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Saethre-Chotzen syndrome

Orpha number ORPHA794
Synonym(s) ACS3
Acrocephalosyndactyly type 3
SCS
Prevalence 1-9 / 100 000
Inheritance
  • Autosomal dominant
Age of onset Neonatal/infancy
ICD-10
  • Q87.0
OMIM
UMLS
  • C0175699
MeSH -
MedDRA -
SNOMED CT
  • 83015004

Summary

Saethre-Chotzen syndrome (SCS) is an inherited craniosynostosis syndrome characterized by unilateral or bilateral coronal synostosis, facial asymmetry, ptosis, strabismus and small ears with prominent crus, among other less common manifestations.

Prevalence ranges from 1/25,000 to 1/50,000 births.

SCS has a variable spectrum of manifestations. Classic SCS presents at birth with synostosis of coronal (or less commonly sagittal, metopic or lambdoid) sutures resulting in abnormal skull shape, facial asymmetry, low frontal hairline, ptosis, strabismus, tear duct stenosis and small ears with prominent crus. Brachydactyly, broad toes, partial cutaneous syndactyly of digits 2 and 3 of the hand, duplicated distal phalanx of the hallux are also often present. Intelligence is normal in most, but mild to severe developmental delay has been reported. Some may experience conductive and/or sensorineural hearing loss during childhood. Less common manifestations include short stature, hypertelorism, cleft palate, bifid uvula, maxillary hypoplasia, vertebral anomalies, obstructive sleep apnea and congenital heart malformations. Vertebral fusions and scoliosis occur in rare cases. A severe phenotype with craniosynostosis, vertebral segmentation defects and radial ray hypoplasia/agenesis has been reported. Mild phenotypes include patients with ptosis or blepharophimosis with or without craniosynostosis and Robinow-Sorauf syndrome (see this term). Elevated intracranial pressure (ICP) associated with severe cases of synostosis may lead to headaches, visual loss, seizures and death if untreated.

SCS is due to point mutations or deletions involving (or removing completely) the TWIST1 gene (7p21), which encodes a basic helix-loop-helix (bHLH) transcription factor responsible for cell lineage determination and differentiation. Loss of function mutations in this gene lead to the induction of premature cranial suture fusion. Gene deletions cause more severe phenotypes, usually associated with significant neurocognitive delays. Mutations in FGFR3, FGFR2 and TCF12 have been reported to cause synostosis conditions that phenotypically overlap with SCS.

Diagnosis is based mainly on the presence of characteristic clinical findings. CT of the head and radiographs are useful in characterizing abnormalities of the skull, spine and limbs. Molecular genetic testing can identify a TWIST1 mutation or deletion, confirming diagnosis.

Although several features (such as 2-3 syndactyly of the hand) are unique to SCS, differential diagnoses include other syndromic forms of craniosynostosis such as Muenke, Baller-Gerold, Pfeiffer, and Crouzon syndromes (see these terms) as well as isolated unilateral coronal synostosis.

Prenatal testing for a TWIST1 mutation is rare, but it can be performed in families with a known mutation or when an ultrasound shows craniosynostosis of unknown etiology.

SCS is inherited as an autosomal dominant trait. Genetic counseling is valuable.

Treatment of SCS requires management by a craniofacial team with follow-up until young adulthood. In general, patients must undergo a cranioplasty in the first year of life to increase the intracranial volume and restore a more normal head shape. Recurrent increased ICP may necessitate further surgical expansion procedures. In childhood, midfacial surgery may be necessary for treatment of airway obstruction and malocclusion. In those with cleft palate, surgical closure can be performed in the context of other malformations and speech therapy offered as necessary. Routine evaluations of facial growth, hearing loss and psychomotor development are needed as well as regular ophthalmologic examinations to monitor strabismus, amblyopia or chronic papilledema (that indicates increased ICP). Early intervention programs should be offered to children with developmental delay.

In most cases, when treated and monitored from an early age, the prognosis is excellent.

Expert reviewer(s)

  • Pr Michael CUNNINGHAM

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Detailed information

Summary information
Clinical genetics review
  • EN (2012)
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