Saethre-Chotzen syndrome (ORPHA:794)
A syndrome characterized by unilateral or bilateral coronal synostosis, facial asymmetry, ptosis, strabismus and small ears with prominent superior and/or inferior crus, among other less common manifestations.
Epidemiology
Saethre-Chotzen syndrome (SCS) prevalence ranges from 1/25,000 to 1/50,000 livebirths.
Clinical description
SCS has a variable spectrum of manifestations. Classic SCS presents at birth with synostosis of coronal (less commonly in conjunction with 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, primarily in cases with a large genomic deletion. Some may experience conductive and/or sensorineural hearing loss. Less common manifestations include short stature, hypertelorism, cleft palate, bifid uvula, maxillary hypoplasia, lacrimal duct stenosis, parietal foramina, vertebral anomalies, radioulnar synostosis, obstructive sleep apnea and congenital heart malformations. Mild phenotypes include patients with ptosis or blepharophimosis with or without craniosynostosis. Elevated intracranial pressure (ICP) associated with severe cases of synostosis may lead to headaches, visual loss, seizures and death if untreated.
Etiology
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.
Diagnostic methods
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.
Differential 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 as well as isolated unilateral coronal synostosis. Robinow-Sorauf syndrome is now considered within the spectrum of SCS, typically with milder features. Mutations in FGFR3, FGFR2, TCF12, RECQL4, and EFNB1 have been reported to cause synostosis conditions that phenotypically overlap with SCS. This is not surprising, as there is evidence that FGFR and TWIST1 may be integrated into overlapping pathways, including in osteoblast differentiation. In addition, TWIST1 mutations have been noted in some cases of isolated single-suture craniosynostosis, including sagittal and unicoronal cases.
Antenatal diagnosis
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.
Genetic counseling
SCS is inherited as an autosomal dominant trait. Genetic counseling is valuable. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
Treatment of SCS requires management by a multidisciplinary craniofacial team with follow-up until young adulthood. In general, patients must undergo 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, orthodontic care and/or 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, with evaluation for velopharyngeal insufficiency 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. Augmentation of hearing and supportive interventions related to deafness should be pursued when indicated.
Prognosis
In most cases, when treated and monitored from an early age, the prognosis is excellent. Developmental prognosis is worse for patients with a TWIST1 deletion, compared to those with point mutations.

                            Last update: 
                            April 2020


                            - Expert reviewer(s): 
                            Dr Matthew BLESSING  - Dr Michael CUNNINGHAM