FGFR2 Genetic Variant C.1019A > G p.(Tyr340Cys) in a Fetus with Pfeiffer Type II Syndrome Diagnosed by a Combination of 3D Ultrasound Phenotyping and DNA Sequencing

• Abstract
• Introduction
• Case Presentation
• Methods
• Genetic Analysis
• Ultrasonography
• Diagnostic Results and Interpretation
• Discussion
• Conclusion
• References

Abstract

A 38-year-old woman was referred at 20 weeks' gestation for multiple fetal anomalies detected on routine ultrasound screening. Initial findings included dolichocephaly, ventriculomegaly, craniofacial abnormalities, and limb anomalies, which led to the suspicion of a skeletal dysplasia. While microarray analysis was normal, rapid fetal exome sequencing identified a de novo pathogenic variant in the FGFR2 gene (c.1019A > G p.(Tyr340Cys)). Initially classified as a variant of uncertain significance due to initial ultrasound suspicion, targeted three and four dimensional ultrasound phenotyping revealed characteristic features of Pfeiffer syndrome type 2, including cloverleaf skull, proptosis, hypertelorism, broad thumbs and big toes, and radial-humeral synostosis. This case demonstrates the crucial interplay between advanced genetic testing and detailed ultrasound assessment in prenatal diagnosis. Accurate interpretation of genetic variants requires meticulous ultrasound phenotyping in a multidisciplinary setting, particularly for complex and rare conditions such as Pfeiffer syndrome type 2.

Introduction

Advances in prenatal diagnosis have revolutionized our ability to detect and characterize fetal anomalies, with genetic testing and ultrasound imaging playing complementary roles. The recent introduction of rapid fetal exome sequencing into clinical practice has particularly enhanced our diagnostic capabilities for rare genetic conditions. However, the interpretation of genetic variants often presents challenges, especially when variants of uncertain significance are identified. Here, we present a case that highlights, via high-quality visual images, the critical importance of integrating advanced genetic testing with comprehensive ultrasound assessment in a multidisciplinary setting for the prenatal diagnosis of rare genetic conditions.

Case Presentation

A 38-year-old woman with unremarkable history, was referred at 20 weeks following screening scan findings of dolichocephaly, mild ventriculomegaly (11 mm), hypertelorism, frontal bossing, kyphosis, single umbilical artery, short thorax, limb abnormalities (in particular short and “bowed long bones”), rocker bottom feet, and talipes. Her combined screening test had been low risk (nuchal translucency measuring 1.6 mm). Specialist fetal medicine assessment at 20 + 6 weeks confirmed these findings, noting mesomelic shortening of the upper limbs and bowing of the long bones. According to these findings, the couple was counseled for the suspicion of a skeletal dysplasia, and amniocentesis was performed. Of note, the father was 38 years old.

After genetic testing and review at the joint fetal medicine-genetic clinic, targeted fetal ultrasound phenotyping was performed with possible differential diagnoses in mind. This revealed the features shown in [Fig. 1A] to [F]. The previously described “bowed long bones” were actually bent humeroradial synostotic bones affecting both upper limbs. No evidence of vertebral column abnormalities was noted.

Methods

Genetic Analysis

Fetal deoxyribonucleic acid (DNA) was extracted from amniocytes and parental blood samples (trio) and subjected to next generation sequencing (NGS) for a virtual panel of genes associated with fetal scan anomalies (Genomics England PanelApp). Analysis was by NGS of the coding region of the genes tested, including intron/exon splice regions. Variants are filtered in accordance with the following criteria: > 1% overall minor allele frequency in gnomAD population database (http://gnomad.broadinstitute.org), outside ± 20 bp from coding exon boundaries of exons in genes analyzed. Analysis pipeline version: Genesisv6.

Ultrasonography

The initial assessment was performed on a Voluson E10 (GE Healthcare) ultrasound machine. Further fetal phenotype genotype correlation used two and three–four dimensional (3-4D) ultrasound with a transabdominal convex 3D probe on a Voluson Expert22 (GE Healthcare).

Diagnostic Results and Interpretation

After the initial assessment, amniocentesis was performed following suspicion of skeletal dysplasia, yielding normal quantitative fluorescent polymerase chain reaction and DNA microarray analysis. After a multidisciplinary team discussion, R21 (rapid fetal exome sequencing according to the UK National Genomic Test Directory) on the stored sample was performed. This identified a de novo, monoallelic, rare missense pathogenic variant in the FGFR2 gene c.1019A > G p.(Tyr340Cys). DNA variants in this codon are associated with several craniofacial disorders, including Pfeiffer syndrome, Apert syndrome, and Crouzon syndrome. Initially classified as a “DNA variant of unknown significance” (VOUS) due to unclear phenotype correlation, targeted fetal ultrasound revealed pathognomonic features consistent with Pfeiffer syndrome type 2. According to local protocol, no further raw data analysis was performed on the stored DNA sample, as the identified pathogenic variant was now fully explained by the prenatal phenotype. After counseling regarding the poor prognosis, high risk of early demise, respiratory morbidity, and likely disability, the couple opted for termination of pregnancy. A feticide was performed at 24 + 1 weeks of gestation through intracardiac KCl administration. No postmortem was performed. Finally, the couple was counseled regarding the recurrence risk in future pregnancies which for the de novo missense variant can be considered below 1%. The option of noninvasive prenatal diagnosis was offered in future pregnancies to rule out the small risk of germline mosaicism.

Discussion

DNA sequencing and specific genetic tests for fetal malformations continue advancing, offering improved diagnosis. R21 has been recently introduced for at risk pregnancies under specific eligibility criteria, in which a genomic diagnosis can guide the clinical management of the pregnancy and perinatal care, with a shorter timeframe of 2 to 4 weeks.[1]

Prenatal DNA sequencing interpretation requires appropriate fetal phenotyping through ultrasound correlation to assess the manifestations of variable conditions. In this case, an FGFR2 gene DNA variant was identified. While FGFR2 gene alterations can occur in Crouzon syndrome, bent bone dysplasia, and other craniosynostosis syndromes,[2] this specific mutation (c.1019A > G p.; Tyr340Cys) has been reported in cases with Pfeiffer syndrome and Apert syndrome, two rather different conditions.[3] [4] For this reason and according to the initial ultrasound features, the laboratory report classified it as a VOUS. Literature review showed this variant in Pfeiffer syndrome type 2 and cases of unclassified severe craniosynostosis syndromes. One case reported Apert syndrome,[5] but we believe this was likely misclassified as Pfeiffer syndrome type II, especially after having examined the manuscript and additional data of the case report.

Conclusion

Advances in 3D/4D ultrasound and genome sequencing have improved our ability to diagnose Mendelian disorders prenatally. In our case, combining 3D/4D ultrasound phenotyping with rapid genotyping enabled accurate diagnosis despite initial misleading findings, demonstrating the value of integrated advanced technologies within a multidisciplinary setting in diagnosing rare genetic conditions.

Conflict of Interest

None declared.

Consent to Publish Statement

Written informed consent was obtained from the mother for the publication of potentially identifying images and clinical details.

Authors' Contributions

Conceptualization: S.M.S., C.J.M., and L.C.C. Methodology: S.M.S. and C.J.M. Case management: H.N.L., C.S.A., and T.D. Informed consent: T.D. Writing—original draft preparation: S.M.S. and C.J.M. Writing—review and editing: L.C.C., H.N.L., C.S.A., and T.D. Supervision: L.C.C. and C.J.M. All authors have read and agreed to the published version of the manuscript.

Data Availability

The authors confirm that the data supporting the findings of this study are available only within the article.

• References

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Address for correspondence

Publication History

Article published online:
01 July 2025

© 2025. Society of Fetal Medicine. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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• References

• 1 Hill M, Ellard S, Fisher J. et al. Optimising Exome Prenatal Sequencing Services (EXPRESS): a study protocol to evaluate rapid prenatal exome sequencing in the NHS Genomic Medicine Service. NIHR Open Res 2022; 2: 10
  PubMedSearch in Google Scholar
• 2 Azoury SC, Reddy S, Shukla V, Deng CX. Fibroblast growth factor receptor 2 (FGFR2) mutation related syndromic craniosynostosis. Int J Biol Sci 2017; 13 (12) 1479-1488
  CrossrefPubMedSearch in Google Scholar
• 3 Passos-Bueno MR, Sertié AL, Jehee FS, Fanganiello R, Yeh E. Genetics of craniosynostosis: genes, syndromes, mutations and genotype-phenotype correlations. Front Oral Biol 2008; 12: 107-143
  PubMedSearch in Google Scholar
• 4 Sargar KM, Singh AK, Kao SC. Imaging of skeletal disorders caused by fibroblast growth factor receptor gene mutations. Radiographics 2017; 37 (06) 1813-1830
  CrossrefPubMedSearch in Google Scholar
• 5 Fu F, Li R, Yu Q. et al. Application of exome sequencing for prenatal diagnosis of fetal structural anomalies: clinical experience and lessons learned from a cohort of 1618 fetuses. Genome Med 2022; 14 (01) 123
  PubMedSearch in Google Scholar