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Saethre-Chotzen syndrome (SCS)
O que é Saethre-Chotzen syndrome (SCS)?
Saethre-Chotzen é uma doença rara (craniossinostose) que causa a fusão prematura dos ossos do crânio.
Essa fusão prematura, por sua vez, afeta o formato da cabeça e do rosto. No entanto, não afeta o desenvolvimento do cérebro e a capacidade intelectual.
Acrocefalosindactilia - tipo III Acrocefalosindactilia tipo III Acrocefalosindactilia, Tipo Iii; Acrocefalia Acs3, assimetria de crânio e sindactilia leve Acs Iii ACSIII Chotzen Síndromes SCS
Quais mudanças genéticas causam Saethre-Chotzen syndrome (SCS)?
A síndromes é herdada e é o resultado de mutações no gene TWIST 1. É herdado em um padrão autossômico dominante.
No caso de herança autossômica dominante, apenas um dos pais é o portador da mutação do gene e eles têm 50% de chance de transmiti-la a cada um de seus filhos. As síndromes herdadas em uma herança autossômica dominante são causadas por apenas uma cópia da mutação do gene.
Quais são os principais sintomas de Saethre-Chotzen syndrome (SCS)?
Características físicas do síndromes incluem correias dos dedos das mãos e dos pés, orelhas pequenas e de formato incomum, baixa estatura, anormalidades nos ossos da coluna, curvatura do dedo mínimo, dedos das mãos e pés curtos e cabeça achatada.
Características faciais únicas do síndromes incluem testa alta, assimetria do rosto, nariz adunco, olhos arregalados e ponte do nariz deprimida.
Possíveis traços / características clínicas:
Nariz estreito, Palato estreito, craniossinostose lambdoidal, Nariz longo, implantação baixa, orelhas giradas posteriormente, orelhas implantadas baixas, linha do cabelo anterior baixa, Microtia, Enxaqueca, Pressão intracraniana aumentada, Forma anormal dos corpos vertebrais, Deficiência intelectual, moderada, Hipertelorismo , Comprometimento cognitivo, Hallux valgus, Testa alta, Deficiência auditiva, Baixa estatura, Deficiência visual, Hipoplasia da maxila, Clinodactilia do 5 dedo, Fenda palatina, Malformação do coração e grandes vasos, Criptocidismo, Craniossinostose, Craniossinostose coronária , Retardo no fechamento da sutura craniana, Deficiência auditiva condutiva, Assimetria facial, Sindactilia dos dedos, Testa plana, Malformação da orelha externa, Atresia do canal auditivo externo, Achatamento do malar, Braquidactilia, Primeiro metatarsal ausente, Apnéia, Carcinoma da mama, Braquicefalia nasal, Buphthalmos Cume, Fenda do queixo, Anormalidade da morfologia do osso da cintura pélvica, Morfologia do sistema nasolacrimal anormal, Domínio autossômico herança t, Plagiocefa
Como alguém faz o teste de Saethre-Chotzen syndrome (SCS)?
O teste inicial para a
Com base nesta consulta clínica com um geneticista, as diferentes opções para testes genéticos serão compartilhadas e o consentimento será solicitado para testes adicionais.
Informações médicas sobre Saethre-Chotzen Síndromes
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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