Saethre-Chotzen syndrome

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Disease entity

Saethre-Chotzen syndrome. ICD-10: Q87.0.


Also known as acrocephalosyndactyly type III, Saethre-Chotzen syndrome (SCS) is characterized by craniofacial abnormalities in conjunction with neurological, skeletal, and cardiac defects. Although the specific phenotypic categorization of SCS remains unclear, characteristics that are typically observed in the condition include coronal craniosynostosis, facial asymmetry, hypertelorism, and maxillary hypoplasia.[1] Other characteristic criteria, although less common, include low-set frontal hairline, strabismus, eye lid ptosis, small palpebral fissures, digital webbing, and prominent helical crura.[1][2] [3]


Based on murine and human genetic analyses, the phenotypic variation in SCS has been attributed to mutations in the TWIST 1 gene. Although the specific mutation e.g., missense, point, etc., may differ, it is likely that ensuing haploinsufficiency is the underlying etiological mechanism.[2][4] TWIST 1 is speculated to play an essential role in the formation of the head mesenchyme and as such, qualitative or quantitative impairment of the protein product leads to the observed craniosynostosis.[5]


The prevalence of SCS is estimated to range from 1 in 25,000 to 1 in 50,000 live births, although this is probably underestimated due to extensive phenotypic variability.[1][6] Occurrence is equal in males and females.[7] Given that this is an autosomal dominant condition, many individuals have an affected parent. However, although rarer, de novo mutations have also been observed.[8]


Diagnosis of SCS is founded primarily on history and physical examination.


Classically, patients will present with typical clinical findings such as craniosynostosis. Given its autosomal dominant inheritance, patients will often have a familial history of related, albeit perhaps less severe, clinical findings e.g., abnormal skull shape.

Physical examination

Physical examination is an integral component of the diagnosis of SCS.

Eyes: Commonly observed aberrations include strabismus, ptosis, amblyopia, and lacrimal duct stenosis.

With regards to conditions that cause craniosynostosis, horizontal strabismus is the most common extraocular motility problem observed. Most patients specifically present with the V pattern, especially when horizontal strabismus co-occurs with exotropia.[9] A variety of mechanisms have been proposed to explain this phenomenon including increased excyclorotation of ocular adductor muscles and sagittalization of the oblique muscles.[10] [11]

Vertical strabismus is another commonly noted abnormality with Jadico, et al. observing it in approximately 60% of their patients with SCS.[9]

Ptosis is commonly reported in patients, although the exact prevalence has varied in studies, ranging from 59% to 82% of patients.[6][12]

Other observed ocular characteristics include astigmatism, amblyopia, myopia/hyperopia, double elevator palsy, rotary nystagmus, extraocular muscle agenesis, and lower lid entropion.[9] Finally, one significant consideration in patients with SCS is an increased probability of optic nerve damage due to a high risk of intracranial hypertension.[2]

Ear: SCS characteristically presents with small, low-set ears that are posteriorly rotated and have prominent crura.[5] Conductive, mixed, and sensorineural hearing deficits may also be present.[13]

Face: Dysmorphic facial findings are a major feature of SCS with typical abnormalities that include facial asymmetry, hypertelorism, and maxillary hypoplasia. Less frequently observed characteristics are a high forehead, low-set frontal hairline, and deviated nasal septum.[1][5]

Musculoskeletal: Commonly noted defects in the skull include craniosynostosis and dilated parietal foramina. Potential limb abnormalities include brachydactyly, cutaneous syndactyly, particularly of the second interdigital space, hallux valgus with bifid distal phalanx, and triangular-shaped epiphyses of the hallux.[1] [2] [5] [14]

Other systems: Orthodontic, cardiac, and neurological problems have also been documented in patients with SCS.[2][15] [16]

Diagnostic procedures

Diagnosis of SCS is primarily clinical, although diagnostic tests are useful for confirmation. Given that most patients have mutations in the TWIST gene, genetic evaluations are integral.[17] Even if the ophthalmologist, or clinician, does not already suspect SCS, patients with craniosynostosis and syndactyly or clinodactyly need to be provided a complete genetic workup. Where SCS is presumed despite normal molecular testing and clinically inconsistent findings, karyotyping should be a consideration.[18] [19]

Ultrasound may be utilized as early as the 19th week to assess for the presence of diagnostic markers such as an irregularly shaped fetal skull, which may be indicative of coronal synostosis. However, given the phenotypic variability of the condition, ultrasound cannot provide a definitive diagnosis. If SCS is suspected prenatally, either due to familial history or suspicious sonographic findings, genetic testing should be offered to families.[20]

Differential diagnosis

Muenke syndrome: Patients may present with features clinically similar to SCS. However, some work has been done to differentiate between the two, with patients with Muenke syndrome having a higher incidence of intellectual disabilities and patients with SCS having a higher incidence of intracranial hypertension and clinically significant ptosis.[2]

Isolated unilateral coronal synostosis: Patients who have this abnormality may develop facial asymmetry if not treated.

Baller-Gerold syndrome: Individuals with this condition have bilateral craniosynostosis with brachycephaly. However, they typically additionally present with proptosis and poikiloderma.[21]

Management and treatment

Given the variety of systems implicated in SCS, a multidisciplinary approach is required for the appropriate management and treatment of this condition. Pediatricians, ophthalmologists, otolaryngologists, and orthopedists should be consulted for comprehensive evaluation and development of a treatment plan for these patients.

Immediate post-natal care

Post-natal care is centered around immediate treatment of airway-related issues, if applicable in that specific case. Nutrition may also be of concern, particularly if facial abnormalities prevent requisite oral intake.

Ophthalmological considerations

Because ophthalmological issues are common within this patient population, routine comprehensive evaluations with an ophthalmologist are indicated. These include assessing for strabismus, amblyopia, nasolacrimal outflow abnormalities, papilledema, and ptosis. Dilated fundoscopic examinations are integral within this population due to the greater prevalence of elevated intracranial pressure.[22] Children who have clinically significant ptosis or strabismus should be treated early and accordingly to prevent amblyopia, either using patching or surgery. There is some debate as to when it is most appropriate to conduct oculoplastic repair for these disorders, although it generally appears that waiting until after craniofacial surgery reduces the likelihood of having to conduct further corrective operations.[9][22]

Craniofacial considerations

Given the possibility of elevated intracranial pressure in patients with SCS, surgical treatment to address this may be necessary within the first year of life. Cranial vault expansion, which is needed to enable appropriate brain growth, traditionally occurs between 9 and 12 months of age. Further corrective procedures may be necessary to further increase cranial volume. And by the age of 3 or 4, surgery can be utilized to close remaining full-thickness cranial defects. If required, patients may also receive corrective surgery for midface hypoplasia during late childhood or early adolescence.[23]

General considerations

Management and treatment of other concerns such as ocular, auditory, cardiac, developmental, etc., also necessitate consideration. Audiologic examination for hearing loss is indicated in these patients. If needed, they are treated in the standard manner using binaural amplification or possibly cochlear implantation.[13] Other routine assessments include a routine cardiac exam, examining for sleep apnea, and screening for musculoskeletal anomalies and developmental delays.[21]


  1. 1.0 1.1 1.2 1.3 1.4 Howard TD, Paznekas WA, Green ED, et al. Mutations in TWIST, a basic helix-loop-helix transcription factor, in Saethre-Chotzen syndrome. Nat Genet. 1997;15(1):36-41. doi:10.1038/ng0197-36
  2. 2.0 2.1 2.2 2.3 2.4 2.5 Kress W, Schropp C, Lieb G, et al. Saethre-Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome. Eur J Hum Genet. 2006;14(1):39-48. doi:10.1038/sj.ejhg.5201507
  3. Pantke OA, Cohen MM Jr, Witkop CJ Jr, et al. The Saethre-Chotzen syndrome. Birth Defects Orig Artic Ser. 1975;11(2):190-225.
  4. El Ghouzzi V, Legeai-Mallet L, Aresta S, et al. Saethre-Chotzen mutations cause TWIST protein degradation or impaired nuclear location. Hum Mol Genet. 2000;9(5):813-819. doi:10.1093/hmg/9.5.813
  5. 5.0 5.1 5.2 5.3 El Ghouzzi V, Le Merrer M, Perrin-Schmitt F, et al. Mutations of the TWIST gene in the Saethre-Chotzen syndrome. Nat Genet. 1997;15(1):42-46. doi:10.1038/ng0197-42
  6. 6.0 6.1 Paznekas WA, Cunningham ML, Howard TD, et al. Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations. Am J Hum Genet. 1998;62(6):1370-1380. doi:10.1086/301855
  7. Chun K, Teebi AS, Jung JH, et al. Genetic analysis of patients with the Saethre-Chotzen phenotype. Am J Med Genet. 2002;110(2):136-143. doi:10.1002/ajmg.10400
  8. Clauser L, Galiè M, Hassanipour A, Calabrese O. Saethre-Chotzen syndrome: review of the literature and report of a case. J Craniofac Surg. 2000;11(5):480-486. doi:10.1097/00001665-200011050-00007
  9. 9.0 9.1 9.2 9.3 Jadico SK, Huebner A, McDonald-McGinn DM, Zackai EH, Young TL. Ocular phenotype correlations in patients with TWIST versus FGFR3 genetic mutations. J AAPOS. 2006;10(5):435-444. doi:10.1016/j.jaapos.2006.06.008
  10. Tan KP, Sargent MA, Poskitt KJ, Lyons CJ. Ocular overelevation in adduction in craniosynostosis: is it the result of excyclorotation of the extraocular muscles?. J AAPOS. 2005;9(6):550-557. doi:10.1016/j.jaapos.2005.07.004
  11. Gobin MH. Sagittalization of the oblique muscles as a possible cause for the "A", "V", and "X" phenomena. Br J Ophthalmol. 1968;52(1):13-18. doi:10.1136/bjo.52.1.13
  12. Foo R, Guo Y, McDonald-McGinn DM, Zackai EH, Whitaker LA, Bartlett SP. The natural history of patients treated for TWIST1-confirmed Saethre-Chotzen syndrome. Plast Reconstr Surg. 2009;124(6):2085-2095. doi:10.1097/PRS.0b013e3181bf83ce
  13. 13.0 13.1 Lee S, Seto M, Sie K, Cunningham M. A child with Saethre-Chotzen syndrome, sensorineural hearing loss, and a TWIST mutation. Cleft Palate Craniofac J. 2002;39(1):110-114. doi:10.1597/1545-1569_2002_039_0110_acwscs_2.0.co_2
  14. Trusen A, Beissert M, Collmann H, Darge K. The pattern of skeletal anomalies in the cervical spine, hands and feet in patients with Saethre-Chotzen syndrome and Muenke-type mutation. Pediatr Radiol. 2003;33(3):168-172. doi:10.1007/s00247-002-0823-3
  15. Molpeceres, R. G., Rodriguez, E. U., García, H. G., Vázquez, M. A., Sanz, J. L., & Guisasola, F. J. A rare case of acrocephaly: Saethre-Chotzen syndrome or Crouzon? Case Reports in Perinatal Medicine. 2016;5(2):151-155. doi:10.1515/crpm-2015-0057
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  18. Shetty S, Boycott KM, Gillan TL, et al. Cytogenetic and molecular characterization of a de-novo cryptic deletion of 7p21 associated with an apparently balanced translocation and complex craniosynostosis. Clin Dysmorphol. 2007;16(4):253-256. doi:10.1097/MCD.0b013e3281e668eb
  19. Touliatou V, Mavrou A, Kolialexi A, Kanavakis E, Kitsiou-Tzeli S. Saethre-Chotzen syndrome with severe developmental delay associated with deletion of chromosomic region 7p15 --> pter. Genet Couns. 2007;18(3):295-301.
  20. Gebb J, Demasio K, Dar P. Prenatal sonographic diagnosis of familial Saethre-Chotzen syndrome. J Ultrasound Med. 2011;30(3):420-422. doi:10.7863/jum.2011.30.3.420
  21. 21.0 21.1 Gallagher ER, Ratisoontorn C, Cunningham ML. Saethre-Chotzen Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; May 16, 2003.
  22. 22.0 22.1 Revere K.E., Forbes B.J., Katowitz W.R., Katowitz J.A. Congenital Craniofacial Deformities: Ophthalmologic Considerations. In Katowitz J., Katowitz W. ed. Pediatric Oculoplastic Surgery. New York: Springer, Cham; 2018: 801-830.
  23. Buchanan EP, Xue AS, Hollier LH Jr. Craniofacial syndromes. Plast Reconstr Surg. 2014;134(1):128e-153e. doi:10.1097/PRS.0000000000000308