Prenatal diagnosis of craniosynostosis: a case description and genetic evaluation

Introduction

Craniosynostosis refers to the premature fusion of one or more cranial sutures, either before or after birth, leading to abnormal skull shape. This is a relatively rare congenital disorder, typically manifested by changes in head shape, with or without associated neurodevelopmental impairments. The mechanisms underlying craniosynostosis are generally related to genetic and environmental factors, and are often associated with various genetic syndromes, such as Crouzon syndrome and Apert syndrome. However, prenatal diagnosis and management remain challenging. This case report describes a case of craniosynostosis diagnosed during the fetal period, and aimed to explore the challenges of prenatal diagnosis and analyze potential etiologies.

Case presentation

A pregnant woman had a history of multiple adverse pregnancy outcomes but had never undergone genetic testing prior to the current pregnancy. In 2015, she underwent cesarean delivery of a male infant who died 5 days after birth. According to the patient, the cause of death was cerebral dysplasia; the specific etiology was unknown, and no genetic testing was performed. In 2019, she delivered a healthy female infant by cesarean section. In 2023, a pregnancy was terminated at 32 weeks of gestation due to fetal craniosynostosis; however, no genetic testing was performed at that time. In the current pregnancy (25⁺ weeks of gestation), a detailed four-dimensional (4D) ultrasound performed at an outside hospital showed a slightly prominent fetal forehead and a mildly depressed nasal root. The patient was therefore referred to our Prenatal Diagnosis Center for prenatal ultrasound consultation. All procedures performed in this study were in accordance with the ethical standards of the Ethics Committee of Gansu Provincial Maternity and Child-care Hospital (approval No. 2023GSFY[98]), and with the Helsinki Declaration and its subsequent amendments. Written informed consent was provided by the patient and her partner for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Ultrasound examination at our center demonstrated a prominent fetal forehead with a nasofrontal angle of 107° (Figure 1A) (1), and disappearance of the coronal suture echo (Figure 1B). The cranial near field was clearly visualized. The biparietal diameter measured 6.06 cm (17.3%), head circumference 22.27 cm (4.2%), abdominal circumference 20.29 cm (25.2%), femur length 4.52 cm (22.2%), humerus length 3.92 cm (6.6%), cerebellar transverse diameter 2.86 cm (44.9%), and cisterna magna width 0.82 cm. The corpus callosum and pericallosal artery appeared normal (Figure 1C). The heart, abdomen, and long bones showed no obvious abnormalities. Fetal biometry was consistent with a gestational age of 24⁺⁵ weeks, based on first-trimester crown-rump length (CRL) data obtained from an outside hospital. The cranial sonographic findings were suggestive of craniosynostosis. Fetal magnetic resonance imaging (MRI) showed no apparent intracranial structural abnormality.

Figure 1 Prenatal ultrasound findings of the fetus with cranial abnormality. (A) Sagittal view showing a prominent fetal forehead with a nasofrontal angle of 107°. (B) Coronal view demonstrating disappearance of the coronal suture echo. (C) Mid-sagittal view showing normal appearance of the corpus callosum and pericallosal artery.

Subsequent prenatal genetic evaluation, including trio-based whole-exome sequencing, identified a heterozygous variant in twist family basic helix-loop-helix transcription factor 1 (TWIST1), c.422A>G, inherited from the father. This variant has been reported in association with Robinow-Sorauf syndrome, Saethre-Chotzen syndrome (with or without eyelid anomalies), and Sweeney-Cox syndrome, all of which fall within the spectrum of TWIST1-associated craniosynostosis [Online Mendelian Inheritance in Man (OMIM): craniosynostosis 1, autosomal dominant], and was therefore classified as a likely pathogenic variant consistent with the proband’s phenotype. In addition, a heterozygous variant in gap junction protein beta 2 (GJB2) (c.109G>A), also inherited from the father, was detected; it is associated with Bart-Pumphrey syndrome and Vohwinkel syndrome (autosomal dominant) but considered unrelated to the fetal phenotype. Examination of the father revealed a broad interorbital distance, low forehead, and reduced anteroposterior cranial diameter. He reported a previous diagnosis of craniosynostosis but was otherwise phenotypically normal. After comprehensive genetic counseling and careful deliberation, the couple made a difficult decision and ultimately chose to terminate the pregnancy.

Discussion

The etiology of craniosynostosis during the fetal period is not yet fully understood. However, it is widely acknowledged that genetic factors play a pivotal role in its pathogenesis. Mutations in fibroblast growth factor receptor (FGFR) genes, particularly FGFR2 and FGFR3, have been associated with cranial suture fusion by disrupting skeletal development (2,3). Additionally, mutations in the TWIST1 gene are closely associated with syndromic craniosynostosis, particularly TWIST1-associated craniosynostosis (OMIM: craniosynostosis 1), which is inherited in an autosomal dominant manner (4). In contrast, nonsyndromic (simple) craniosynostosis is characterized by the premature fusion of a single cranial suture in the absence of an identifiable genetic syndrome. This condition typically presents with the premature fusion of a single cranial suture, often without systemic involvement. The clinical presentation is dominated by abnormal cranial morphology, with characteristic head-shape deformities depending on the affected suture, such as scaphocephaly in sagittal synostosis, anterior plagiocephaly in unilateral coronal synostosis, and trigonocephaly in metopic synostosis. Patients with isolated craniosynostosis tend to exhibit normal neurodevelopment, and the prognosis is generally favorable, as there are no significant associated genetic syndromes (5). From an epidemiological perspective, craniosynostosis occurs in approximately 1 in 2,000–2,500 live births, with nonsyndromic forms accounting for the majority of cases. A male predominance has been reported, particularly in sagittal synostosis.

In this case, genetic testing revealed a heterozygous TWIST1 variant (c.422A>G) inherited from the father, consistent with TWIST1-associated craniosynostosis (OMIM: craniosynostosis 1). The father exhibited mild craniofacial features compatible with craniosynostosis, without significant functional impairment. In the present case, pregnancy termination was not recommended as a medically mandatory option. Instead, following comprehensive prenatal counseling regarding the generally favorable prognosis and potential postnatal management, the decision to terminate the pregnancy was made by the family based on their previous adverse obstetric history and personal considerations. By contrast, in addition to isolated cases, various instances of craniosynostosis associated with genetic syndromes have been reported in the literature, such as Crouzon syndrome, Apert syndrome, and others. These syndromes not only present with craniosynostosis but may also be accompanied by facial deformities, hearing loss, intellectual disability, and other symptoms (6). Differentiating isolated craniosynostosis from syndromic forms is therefore a key aspect of prenatal differential diagnosis, as prognosis and postnatal management strategies differ substantially between these entities. Prenatal ultrasound provides initial diagnostic clues, whereas genetic testing plays a decisive role in achieving an accurate and definitive classification. These observations reinforce the importance of recognizing variable expressivity and incomplete penetrance in genetic conditions. In the present case, despite the family history of multiple adverse pregnancies, including a previous pregnancy terminated for craniosynostosis, no genetic testing had been conducted. This highlights a critical gap in clinical practice, emphasizing the need for early genetic screening in cases of recurrent pregnancy loss or abnormal outcomes.

Ultrasound examination is the primary tool for screening craniosynostosis during the fetal period, but its diagnostic accuracy is highly dependent on the skill and experience of the sonographer (7). Prenatal diagnosis may be aided by specific sonographic markers. For example, in isolated fetal sagittal craniosynostosis, a progressive reduction in the cephalic index during the second half of pregnancy has been reported and may also assist in delivery planning due to increased rates of malpresentation and operative delivery (8). Despite these reported sonographic markers, the diagnosis of craniosynostosis in utero is particularly challenging due to the subtle nature of the cranial changes. In this case, prenatal ultrasound consultation and examination revealed findings suggestive of craniosynostosis, such as the loss of the coronal suture echo. In addition to these qualitative sonographic features, the nasofrontal [frontomaxillary facial (FMF)] angle was measured as a descriptive parameter of fetal craniofacial morphology. It is important to emphasize that this measurement was not intended as a diagnostic criterion for craniosynostosis, as the FMF angle is primarily used in the assessment of facial profile abnormalities such as flat face rather than frontal bossing. Instead, its inclusion was meant to illustrate that prenatal craniofacial morphology may differ from postnatal or familial phenotypes and that craniosynostosis-related features during the fetal period are heterogeneous. This observation suggests that the absence of frontal flattening or an abnormal FMF angle in utero does not exclude the presence of craniosynostosis. Fetal cranial development is dynamic, and characteristic cranial deformities may evolve later in gestation or become more evident after birth. Therefore, isolated craniofacial measurements should be interpreted cautiously and always in conjunction with other sonographic findings, longitudinal assessment, and genetic information. Consistent with an isolated form of craniosynostosis, MRI did not show any significant intracranial abnormalities. Literature suggests that MRI has limited diagnostic value in cases of isolated craniosynostosis, as structural changes in the intracranial tissues are often absent (9). Therefore, ultrasound remains crucial in the prenatal diagnosis of craniosynostosis, but the accuracy of diagnosis is largely influenced by the experience of the sonographer. Given the challenges in assessing near-field cranial structures, there is potential for future advancements in quantifying diagnostic standards through the comparison of the same fetus’s far-field cranial two-dimensional (2D) echo using gray-scale quantification parameters. This could help to establish standardized diagnostic criteria and improve the reliability and consistency of assessments (10,11). Although three-dimensional (3D) ultrasound offers enhanced visualization of cranial sutures and skull morphology, its diagnostic effectiveness can still be influenced by factors such as fetal positioning and image quality. Although 3D imaging allows for 3D visualization and multi-plane reconstructions, 2D ultrasound remains the primary method for early identification of key diagnostic indicators, especially in clinical practice.

In cases where prenatal ultrasound suggests craniosynostosis, genetic testing is an essential next step. It helps to determine whether the craniosynostosis is isolated or part of a syndrome, such as Crouzon syndrome or Apert syndrome, and guides clinical management (12). For this patient, genetic testing confirmed a mutation associated with isolated craniosynostosis, providing clarity for the family’s decision-making. The fetus’s father also has craniosynostosis, but without any functional impairments. However, prenatal diagnosis of isolated craniosynostosis remains challenging due to the rarity of the condition. Given the limited number of cases, further research is needed to explore the genetic correlation with isolated craniosynostosis. In the future, combining ultrasound imaging with genetic testing could help to achieve more accurate diagnoses of isolated craniosynostosis, offering families greater confidence and support in making informed decisions.

Therapeutic options for craniosynostosis are predominantly implemented after birth. Postnatal management typically involves surgical intervention to correct cranial deformities and prevent potential complications, such as elevated intracranial pressure, when clinically indicated. Consequently, prenatal management focuses primarily on accurate diagnosis, subtype classification, and comprehensive counseling, rather than active fetal treatment. Precise prenatal identification of isolated versus syndromic craniosynostosis provides essential information for prognostic assessment and planning appropriate postnatal therapeutic strategies.

Conclusions

The integration of ultrasound imaging with genetic testing presents a new frontier in precision medicine. Genetic testing uncovers underlying hereditary factors, whereas ultrasound provides real-time, dynamic information about the patient’s physical condition. Together, these approaches enhance early disease detection accuracy and provide a scientific basis for individualized treatment and prognostic evaluation. Therefore, the combined use of ultrasound imaging and genetic testing holds great clinical significance, particularly in the diagnosis and treatment of complex and rare diseases (13-15).

Moreover, prenatal counseling is playing an increasingly crucial role in modern medicine. Through comprehensive prenatal counseling, parents can gain a better understanding of common pregnancy risks and receive accurate assessments of the risks associated with rare diseases, thereby helping families to make more informed decisions. With professional evaluation and guidance, families are better equipped to understand the prognosis of such conditions and decide whether to continue the pregnancy or consider interventions, ultimately ensuring the health of both the mother and the baby at a higher level (16).

In the current development of medical imaging, artificial intelligence (AI) and machine learning technologies have made remarkable progress in the field of radiological imaging. Looking to the future, the successful integration of these advanced technologies into ultrasound imaging, coupled with quantified grayscale parameters, holds the potential to significantly enhance the accuracy of image analysis and improve diagnostic efficiency for complex and challenging cases. Compared to radiological imaging, ultrasound offers the advantages of being non-invasive and real-time. However, the challenges in its operation and image interpretation make the introduction of AI a transformative possibility for this field.

Acknowledgments

None.

Footnote

Funding: This study was supported by Lanzhou Talent Innovation and Entrepreneurship Project (No. 2023-RC-23 to L.Y.); Gansu Provincial Natural Science Foundation (No. 25JRRA334 to L.Y.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2282/coif). L.Y. reports receiving research grants from the Lanzhou Talent Innovation and Entrepreneurship Project (No. 2023-RC-23) and the Gansu Provincial Natural Science Foundation (No. 25JRRA334). The other 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 ethics committee of Gansu Provincial Maternity and Child-care Hospital (approval No. 2023GSFY[98]), and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient and her partner for publication of this article 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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