Craniosynostosis is a condition in which one or more cranial sutures fuse prematurely during fetal development or after birth. The prevalence is estimated at 1 in 1,400–2,100 births 4). Isolated, sporadic non-syndromic craniosynostosis accounts for about 85%, while the remaining 15% are part of a syndrome with other abnormalities 1).
There are approximately 200 known craniosynostosis syndromes, classified by the affected suture site and genetic mutation. Representative syndromes include:
Without treatment, it can lead not only to abnormal skull shape but also to neurological, visual, and respiratory complications.
There are about 200 known syndromes. Representative ones include Crouzon syndrome, Apert syndrome, Pfeiffer syndrome, and Muenke syndrome. They are classified by the affected suture site and causative gene.
Symptoms of craniosynostosis syndrome vary depending on the affected suture site and the timing of diagnosis. In infancy, caregivers often notice an abnormal skull shape.
Characteristic skull deformities occur depending on the affected suture.
Ophthalmic complications are one of the most important aspects of managing this group of disorders.
Crouzon Syndrome
Exorbitism: Present in nearly all cases; the most common ophthalmic manifestation.
Strabismus: Exotropia with loss of binocular vision is typical.
Midface hypoplasia: Associated with V-shaped palate and malocclusion2).
Limb abnormalities: None (differentiating point from Apert syndrome).
Apert syndrome
Syndactyly: Bony fusion of fingers and toes. Appears webbed8).
Acrocephaly: Abnormally tall and wide skull.
Developmental disability: More likely to present with severe intellectual disability than Crouzon syndrome.
Cause: FGFR2 gene mutation.
Pfeiffer syndrome
Broad thumbs and big toes: Characteristic limb findings.
Type 3 classification: Type 1 has good prognosis, type 2 has cloverleaf skull5), type 3 involves visceral malformations.
Severe proptosis: Prominent in types 2 and 3.
Prognosis: Types 2 and 3 often result in intrauterine death or early infant death5).
Craniosynostosis syndromes are primarily caused by genetic mutations. Most are autosomal dominant, requiring one copy of the mutated gene to manifest. A few are autosomal recessive. 30–60% are sporadic cases with no family history (de novo mutations)2).
The main causative genes and associated syndromes are listed below.
| Gene | Associated syndrome | Notes |
|---|---|---|
| FGFR2 | Crouzon, Apert, Pfeiffer | Most common causative gene |
| FGFR3 | Muenke, Crouzon with acanthosis nigricans | c.749C>G mutation is characteristic3) |
| FGFR1 | Pfeiffer type 1 | |
| TWIST1 | Saethre-Chotzen | |
| EFNB1 | Craniofrontonasal dysplasia |
FGFR (fibroblast growth factor receptor) normally functions to suppress excessive tissue growth. FGFR mutations in craniosynostosis syndromes are hypermorphic, meaning the function of the gene product is excessively enhanced. Despite the variety of mutations, the relatively similar phenotypic expression is an example of allelic heterogeneity.
In non-syndromic craniosynostosis, SMAD6 is the most frequently mutated gene as an inhibitor of the BMP signaling pathway, found in 6–7% of cases involving midline (sagittal or metopic) suture fusion 1). SMAD6 mutations show incomplete penetrance (approximately 24%), and the disease is thought to develop through digenic inheritance with a risk allele near the BMP2 gene 1).
Recently, BCL11B has gained attention as a new causative gene for craniosynostosis. A systematic review of 51 cases identified neurodevelopmental disorders (98%), characteristic facial features (98%), and immune dysregulation (93%) as three core features, with craniosynostosis observed in 12 cases 4).
Sporadic cases (de novo mutations) account for 30–60% of cases, so a child can develop the condition even if both parents are unaffected 2). However, if the inheritance pattern is autosomal dominant, an affected parent has a 50% chance of passing on the mutation.
It may be detected early by ultrasound. Findings such as ventriculomegaly, increased biparietal diameter, and cloverleaf skull provide clues. In Pfeiffer syndrome type 2, increased nuchal translucency (NT) in the first trimester has been reported as the earliest ultrasound finding 5). Preimplantation genetic diagnosis (PGD) is possible as a molecular genetic test, but the mutation must be identified in advance.
Muenke syndrome clinically resembles other craniosynostosis syndromes, so differentiation by FGFR3 genetic testing is important 3). Deformational plagiocephaly is a non-surgically treatable deformity without suture fusion, occurring in 5–45% of healthy infants, and must be distinguished from true craniosynostosis.
Treatment of craniosynostosis syndromes is multifaceted and individualized according to age, affected sutures, severity, and complications. Management requires a multidisciplinary team including facial plastic surgeons, neurosurgeons, pediatricians, otolaryngologists, orthodontists, and ophthalmologists (pediatric ophthalmologists and oculoplastic surgeons).
The main goal of treatment is to ensure cranial volume for the developing brain and minimize intracranial pressure. Early initiation of treatment is desirable.
Endoscopic surgery
Indication: Infants younger than 3 months of age.
Procedure: Release of fused sutures under endoscopic guidance through small scalp incisions (endoscopic craniectomy) 7).
Advantages: Small incisions, reduced blood loss, decreased need for transfusion, shorter hospital stay 7).
Postoperative: Custom-made helmet therapy is used 7).
Craniotomy
Indications: Infants aged 6 months or older.
Procedure: Calvarial vault remodeling. In fronto-orbital advancement (FOAR), the frontal and supraorbital bones are reshaped.
Features: The affected areas are moved to reshape the skull. Helmet therapy may be used if necessary.
For midface hypoplasia, midface advancement is performed after skeletal maturity (13–21 years of age).
Upper airway obstruction due to midface hypoplasia causes obstructive sleep apnea (OSA). Nasal resistance in children with Crouzon syndrome is significantly higher than normal2).
Continuous monitoring by a pediatric ophthalmologist is essential.
Endoscopic surgery is indicated before 3 months of age, and open surgery (cranial vault remodeling) after 6 months of age. Midface advancement is often performed between 13 and 21 years of age after permanent dentition is complete. Timing is determined by the severity of each case and associated complications.
Corneal protection for exposure keratopathy, evaluation and surgery for strabismus, correction of refractive errors, amblyopia treatment, and monitoring for papilledema and optic atrophy are necessary. Children with craniosynostosis syndromes require long-term ophthalmic follow-up.
FGFR (fibroblast growth factor receptor) belongs to the tyrosine kinase receptor family involved in cell proliferation, differentiation, and migration. Mutations in craniosynostosis syndromes overactivate FGFR function, enhancing downstream signals and promoting osteoblast differentiation, leading to premature fusion of cranial sutures 2). FGF/FGFR signaling plays important roles not only in cranial sutures but also in tracheal branching, lung development, limb formation, and angiogenesis 5).
In nonsyndromic midline craniosynostosis, abnormalities in the BMP signaling pathway are a major causative mechanism. The three signaling pathways—Wnt, BMP, and FGF/ERK—converge on nuclear regulators of osteoblast differentiation and are essential for the differentiation of cranial neural crest cells into cartilage and bone 1).
SMAD6 is a master regulator of BMP signaling (inhibitory SMAD family). Loss-of-function mutations in SMAD6 show incomplete penetrance (approximately 24%), and a risk allele (rs1884302) downstream of the BMP2 gene enhances BMP2 expression in the skull, modifying penetrance 1). That is, the combination of enhanced BMP2 expression and loss of BMP signaling inhibition by SMAD6 leads to premature fusion of cranial sutures 1).
Timberlake (2023) proposed a two-locus model in which SMAD6 mutations are found in 6–7% of midline nonsyndromic craniosynostosis cases, and the BMP2 risk allele modifies the penetrance of SMAD6 mutations. Children with SMAD6 mutations showed delayed language development 1).
Patients with Crouzon, Apert, and Pfeiffer syndromes are at high risk for increased intracranial pressure (ICP). Previously, cranio-cephalic disproportion was considered the main cause, but the correlation between intracranial volume and ICP is poor. Currently, the following three factors are considered the main causes.
Increased ICP leads to neuronal death, optic atrophy, and vision loss. Additionally, chronic compression of the optic nerve due to abnormalities of the orbit and optic canal can also cause optic atrophy.
V-pattern strabismus associated with craniosynostosis syndromes results from abnormal bone development at the orbital apex. The superior rectus muscle is displaced laterally, and the lateral rectus muscle is displaced inferiorly, increasing excyclotorsion of the adductors. Recession of the superior orbital rim and trochlea causes overelevation in adduction (pseudo-inferior oblique overaction) and superior oblique underaction. Deficiencies and abnormal insertions of extraocular muscles are also contributing factors.
Vedovato-dos-Santos et al. (2025) systematically reviewed 51 cases with pathogenic variants in the BCL11B gene and reported that 12 cases had craniosynostosis. Coronal suture fusion was relatively common (67%), and fusion of the sagittal, lambdoid, and squamosal sutures was also reported. The core features of BCL11B-related disorders are neurodevelopmental disability (98%), distinctive facial features (98%), and immune dysregulation (93%). Since these are not detected by standard 7-gene panels, genomic sequencing is important for diagnosis 4).
Timberlake (2023) explained the sporadic occurrence pattern of nonsyndromic midline craniosynostosis using a two-locus model of SMAD6 mutation and BMP2 risk allele. Children with SMAD6 mutations may have adverse neurodevelopmental outcomes, and genetic testing and referral to early intervention programs are recommended for midline nonsyndromic cases 1).
Ravi et al. (2023) performed the first endoscopic surgery for isolated frontosphenoidal craniosynostosis (only 49 cases reported in the literature). The fused frontosphenoidal suture was resected through a 2.5 cm temporal incision, combined with postoperative helmet therapy. At 9-month follow-up, the cranial asymmetry index improved from 3.74 to 0.55, indicating a good outcome 7).
Hu et al. (2021) reported that in a case of Pfeiffer syndrome type 2, increased nuchal translucency (NT) of 3.1 mm at the first trimester (12 weeks) was the earliest ultrasound abnormality. An FGFR2 Trp290Cys mutation was confirmed, and increased NT may be related to abnormal angiogenesis due to FGFR mutations 5).
