American Journal of Medical Genetics Part C: Seminars in Medical Genetics最新文献

Turner Syndrome (TS) is a sex chromosomal disorder associated with karyotype heterogeneity. Although TS can be associated with severe prenatal findings, most often linked to the 45, X karyotype, the majority of TS fetuses have no overt phenotype, resulting in delayed diagnosis and management. The objective of this study is to assess the efficacy of non-invasive prenatal testing by cell-free DNA (cfNIPT) in detecting TS fetuses with different TS karyotype variants and to examine the phenotypic variations and clinical outcomes.Data on pregnancies with confirmed or suspected TS from 2000 to 2024 were collected from specialists in fetal ultrasound in Germany. In addition, a small number of Danish cases with 45, X mosaicism in the placenta was included. Data were collected regarding cfNIPT results, karyotypes, prenatal ultrasound findings, and pregnancy outcomes.Of the 114 cases included, 100 (87.7%) had a high-risk cfNIPT result for monosomy X, 53 (46.5%) were true positives (TP), and 47 (41.2%) were false positives (FP). Fourteen (12.3%) were false negatives (FN). No differences in congenital malformation or nuchal translucency were seen between TP and FN. Data on karyotype were available for 67 cases. Fourty (59.7%) had a 45, X karyotype, 16 (23.9%) 45, X mosaicism, and 11 (16.4%) had a structural variant. The 45, X karyotype was associated with a higher prevalence of congenital malformation and increased nuchal translucency (ps ≤ 0.001). The live birth rate was higher in cases with 45, X mosaicism or structural variants compared to cases with a 45, X karyotype (ps ≤ 0.03). Postnatal phenotypes were often mild.cfNIPT represents a valuable tool for the early identification of fetuses with TS karyotype variants, enabling timely intervention and targeted management. However, the high false-positive rate underscores the need for careful counseling.

The expansion of prenatal genetic screening and diagnosis warrants the evaluation of approved postnatal therapies that may be safely and feasibly translated to prenatal administration to a fetus affected by monogenic disease. For lysosomal storage diseases (LSDs), enzyme replacement therapy (ERT) often represents the main therapeutic approach. In utero enzyme replacement therapy (IUERT) has several potential benefits compared to postnatal therapy, such as: (1) delivering enzyme before the onset of irreversible organ damage; (2) developing tolerance toward the recombinant enzyme; and (3) targeting the central nervous system through a more permeable blood-brain barrier. In this review, we examine the general and disease-specific rationale for IUERT, and provide an overview of the main elements of our current clinical trial for the prenatal treatment of early-onset lysosomal storage diseases. Trial Registration: IUERT clinical trial: NCT04532047; Alpha thalassemia clinical trial: NCT02986698.

Patients with Turner Syndrome (TS) and those exposed to high concentrations of glucocorticoids have a number of characteristics in common, including an increased risk of cardiovascular disease. Pediatric TS patients underwent studies of salivary cortisol (SC) and cortisone (SCn), body composition, continuous glucose monitoring, vascular function, and ambulatory blood pressure (BP). Biochemical indicators of cardiovascular risk were also measured. Data were compared to matched healthy controls (HCs) or interpreted according to reference populations. Ten patients, aged 14.1 ± 2.3 years participated. Mean SC was higher in girls with TS, although the early morning measurement was lower resulting in a flatter diurnal profile. Body mass index was > 1.0 SDS in five and muscle-to-fat ratio was low (< 0.8) in six participants. Four had proatherogenic lipid profiles and six had raised clotting and/or inflammatory markers. Mean glucose concentration was higher in TS than in HCs (109.8 vs. 102.6 mg/dL, p = 0.003). Loss of nocturnal dipping in BP was universal, and hypertension was present in three patients. TS participants had an adverse cardiovascular profile. The same cohort also exhibited increased cortisol exposure and the clinical significance of these dual findings warrants further investigation.

Health care transition is a process by which children with chronic medical conditions gradually and purposefully move from pediatric to adult-centered health care systems. While transition guidelines have been published by multiple national and international organizations, transition processes have not been optimized for many populations, including youth with Turner syndrome (TS). Numerous barriers exist, at both the system and individual/family level. Mitigating transition-related barriers requires a multi-faceted approach, including: conducting research to assess TS specific transition interventions and outcomes; developing educational/training initiatives and quality improvement efforts; engaging in advocacy/policy change; and implementing evidence-based strategies to optimize transition. The goals of this manuscript are to outline key research gaps that need to be addressed regarding health care transition in TS and to suggest strategies to optimize transition outcomes. Given the importance of a multi-disciplinary and patient-centered approach, we specifically outline the roles of pediatric health care teams (including navigators), adult health care teams, patients, caregivers, and institutional resources.

RET gene is a driver of thyroid cancer (TC) tumorigenesis. The incidence of TC has increased worldwide in the last few decades, both in medullary and follicular-derived subtypes. Several drugs, including multikinase and selective inhibitors, have been explored. Selpercatinib and pralsetinib are selective RET inhibitors that have shown clear clinical benefits for patients in the LIBRETTO and ARROW trials, respectively. Currently, their development and application in clinical practice are ongoing. However, its efficacy in different RET pathogenic variants has not yet been well established. Although selpercatinib and pralsetinib achieved a high ORR, no data are available regarding the differences in tumor responses of both TC groups according to RET pathogenic variants. Clinical trials and literature have analyzed the efficacy of selective RET inhibitors with a special interest in the most common variants. A review of LIBRETTO and ARROW trials was made regarding the change in tumor size depending on the pathogenic variants. M918T pathogenic variant resulted in a higher complete response rate. Patients who underwent fusion had the highest ORR (objective response rate). MKi-treated patients did not exhibit significant differences from untreated patients. Different RET pathogenic variants are not biomarkers of RETi response in TC. Selpercatinib showed a tendency to achieve a complete response. All patients with RET pathogenic variants should receive treatment with selpercatinib or pralsetinib at any moment of the therapeutic schedule owing to off-target inhibition and toxicity. Therefore, new targets for drug sensitivity and resistance should be explored.

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