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

This systematic review investigates factors influencing parental decision-making following a prenatal diagnosis (PND) of Turner syndrome (TS), aiming to enhance the foundation for tailored and supportive genetic counseling. A comprehensive literature search was conducted in the medical databases PubMed, Embase, and CINAHL. The selection of studies was guided by specific eligibility criteria. Extracted data was arranged in a review matrix, and study quality was assessed using a methodological quality score (MQS). Twenty-seven studies were selected for review, including 21 retrospective studies, five case reports, and one prospective study. The mean MQS across studies was 9.7 points (low to moderate). Across the included studies, nine categories of factors were investigated in association with parental decisions, including five pregnancy-related categories (ultrasound-detected abnormalities, karyotype, gestational age at diagnosis, time period of diagnosis, and prenatal counseling) and four categories related to expectant parents (age, reproductive history, expectations/concerns about the child's prognosis, and socio-demographic characteristics). Among these, ultrasound-detected abnormalities, karyotype, and counseling emerged as key factors influencing parental decisions. Parental decisions following a PND of TS are influenced by a complex interplay of medical, psychological, and socio-cultural factors. Addressing these determinants through patient-centered, non-directive counseling and equitable access to genetic expertise can support informed decision making.

Rare diseases impact approximately 1 in 10 people worldwide, and yet, less than 5% of all rare diseases currently have an approved treatment option available. This is due to many challenges unique to rare diseases, including small, diverse patient populations, the cost of drug development that is not proportionate to the number of patients who could potentially benefit from treatment, and difficulty with clinical trial design to validate new therapeutics. As a result, drug repurposing has become an increasingly promising option for finding treatment options for rare diseases. First described in 2018, Bachmann-Bupp Syndrome (BABS) is a rare neurodevelopmental disorder that is caused by gain-of-function variants in the ornithine decarboxylase (ODC1) gene and is characterized by developmental delay, hypotonia, and alopecia. Through collaboration and the use of a unique drug repurposing strategy, the first patient identified with BABS was treated with the repurposed drug eflornithine, also known as α-difluoromethylornithine (DFMO), in just 16 months. Currently, five additional patients with BABS are being treated with DFMO. This model of drug repurposing of an FDA-approved drug for use in another indication can serve as an example of what is possible in the scope of other rare diseases, specifically in other polyaminopathies.

Turner syndrome (TS) is frequently complicated by congenital heart disease (CHD). While left-sided lesions such as bicuspid aortic valve (BAV) and coarctation of the aorta are the most common structural heart lesions in TS, other anomalies, such as aortic arch malformations, hypoplastic left heart syndrome (HLHS), persistent left superior vena cava (LSVC), and partial anomalous pulmonary venous return (PAPVR), are also relatively frequent. Standardized mortality is increased threefold in individuals with TS compared to the general population, with cardiovascular complications, including aortic dissection, being the leading cause of death. The publication of the 2024 Clinical Practice Guidelines for TS marks an important opportunity to remind clinicians about the burden of congenital heart and vascular lesions in TS and the need for lifelong cardiovascular surveillance. In this expert panel statement, we will focus on the rationale for clinical management of CHD in TS, emphasizing TS-specific features of CHD that influence clinical decision making about therapeutic options and follow-up care.

Advancements in molecular diagnostics and the expanded understanding of pathophysiologic processes underlying a variety of genetic conditions have led to the design and implementation of many targeted therapies in the past decade. In the prenatal space, these advancements have rapidly changed the field of prenatal diagnosis and have garnered enthusiasm toward interventions aimed at correcting specific disease mechanisms in utero to prevent irreversible injury and/or leverage fetal physiology to increase the effectiveness of these treatments. Although many promising trials are underway, continued efforts to fully elucidate the intricacies of fetal immunology, the fetal blood-brain barrier and precise molecular processes during different stages of development will be paramount to continued refinement of in utero therapies. The social and ethical implications of fetal therapy are also of utmost importance, especially in an era of increasing restrictions on reproductive autonomy. This review aims to summarize current efforts toward in utero targeted fetal therapies as well as the history and ethical implications of such endeavors.

In this study, we propose a definition of targeted therapy and use GeneReviews, a peer-reviewed, online point-of-care resource for primarily constitutional (or rare congenital mosaic) genetic conditions, to compile a list of primarily heritable genetic disorders for which such targeted therapy is available. This study aims to give a high-level view of the types of targeted therapies and the proportion of congenital genetic disorders for which a targeted therapy is available. We propose that a targeted therapy is one that addresses the underlying molecular mechanism of the disorder and/or can alter the disease course (including by providing a cure in some instances) but may not be an obvious treatment option without knowledge of the patient's underlying genetic condition. For the purposes of this study, a treatment meeting one or both of these criteria was categorized as targeted. This means that the clinician might not consider the specific treatment option unless the patient was known to have the genetic diagnosis. This definition does not include therapies based on symptoms alone, which does not rely on the clinician being aware of a patient's genetic diagnosis. As most of the congenital genetic conditions in this study are rare and often diagnosed in a pediatric age group, determining efficacy for the specific use of most of the targeted therapies is not possible, although any drug or medication in the Management section of GeneReviews is approved by the Food and Drug Administration (FDA), with rare exceptions for drugs approved by the European Medicines Agency (EMA) of the European Union (EU) but not yet FDA approved. Of 790 GeneReviews chapters on primarily constitutional genetic conditions included in this study, 176 chapters representing over 255 genes meet the definition of having a targeted therapy.

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.

Short stature is a common presenting feature and an important concern for families of children with Turner syndrome. In this review, we summarize the data that shaped the updated international consensus guidelines for Turner syndrome published in 2024. The natural history of growth in Turner syndrome, the safety and efficacy of recombinant human growth hormone therapy, and the alternate growth promoting agents under consideration are presented. Timely, adequate growth hormone therapy can counter growth failure in childhood, promote catch-up growth and help many individuals with Turner syndrome attain a near-normal adult height. However, individual responses to growth hormone treatment are highly variable and are influenced by factors such as parental heights, age, baseline height, timing of estrogen initiation and pubertal status. Shared decision making on initiation of treatment, a candid conversation regarding the modest gradual height gain resulting from growth hormone therapy, and individualization of therapeutic goals can facilitate realistic expectations of growth promoting therapy in Turner syndrome.

Individuals with Turner Syndrome (TS) can experience not only physical and medical differences but are also at risk for neurocognitive and associated psychosocial challenges. Specifically, research shows increased likelihood of difficulties with visual-spatial reasoning, executive functioning, attention, and mathematics skills. One emerging area of research focuses on deficits in social skills and increased prevalence of anxiety within this population. This review introduces relevant genetic influences of TS and examines existing research on social skills and anxiety in individuals with TS. The importance of collaboration between the medical team and school personnel for patients with TS is emphasized, and specific clinical recommendations, such as the use of the TS School Support Plan, are provided to facilitate this collaboration. This paper services as a brief introduction to orient the reader to considerations of strengthening collaboration between medical and school systems; however, future research is needed to investigate the effectiveness and acceptability of the School Support Plan to enhance liaison between the patient's medical and school teams.

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.