VATER症候群

BACKGROUND/PURPOSE: Vaginal anomalies frequently accompany anorectal malformations (ARMs) in females, yet management strategies remain poorly standardized. This study presents our 17-year single-center experience with vaginal reconstruction in ARM patients with documented Müllerian and/or vaginal anomalies, focusing on surgical decision-making, technique selection, and outcomes. METHODS: This study was conducted retrospectively on all children with ARMs who had documented Müllerian and/or vaginal anomalies who underwent vaginal reconstruction at our tertiary referral center between January 2004 and January 2021. Patient demographics, ARM types, vaginal anomaly types, associated anomalies, surgical approaches, vaginal reconstruction techniques, complications, and long-term outcomes were analyzed. Categorical variables were compared using Fisher's exact test. RESULTS: Eighteen patients underwent vaginal reconstruction: 11 (61%) had persistent cloaca (PC), 6 (33%) had rectovestibular fistula with anal atresia (RVFAA), and 1 (6%) had cloacal exstrophy. Eleven patients (61%) had duplicated vaginas; distal vaginal agenesis was present in 6 (33%). Associated anomalies were highly prevalent: vertebral (72%), gastrointestinal (39%), urinary (39%), cardiac (27%), and VATER/VACTERL association (22%). Mean age at definitive surgery was 2.50 ± 1.53 years. Vaginal reconstruction methods included introitoplasty (28%), vaginal septum excision (33%), and vaginal replacement using bowel segments and/or rectovestibular fistula tissue (33%). Mean achieved vaginal length was 60.56 ± 13.16 mm. Complications occurred in 44% of patients, predominantly wound dehiscence (33%) and fistula formation (28%). Fistula formation was significantly associated with prior wound dehiscence (p < 0.001). Mean follow-up was 7.18 ± 3.66 years (range 2.3-14.3 years). CONCLUSIONS: Vaginal anomalies in ARMs require individualized reconstruction approaches. No single technique is universally applicable. The surgical algorithm should prioritize maximal native vaginal tissue use, appropriate replacement tissue selection when needed, protective colostomy for complex cases, and long-term follow-up through puberty.

INTRODUCTION: VACTERL association is a congenital disorder characterized by the non-random co-occurrence of vertebral, anal, cardiac, tracheo-esophageal, renal, and limb anomalies. WBP11 has been identified as a candidate causative gene; however, existing heterozygous Wbp11 knockout mice recapitulate only a subset of the patient phenotypes, most notably lacking the cardiac defects, which limits a comprehensive understanding of the pathogenic mechanisms. Whether WBP11 loss of function is sufficient to induce the full multi-system spectrum of VACTERL association in a vertebrate model remains unexplored. METHODS: We established a wbp11 knockdown zebrafish model by microinjecting a translation-blocking morpholino (wbp11-MO) at the optimized concentration of 0.25 mM. Knockdown efficiency was validated by Western blot. Bioinformatics analysis of public single cell and expression atlas datasets was combined with whole-mount in situ hybridization to characterize the spatiotemporal expression of wbp11. Phenotypic defects across cardiac, vascular, spinal, fin, and renal systems were assessed by stereomicroscopy, transgenic reporter lines (Tg(myl7:EGFP) and Tg(flila:EGFP)), and whole mount in situ hybridization. Underlying molecular changes were interrogated by transcriptome sequencing (RNA-seq) coupled with differential alternative splicing analysis (rMATS) and quantitative real-time PCR validation. Rescue experiments were performed by co-injection of capped wbp11 mRNA. RESULTS: wbp11 is evolutionarily conserved and maternally expressed, peaking at the gastrula stage with elevated signals in the head, skeletal muscle, and heart. wbp11-MO injection reduced Wbp11 protein levels, induced a 70% overall malformation rate, and caused a general delay in embryonic development. wbp11-deficient larvae exhibited multi-system developmental defects that closely mirror the core clinical features of VACTERL association: cardiac malformations with pericardial edema and impaired heart looping; vascular defects including underdeveloped subintestinal vessels and reduced cranial vasculature; spinal curvature with aberrant notochord structure; hypoplasia of the pectoral, pelvic, anal, and caudal fins; and transcriptional dysregulation of kidney developmental markers. Transcriptomic and alternative splicing analyses revealed significant dysregulation of genes associated with cardiac function, angiogenesis, skeletal patterning, fin development, and kidney development, accompanied by widespread splicing aberrations. DISCUSSION: This study establishes the first wbp11-knockdown zebrafish model that partially recapitulates the key organ phenotypes of human VACTERL association notably including the cardiac defects absent in the mouse model and thereby provides a powerful platform for dissecting the splicing dependent molecular mechanisms underlying this disorder and for exploring potential therapeutic interventions.

IMPORTANCE: The VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal defects, and limb defects) pattern of birth defects is a complex congenital condition with largely unknown causes. Studies suggest a link between in vitro fertilization (IVF) and birth defects, including VACTERL, but it remains unknown whether IVF has a unique association with VACTERL. OBJECTIVE: To characterize the association between IVF and VACTERL. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included 1 555 936 live births in 4 US States (Massachusetts, New York, North Carolina, and Texas) between January 1, 2004, and December 31, 2018. A total of 175 161 births were IVF conceived, and 1 380 775 naturally conceived children were selected as a 10:1 comparison group. Births were linked to IVF cycle data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System. Data were analyzed from August 2 to October 30, 2025. EXPOSURES: Method of conception (IVF vs natural) and IVF treatment parameter information. MAIN OUTCOMES AND MEASURES: VACTERL, defined as 3 or more of the defects included in the pattern. Multivariable logistic regression models were used to estimate adjusted odds ratios and 95% CIs. RESULTS: A total of 1 555 936 live births were included in the analysis (796 892 males [51.2%]). The naturally conceived group included 1 380 775 children; the IVF-conceived group, 175 161. Approximately half of children were male in both groups, while IVF-conceived children were more often born to older mothers and those with a higher educational level and were from multiple-gestation pregnancies. Two hundred children with VACTERL (41 IVF and 159 non-IVF) were identified. The prevalence of VACTERL among IVF-conceived births was 2.3 (95% CI, 1.7-3.2) per 10 000 live births. After adjusting for demographic, socioeconomic, and pregnancy-related factors, IVF conception was associated with increased odds of VACTERL (adjusted odds ratio, 1.86; 95% CI, 1.16-2.98). CONCLUSIONS AND RELEVANCE: This population-based prospective cohort study identified an association of IVF with the multiple congenital anomaly pattern VACTERL. Although the absolute risk among live births remains low, these findings highlight the need for further investigations of child health outcomes by method of conception.

MED14 is the largest subunit in the Mediator complex and plays a key role in regulating RNA polymerase II-mediated transcription, but its developmental function remains largely unknown. Here, we show that med14 is required for the proper formation of multi-organs, including the heart, pectoral fin, vertebrae, cloaca, and pronephros, most of which are derived from the mesoderm and are generally affected by VACTERL association, a syndrome with higher prevalence in males. Using this animal model, we further demonstrated that failures in cell fate decisions during organogenesis, but not in early mesoderm formation and subsequent medio-lateral patterning, were the cause of the multi-organ malformations. Importantly, we identified a novel missense mutation in the MED14 gene (p.Ile550Val) located on the X chromosome in a patient and his family, and neonatal mice carrying the corresponding mutation displayed diagnostic features of VACTERL association. Further investigation revealed that this mutation impairs the structural role of MED14 in the recruitment of specific subunits, such as MED7 and MED17, to the Mediator complex, thereby compromising the interaction between the Mediator complex and RNA polymerase II and decreasing the expression of a set of downstream genes required for the organogenesis of VACTERL-related systems. Taken together, our work uncovers an essential role of MED14 in fetal organogenesis and provides mechanistic insights into the connection between VACTERL association and the Mediator complex.