Clinical characteristics: Classic Saethre-Chotzen syndrome (SCS) is characterized by coronal synostosis (unilateral or bilateral), facial asymmetry (particularly in individuals with unicoronal synostosis), strabismus, ptosis, and characteristic appearance of the ear (small pinna with a prominent superior and/or inferior crus). Syndactyly of digits two and three of the hand is variably present. Cognitive development is usually normal, although those with a large genomic deletion are at an increased risk for intellectual challenges. Less common manifestations of SCS include other skeletal findings (parietal foramina, vertebral segmentation defects, radioulnar synostosis, maxillary hypoplasia, ocular hypertelorism, hallux valgus, duplicated or curved distal hallux), hypertelorism, palatal anomalies, obstructive sleep apnea, increased intracranial pressure, short stature, and congenital heart malformations.
Diagnosis/testing: The diagnosis of SCS is established in a proband with typical clinical findings and a heterozygous pathogenic (or likely pathogenic) variant in TWIST1 identified by molecular genetic testing.
Management: Treatment of manifestations: Ongoing management by an established craniofacial team which may include cranioplasty in the first year of life and midface surgery in childhood as needed for dental malocclusion, swallowing difficulties, and respiratory problems. If a cleft palate is present, surgical repair usually follows cranioplasty. As needed: orthodontic treatment and/or orthognathic surgery at the completion of facial growth; developmental intervention; routine treatment of hearing loss; ophthalmologic evaluation and, if ptosis is present, intervention to prevent amblyopia, with surgical repair during early childhood as needed.
Surveillance: Annual ophthalmologic evaluation for papilledema; brain imaging for additional evaluation when there is evidence of increased intracranial pressure; clinical examination for facial asymmetry as needed; annual speech evaluation starting at age 12 months in those with a cleft palate. Audiology evaluations every 6-12 months; annual clinical evaluation for sleep-disordered breathing and developmental delays.
Agents/circumstances to avoid: If cervical spine abnormality with instability is present in an individual, activities that put the spine at risk should be limited.
Genetic counseling: SCS is inherited in an autosomal dominant manner. Many individuals diagnosed with SCS have an affected parent; the proportion of cases caused by a de novo pathogenic variant is unknown. The family history of some individuals diagnosed with SCS may appear to be negative because of failure to recognize the disorder in family members (wide phenotypic variability is observed within families with SCS) or reduced penetrance. Each child of an individual with SCS has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible if the pathogenic variant has been identified in the family.
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