Saethre-Chotzen Syndrome (SCS) is also known as acrocephalosyndactyly type III. It is a syndrome characterized by craniofacial abnormalities along with neurological, skeletal, and cardiac defects. The ICD-10 code is Q87.0.
The prevalence is estimated at 1 in 25,000 to 50,000 births. There is no gender difference, and it follows an autosomal dominant inheritance pattern. Due to the wide phenotypic variability, it may be underdiagnosed.
Many individuals have an affected parent, but de novo mutations are also observed. Intelligence is usually normal, but mild to moderate intellectual disability, epilepsy, and schizophrenia have been reported.
QIs Saethre-Chotzen syndrome a genetic disease?
A
It is autosomal dominant, so if a parent is affected, the risk of inheritance to a child is 50%. However, de novo mutations also occur, so it can occur without a family history. Genetic counseling is recommended.
Because this is a congenital condition, subjective symptoms are often noticed by parents during infancy.
Visual field limitation due to ptosis: The upper visual field is obstructed, and the patient may adopt a compensatory head posture with the chin raised.
Decreased visual acuity: Associated with amblyopia and refractive errors.
Abnormal head posture due to strabismus: An abnormal head posture to avoid double vision.
Ptosis: Prevalence 59–82% (varies by study). Caused by dysfunction or agenesis of the levator palpebrae superioris muscle.
Strabismus: Present in >50%. V-pattern exotropia (exotropia increases on upgaze) is common. Vertical strabismus is seen in about 60%. Often accompanied by over-elevation in adduction (pseudo-inferior oblique overaction).
Telecanthus: Inner canthal distance ≥65% of interpupillary distance (ocular hypertelorism).
Systemic Findings
Craniosynostosis: The coronal suture is most commonly affected (74% have brachycephaly), causing facial asymmetry.
Ear abnormalities: Small, low-set ears with posterior rotation and prominent helical crura. Conductive, mixed, or sensorineural hearing loss may occur.
Skeletal abnormalities: Cutaneous syndactyly (especially of the second interdigital space), brachydactyly, hallux valgus.
Other ophthalmic findings include monocular upgaze palsy, rotary nystagmus, extraocular muscle defects, lower eyelid entropion, lacrimal duct stenosis, downslanting palpebral fissures, and epicanthal folds. Superior oblique dysfunction may occur on the same side as the fused coronal suture.
QWhat is the most common ocular abnormality in Saethre-Chotzen syndrome?
A
Ptosis is the most common finding, occurring in up to 90% of patients. Strabismus (more than 50%) is also frequent, with V-pattern strabismus being characteristic. These can cause amblyopia, so early ophthalmologic evaluation and intervention are important.
The causative gene is TWIST1 (7p21.1), and over 100 mutations have been identified. Haploinsufficiency (loss of function of one allele) is the pathogenesis, and mutation types such as missense and point mutations are diverse.
TWIST1 is a transcription factor essential for the formation of head mesenchyme. Qualitative or quantitative defects in its product cause premature fusion of cranial sutures.
The remarkable diversity of mutations reflects the variability in phenotype. Patients with TWIST1 gene deletions have a higher frequency of intellectual disability than those with point mutations.
Diagnoses of Hodgkin disease, testicular cancer, and nasopharyngeal carcinoma have been reported in several families of patients with Saethre-Chotzen syndrome.
QDoes the severity differ between TWIST1 gene deletions and mutations?
A
Patients with TWIST1 gene deletions (large chromosomal deletions) are known to have a higher frequency of intellectual disability compared to those with point mutations. The relationship between mutation type and phenotype is complex, and individual assessment through genetic testing and genetic counseling is important.
Diagnosis begins with medical history and physical examination. However, there is no single pathognomonic feature, and definitive diagnosis based solely on clinical features is difficult.
Genetic testing is essential for a definitive diagnosis, and most patients have mutations in the TWIST1 gene. Patients with craniosynostosis accompanied by syndactyly and clinodactyly should undergo complete genetic testing. If molecular targeted testing is normal and inconsistent with clinical findings, consider karyotyping.
Prenatal diagnosis: Ultrasound is available from 19 weeks (to assess irregular fetal skull shape) but cannot provide a definitive diagnosis. Genetic testing is offered if there is a family history or suspicious findings.
Imaging: Orbital MRI (T2 fast spin-echo, direct coronal view) visualizes the extraocular muscles and guides surgical planning. Brain MRI is also performed if increased intracranial pressure is suspected.
Ophthalmic examination: Sensorimotor function testing, strabismus assessment in primary gaze (to identify V-pattern strabismus), measurement of MRD1 and levator function, and dilated fundus examination (to check for optic disc edema) are performed.
The recommended schedule for regular comprehensive ophthalmic evaluations is as follows:
At diagnosis: Perform initial comprehensive evaluation
Before and after craniofacial surgery: Ophthalmic evaluation at each time point
Until 7–9 years of age: Every six months
Until adolescence: Annually
Evaluation items include strabismus, amblyopia, refractive error, keratopathy, optic neuropathy, nasolacrimal duct obstruction, optic disc edema, and ptosis. Dilated fundus examination is essential due to the high prevalence of elevated intracranial pressure.
Amblyopia prevention: Children with clinically significant ptosis or strabismus should receive early treatment with occlusion therapy or surgery.
Timing of strabismus surgery: There are two schools of thought. Some studies suggest that waiting until after craniofacial surgery reduces the likelihood of additional corrective surgery, while others indicate that early strabismus surgery may improve binocular vision, outweighing the risk of future anatomical changes. Individualized decision-making is required.
Ptosis: Due to dysfunction or absence of the levator palpebrae superioris muscle, surgical indication based on functional assessment (MRD1 and levator function) is important.
Cranial expansion surgery: Performed at 9–12 months of age. Addresses increased intracranial pressure and ensures brain growth.
Airway and nutritional management: Management of oral intake difficulties due to facial abnormalities is initiated immediately after birth.
Childhood and beyond
Closure of full-thickness cranial defects: Surgery performed by 3–4 years of age.
Correction of midface hypoplasia: Performed in late childhood to early adolescence.
Additional cranial volume expansion: Performed when further increase in cranial volume is needed.
Postoperatively, ophthalmologic follow-up is performed after 2 months to check for exposure keratopathy and proptosis. For exposure keratopathy, corneal protection is provided with eye drops and ointments. If lagophthalmos is severe and spontaneous eyelid closure is impossible, consider nighttime taping for eyelid closure; in severe cases, temporary tarsorrhaphy may also be considered.
Hearing: Perform regular hearing tests and consider bilateral hearing aids or cochlear implantation.
Heart: Regular cardiac examinations.
Sleep: Screening for sleep apnea.
Development: Screening for musculoskeletal abnormalities and developmental delay.
QWhen is the best time to perform surgery for strabismus or ptosis?
A
For strabismus surgery, some studies suggest that waiting until after craniofacial surgery reduces the likelihood of additional corrective surgery, while others believe the benefit of early surgery for binocular vision improvement outweighs the risk of future anatomical changes; there is no uniform standard. Ptosis surgery is decided based on levator function assessment (MRD1 and levator function). From the perspective of amblyopia prevention, early intervention is recommended when clinically significant.
The TWIST1 gene encodes a bHLH (basic helix-loop-helix) transcription factor and plays an essential role in the formation of the cranial mesenchyme.
Haploinsufficiency is the main pathogenic mechanism. Loss of function of one allele of TWIST1 causes qualitative and quantitative impairment of the protein product. This abnormally promotes osteoblast differentiation in the cranial sutures, leading to premature suture fusion.
More than 100 mutations have been identified, including missense mutations, point mutations, and deletions. This diversity of mutations reflects the variability in phenotypes. TWIST1 deletions (large chromosomal deletions) are associated with a higher frequency of intellectual disability than TWIST1 point mutations, indicating a genotype-phenotype correlation.
Mechanism of strabismus: V-pattern strabismus is common. Dysfunction of the superior oblique muscle ipsilateral to the fused coronal suture is involved, and agenesis of extraocular muscles has also been reported. Overelevation in adduction is thought to be due to pseudo-inferior oblique overaction (abnormal position of the orbital pulley). Mouse models have shown that conditional inactivation of TWIST1 disrupts the tissue architecture of extraocular muscles and causes abnormal tendon formation at the origin and insertion, suggesting that strabismus in patients with TWIST1 mutations may be directly due to abnormal development of extraocular muscles.
Mechanism of ptosis: Caused by dysfunction or agenesis of the levator palpebrae superioris muscle. Severity ranges from simple levator weakness to complete muscle absence.
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