, parietal foramina, a broad forehead, ptosis, a beaked nose, loss of the frontonasal angle, low-set ears with folded pinnae and prominent cruri, and minor abnormalities of the hands and feet. The latter consist of soft tissue syndactyly, mild brachydactyly, clinodactyly and hallux valgus. The hallux can be quite broad but is not in varus as seen in Pfeiffer syndrome. Some cases are mistakenly reported as Pfeiffer syndrome because of the broad halluces (see Naveh and Friedman, (1976) for example). Mild mental retardation may be present and craniostenosis can be demonstrated in about 90% of patients.
Cases with 7p21 deletions have many similarities including craniosynostosis and parietal foramina (see Motegi et al., (1985), Kikkawa et al., (1993) and Chotai et al., (1994) for good reviews). The case reported by Grebe et al., (1992) with a 7p15.3-p21.2 or 7p21.3 deletion had many similarities. Note that there may be a gene more proximal to 7p21 that also causes craniosynostosis (Aughton et al., 1991). This gene is probably distinct from the Greig syndrome gene at 7p13. Van Allen et al., (1992) discuss the evidence for a 'craniosynostosis gene' on 15q. They point out that in the mouse there are contiguous homologous regions to human 7p and 15q on mouse chromosome 2, suggesting a cluster of genes important in suture formation in the mouse that has become separated in the human. Zollino et al., (1999) report other cases with a duplication of 15q25.1-qter associated with craniosynostosis. There may be another gene for coronal craniosynostosis on 8q (Fryburg and Golden, 1993). Brueton et al., (1992) found evidence of linkage to markers around 7p21 in Saethre-Chotzen families. Refined localisation was reported by Lewanda et al., (1994) and van Herwerden et al., (1994). Reardon et al., (1993) identified a de novo translocation case with breakpoints at 7p21.2; Reid et al., (1993) similarly identified a translocation case with breakpoints at 7p22. Tsuji et al., (1994) reported a further case with an apparently balanced 6;7 translocation. The breakpoints on 7 were reported as 7p15.3. The explanation for the discrepancy between these breakpoints is not clear. Ma et al., (1996) carried out further linkage studies and discussed the evidence for possibly two loci on 7p. Rose et al., (1994) carried out FISH studies using YACs from the 7p21 region in four translocation cases, including that of Reardon et al., (1993). Wilkie et al., (1995) described the clinical features of the cases in the paper of Rose et al., (1994) in detail. Von Gernet et al., (1996) reported a four-generation family where at least seven individuals have convincing features of Saethre-Chotzen syndrome, but the locus does not appear to map to 7p. Howard et al., (1997) and El Ghouzzi et al., (1997) described mutations in the TWIST gene, which codes for a basic helix-loop-helix transcription factor. Nonsense, missense, insertion and deletion mutations were described. Some of the insertions were in a region of the gene encoding a glycine-rich sequence (Gly)5Ala(Gly)5. However, Elanko et al., (2001) suggest that either deletion of 18 nucleotides or insertion of 3, 15 or 21 nucleotides may be low-frequency polymorphisms without pathological significance. Krebs et al., (1997) showed a breakpoint in a translocation case first reported by Tsuji et al., (1984) mapping 5 kb 3 ' from TWIST, suggesting a positional effect. Further mutations were reported by El Ghouzzi et al., (1999). Further mutations in the TWIST gene were reported by Rose et al., (1997), including 3 cases with a 21bp duplication. Four translocation cases were also examined, and the breakpoints were at least 5kb from TWIST, suggesting a positional effect. Johnson et al., (1998) studied ten patients with Saethre-Chotzen syndrome and found mutations in eight. They also found mutations in two patients out of 43 cases with no clear diagnostic label. Of the ten mutations, four represented significant deletions, one in a 7;8 balanced translocation case. Paznekas et al., (1998) studied 32 cases with a Saethre-Chotzen phenotype and found TWIST mutations in twelve. A Pro250Arg mutation of the FGFR3 gene was found in seven cases and a 6-bp in-frame deletion of the IgII, IgIII linker region of the FGFR2 gene was found in one family. Gripp et al., (1999) reported a case with a stop mutation in TWIST where there was radial aplasia.
El-Ghouzzi et al., (2000) presented evidence suggesting that TWIST mutations resulted in protein degradation or abnormal sub-cellular localisation.
Seto et al., (2001) reported a father and son. The father had very mild features of Saethre-Chotzen syndrome, whereas the son had coronal, metopic and sagittal synostosis together with bilateral radial ray aplasia with an absent thumb on the right. An A466G leading to an Ile156Val substitution was detected. The cases of Gripp et al., (1999) and Seto et al., (2001) have overlap with Baller-Gerold syndrome. Boeck et al., (2001) reported a mother and son with a condition where there was an 11 bp deletion (127del11). The son had recurrent infections and hyper IgE. However, this was not seen in the mother. Two other cases had a large deletion (3.5-10.2Mb) and were associated with developmental delay. Further cases with submicroscopic deletions involving the TWIST gene were reported by Gripp et al., (2001). The family reported by Maw et al., (1996) with an atypical form of Blepharophimosis-ptosis-epicanthus inversus syndrome mapping to 7p13-7p21 have now been found to carry a TWIST mutation (Dollfus et al., 2001).
Chun et al., (2002) studied nine families and FGFR3 Pro250Arg mutations in four cases, TWIST mutations in three cases and a deletion involving the TWIST gene in two cases. Cai et al., (2003) studied 55 patients with features of Saethre-Chotzen syndrome, 11% were detected to have deletions by real-time gene dosage analysis. Two patients had a translocation or inversion at least 260 kb 3' of the gene, suggesting they had position-effect mutations. Of the 37 patients with classic features of Saethre-Chotzen syndrome, the overall detection rate for TWIST mutations was 68%. The risk for developmental delay in patients with deletions involving the TWIST gene was approximately 90%. Gripp et al., (2003) comment that anal atresia may be a low-frequency association.
De Heer et al., (2004), reported an interesting family with many features of BPES (see elsewhere). Two had a craniosynostosis, and they turned out to have TWIST mutations as found in Saethre-Chotzen syndrome. Of 47 patients with unilateral coronal synostosis studied by Mulliken et al., (2004), 3 had TWIST mutations, and 2 had FGFR2 mutations. Another FGFR2 mutation was found by Burrone de Freitas et al., (2006), but this family is more likely to have Pfeifer syndrome.
Corsi et al., (2002) studied a semi-dominant allele in the TWIST gene in C.elegans and showed possible dominant negative activity. Similar phenotypes were caused when amino acid substitutions in the DNA binding domain of the protein, associated with Saethre-Chotzen syndrome were engineered into the C.elegans protein. TWIST has been shown to promote tumour growth, so note the case of Saethre-Chotzen reported by Seifert et al., (2006) with a renal cell carcinoma.
Shimada et al. (2013) described a male with Saethre-Chotzen syndrome and microdeletions of 5.5 Mb (4q13.2–q13.3) and 4.1 Mb (7p15.3–p21.1, including TWIST1) with a Saethre–Chotzen-like phenotype, severe intellectual disability and autism. Clinical characteristics were developmental delay, autistic behavior, brachycephalic and acrocephalic head, facial asymmetry, high and narrow forehead, sparse and arched eyebrows, hypertelorism, bilateral blepharophimosis and ptosis, epicanthus inversus, strabismus, depressed and deviated nasal bridge, anteverted nares, maxillary hypoplasia, low set and posteriorly angulated ear with uplifted lobe and prominent crus helices and cutaneous syndactyly between 2nd and 3rd fingers.
Cho et al. (2013) described a male with Saethre-Chotzen syndrome and a148 kb deletion in 7p21.1 region comprising TWIST1 gene. Clinical features were microcephaly, delayed development, hypertelorism, frontal bossing, low-set ears, small pinna with prominent crura, high-arched palate, and single transverse crease on the left hand, but no other limb anomalies. Brain MRI showed fusion of the left coronal and metopic sutures.
Shimbo et al. (2017) reported a male with Saethre-Chotzen syndrome and a de novo 0.9-Mb microdeletion in 7p21 region including TWIST1, NPMIP13, FERD3L, TWISTNB, and HDAC9 genes. Clinical characteristics were unilateral craniosynostosis, plagiocephaly, brachycephaly, wide anterior fontanelle, mild developmental delay, facial asymmetry, low-set frontal hairline, ptosis, hypertelorism, posteriorly rotated ears, mild syndactyly, and cleft palate.
Zhou et. al. (2018) described two unrelated patients with heterozygous mutations in the 5′ untranslated region of the TWIST1 gene. Clinical characteristics did not differ from previously reported.
* This information is courtesy of the L M D.
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