Isolated frontosphenoidal craniosynostosis with pathogenic FGFR3 variant: a case report and genetic insights

Introduction

Craniosynostosis, a congenital disorder involving premature fusion of calvarial sutures, disrupts skull development, leading to cranial deformities such as plagiocephaly or severe impairments from restricted brain growth and increased intracranial pressure (1). It may occur as an isolated non-syndromic condition or within genetic syndromes, typically affecting the sagittal, coronal, or metopic sutures (2). Frontosphenoidal craniosynostosis (FSC) specifically involves the frontosphenoidal suture, with isolated FSC (IFSC) limited to this suture (3). IFSC has an incidence of 1/100,000 and accounts for ~12.5% of frontal plagiocephaly cases (4). Since 1995, nearly 50 IFSC cases have been reported in surgical literature (3,5-8).

Historically, limited imaging resolution resulted in the misdiagnosis of IFSC as coronal synostosis (5). Given their phenotypic overlap, IFSC cases in the literature were often incidental findings in patients initially diagnosed with coronal synostosis (9,10). The introduction of high-resolution three-dimensional (3D) computed tomography (CT) imaging has since enabled the accurate identification of subtle suture anomalies, including FSC (11). IFSC has been predominantly viewed as a sporadic condition, leading to minimal genetic investigation and a lack of understanding of its genetic basis (12). Consequently, molecular studies on IFSC remain scarce, as it has not been traditionally considered a genetically driven disorder.

Fibroblast growth factor receptor 3 (FGFR3), a member of the FGFR family (FGFR1, FGFR2, and FGFR3), is critical in facial morphogenesis, with variants in FGFR genes implicated in craniofacial anomalies. Studies demonstrate that FGFR3 variants are the most frequent genetic cause of syndromic craniosynostosis (Muenke syndrome), accounting for 24% of genetically identified cases (13). Notably, Hodapp et al. recently identified a pathogenic FGFR3 c.749C>G (p.Pro250Arg) variant in an IFSC patient with familial hearing loss and a maternal uncle diagnosed with Muenke syndrome, suggesting a potential genetic basis for IFSC and underscoring the need for genetic evaluation in such cases (12).

Our case highlights that premature fusion of the IFSC leads to pronounced cranial asymmetry and mild plagiocephaly. Additionally, we identified a heterozygous pathogenic FGFR3 missense variant (c.749C>G; p.Pro250Arg). These findings establish a link between IFSC and causative genetic variants, emphasizing the role of genetic testing in enhancing diagnosis, treatment, and genetic counseling. We present this case in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-417/rc).

Case presentation

A 10-month-old female infant was referred to our clinic for evaluation of cranial asymmetry. The parents reported progressive flattening of the left skull, with increasing asymmetry over time. The child exhibited no developmental delays or history of trauma. Clinical examination demonstrated right frontal bossing and left frontal flattening, cranial vault asymmetry index (CVAI) =4%, consistent with left anterior plagiocephaly. No additional abnormalities were observed, including hearing impairment, or limb malformations (e.g., brachydactyly, syndactyly, carpal/tarsal coalition, or broad halluces). No other family members exhibited similar cranial dysmorphology.

To evaluate the cranial deformity, a high-resolution 3D CT scan was performed, revealing premature fusion of the left frontosphenoidal suture while other cranial sutures remained patent (Figure 1). Significant left forehead flattening and compression of the underlying left frontal lobe parenchyma were observed. Magnetic resonance imaging (MRI) of the cranium and spine confirmed left anterior plagiocephaly without additional anomalies. Radiographic analysis demonstrated patency of the posterior sutures, with no pathological involvement of the sagittal or coronal sutures, confirming the IFSC as the primary etiology of the cranial deformity.

Figure 1 Preoperative high-resolution 3D CT reconstruction and morphology. Vertex view (A), anterior view (B), right lateral view (C), posterior view (D), and left lateral view (E) demonstrate complete closure of the left frontosphenoidal suture (red arrow) with associated left frontal depression. 3D, three-dimensional; CT, computed tomography.

While the diagnosis of IFSC in this pediatric patient was confirmed through clinical and imaging findings, genetic testing was conducted to elucidate the underlying genetic etiology. Proband-only exome sequencing was performed and analyzed as described previously (14,15). In brief, IDT Exome research V1.0 probe was used to capture the coding regions following the manufacturer’s protocol. The captured DNA fragments were sequenced by Illumina NovaSeq (Illumina) in paired-end mode. One hundred and fifty base pair (bp) reads were generated. Small variant calling was performed following GATK best practice (version 3). The output variants in VCF format were annotated by SnpEff (v4.2). Variants with high frequency in population databases [>1% in Genome Aggregation Database (gnomAD) or 1,000 Genomes project, or >5% in a local database with more than 10,000 exomes] were filtered out. Copy number variations (CNV) were called from the aligned bam file using XHMM and CNVkit. Candidate variants were evaluated following the American College of Medical Genetics and Genomics (ACMG) variant interpretation guideline. Sanger sequencing was performed in the family to validate the disease-causing variant and the segregation. Whole-exome sequencing (WES) of peripheral blood identified a heterozygous pathogenic FGFR3 (NM_000142.3) variant, c.749C>G (p.Pro250Arg), classified as pathogenic according to ACMG guidelines. Sanger sequencing revealed the mother as a heterozygous carrier of the variant, while the father tested negative. The genetic findings are summarized in Figure 2. The WES data have been deposited in the ClinVar database (https://trace.ncbi.nlm.nih.gov/Traces/sra/?run=SRR34745396).

Figure 2 Pathogenic gene profile. The pedigree (A) and Sanger sequencing chromatogram (B) demonstrate that the proband’s mother is a carrier of the pathogenic variant, while the father is unaffected.

Following comprehensive consultation with the parents, surgical intervention was pursued. The patient underwent unilateral fronto-orbital advancement and remodeling (FOAR), a standard procedure for craniosynostosis to address cranial asymmetry and restore normal morphology. The procedure involved resection of the prematurely fused suture and recontouring of the affected cranial region under general anesthesia, with meticulous advancement of the frontal and orbital bones to achieve symmetry. The specific surgical procedure was performed as follows: first, the left coronal suture was resected following the standard protocol for unilateral coronal synostosis. Subsequently, the left orbital bandeau was osteotomized and advanced anteriorly by 0.5 cm to achieve symmetry with the right orbital plane. Radial osteotomies were then performed on the temporal bone adjacent to the original left coronal suture. The frontal bone was inverted 180° along its superior-inferior axis before being rigidly fixated. This surgical approach effectively corrected the left frontal depression and right frontal bossing deformity. The surgery was completed without intraoperative complications, and the patient experienced no significant postoperative adverse events. After a short hospitalization, the child was discharged with appropriate postoperative care instructions.

At 3- and 6-month postoperative follow-ups, the child underwent repeat CT imaging, which revealed substantial improvement in cranial symmetry and a notable reduction in plagiocephaly severity, with a CVAI of ~2% (Figure 3). The forehead exhibited enhanced symmetry, and left occipital flattening had significantly resolved. Clinically, the child demonstrated age-appropriate cognitive and motor development. Recovery was uncomplicated, with continued progress in both cognitive and physical domains. Parental observations corroborated the improvement, with a marked reduction in cranial asymmetry noted.

Figure 3 Postoperative high-resolution 3D CT reconstruction and morphology. Postoperative day 2 (A-D) demonstrate the technique of cranial suture reconstruction and cranial vault remodeling. Postoperative 3 months (E-H) and 6 months (I-L) demonstrate bone formation following cranial suture reconstruction. 3D, three-dimensional; CT, computed tomography.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the parents of the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Craniosynostosis, characterized by premature closure of one or more cranial sutures, can result in abnormal skull morphology and cognitive impairment, with an estimated incidence of 1 in 2,000–2,500 live births. The non-syndromic subtype occurs in 1.2–3.7 per 10,000 live births (16). While extensively studied, reports on IFSC as a cause of significant cranial deformities are limited, with most research focusing on more common forms such as sagittal or coronal suture synostosis (17,18). However, emerging evidence suggests a potential association between IFSC and the development of frontal plagiocephaly (19,20). This case contributes to the literature by detailing a severe instance of plagiocephaly resulting from IFSC, emphasizing the importance of recognizing rare sutural closures in cranial deformity.

FOAR, a standard surgical intervention for craniosynostosis, effectively corrects cranial deformities by reshaping the skull and advancing the frontal and orbital bones (21). In this case, FOAR successfully restored cranial symmetry and mitigated developmental risks. Early diagnosis and intervention are crucial in preventing long-term complications associated with craniosynostosis (22). This report highlights that while IFSC is a rare cause of plagiocephaly, it can lead to significant cranial deformities, underscoring the importance of timely surgical intervention to prevent asymmetry and ensure normal development.

Syndromic craniosynostosis, including Apert, Crouzon, Muenke, and Saethre-Chotzen syndromes, is predominantly associated with genetic variants and often presents with coronal or multi-suture involvement (16). The p.Pro250Arg variant in FGFR3 is the hallmark of Muenke syndrome (23), but is also the most prevalent genetic etiology in nonsyndromic craniosynostosis (24). The low penetrance of the p.Pro250Arg variant in FGFR3 supports classifying this IFSC as a phenotypic variant within the nonsyndromic craniosynostosis spectrum. This variant occurs in approximately 1 in 10,000 live births and accounts for 8–10% of coronal synostosis cases (25). Given its variable expressivity and diagnostic significance in craniosynostosis syndromes, testing for p.Pro250Arg in FGFR3 is also recommended as a first-line genetic investigation in nonsyndromic craniosynostosis patients (26).

IFSC, a rare congenital anomaly with historically undefined etiology, may have a molecular genetic basis, as demonstrated in this case. Historically, the scarcity of reported IFSC cases linked to pathogenic variants has limited genetic testing to syndromic craniosynostosis. However, our findings emphasize an association between IFSC and pathogenic variants, particularly in FGFR3, warranting consideration of genetic evaluation even in nonsyndromic presentations.

The identification of these associations enhances the diagnosis, treatment, and counseling of IFSC patients, while also raising awareness of IFSC in infants with frontal plagiocephaly. We propose a staged genetic testing algorithm, starting with chromosomal microarray and progressing to exome sequencing, particularly in cases lacking classic syndromic features. This study highlights the association of IFSC with known genetic conditions. This case of IFSC with gene variants underscores the potential utility of molecular genetic testing in this population.

Conclusions

This case emphasizes the significance of considering rare etiologies of cranial deformities, such as premature frontosphenoidal suture fusion, which, though infrequently reported, can lead to severe plagiocephaly necessitating surgical correction. It also establishes a link between IFSC and pathogenic variants, particularly in FGFR3, highlighting the utility of molecular genetic testing in such cases. Early diagnosis and timely intervention are critical to optimizing outcomes and mitigating long-term developmental sequelae. This report underscores the importance of vigilance in identifying and managing uncommon craniosynostosis variants.

Acknowledgments

We gratefully acknowledge the substantial and dedicated contributions of all staff involved in the implementation of the study’s evaluation and intervention components. We extend particular appreciation to Professor Sun Yu from the Pediatric Research Institute at Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, for her insightful input on the testing methodology. Furthermore, we sincerely appreciate the trust extended to us by the child and her families.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-417/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-417/prf

Funding: This study was funded by Wuxi Children’s Hospital through the Xinhua Hospital Expert Team Program (No. 2025XHYY-WXQ, to X.W.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-417/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the parents of the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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