Multiple Malformations Research Articles

To evaluate valproic acid (VPA) safety in pregnancy versus other antiepileptic drugs (AEDs), focusing on fetal malformation risks. A literature search was conducted across PUBMED, MEDLINE, EMBASE, and Web of Science databases. Two researchers independently screened studies, extracted data, assessed quality, and analyzed VPA safety. This meta-analysis of 25 safety studies showed that compared with other AEDs, VPA's teratogenic risks were as follows: combined major congenital malformations (RR = 2.36, 95% CI: 2.17-2.56), neural tube defects (RR = 6.54, 95% CI: 4.51-9.47), congenital heart defects (RR = 2.53, 95% CI: 2.16-2.96), cleft lip and/or palate (RR = 4.31, 95% CI: 3.06-6.08), genitourinary anomalies (RR = 3.32, 95% CI: 2.67-4.14), and musculoskeletal anomalies (RR = 2.88, 95% CI: 1.98-4.19). Additional analyses stratified by calendar era yielded consistent results, with the corresponding RR values for the above malformations being 2.43 (95% CI: 2.13-2.77), 6.64 (95% CI: 4.50-9.79), 2.64 (95% CI: 2.14-3.26), 4.27 (95% CI: 2.98-6.12), 3.45 (95% CI: 2.76-4.31), and 2.99 (95% CI: 2.00-4.46), indicating a higher risk of multiple malformations with VPA. VPA monotherapy significantly increases teratogenic risk, especially for neural tube defects and cleft lip/palate. Newer AEDs with lower risk profiles are preferred for epilepsy treatment during pregnancy. If VPA use is unavoidable, low doses and blood concentration monitoring are recommended to mitigate risk.

Limb body wall complex (LBWC) is a rare syndrome that consists of, combination of multiple fetal malformations of the thoracoabdominal wall, extremities, cranium, facial and spine. The sonographic hallmarks are abdominal/thoracic wall defect, neural tube defect, severe scoliosis, positional deformity and abnormal fetal membranes. Authors present a case of LBWC abnormality, which was detected in the antenatal ultrasonography at the POG of 13 weeks and later confirmed in the abortus. Early diagnosis of LBWC is only possible through ultrasonography, and it being a fatal condition needs to be distinguished from gastroschisis and omphalocele, which has a better prognosis.

Segmental spinal dysgenesis is a rare and complex congenital anomaly that affects the spinal cord. It is hypothesized to be a notochord malformation. Patients generally present with spastic paraparesis and a neurogenic bladder. It is characterized by focal spinal cord dysgenesis and kyphoscoliotic deformity. We present the case of a 2-year-old boy who presented to the outpatient department of our hospital with complaints of recurrent urinary tract infection and fever. On examination, he had bilateral clubfoot, kyphoscoliotic deformity, and paraparesis. Further examination by micturating cystourethrogram revealed bilateral grade V vesico-ureteric reflux. Cystoscopy ruled out a posterior urethral valve. Magnetic resonance imaging of the spine was conducted to evaluate any neurological cause, which revealed a high blunt ending of the spinal cord at the dorsal level 10, with the absence of spinal cord tissue between dorsal 10 and sacral 2 level. Bulky cord-like tissue was noted from the sacral 2-4 level. These findings were associated with a syrinx formation and multiple vertebral malformations. The patient was managed conservatively.

Introduction: Neurodevelopmental and multiple malformation disorders spanning large phenotypic series can often lead to obscure diagnoses in the clinic. Blended phenotypes from multiple etiologies can compound this issue. We present a rare familial case of two siblings with Nicolaides-Baraitser Syndrome (NCBRS) complicated by an initial diagnosis of syndromic craniosynostosis in one of the patients. Case Presentation: Whole Exome Sequencing (WES) was performed for the affected siblings using the Agilent SureSelect kit and Illumina HiSeq 2500 system, followed by GATK variant calling and in-house annotation. Sanger sequencing was used to validate candidate variants in all immediate family members. A pathogenic de novo variant in TCF12 (p.Gln646Ter), consistent with craniosynostosis type 3 (CRS3) was identified in the proband, along with a novel likely pathogenic variant in SMARCA2 (p.Ile833Phe) involved in NCBRS. The latter was also detected in the sister and is thus suspected to have arisen through germline mosaicism. Various overlapping phenotypic manifestations complicated clinical diagnosis. Conclusion: This case expands the molecular and clinical spectrum of NCBRS and CRS3 and underscores the utility of trio-based WES in detecting blended phenotypes of disorders with growing phenotypic spectrums. Paternal germline mosaicism may underlie high recurrence and inform reproductive counseling.

Background. The presented case report demonstrates a rarely described in the literature combination of a sporadic mutation of the TP63 gene with a previously unreported genetic mutation of HG3B, which led to a combined immunodeficiency with multiple congenital malformations. The uniqueness of the case is determined by an atypical combination of genetic disorders and their clinical manifestations. Case Report. A 5-month-old male patient with widespread erythematous-squamous skin lesions on the scalp, face, and extremities, as well as multiple congenital malformations, including cleft palate, hypospadias, and renal abnormalities. The patient was diagnosed with combined immunodeficiency with a T-cell defect, which manifested as recurrent infections. Based on a comprehensive examination, a diagnosis of combined immunodeficiency with a T-cell defect associated with a TP63 gene mutation and an HG3B mutation was made. A comprehensive therapy was carried out, including replacement therapy with immunoglobulins, antibacterial treatment, and the placement of a gastrostomy. As a result of the treatment, the patient’s condition was relatively stabilized. Conclusion. The described case report expands the understanding of the spectrum of clinical manifestations in TP63 gene mutations and demonstrates the need for further study of the role of new genetic mutations in the pathogenesis of immunodeficiency conditions. This case report highlights the importance of a multidisciplinary approach in the diagnosis and treatment of rare genetic diseases.

Background: Foetal structural abnormalities can be detected in approximately 3% of all pregnancies and frequently remain without a genetic diagnosis. This study aims to apply an integrated approach with the final goal of providing a molecular diagnosis in the challenging Italian setting of early termination of pregnancy. Methods: In a cohort of 86 foetuses, post-mortem dysmorphological examination, radiological assessments, and molecular autopsy through Whole-Exome Sequencing—WES—analysis were performed. Results: Forty-two foetuses were phenotypically classified as presenting a single major malformation (i.e., central nervous system, skeletal, urogenital, or cardiac anomalies, or fluid accumulation), while 44 foetuses presented multiple malformations and/or dysmorphic features. Overall, WES provided a diagnostic yield of 26.7%; additionally, seven Variants of Uncertain Significance (VUS) potentially liked to the foetal phenotype were identified. The highest detection rate was achieved for foetuses presenting a single major urogenital (50%) or skeletal (42.9%) malformation, followed by foetuses presenting multiple malformations (27.3%). Peculiar results of particular interest were (1) the identification of two splicing variants (within the INPPL1 and RHOA genes), functionally characterised through minigene assay, which contributed to evaluate their pathogenicity, and (2) the identification of a novel de novo missense ZNF292 variant (NM_015021.3:c.6325A>C p.(Ser2109Arg)) in a foetus affected by corpus callosum hypoplasia. The ZNF292 gene is associated with the Intellectual developmental disorder, autosomal dominant 64 and this finding represents the first report of prenatally detected anomalies of the central nervous system in a foetus carrying a ZNF292 variant. Conclusions: This study underlines the diagnostic utility of an integrated approach to achieve a precise genetic diagnosis for structural foetal abnormalities, thus providing families with precise recurrence risk estimations and detailed options about future pregnancies. Additionally, a systematic implementation of this strategy could be crucial to better characterise new variants and discover new genes involved in embryonic and foetal development.

Blue rubber bleb nevus syndrome (Bean syndrome) is a rare congenital venous malformation most frequently localized in the skin and gastrointestinal tract. Gastrointestinal involvement may manifest with recurrent intestinal bleeding, chronic anemia, and abdominal pain. This article presents a clinical case of a rare congenital disease in an adolescent and the use of a hybrid surgical approach for vascular malformations at multiple sites. The patient, a boy, was born with a vascular lesion in the area of the anterior fontanelle. In early childhood, he underwent neurosurgery for a cerebral angioma. At the age of 13, he developed abdominal pain and was diagnosed with severe anemia, requiring blood transfusion and iron supplementation. Due to persistent anemia, further evaluation was conducted at his local healthcare facility. Fibrocolonoscopy revealed and removed a vascular lesion in the transverse colon. Repeat fibrocolonoscopy demonstrated recurrent venous malformations and new vascular lesions. To clarify the diagnosis and determine further management, the patient was referred to the Federal Scientific and Clinical Center for Children and Adolescents of the Federal Medical-Biological Agency of Russia. Based on the history, clinical examination, and diagnostic findings, Bean syndrome was suspected. A combined (hybrid) surgical procedure was performed. At the first stage, diagnostic laparoscopy revealed multiple venous malformations in the parietal peritoneum and small intestine. At the second stage, under laparoscopic control of the intestinal wall at the sites of hemangiomas, endoscopic submucosal resection of the largest venous malformation in the sigmoid colon was performed. At the final stage of the hybrid operation, wedge resection of the jejunum with a vascular lesion was carried out. Histological examination confirmed venous malformations of the small and large intestines. The patient was referred to a specialized department for targeted sirolimus therapy. This case demonstrates the potential of combined surgical intervention in pediatric patients with multiple vascular malformations. A careful analysis of clinical and anamnestic data, together with laboratory and instrumental findings, made it possible to suspect this rare syndromic condition and to plan a staged hybrid laparo-endoscopic intervention.

Expert consensus on the treatment timing calender of congenital ear malformation with multiple malformations

Fraser syndrome is a rare autosomal recessive disorder characterized by multiple congenital malformations, including cryptophthalmos, syndactyly, and renal agenesis, which can lead to severe complications beginning at the embryonic stage. Mutations in genes encoding extracellular matrix proteins such as FRAS1, FREM1, FREM2, and the associated trafficking protein GRIP1, are implicated in Fraser syndrome. These proteins are critical for maintaining epithelial integrity during embryogenesis, with deficiencies leading to tissue detachment and blistering phenotypes in mouse models. The FREM2 protein is a single-pass membrane protein of 3169 amino acids. While Frem2-deficient mouse models encoding missense variants found in patients, or a truncated FREM2 protein product were previously reported, it has not been studied in a constitutive knockout (KO) mouse model. Here, we developed constitutive Frem2-KO mice exhibiting neonatal lethality, mainly due to bilateral renal agenesis, along with blood-filled blisters, cryptophthalmos, and syndactyly. Only one mouse survived to adulthood exhibiting unilateral renal agenesis and Fraser syndrome-like phenotypes. These findings confirm FREM2’s crucial role in the development of the kidneys, skin, and eyes and provide an animal model for further studies of FREM2-related developmental disorders.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-14737-y.

Ambroxol (AMB), a common expectorant, enters aquatic environments via wastewater, yet its ecological risks remain unclear. Under UV exposure (15 mJ·cm-2, λ = 185-400 nm), AMB undergoes photolysis, among the photoproducts, 4-((2-amino-3-bromobenzyl)amino) cyclohexanol (P1) and 2-amino-3,5-dibromobenzaldehyde (DBA) are major species, comprising over 50% of the total photoproduct peak area at the photolytic plateau. Acute toxicity tests with AMB, P1, and DBA in four aquatic species at different trophic levels revealed: the highest sensitivity in Danio rerio (LC50 = 0.56-51 ng/L), intermediate sensitivity in D. rerio embryos (LC50 = 4.8-240 ng/L), and relative tolerance in Artemia salina (LC50 = 8.4-265.7 ng/L) and Chlorella (LC50 = 138.4-450.6 μg/L), illustrating clear trophic-level differences. UV-irradiation significantly potentiated the AMB toxicity in zebrafish by promoting reactive oxygen species (ROS) generation and inducing oxidative stress, leading to multiple developmental malformations. Integrated biomarker response and metabolomic analyses confirmed that UV-irradiation aggravated AMB-induced oxidative damage and disrupted key metabolic pathways, including purine metabolism, CoA-biosynthesis, and cytochrome-P450 metabolism. Western blot analysis revealed that UV-irradiated AMB activated apoptotic pathways via oxidative stress. These results underscore the necessity of including photochemically induced aquatic toxicity risk assessments for AMB and similar bromine-containing pharmaceuticals.

Introduction: Down syndrome is the most common genetic cause of multiple congenital malformations and intellectual disability. The prevalence of the disorder and accompanying malformations, prenatal and postnatal features, and clinical approach to the syndrome vary across different regions worldwide. This study aims to share our clinic’s experience with Down syndrome from pregnancy through childhood from a medical geneticist’s perspective and to summarize the prenatal and postnatal characteristics of our patients. Methods: A 10-year review of medical records was conducted for patients with Down syndrome who were followed between 2010 and 2021. Patient data including sex, karyotype, follow-up period, age at first and last visit, congenital malformations, organic disorders, prenatal screening data, neonatal history, neuromotor developmental milestones, and growth parameters were evaluated. Results: Overall, 324 children with Down syndrome were evaluated. Overall, 95% (308) had regular trisomy 21. The mean age at admission was 6.09 ± 1.99 months, and patients were followed for an average of 32.7 ± 3.97 months. Overall, 51% of neonates and 53.5% overall were hospitalized. While common disorders such as congenital heart defects (57.5%), neonatal hyperbilirubinemia (19.7%), and hypothyroidism (39%) were observed, rare conditions such as polydactyly, Ebstein anomaly, epilepsy, epileptic encephalopathy, nephrolithiasis, and cholelithiasis were also reported. Conclusion: The clinical features of Down syndrome observed in Türkiye have been summarized through our cohort. Medical teams need comprehensive knowledge about Down syndrome management. Childhood is recognized as a critical period in Down syndrome care, particularly regarding early diagnosis and treatment of congenital malformations and management of developmental delays.

To evaluate the diagnostic utility of exome sequencing (ES) in structurally abnormal fetuses and infants with suspected severe Mendelian developmental defects. This retrospective study included fetuses (≥12weeks) and infants (≤6months old) with suspected severe Mendelian disorders, clinically categorized as multiple malformations (MM), non-immune hydrops (NIH), and skeletal dysplasia (SKD). All subjects underwent detailed evaluation by a clinical geneticist, which included a clinical examination or fetal autopsy, as applicable, with parental consent. Based on the type of anomaly, investigations such as karyotype, chromosomal microarray (CMA), and/or proband exome sequencing (ES) were performed. Ninety-seven unrelated subjects were enrolled, including 25 (25.8%) multiplex and 17 (17.5%) consanguineous families. They were categorized as multiple malformations (MM) (60/97), skeletal dysplasia (SKD) (19/97), and non-immune hydrops (NIH) (18/97), respectively. The CMA performed in 23 subjects was normal. The overall diagnostic yield of ES for pathogenic/likely pathogenic variants was 40.2% (39/97) and was higher in SKD (57.9%, 11/19), followed by NIH (44.4%, 8/18) and MM (33.3%, 20/60). Eighteen novel variants were identified in 16 genes in various categories. Additional findings on fetal autopsy helped in making a precise diagnosis in 8/21 (38%) subjects. This study elucidates the molecular basis of severe Mendelian developmental defects in early life. Proband-only ES helps in reaching a precise diagnosis in combination with deep phenotyping using fetal autopsy and has a good diagnostic yield. It could be used as a first-tier test, especially in resource-poor settings.

Multiple congenital pulmonary malformations in a black-capped Bolivian squirrel monkey (Saimiri boliviensis boliviensis).

Cavernous malformations (CMs) are vascular malformations characterized by enlarged, thin-walled blood vessels composed of dysplastic endothelial cells and pericytes within a loose extracellular matrix. Endothelial cell dysplasia leads to increased permeability and portends an increased risk of hemorrhage within these malformations, and hemorrhage often manifests with acute-onset neurological deficits due to mass effect and irritation of surrounding neural tissue within the brain and spinal cord. A 5-month-old male presented with concern for possible tethered cord syndrome in the setting of forked gluteal cleft and lower extremity hyperreflexia. He was ultimately determined to have three intramedullary spinal CMs. These were resected with laminoplasty performed. Follow-up imaging demonstrated preservation of spinal alignment and no intraspinal lesion recurrence, with corresponding improvement in the patient's neurological strength examination despite some persistent motor developmental milestone delay. Hemorrhage and rehemorrhage rates of intramedullary spinal CMs are higher in the pediatric population than in the adult population. Hence, early resection of these lesions, when feasible, reduces the risk of long-term neurological deficit. Resection in infancy can be augmented by laminoplasty to preserve the posterior tension band within the spinal column, promote bony regrowth, and significantly reduce the risk of delayed deformity. https://thejns.org/doi/10.3171/CASE2557.

Rationale:Contractures, pterygia, and spondylocarpotarsal fusion syndrome (CPSFS) comprises a group of extremely rare genetic disorders characterized by congenital craniofacial and musculoskeletal abnormalities. With fewer than 500 cases reported globally, this scarcity contributes to limited clinical recognition, frequent diagnostic delays or errors, and missed opportunities for timely intervention. We present this case to enhance awareness of CPSFS and report a novel pathogenic variant in MYH3 (previously undocumented in the literature) that broadens the known mutational spectrum of MYH3 and enriches the phenotypic profile of CPSFS.Patient concerns:A female neonate was born at 29 weeks, prenatal ultrasound and magnetic resonance imaging revealed scoliosis and vertebral fusion. The postnatal examination showed microstomia, low-set ears, a short neck with webbing, and flexion contractures at shoulders, elbows, knees, and hands. The whole genome sequencing found novel variants, namely NM_002470.4: c.1914del C; p. Lys639Argfs*18 and NM_002470.4: c.-68 + 4A > T, in the MYH3.Diagnoses:CPSFS 1.Interventions:Immediately after birth, noninvasive ventilatory support was initiated. The surgical team conducted comprehensive evaluations, while concurrent genetic testing was performed. Given the infant’s multiple systemic skeletal malformations and inability to sustain spontaneous respiration, surgical intervention was deemed nonviable.Outcomes:Due to severe thoracic deformity and bronchopulmonary dysplasia, the infant required continuous noninvasive ventilation from birth and remained ventilator-dependent. At a corrected gestational age of 36 weeks and 4 days, life-sustaining therapy was withdrawn following thorough counseling and parental deliberation. The infant died shortly thereafter.Lessons:Prenatal ultrasound and fetal magnetic resonance imaging can reliably detect characteristic manifestations including scoliosis, joint developmental abnormalities, and clubfoot. Thus, regular prenatal surveillance plays a critical role in early disease identification. For suspected cases, genetic counseling and diagnostic testing enable informed parental decision-making regarding management of affected offspring and future reproductive planning.

IntroductionLenz-Majewski syndrome (LMS) is an ultra-rare congenital disorder with progressive skeletal dysplasia, cutis laxa, and intellectual disability, typically caused by pathogenic variants in the PTDSS1 gene.MethodsOur patient with multiple malformations and developmental delay who was treated at the Women and Children's Hospital of Ningbo University in September 2023 was selected as the research subject. Whole exome sequencing (WES) technology was used to test the child, and Sanger sequencing verification and pathogenicity analysis were carried out for the suspected variations.ResultsWe report the first molecularly confirmed case of LMS in a Chinese patient, a male infant presenting with classic features such as craniofacial dysmorphism, hyperostosis, loose skin, syndactyly, and short stature, together with mild global developmental delay and thyroid dysfunction. Whole exome sequencing (WES) identified a heterozygous c.806C > T (p. Pro269Leu) variant in the PTDSS1 gene, which was validated by Sanger sequencing and functionally assessed for pathogenicity. We further reviewed 12 previously reported cases with PTDSS1 variants and compared phenotypes, highlighting both shared and unique features.DiscussionThis case expands the ethnic and phenotypic spectrum of LMS and reinforces the association between the c.806C > T (p. Pro269Leu) variant and LMS. Early genetic testing facilitates recognition of atypical presentations and enables timely diagnosis and management.

Fraser syndrome is a rare autosomal recessive disorder characterized by multiple congenital malformations, including cryptophthalmos, syndactyly, and renal agenesis, which can lead to severe complications beginning at the embryonic stage. Mutations in genes encoding extracellular matrix proteins such as FRAS1, FREM1, FREM2, and the associated trafficking protein GRIP1, are implicated in Fraser syndrome. These proteins are critical for maintaining epithelial integrity during embryogenesis, with deficiencies leading to tissue detachment and blistering phenotypes in mouse models. The FREM2 protein is a single-pass membrane protein of 3169 amino acids. While Frem2-deficient mouse models encoding missense variants found in patients, or a truncated FREM2 protein product were previously reported, it has not been studied in a constitutive knockout (KO) mouse model.Here, we developed constitutive Frem2-KO mice exhibiting neonatal lethality, mainly due to bilateral renal agenesis, along with blood-filled blisters, cryptophthalmos, and syndactyly. Only one mouse survived to adulthood exhibiting unilateral renal agenesis and Fraser syndrome-like phenotypes. These findings confirm FREM2’s crucial role in the development of the kidneys, skin, and eyes and provide an animal model for further studies of FREM2-related developmental disorders.

ObjectiveTranslation of fertility risks through whole-exome sequencing of family lines to identify variants that explain patient’s clinical phenotypes.Methods1. Using techniques such as amniotic fluid, chorionic villus, or umbilical cord blood sampling, intact fetal cells were extracted for cell culture and subsequently analyzed using chromosomal karyotyping and chromosomal microarray techniques. 2. With fully informed consent, fetuses and their parents whose genetic etiology could not be detected by karyotyping combined with chromosomal microarray technology had their cellular DNA subjected to whole-exome sequencing of the pedigree. 3. Pathogenic variants were screened in combination with fetal ultrasound phenotyping and ACMG variant rating guidelines for variant interpretation, followed by inviting multidisciplinary experts to conduct an in-depth analysis and indicate fetal-related ultrasound abnormalities. 4. Genetic counseling is assisted based on the results.Results1. Of the 357 fetuses included in the study, 33 (33/357, 9.24%) had a successful genetic etiology identified through family-wide exome sequencing combined with ultrasound phenotyping. 2. The results showed that skeletal anomalies were the most frequent, accounting for 15 cases (15/33, 45.45%), followed by multiple malformations in 7 cases (7/33, 21.21%), renal anomalies in 3 cases (3/33, 9.09%), soft index anomalies in 2 cases (2/33, 6.06%), neurological anomalies in 2 cases (2/33, 6.06%), cleft lip and palate in 1 case (1/33, 3.03%), cardiac abnormality in 1 case (1/33, 3.03%), hydatidiform mole in 1 case (1/33, 3.03%), and cataract in 1 case (1/33, 3.03%). 3. During whole-exome sequencing, three previously unreported variant sites were identified: MSX2 (NM_002449.4: c.423_427dupCAATC, p.Arg143Profs*39), EVC (NM_153717.2: c.130delC, p.Leu44Phefs*72), and RYR1 (NM_000540.2: c.14129 + 1 G > A).Conclusion1. This study provides robust data supporting the application of whole-exome sequencing of family lines in clinical practice, offering valuable reference information for clinicians. 2. The newly discovered variants significantly enhance the relevant genetic databases. 3. Genetic diagnosis can offer clear guidance regarding the decision to continue with the pregnancy and future reproductive choices.

Congenital malformations constitute anomalies of structure and/or function of prenatal origin, which are often asymptomatic or cause few symptoms, but currently have a high incidence. With the aim of showing the findings detected in the imaging studies carried out, the case of a young adult with repeated mild urinary sepsis is presented, who was diagnosed with multiple and bilateral renoureteral malformations in the infertility consultation. The majority of congenital renoureteral malformations imply serious biopsychosocial problems for the patient, with the consequent impact on the psychological sphere and the social life of family members when diagnosed in the prenatal stage, so they inevitably constitute a health problem, since they contribute to fetal and infant mortality or increased morbidity in any age group. For this reason, early diagnosis is essential to guarantee appropriate behavior and quality of life. Keywords: congenital malformations; renoureteral malformations; early diagnostic; ultrasound; descending urogram; double excretory system; ureterocele; reflux vesicoureteral

The first case of Al-Raqad syndrome in Japan is associated with a homozygous DCPS exonic variant resulting in aberrant splicing.