Search Results (246)

Objectives: The increasing use of fetal MRI has increased the diagnosis of posterior fossa malformations, yet the long-term neurodevelopmental outcomes of affected fetuses remain unclear. This study aims to examine the long-term neurodevelopmental outcomes of fetuses with structural posterior fossa malformation diagnosed on fetal MRI. Methods: A historical cohort study was conducted at a single tertiary referral center, including fetuses diagnosed with structural posterior fossa malformations and apparently healthy fetuses who underwent fetal brain MRI between 2011 and 2019. Maternal, pregnancy, and newborn characteristics were compared between groups, alongside long-term neurodevelopmental outcomes using the Vineland Adaptive Behavior Scales II (VABS-II) questionnaire. This included an extensive assessment of malformation types, additional structural, genetic, or neurodevelopmental anomalies, and outcomes. Results: A total of 126 fetuses met the inclusion criteria, of which 70 were apparently healthy fetuses, and 56 had structural posterior fossa malformations. Among the latter, 18 pregnancies were terminated, 4 resulted in neonatal death, and 11 were lost to follow-up. No significant differences were found in the overall neurodevelopmental outcomes between fetuses with structural posterior fossa malformation (93.4 ± 19.0) and apparently healthy fetuses (99.8 ± 13.8). Motor skills scores were lower among fetuses with structural posterior fossa malformations (87.7 ± 16.5 vs. 99.3 ± 17.2, p = 0.01) but remained within the normal range. Conclusion: Fetuses with structural posterior fossa malformations may exhibit normal long-term neurodevelopmental outcomes if no additional anomalies are detected during thorough prenatal screening that includes proper sonographic, biochemical and genetic screening, as well as fetal MRI. Further research with larger cohorts and longer-term assessments is recommended to validate these findings and support clinical decision-making. Full article

Fragile X syndrome (FXS) is the most common form of X-linked intellectual disability (ID). This study aimed to share 30 years of experience in diagnosing FXS and determine its frequency in Thailand. We retrospectively reviewed 1480 unrelated patients (1390 males and 90 females) with ID, developmental delay, or autism spectrum disorder, or individuals referred for FXS DNA testing at Songklanagarind Hospital, Thailand, over a 30-year period. The samples were analyzed using cytogenetic methods, PCR-based techniques, and/or Southern blot analysis. Full mutations (>200 CGG repeats) were identified in 100 males (7.2%) and three females (3.3%). An intermediate allele was detected in one male, while no premutation was found in the index cases. Two males were suspected to have FMR1 gene deletions. Twelve families underwent prenatal testing during this study. Most families undergoing prenatal FXS diagnosis involved mothers who were premutation carriers and had given birth to children affected by FXS. This study represents the largest series of molecular genetic FXS testing cases reported in Thailand. The frequency of FXS identified in different cohorts of Thai patients across various periods was approximately 7%. This study enhances public awareness of at-risk populations and highlights the importance of prenatal testing and genetic counseling for vulnerable families. Full article

Background/Objectives: Cystic fibrosis (CF) is a rare autosomal recessive genetic disease that has a progressive and multisystemic course. The spectrum and frequency of mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) vary both in European countries and in other geographical regions. The aim of our retrospective study was to present the genetic variants identified in a group of 48 CF patients from the Moldova region (Romania), as well as to establish genotype–phenotype correlations. Methods: Genetic testing was initially performed for 38 CFTR mutations, and in heterozygous patients or those in whom no mutation was detected, CFTR gene sequencing (NGS) was performed. Results: The compound heterozygous genotype was identified in 26 (54.16%) of the patients (with one of the alleles being F508del), while 22 (45.83%) patients had the homozygous F508del genotype. The F508del variant was the most frequent (69.79%), followed by G542X (6.25%, 6/96). Several new variants were also identified that had not been reported in other studies from Romania (R1158X, K598*, R347H, c.2589_2599del, R496H, and CFTRdele2). Phenotypic manifestations in patients with CFTR class I, II, III and VII variants (homozygous and compound heterozygous) were more severe compared to those in patients with CFTR class IV, V and VI mutations, with the data obtained being consistent with those in the literature. Respiratory tract involvement was present in 77.08% of the patients, being more frequent in patients with the compound heterozygous genotype compared to the homozygous F508del genotype. Most patients had exocrine pancreatic insufficiency (EPI) (85.41%). Gastrointestinal manifestations included hepatocytolysis (66.66%) and biliary cirrhosis (0.41%). Meconium ileus was detected in 18.75% of patients, all with a compound heterozygous genotype. Conclusions: We compared the results obtained with data from the literature and correlated the detected CFTR variant (genotype) with the phenotypic manifestations, highlighting certain particularities present in some patients. Genetic testing allows for early diagnosis and adapted management, including personalized treatment for each patient. Identification of novel unclassified CFTR variants still remains a challenge for clinicians. NGS-based screening of heterozygous healthy carriers is important for both genetic counseling and prenatal diagnosis. Full article

Myocardial hypertrophy (MH) represents a complex and heterogeneous condition in the pediatric and young adult population. While rare in children, MH encompasses a wide spectrum of physiological and pathological entities, ranging from transient hypertrophy in the infants of diabetic mothers to progressive genetic hypertrophic cardiomyopathies (HCM) with significant morbidity and mortality. Differential diagnosis is critical, as many phenocopies—including metabolic, mitochondrial, and syndromic diseases—can mimic HCM. Echocardiography remains the first-line imaging modality, with cardiac magnetic resonance (CMR) and molecular diagnostics increasingly used for detailed characterization. Risk stratification tools, such as the HCM Risk-Kids model, support clinical decision-making but must be integrated with individualized assessment. Advances in prenatal screening and genetic testing have significantly improved outcomes, though long-term management requires multidisciplinary care. Understanding age-specific presentations and the underlying etiologies is essential for accurate diagnosis and targeted treatment. This review provides a comprehensive overview of cardiac hypertrophy from fetal life through young adulthood, with a focus on etiologies, diagnostic approaches, imaging modalities, and therapeutic strategies, and aims to guide clinicians through the evolving landscape of MH, emphasizing early recognition, comprehensive evaluation, and personalized care. Full article

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare, often fatal congenital disorder characterized by severe neonatal respiratory distress and associated with complex multisystem malformations. In approximately 90% of cases, the condition is linked to deletions or mutations affecting the FOXF1 gene or its upstream enhancer region on chromosome 16q24.1. This review analyzes reported prenatal cases with 16q24.1 deletion involving FOXF1, aiming to identify recurrent sonographic features and elucidate the underlying genomic and epigenetic mechanisms. We reviewed prenatal cases reported in the literature involving deletions of the 16q24.1 region, including the FOXF1 gene. Here, we expand the case series by reporting a fetus with increased nuchal translucency measuring 8 mm and a de novo 16q24.1 deletion. We identified nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward. Prenatal diagnosis of ACDMPV based solely on ultrasound findings is challenging. In most reported cases, the pregnancy was carried to term, with the diagnosis being confirmed by post-mortem histopathological examination. In the only case in which the pregnancy was terminated at 14 weeks’ gestation, histological examination of the fetal lungs, despite them being in the early stages of development, revealed misaligned pulmonary veins in close proximity to the pulmonary arteries and bronchioles. Evidence highlights the significance of non-coding regulatory regions in the regulation of FOXF1 expression. Differential methylation patterns, and possible contributions of parental imprinting, highlight the complexity of FOXF1 regulation. Early detection through array comparative genomic hybridization (array CGH) or next-generation sequencing to identify point mutations in the FOXF1 gene, combined with increased awareness of ultrasound markers suggestive of the condition, could improve the accuracy of prenatal diagnosis and genetic counseling. Further research into the epigenetic regulation of FOXF1 is crucial for refining recurrence risk estimates and improving genetic counseling practices. Full article

Spinal muscular atrophy (SMA) is a severe autosomal recessive neuromuscular disorder and a leading genetic cause of infant mortality. Advances in disease-modifying therapies have significantly improved outcomes when treatment is initiated early, underscoring the importance of timely diagnosis. With the growing availability of prenatal genetic screening and high-resolution molecular diagnostics, opportunities for early detection, and potentially in utero intervention, are rapidly expanding. This narrative review synthesizes current evidence on the prenatal management of SMA, focusing on diagnostic strategies, the clinical application of fetal genetic testing, and the emerging potential of fetal therapy. We explore both invasive and non-invasive diagnostic approaches and evaluate experimental prenatal treatment modalities, while critically addressing the associated ethical, regulatory, and economic considerations. As the field progresses, integrating in utero strategies into clinical care may reshape perinatal medicine and offer transformative potential for genetic neurodegenerative disorders diagnosed before birth. The convergence of early diagnosis, fetal intervention, and personalized genetic counseling will be central to optimizing care pathways and outcomes in the era of precision medicine. Although significant challenges remain, the translation of fetal therapy into routine clinical practice is approaching feasibility. Future clinical trials, anchored in definitive prenatal diagnosis, will be essential, with benefits potentially outweighing the inherent procedural risks. Full article

Background and Clinical Significance: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by pathogenic variants in TSC1 or TSC2. Cardiac rhabdomyoma is a common prenatal finding and can be associated with severe complications, including pericardial effusion. We administered prenatal sirolimus to mitigate pericardial effusion, which led to postnatal complications. Case Presentation: A 28-year-old pregnant woman with no significant family history underwent routine fetal ultrasound at 28.1 weeks of gestation, which identified a large right ventricular mass consistent with rhabdomyoma. Further fetal brain MRI revealed cortical-subcortical tubers and subependymal nodules, leading to a clinical diagnosis of TSC. At 30.4 weeks, oral sirolimus (3 mg/day) was started due to the significant pericardial effusion. The effusion remained after treatment, requiring pericardiocentesis at 33.6 weeks. The sirolimus dosage was raised to 6 mg/day at 35.6 weeks, reaching a plasma level of 3.76 ng/mL, but there was no discernible improvement because of the continued fluid accumulation. The mother did not experience any adverse side effects from the procedure. Genetic testing confirmed a pathogenic variant in TSC2 (c.1372C>T). After birth, the neonate received a single dose of sirolimus but subsequently developed necrotizing enterocolitis (NEC), highlighting the potential adverse effects and the need for cautious consideration of treatment options. Conclusions: This case illustrates the complexities of managing prenatal tuberous sclerosis complex (TSC). While sirolimus has been explored for fetal cardiac rhabdomyoma and associated complications, its effectiveness in resolving pericardial effusion remains uncertain. Additionally, the development of NEC postnatally raises concerns about the safety of mTOR inhibitors in this context. Further studies are necessary to assess the risks and benefits of this approach in fetal therapy. Full article

Background and Clinical Significance: Prader–Willi syndrome (PWS) is a rare genetic disease caused by imprinted gene dysfunction, typically involving deletion of the chromosome 15q11.2-q13 region, balanced translocation, or related gene mutations in this region. PWS presents with complex and varied clinical manifestations. Abnormalities can be observed from the fetal stage and change with age, resulting in growth, developmental, and metabolic issues throughout different life stages. Case Presentation: We report the prenatal characteristics observed from the second to third trimester of pregnancy in a neonate with PWS. Prenatal ultrasound findings included a single umbilical artery, poor abdominal circumference growth from 26 weeks, normal head circumference and femur length growth, increased amniotic fluid volume after 30 weeks, undescended fetal testicles in the third trimester, small kidneys, and reduced fetal movement. The male infant was born at 38 weeks of gestation with a birth weight of 2580 g. He had a weak cry; severe hypotonia; small eyelid clefts; bilateral cryptorchidism; low responsiveness to medical procedures such as blood drawing; and poor sucking, necessitating tube feeding. Blood methylation-specific multiple ligation-dependent probe amplification (MS-MLPA) showed paternal deletion PWS. Notably, this case revealed two previously unreported prenatal features in PWS: a single umbilical artery and small kidneys. Conclusions: Through literature review and our case presentation, we suggest that a combination of specific sonographic features, including these newly identified markers, may aid clinicians in the early diagnosis of PWS. Full article

Tay–Sachs disease (TSD) is a rare and severe neurodegenerative disorder inherited in an autosomal recessive manner. It is caused by a deficiency of the enzyme hexosaminidase A, which is responsible for the degradation of GM2 gangliosides—lipids that accumulate in the nerve cells of the central nervous system. The inability to break down these lipids leads to their progressive accumulation, resulting in irreversible brain damage. Mechanistically, TSD is caused by mutations in the HEXA gene, which encodes the alpha subunit of hexosaminidase A. These mutations disrupt enzyme activity and alter cellular pathways involved in lysosomal lipid degradation. Although Tay–Sachs specifically involves the alpha subunit, similar clinical features can be seen in Sandhoff disease, a related disorder caused by mutations in the HEXB gene, which encodes the beta subunit shared by hexosaminidase A and B. Tay–Sachs is classified into three clinical forms according to age of onset and symptom severity: the classic infantile form, which is the most common and severe; a juvenile (subacute) form; and an adult-onset form, which progresses more slowly and tends to present with milder symptoms. Diagnosis is based on enzymatic testing showing reduced or absent hexosaminidase A activity, confirmed by genetic testing. Prenatal diagnosis and genetic counseling play a key role in prevention and reproductive decision-making, especially in high-risk populations. Although no curative treatment currently exists, ongoing research is exploring gene therapy, enzyme replacement, and pharmacological approaches. Certain compounds, such as gemfibrozil, have shown potential to slow symptom progression. Early diagnosis and multidisciplinary care are essential to improving quality of life, although therapeutic options remain limited due to the progressive nature of the disease. Full article

Introduction: Fraser syndrome (FS) is a rare autosomal recessive disorder. However, the clinical presentation remains variable. Diagnosis is based on a series of major and minor clinical criteria that can be supported by genetic tests. Prenatal diagnosis remains challenging. Methods: Herein, we reported a case of Fraser syndrome that was missed by ultrasound and diagnosed late at birth. The newborn presented with cryptophthalmos–syndactyly syndrome and absence of the right kidney. Based on a literature review of articles from the past 20 years, the authors found 40 cases, including indexed cases on PUBMED, Scopus, Web of Science, and Scholar using keywords related to “Fraser syndrome”. Through this report, we discuss the polymalformative syndrome, the clinical and paraclinical aspects of this syndrome, its clinical management, and highlight the importance of prenatal diagnosis in the light of research. Results: Our study found that consanguine parents (41.0%) were increasing risk factors for FS and poor socio-economic status delayed the early detection of FS. Among the 40 cases, 27 cases were detected postnatally. More than half of the cases resulted in poor perinatal outcomes. The common findings were cryptophthalmos (87.5%), syndactyly (87.5%), renal abnormalities (55.5%), and genital abnormalities (42.5%). Conclusions: A prenatal diagnosis of Fraser syndrome is still difficult. Thus, a counseled ultrasound scan at a specialized center should be recommended in suspected cases with indirect signs and risk factors of consanguinity. Full article

Background: Charcot–Marie–Tooth disease (CMT) is a genetically and clinically heterogeneous group of progressive peripheral neuropathies. Preimplantation genetic testing for monogenic disorders (PGT-M), a well-established assisted reproductive technology used to detect specific genetic mutations in embryos before implantation, has been used in common CMT subtypes (e.g., CMT1A); however, data on its application across rarer subtypes and in de novo cases remain limited. In this study, we aimed to evaluate the effectiveness of PGT-M using karyomapping in achieving clinical pregnancies and healthy births in families affected by various CMT types, including the previously unreported subtypes CMT1B and CMT2. Methods: We analyzed 31 PGT-M cycles from 13 families with genetically confirmed CMT, including cases of previously unreported subtypes CMT1B and CMT2. A total of 150 embryos were biopsied. Through 19 embryo transfer cycles, 21 embryos were transferred. In one de novo case, karyomapping was performed using amniotic fluid from an affected fetus as a reference. Results: Of the 19 embryo transfers, 15 resulted in clinical pregnancies. Prenatal diagnosis confirmed that all fetuses were unaffected, and all pregnancies resulted in healthy live births. Successful phasing using amniotic fluid from an affected fetus enabled accurate embryo selection and led to the birth of healthy twins. Conclusions: PGT-M using karyomapping is a rapid and reliable method for achieving successful pregnancies in families affected by diverse CMT subtypes, including de novo cases, and supports broader applicability to other monogenic disorders. Full article

Meckel–Gruber syndrome (MKS) is a rare autosomal recessive lethal ciliopathy, characterized by occipital encephalocele, cystic kidneys, and postaxial polydactyly, caused by mutations in different genes. Its significant genetic heterogeneity along with its clinical overlap with other ciliopathies makes early diagnosis essential for clinical management, accurate genetic counseling, and informing future reproductive decisions. Objectives: This study aims to describe a prenatally diagnosed case carrying a homozygous B9D1 variant and to examine the current literature on all variants reported in this gene associated with MKS. Methods: We comprehensively review the current literature on pathogenic B9D1 variants implicated in this syndrome. Additionally, we describe a case, presenting multiple congenital anomalies suggestive of MKS, genetically diagnosed by clinical exome sequencing on chorionic villi. Results: Occipital encephalocele and polycystic kidneys were revealed via ultrasound, thus suggesting MKS. Genetic testing identified the homozygous c.151T>C (p.Ser51Pro) variant in the B9D1 gene, inherited from healthy parents. Conclusions: This case supports the pathogenicity of the homozygous B9D1 c.151T>C variant and underscores the importance of timely prenatal assessment and targeted genetic testing for the detection of MKS risk in heterozygous subjects, enabling appropriate pregnancy management and informed reproductive choices. Full article

Rubinstein–Taybi syndrome (RSTS) is a rare genetic disorder characterized by distinctive craniofacial, limb, and developmental abnormalities, often identified postnatally. Prenatal diagnosis remains challenging due to a scarcity of ultrasound diagnostic markers and a wide range of phenotypic manifestations. We describe the case of a 28-year-old pregnant patient who presented to our center after fetal abnormalities such as aberrant cranial morphology, a shorter femur, and rocker-bottom feet were detected. A comprehensive ultrasound examination at 26 weeks revealed skeletal and craniofacial characteristics suggestive of RSTS, which prompted genetic counseling and molecular karyotyping. Single-nucleotide polymorphism (SNP) array analysis confirmed a loss on chromosome 16p13.3, including the CREB-binding protein (CREBBP) gene, confirming the suspicion. This case emphasizes the importance of genetic testing and sophisticated prenatal imaging in enabling an early and precise diagnosis of RSTS, offering important information on its prenatal phenotype and supporting family counseling. Extensive research becomes vital in establishing precise ultrasound markers for the early detection of RSTS during pregnancy. Full article

Background/Objectives: Rare diseases are predominantly genetic in etiology and characterized by a prolonged ‘diagnostic odyssey’. Advances in genetic testing (GT) have helped shorten the time to diagnosis for rare/undiagnosed conditions. We aimed to synthesize the evidence on psychosocial factors related to GT for rare diseases to inform more person-centered approaches to care. Methods: We conducted a systematic literature search in six databases using structured terms (September 2024). Retrieved articles underwent independent dual review. Data were extracted and collated in tables for analysis. Thematic analysis was used to identify promoters/barriers to GT for patients and families. Findings were validated by a patient advocate and were reported using PRISMA-ScR guidelines. Synthesized findings were mapped to the Theory of Planned Behavior to inform intervention development. Results: Of 1730 retrieved articles, 32 were included for data extraction/synthesis. Studies employed qualitative (n = 19), quantitative (n = 10), and mixed-methods (n = 3) approaches. Nearly all (29/32, 91%) were non-interventional, reporting on decision-making cognitions/processes (19/32, 59%), attitudes/preferences (15/32, 47%), psychosocial impact (6/32, 19%), and knowledge/awareness (4/32, 8%) of pre-conception/prenatal/diagnostic GT and carrier screening. Promoters included understanding GT, ending the diagnostic odyssey, actionable outcomes, personal/family history, altruism, and reproductive decision-making. Barriers included logistical (e.g., distance, cost), psychological burden, perceived lack of benefit, and discrimination/social stigma concerns. Conclusions: Some psychosocial factors related to GT for rare diseases overlap with those in literature on GT for common conditions. Identified factors represent targets for theory-informed, person-centered interventions to support high-quality GT decisions that are informed and aligned with patient/family values and preferences. Full article

Background/Objective: The accurate diagnosis of congenital central nervous system abnormalities is critical to pre- and postnatal prognostication and management. When an abnormality is found in the posterior fossa of the fetal brain, parental counseling is challenging because of the wide spectrum of clinical and neurodevelopmental outcomes in patients with Dandy–Walker (DW) spectrum posterior malformations. The objective of this study was to evaluate the utility of biometric measurements obtained from fetal magnetic resonance imaging (MRI) to facilitate the prenatal differentiation of Dandy–Walker (DW) spectrum malformations, including vermian hypoplasia (VH), Blake’s pouch cyst (BPC), and classic Dandy–Walker malformation (DWM). Methods: This retrospective single-center study evaluated 34 maternal–infant dyads referred for fetal MRI evaluation of suspected DW spectrum malformations identified on antenatal ultrasound. Radiologists took posterior fossa measurements, including the vermis anteroposterior (AP) diameter, vermis height (VH), and tegmento–vermian angle (TVA). The posterior fossa, fourth ventricle, and cisterna magna were classified as normal, large, or dilated. The postnatal imaging findings were evaluated for concordance. The acquired values were compared between the groups and with normative data. The genetic testing results are reported when available. Results: A total of 27 DW spectrum fetal MRI cases were identified, including 7 classic DWMs, 14 VHs, and 6 BPCs. The TVA was significantly higher in the DWM group compared with the VH and BPC groups (p < 0.001). All three groups had reduced AP vermis measurements for gestational age compared with normal fetal brains, as well as differences in the means across the groups (p = 0.002). Conclusions: Biometric measurements derived from fetal MRI can effectively facilitate the prenatal differentiation of VH, BPC, and classic DWM when assessing DW spectrum posterior fossa lesions. Standardizing biometric measurements may increase the diagnostic utility of fetal MRI and facilitate improved antenatal counseling and clinical decision-making. Full article