Diagnosing fetal apert syndrome: a case study on prenatal diagnosis and genetic insights

Introduction

Apert syndrome (AS), also known as acrocephalosyndactyly type I, was first identified by the French physician Apert in 1906. This rare condition occurs in about one in 60,000 individuals, and is mainly caused by variants in the FGFR2 gene. Typical signs include premature skull suture fusion, midface hypoplasia, symmetrical webbing or fusion of fingers and toes with bone abnormalities, and possible involvement of the skin, skeletal system, central nervous system, and other organs (1,2). This study reports a case of AS that was highly suspected on prenatal ultrasound and subsequently confirmed by genetic analysis. It aims to provide valuable insights for antenatal counseling and the early detection of AS in fetuses.

Case presentation

The patient, a 30-year-old primigravida (G1P0), conceived naturally. Both she and her husband were in good health, with no consanguinity. There was no prior or prenatal exposure to toxins or radiation, nor any notable family history of genetic disorders. Nuchal translucency (NT) measured 2.0 mm, and the Trisomy 21 screening indicated a low risk.

At 24 (3/7) weeks of gestation, the patient was transferred from another hospital to Gansu Provincial Maternity and Child-Care Hospital (Gansu Provincial Central Hospital) for further evaluation. Subsequent ultrasound examination revealed craniosynostosis, midface hypoplasia, and syndactyly of the second to fifth fingers (Figure 1). These ultrasound signs strongly suggested that the fetus had AS.

Figure 1 Ultrasound image of the fetus at 24 weeks of gestation. (A) Craniosynostosis. (B) Finger syndactyly. (C) Midfacial hypoplasia.

Amniotic fluid (15 mL) from the fetus and peripheral venous blood (2–3 mL) from both parents were collected for genomic DNA extraction, followed by whole exome sequencing (WES) and Sanger sequencing for verification. The analysis revealed that the fetus harbored a heterozygous variant p.Ser252Trp (c.755C>G chr10:123279677) in the FGFR2 gene (NM_000141.4;EX7). According to the American College of Medical Genetics and Genomics guidelines, this variant was classified as pathogenic and diagnosed as AS. Both parents were found to carry the wild-type allele (Figure 2).

Figure 2 Sanger sequencing results. (A) The fetus was found to carry a p.Ser252Trp (c.755C>G chr10:123279677) variant in the FGFR2 gene. (B) The fetus’s father carried the wild-type allele. (C) The fetus’s mother carried the wild-type allele.

Following genetic counseling, the pregnant woman opted to terminate the pregnancy. A stillborn male infant was delivered vaginally, with a birth weight of 560 grams. The phenotypic examination revealed a flat midface, low-set ears, syndactyly of the second to fifth fingers on both hands, abnormal foot posture, and toe fusion (Figure 3).

Figure 3 The dead fetus after induced labor. (A) Midfacial hypoplasia of the gross specimen. (B) Physical characteristics of acrocephalosyndactyly. This image is published with the consent of the parents of the patient.

All the procedures in this study were performed in accordance with the ethical standards of the Gansu Provincial Maternity and Child-Care Hospital (Gansu Provincial Central Hospital) (No. 2024GSFY07), and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was provided by the pregnant woman and her husband for the publication of this article and the accompanying images. A copy of the written consent form is available for review by the editorial office of this journal.

Discussion

The FGFR2 gene, situated on chromosome 10, is a member of the fibroblast growth factor receptor (FGFR) family. It comprises three distinct regions: the extracellular ligand-binding domain, which includes three immunoglobulin-like domains, the transmembrane helix, and the intracellular tyrosine kinase domain. Research involving animal models has demonstrated that defects in fibroblast growth factor signaling, attributable to the FGFR variant, can result in the arrested development of the skull and midface (3).

Several syndromes are associated with premature cranial suture closure, among which those caused by FGFR2 missense variants include AS, Pfeiffer syndrome, and Crouzon syndrome (4). The phenotypic expressions of these conditions are notably heterogeneous. Differential diagnosis is typically informed by the presence of distinct limb anomalies, with syndactyly being a hallmark feature of AS (5). The syndrome can be distinguished from other conditions based on specific clinical and genetic findings.

In the present case, the suspicion of characteristic malformations of hands and face led to the timely diagnosis of AS. The prenatal diagnosis of this syndrome was based on an ultrasonographic examination. WES revealed that the fetus harbored a heterozygous variant in the FGFR2 gene (c.755C>G, p.Ser252Trp) on transcript NM_000141, while both parents exhibited the wild-type genotype. Consequently, a diagnosis of AS in the fetus was established.

AS is attributed to variants in the FGFR2 gene, with approximately 98% of affected individuals harboring missense variants such as p.Ser252Trp (66%) or p.Pro253Arg (32%). Characteristic clinical manifestations include premature cranial suture closure, midfacial hypoplasia, symmetrical syndactyly with osseous fusion, and potential involvement of the skin, skeletal system, brain, and other internal organs (2). When prenatal ultrasound reveals premature cranial suture closure and incomplete midfacial development in a fetus, it is imperative to assess for additional structural abnormalities, particularly syndactyly of the fingers and toes. WES should be conducted to facilitate a timely diagnosis of AS and prevent missed diagnoses.

Despite the numerous characteristic manifestations of AS, the typical gestational age for ultrasound diagnosis is approximately 21.3 weeks (range, 17.3–24 weeks), with 96.8% of fetuses exhibiting altered head shapes. Anomalies of the fingers (syndactyly) are diagnosed by prenatal imaging in 87.5% of cases (6). However, these characteristic manifestations can only be detected during the second trimester of pregnancy.

Due to the insufficient sonographic resolution of developing fetal structures, such as the fingers, there is no specific sign of AS in the first trimester. AS may be associated with increased NT. In this case, we also observed that the fetus exhibited midfacial hypoplasia and an enlarged frontal nasal angle. These abnormalities may be detectable at an earlier gestational age, such as during the NT examination at 11 to 13⁺⁶ weeks, when fetal midfacial hypoplasia may be observed (7). Regrettably, in this particular case, the early pregnancy examination was performed at a local healthcare facility, and no abnormalities were detected during early pregnancy. Presently, the early detection of AS remains challenging, complicating efforts for early diagnosis.

Conclusions

This case study details a prenatal ultrasound diagnosis of premature fetal cranial suture closure, midfacial hypoplasia, and syndactyly. WES revealed that the fetus harbored a heterozygous variant, c.755C>G (p.Ser252Trp) in the FGFR2 gene (NM_000141), leading to a diagnosis of AS. The objective of reporting this case is to contribute clinical evidence to support prenatal consultation and the diagnosis of fetal AS.

Acknowledgments

None.

Footnote

Funding: This work was supported by the Science and Technology Project of Gansu Province (Youth Science and Technology Fund) (No. 23JRRA1752), National Natural Science Foundation of China (No. 82560331), Lanzhou Science and Technology Plan Project (No. 2022-3-15), Gansu Provincial Science and Technology Plan Project (Nos. 21JR11RA171 and 22YF7FA094) and Hospital Research Fund Project Support Project (Nos. GMCCH2024-2-2 and GMCCH2025-2-3-08).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-2088/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 Gansu Provincial Maternity and Child-Care Hospital (Gansu Provincial Central Hospital) (No. 2024GSFY07) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was provided by the pregnant woman and her husband 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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