Prenatal diagnosis of a fetus with cri-du-chat syndrome accompanied by 18q duplication: a case description
Introduction
Cri-du-chat syndrome (CDCS), also known as 5p deletion syndrome [Online Mendelian Inheritance in Man (OMIM): 123450], is a rare chromosomal microdeletion syndrome caused by deletion of the short arm of chromosome 5, with intellectual disability, developmental delay, and multiple congenital malformations as its core phenotypes. Existing studies mainly focus on cases with isolated 5p deletion. Compound cases of CDCS combined with large de novo copy number variations (CNVs) of other chromosomes are extremely rare. Prenatal cases concurrent with large-segment duplication of the 18q region have not been fully recognized, and the underlying mechanism linking genotype to fetal phenotype remains unclear. Prenatal ultrasonography serves as the primary modality for screening fetal structural malformations. Combined with CNV sequencing and familial genetic testing, it enables molecular etiological diagnosis for unexplained multiple fetal malformations. Compared with classic isolated CDCS, fetuses accompanied by additional chromosomal microduplications often present with more severe and extensive multisystem malformations, yet unified criteria for clinical management and genetic counseling are still lacking. This article reports a rare prenatal case of CDCS complicated with de novo large-segment duplication at 18q21.31q23. We mainly analyze the clinical genetic characteristics, synergistic pathogenic effects, and ultrasonic phenotypic features of this compound CNV. This study expands the genetic variation spectrum and prenatal phenotypic spectrum of CDCS, and provides evidence-based references for prenatal diagnosis and genetic counseling of similar rare complex chromosomal microdeletion and microduplication disorders.
Case presentation
A 22-year-old primigravida (G1P0) was referred to our hospital for further prenatal diagnosis due to fetal malformation detected by prenatal ultrasonography at an outside institution. The patient had regular menstrual cycles and an unremarkable health history. She denied a history of chronic infectious diseases including hepatitis B and tuberculosis, and had no medical history of chronic disorders such as hypertension and diabetes mellitus. Both the patient and her spouse denied a family history of genetic diseases and consanguineous marriage. Nuchal translucency (NT) screening at the outside hospital showed an NT thickness of 1.4 mm. Prenatal ultrasonography at 26 gestational weeks identified an approximately 13 mm × 9 mm anechoic lesion in the fetal fourth ventricle, an internal diameter of the main pulmonary artery of 0.94 cm, and an decreased ratio of ascending aorta to main pulmonary artery. Consequently, the patient was referred to our hospital for further prenatal ultrasound consultation.
Targeted prenatal color Doppler ultrasonography was performed in our Prenatal Diagnosis Center. Ultrasonographic findings were summarized as follows: (I) Intrauterine single live fetus, with a menstrual age of 26+ weeks; fetal biometric parameters were equivalent to a gestational age of 22+6 weeks, indicating significant fetal growth restriction. Fetal biometric parameters, including biparietal diameter, head circumference, femur length, humerus length, and transcerebellar diameter, were all below −2 SD relative to the mean for gestational age, consistent with fetal growth restriction (FGR). (II) Fetal central nervous system malformations: cerebellar hypoplasia, Dandy-Walker malformation, intracranial anechoic lesion (venous angioma could not be excluded) (Figure 1A,1B). (III) Fetal congenital heart disease: aortic atresia complicated by aortic hypoplasia, ventricular septal defect, reverse perfusion of the ductus arteriosus, pulmonary artery dilatation (Figure 1C,1D). Serial fetal growth parameters were plotted as growth curves for fetal growth and development assessment (Figure 2).
After comprehensive prenatal counseling and full informed consent, the parents opted for termination of pregnancy. Subsequently, trio whole-exome sequencing (trio-WES) and CNV sequencing (CNV-seq) were performed on the trio (fetus and both parents). Genetic testing revealed a heterozygous deletion of approximately 34.73 Mb in the 5p15.33p13.2 region (chr5:15552-34740886) (Figure 3A) and a heterozygous duplication of approximately 23.30 Mb in the 18q21.31q23 region (chr18:54718129-78017248) in the fetus (Figure 3B). Combined with whole-exome sequencing (WES) data, both CNVs were confirmed as de novo mutations, with wild-type genotypes in both parents. Hemizygosity was detected in the chr5:15552-34740886 region, confirming the diagnosis of 5p deletion syndrome (CDCS, OMIM: 123450).
The case was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This case was approved by the Ethics Committee of Gansu Provincial Maternity and Child-care Hospital. Patients and their families signed informed consent and agreed to publish this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.
Discussion
CDCS, also referred to as 5p deletion syndrome (OMIM: 123450), is predominantly caused by partial deletion of the short arm of chromosome 5 (1). Most previously reported cases presented with an isolated 5p microdeletion, and the abnormal fetal and neonatal phenotypes were largely attributed to gene deletion within the critical 5p region. Distinct from conventional simple CDCS, genetic analysis identified a de novo heterozygous deletion of approximately 34.73 Mb at 5p15.33p13.2 in the fetus, accompanied by a 23.30 Mb duplication at 18q21.31q23. Trio-WES combined with CNV-seq confirmed that both CNVs were de novo mutations. Both parents exhibited wild-type genotypes, with no family history of genetic disorders or consanguineous marriage. This case represents a rare complex chromosomal microdeletion and microduplication syndrome involving concurrent 5p deletion and large-segment 18q duplication, which serves as the primary genetic feature differentiating it from typical CDCS (2).
In terms of gene dosage effect, the 5p15.33p13.2 region contains numerous essential genes responsible for cranial neurogenesis, skeletal linear growth, and cardiovascular morphogenesis. Large heterozygous deletion within this region directly induces posterior fossa dysplasia, long bone growth retardation, and cardiac outflow tract malformation, which closely correspond to the ultrasonic findings of cerebellar hypoplasia, Dandy-Walker malformation, skeletal growth delay, and great artery disproportion. The 18q21.31q23 region harbors multiple functional genes involved in embryogenesis, vascular remodeling, and myocardial differentiation. Haploduplication of this segment leads to gene dosage overload, further disturbing neural crest cell migration, cardiovascular differentiation, and intracranial angiogenesis (3). This mechanism accounts for the atypical ultrasonic manifestations beyond the typical spectrum of CDCS, including aortic atresia, reversed ductal perfusion, pulmonary artery dilatation, and suspected intracranial vascular lesion. In conclusion, 5p deletion establishes a genetic predisposition to basic structural malformations, whereas de novo large-segment 18q duplication exerts a synergistic aggravating effect. The combination of the two variants contributes to severe FGR and extensive multisystem malformations (4).
Most prenatal CDCS cases reported both in China and internationally are characterized by isolated 5p deletion or accompanied by clinically insignificant small CNVs. Rare cases of CDCS combined with de novo large-segment 18q duplication have been documented. Familial genetic verification confirmed that both CNVs were de novo mutations, excluding parental balanced translocation and familial inheritance (5). The compound genotype of concurrent 5p deletion and 18q duplication was confirmed as the unique pathogenic variant in this fetus. This case expands the genetic variation spectrum and prenatal phenotypic spectrum of CDCS, and provides valuable references for genotype-phenotype correlation analysis in similar complex chromosomal microdeletion and microduplication disorders.
Prenatal ultrasonography plays an irreplaceable role in early screening, structural malformation detection, and phenotypic evaluation in this case. Second-trimester ultrasound from an external institution identified a fetal anechoic lesion in the fourth ventricle, a narrowed pulmonary artery diameter, and an abnormal aorta-to-pulmonary artery ratio, providing critical clues for referral to specialized prenatal diagnostic ultrasound (6). Targeted color Doppler ultrasonography in our center accurately evaluated fetal growth parameters and confirmed combined posterior fossa malformation and complex cardiac defects, indicating a condition beyond common chromosomal aneuploidy and isolated CDCS. Accordingly, CNV-seq combined with trio-WES, rather than conventional karyotyping, should be performed promptly (7). Meanwhile, the compound genetic variant of 5p deletion combined with 18q duplication molecularly explains the severe growth restriction, concurrent neurological and cardiovascular involvement, and aggravated clinical phenotype, enabling a precise correlation between prenatal ultrasonic phenotype and molecular genotype (8).
Regarding genetic counseling and reproductive guidance, both CNVs in this fetus were verified as de novo mutations, and the parental genetic background was normal, indicating a relatively low recurrence risk for subsequent pregnancies (9). However, considering the extreme rarity of this compound microdeletion and microduplication syndrome, standardized early prenatal ultrasound screening is recommended for subsequent gestation, and invasive prenatal diagnosis and genetic verification should be performed when necessary. Clinically, for fetuses presenting with unexplained severe growth restriction, posterior fossa structural anomalies, and complex cardiac outflow tract malformations, screening should not be limited to common chromosomal aneuploidy and isolated CDCS (10). Routine application of CNV-seq and WES is strongly advised to rule out multiple combined chromosomal microdeletions and microduplications, avoid missed diagnosis of CNVs with synergistic pathogenic effects, and provide reliable molecular genetic evidence for prenatal counseling and pregnancy decision-making.
Acknowledgments
None.
Footnote
Funding: The study was supported by
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-2389/coif). All authors report that this study was supported by the Natural Science Foundation of Gansu Province (Grant No. 25JRRA334) and the Talent Innovation and Entrepreneurship Project of Lanzhou City (Grant No. 2023-RC-23). The authors have no other 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. This case was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This case was approved by the Ethics Committee of Gansu Provincial Maternity and Child-care Hospital. Patients and their families signed informed consent and agreed to publish this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.
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