Clinical Observation of Prenatal Diagnosis of Simpson–Golabi–Behmel Syndrome via Chorionic Villus Sampling Following Increased Nuchal Translucency

Introduction Simpson–Golabi–Behmel syndrome (SGBS) is a rare X-linked genetic disorder with an estimated incidence ranging from 1:50,000 to 1:100,000.1 It is characterized by prenatal and postnatal overgrowth (macrosomia) and craniofacial abnormalities (macrocephaly and cleft palate). Furthermore, it involves multiple organ systems, for example, congenital cardiac anomalies and diaphragmatic hernia, posing substantial risks to fetal survival and maternal health. Most cases of SGBS are diagnosed postnatally or during mid-trimester amniocentesis; however, the present case demonstrates the feasibility of early prenatal detection through chorionic villus sampling (CVS) at approximately 12 weeks of gestation. In contrast to prior reports, which have necessitated multiple phenotypic abnormalities, such as cleft palate and organomegaly, the current case was diagnosed solely based on increased nuchal translucency (NT) thickness and chromosomal copy number variation (CNV) analysis. This finding underscores the critical role of genetic testing in atypical clinical presentations, particularly given the rarity of early prenatal diagnoses via CVS. The present report details a case in which increased NT thickness prompted CVS, facilitating the early diagnosis of SGBS and clinical decision-making. Clinical observation A 35-year-old Chinese woman (gravida 2, para 0), whose last menstrual period commenced on June 10, 2024, underwent in vitro fertilization and embryo transfer (IVF-ET) on July 1, 2024. At approximately 12 weeks’ gestation, ultrasonography revealed increased NT thickness (3.9 mm; Supplementary Fig. 1A, https://links.lww.com/MFM/A117) and mild bowel hyperechogenicity (Supplementary Fig. 1B, https://links.lww.com/MFM/A117). Additionally, fetal biometric measurements included a crown–rump length of 6.2 cm, biparietal diameter of 2.06 cm, head circumference of 7.6 cm, abdominal circumference of 5.9 cm, femur length of 0.79 cm, and humerus length of 0.99 cm, corresponding to a gestational age of 12 weeks and 5 days (Supplementary Fig. 1C and D, https://links.lww.com/MFM/A117). Subsequently, the patient attended our genetic counseling clinic. Her prior spontaneous pregnancy had been terminated at 22 weeks of gestation due to fetal anomalies (increased NT thickness, cleft lip and palate, and congenital cardiac defects); however, no genetic testing was performed on fetal tissues at that time. Both the patient and her spouse were healthy and had normal karyotype analyses (46, XX and 46, XY, respectively) conducted prior to IVF-ET. The couple reported no consanguinity or family history of genetic disorders. After informed consent was obtained, CVS was performed for chromosomal CNV analysis. The study was approved by Medical Ethics Committee of the Second Affiliated Hospital of Harbin Medical University (approval no.: KY2023-91). Participants gave informed consent to participate in the study before taking part. Laboratory analysis Chromosomal microarray analysis of chorionic villi identified a 705.19-kb deletion (copy number: 0) at the Xq26.2q26.2 region (Supplementary Fig. 2E and F, https://links.lww.com/MFM/A117). This deletion encompassed five protein-coding genes: GPC3, GPC4, HS6ST2, TFDP3, and USP26, with GPC3 being the critical gene implicated in SGBS. Combined with ultrasonographic findings, the fetus was preliminarily diagnosed with SGBS. Subsequent genetic testing confirmed the presence of a male fetus. Parental CNV analyses revealed no abnormal findings in the husband (Supplementary Fig. 2G, https://links.lww.com/MFM/A117). In contrast, the patient carried a 692.36-kb deletion (copy number: 1) at the identical Xq26.2q26.2 region (Supplementary Fig. 2H, https://links.lww.com/MFM/A117), consistent with the deletion detected in the fetal chorionic villi. A retrospective review of medical records from the patient’s prior pregnancy termination revealed a male fetus with cardiac anomalies and cleft lip and palate. After comprehensive genetic counseling and informed discussion regarding the likelihood of SGBS, the couple opted to terminate the current pregnancy at 17 weeks’ gestation. The fetus was confirmed as male and exhibited a cleft lip and palate at delivery; however, no further autopsy was performed to verify other phenotypic abnormalities. Discussion SGBS is a rare X-linked disorder with a low incidence, often resulting in lack of sufficient recognition and missed diagnoses among clinicians. A review of the literature over the last 15 years on prenatal SGBS diagnoses revealed that most reported cases exhibited one or more characteristic features in addition to increased NT thickness. These features are uncommon in early pregnancy but become more evident during the second and third trimesters (Supplementary Table 1, https://links.lww.com/MFM/A117). In contrast, the present case lacked overt phenotypic abnormalities, likely due to early detection via CVS, a notable distinction from previously reported cases diagnosed via mid-trimester amniocentesis, genetic analysis of terminated fetal tissue, or postnatal testing (Supplementary Table 1, https://links.lww.com/MFM/A117). Since early-stage SGBS may not yet involve multiple organ systems, prenatal or preimplantation genetic testing is essential for identifying potential pathogenic variants. Patients presenting with isolated NT thickening or other nonspecific findings should be encouraged to pursue genetic counseling and appropriate prenatal diagnostic testing. Heidi et al. reported a CVS-based prenatal diagnosis of SGBS in a 46, XX female fetus without significant NT thickening but showing relevant clinical features; autopsy following mid-trimester termination confirmed more typical SGBS manifestations.2 Furthermore, familial genetic analysis indicated that the fetal microdeletion was inherited from the phenotypically normal father, whereas the mother showed normal findings. Although the etiology remains incompletely understood, random X-chromosome inactivation has been proposed as a contributing factor in some female patients. Specifically, when the X-chromosome carrying the pathogenic allele is inactivated, the mutant gene and its descendant cells are silenced, leading to the absence of clinical symptoms. Conversely, inactivation of the normal X-chromosome allows the pathogenic allele to be expressed, resulting in variable disease phenotypes. The molecular genetic etiology of SGBS is heterogeneous and includes point mutations or deletions of GPC3, contiguous co-deletions of GPC3 and GPC4, as well as duplications affecting GPC3 and GPC4. Among patients with SGBS who harbor genomic deletions, approximately 50% have deletions encompassing exon 8 of the GPC3 gene. Specifically, GPC3 encodes Glypican 3, a protein that negatively regulates the hedgehog signaling pathway during development. Loss-of-function mutations in GPC3 result in hyperactivation of this signaling pathway, contributing to fetal overgrowth and an increased risk of cancer. SGBS exhibits substantial phenotypic variability, ranging from infantile lethal phenotypes to milder presentations compatible with normal reproductive outcomes. The intrauterine phenotype evolves with gestational age, leading to significant interindividual clinical variability. In the current case, prior clinical information was unavailable, and the early-pregnancy ultrasound presented atypical findings. The prenatal diagnosis was initiated solely due to increased NT thickness. By identifying pathogenic fetal genetic fragments, determining fetal sex, performing familial genetic analyses, and reviewing the medical history, we were able to provide informed fertility guidance to the family. Chumei et al.3 previously described a case characterized by increased NT thickness during early pregnancy; however, the patient did not pursue an immediate prenatal diagnosis. By 30 weeks’ gestation, ultrasonography demonstrated typical SGBS features, including excessive fetal growth, cleft lip and palate, and organomegaly. Postpartum genetic testing following cesarean delivery at 37 weeks confirmed SGBS. Similar clinical presentations have been reported in other case reports, highlighting the phenotypic variability and unpredictable nature of SGBS manifestations. Such awareness can enhance diagnostic accuracy and reduce missed diagnoses. In another case described by Karen et al.4, genetic testing was performed for both the mother and her first child. Upon identification of clinical features suggestive of SGBS in the subsequent pregnancy, timely CVS was conducted to confirm the diagnosis. In this case, although the first fetus exhibited significant abnormalities, genetic testing was not performed following pregnancy termination. As a result, a diagnosis of SGBS was confirmed only in the current pregnancy. Clinically, such cases warrant close monitoring; pregnant women should be advised to seek prompt genetic counseling and screening for relevant disorders. Additionally, although both partners in the current case had normal chromosomal karyotypes before pregnancy, the possibility of carrying submicroscopic pathogenic variants could not be excluded due to limitations in detection technology and resolution. Therefore, CNV analysis should be considered as a supplementary diagnostic tool, particularly in families with histories of abnormal pregnancy outcomes. In addition, it should be noted that results from CVS do not necessarily accurately reflect fetal genetic status, as maternal cell contamination can occur. Therefore, a single CVS result may not be sufficient for definitive fetal diagnosis. In this case, after careful consideration of ultrasound findings, medical history, CVS results, and thorough communication with the patient and her family, the decision was made to terminate the pregnancy. An examination of the fetal tissue at 17 weeks’ gestation confirmed cleft lip and palate, validating the CVS findings. Regrettably, no further autopsy was conducted to assess additional phenotypic features. Clinical implications For pregnant women with a history of abnormal pregnancy or a family history of genetic disorders, CVS can be performed during early pregnancy. Amniocentesis remains the standard diagnostic procedure in the second trimester. For patients in later stages of pregnancy whose fetuses present with structural abnormalities or abnormal growth and development, selective use of cordocentesis, magnetic resonance imaging, and other diagnostic modalities can further refine the diagnosis and guide perinatal management. Conclusion We report a case of prenatal diagnosis of SGBS made through CVS due to increased NT thickness. This case demonstrates that SGBS can be diagnosed at an early gestational stage by combining CVS with CNV analysis, even when increased NT thickness is the only nonspecific marker. This diagnostic approach mitigates the physical and psychological burden associated with mid-trimester pregnancy termination resulting from delayed diagnosis. Additionally, the case underscores the importance of maintaining vigilance toward increased NT and other early ultrasonographic abnormalities, as well as the need for timely genetic counseling and prenatal testing, even in the absence of a known family history of genetic disorders. Early diagnosis not only facilitates comprehensive reproductive guidance for affected families but also constitutes a crucial step toward the primary prevention of congenital anomalies. Funding Funded project: “study on the construction of a preeclampsia risk prediction model based on combined detection of comprehensive pregnancy indicators in Heilongjiang region”, funded by the Scientific Research Special Fund Project of the Wu Jieping Medical Foundation. Project number: 320.67502024-03-35. “Study on the pregnancy cohort in cold regions of China”, funded by the Key Project of Medical and Health Scientific Research in Heilongjiang Province. Author Contributions LC (first author) was responsible for the overall idea of this report and drafted this manuscript. CW participated in the case investigation and discussion. GC and ZD were responsible for the ultrasonic analysis work. LL read the literature and summarized them. YL and SL were responsible for the analysis and review of the genetic report. RW conducted an in-depth analysis of the collected reports. ML(corresponding author, the guarantor) conceived of the report, and she was responsible for the authenticity and integrity of the research as well as the content of the manuscript. All authors read and approved the final manuscript. Conflicts of Interest The authors declare no conflicts of interest. Data Availability Consent obtained from parent(s)/guardian(s).