17q12 Microduplication Syndrome: The Need for Clinical Vigilance in Fetuses with Double Bubble Sign in the Era of Noninvasive Prenatal Testing

Dear Editor, A 26-year-old woman, G2P1A0, underwent a normal nuchal translucency scan and received normal results from noninvasive prenatal testing (NIPT) for aneuploidy screening. Her previous pregnancy resulted in the birth of a healthy boy. This current pregnancy was conceived spontaneously. The couple is healthy and nonconsanguineous, with no significant family histories reported. The woman denied the use of any medications or substances before conception. At 22-week gestation, a routine second-trimester ultrasound revealed a double bubble sign in the fetus [Figure 1a]. Fetal growth metrics and amniotic fluid volume were both within normal limits, and no extra-gastrointestinal anomalies were identified. The woman was informed that duodenal obstruction (DUO) might be responsible for the abnormal ultrasound finding. Amniocentesis was performed for genetic investigations. Chromosomal G-banding on cultured amniocytes revealed a karyotype of 46, XY. Chromosomal microarray analysis conducted on DNA from uncultured amniocytes detected a 1.58-Mb copy number variation (CNV) in the region of 17q12: Arr17q12 (hg19) (34,822,466–36,404,555) × 3 [Figure 1b]. To further exclude the possibility of monogenic conditions affecting the fetus, trio exome sequencing was also performed; this analysis did not identify any pathogenic single-nucleotide variants or insertion-deletion variants but confirmed de novo occurrence of the 17q12 CNV within this family. This CNV has been classified as pathogenic according to ACMG guidelines. Following genetic counseling regarding neuropsychiatric disorders associated with 17q12 microduplication, the couple made the decision to terminate the pregnancy at 24-week gestation. Just prior to the termination, a targeted scan still revealed only the double bubble sign, accompanied by normal biometrics, facial profile, cardiac, and central nervous system morphology.Figure 1: A fetal case of 17q12 microduplication with double bubble sign. (a) Double bubble sign at 22-week gestation; (b) Chromosomal microarray analysis detected a 1.58-Mb microduplication in the region of 17q12 (arr17q12 [hg19] [34,822,466–36,404,555] ×3). The red box indicates the duplicated region on the 17q12 segment. DUO: Duodenal obstruction, ST: StomachThe detection of the fetal double bubble sign is highly indicative of DUO. This sign may also be observed in conditions such as annular pancreas, duodenal webs leading to duodenal stenosis, proximal jejunal atresia, and midgut volvulus. Approximately one-third of individuals diagnosed prenatally with DUO have Down syndrome, and overall, 3%–5% of those with trisomy 21 present with DUO.[1] The double bubble sign typically manifests in late pregnancy; however, current prenatal care practices suggest a significantly reduced likelihood of common aneuploidies due to the routine implementation of first-trimester screening strategies with NIPT. The 17q12 duplication syndrome involves a specific ~1.4 Mb region at 17q12. Despite its incomplete penetrance and variable expressivity, certain phenotypes are more consistently associated with the 17q12 microduplication. These include cognitive impairment, speech and motor developmental delays, brain anomalies, dysmorphic facial features, behavioral abnormalities, and epilepsy.[2] Consequently, prenatal diagnosis is essential for this syndrome. We present a fetal case exhibiting a 17q12 microduplication characterized by an isolated double bubble sign. Notably, this sonographic feature has been recurrently documented in cases involving this microduplication;[3-5] it appears that the double bubble sign is a common fetal phenotype linked to this genetic alteration. Other identified phenotypes encompass cardiac anomalies, agenesis of the corpus callosum, and fetal growth restriction.Abbreviations ACMG American College of Medical Genetics and Genomics CNV Copy number variation DNA Deoxyribonucleic acid DUO Duodenal obstruction G2P1A0 Gravida 2, para 1, abortion 0 G-banding Giemsa banding Mb Megabytes NIPT Noninvasive prenatal testing ST StomachOur case provides further evidence that consideration should be given to the possibility of a 17q12 microduplication in fetuses presenting with a double bubble sign, particularly among those classified as low-risk based on aneuploidy screening results. The early identification of pathogenic CNVs during pregnancy enables timely evaluation and clinical management for potential complications. Ethics statement This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and its amendments. The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.