{"title":"Treatment of PDGFRB-Related Penttinen Syndrome With Imatinib in a Young Child.","authors":"Molly McPheron, Katelyn Burns, Tara L Wenger","doi":"10.1002/ajmg.c.32148","DOIUrl":"https://doi.org/10.1002/ajmg.c.32148","url":null,"abstract":"<p><p>PDGFRB-related Penttinen syndrome is characterized by progressive progeroid features, acroosteolysis, and development of aneurysms, structural anomalies of the posterior fossa, variable myofibromatosis, and overgrowth. PDGFRB-related disorders, including Penttinen syndrome, Kosaki syndrome, and infantile myofibromatosis, have been successfully treated using imatinib. Here, we report a child diagnosed in infancy who initiated imatinib monotherapy at 8 months of age and has continued treatment for 4 years. At the time of diagnosis, he was known to have structural anomalies of the posterior fossa, sparse hair, joint stiffness, myofibromatosis, thin and fragile skin, decreased subcutaneous fat, and prominent vasculature. Imatinib has been well tolerated without apparent side effects. Within weeks to months after initiating imatinib, he grew thick curly hair, and the texture of his skin and joint stiffness had marked improvement. Over the past 4 years, he has not developed acroosteolysis and continues to have normal hair growth. Surveillance MRA has not identified aneurysms or vessel ectasia. Height decreased from 90th to 75th percentile. He has mild developmental delays and is awaiting formal evaluation for autism spectrum disorder. Overall, early imatinib treatment has been successful in ameliorating and preventing the development of some features of Penttinen syndrome.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rachel Gottlieb, Ashley W Wong, Allison L Cirino, Eleanor R Scimone, Angela E Lin
{"title":"Journaling for Parents and Adults With Myhre Syndrome: Using Reflective Writing to Help Cope.","authors":"Rachel Gottlieb, Ashley W Wong, Allison L Cirino, Eleanor R Scimone, Angela E Lin","doi":"10.1002/ajmg.c.32147","DOIUrl":"https://doi.org/10.1002/ajmg.c.32147","url":null,"abstract":"<p><p>Myhre syndrome is a rare progressive genetic disorder characterized by hearing loss, cardiovascular and joint problems, neoplasia, and neuropsychologic disabilities. Parents of children with Myhre syndrome and adults themselves face unique challenges, stresses, and fears associated with this diagnosis. Reflective writing in the form of journaling can provide psychosocial support and help individuals cope with this diagnosis. Adult patients and parents whose children were evaluated at the Massachusetts General Hospital Myhre Syndrome Clinic were invited to participate in a three-month journaling intervention. Participation in the study required the completion of a series of surveys prior to starting and upon completion of the study. Data from these surveys were analyzed to assess for change in mental well-being. Eleven individuals participated, six of whom completed the three-month journaling intervention and post-journaling surveys. Three participants indicated that journaling had an impact on their mental well-being, and of these, two planned to continue journaling. However, there was no statistically significant difference in mental well-being scores pre- and post-journaling intervention. The very small size of the study limits interpretation, but we think it is reasonable to suggest that expressive writing through journaling may be a coping mechanism and means of improving well-being for some individuals in the Myhre syndrome community.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":"e32147"},"PeriodicalIF":2.8,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Francisco Álvarez-Nava, Melissa L Crenshaw, Ivonne Bedei, Marisol Soto, Andréa T Maciel-Guerra, Anne Skakkebæk
{"title":"The Impact of Karyotype on Congenital Heart Diseases in Turner Syndrome: A Systematic Review and Meta-Analysis.","authors":"Francisco Álvarez-Nava, Melissa L Crenshaw, Ivonne Bedei, Marisol Soto, Andréa T Maciel-Guerra, Anne Skakkebæk","doi":"10.1002/ajmg.c.32146","DOIUrl":"https://doi.org/10.1002/ajmg.c.32146","url":null,"abstract":"<p><p>It is evident that Turner syndrome (TS) impacts almost all developmental stages of the fetal heart with congenital heart disease (CHD) being seen in 23%-50% of individuals. Although the spectrum of CHDs in TS is well-established, with left-sided lesions predominating, the influence of specific karyotypes on the prevalence and types of CHDs remains incompletely understood. The primary objective of this systematic review/meta-analysis was to quantitatively synthesize the existing evidence on the association between specific karyotypes in TS and the risk of various CHDs. A systematic literature search was conducted through December 2023 to identify studies reporting the prevalence of CHDs in relation to TS karyotype. The quality of the individual studies was assessed using the Joanna Briggs Institute critical appraisal tools for systematic reviews. The overall estimates were pooled using both fixed- and random-effects models. Sensitivity and subgroup analysis were performed. Twenty-five studies were included in the analysis. TS individuals with a 45,X karyotype showed a significantly higher likelihood of bicuspid aortic valve (BAV) (pooled OR, 3.14 [95% CI: 2.49-3.94]), aortic coarctation (CoA) (pooled OR, 4.16 [95% CI: 2.74-6.31]), and partial anomalous pulmonary venous return (PAPVR) (pooled OR, 4.86 [2.31-10.2]) compared with TS individuals with a non-45,X karyotype. In addition, TS individuals with a 45,X karyotype also showed a significantly higher likelihood of BAV (pooled OR, 2.72 [95% CI: 1.62-4.56]) when compared with TS individuals with 45,X/46,XX mosaicism. TS individuals with a 45,X karyotype showed a significantly higher risk of BAV (pooled OR, 2.13 [95% CI: 1.42-3.21]) and CoA (pooled OR, 4.52 [95% CI: 1.58-13.0]) when compared with TS individuals with an isochromosome Xq. A significantly higher likelihood of BAV was also found in 45,X compared to other karyotypes (e.g., 45,X/46,XY and TS karyotypes with ring X chromosome). Some heterogeneity was evident, but publication was low. This meta-analysis confirms a strong association between the 45,X karyotype and increased prevalence of BAV, CoA, and PAPVR in TS. While 45,X/46,XX mosaicism and karyotypes with an isochromosome Xq mitigate risk, the findings emphasize the need for large-scale studies to refine risk assessment and management strategies.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":"e32146"},"PeriodicalIF":2.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maggie R Brand, Ryan Monsberger, Robert J Hopkin, Angela E Lin
{"title":"Research Review of Myhre Syndrome.","authors":"Maggie R Brand, Ryan Monsberger, Robert J Hopkin, Angela E Lin","doi":"10.1002/ajmg.c.32145","DOIUrl":"https://doi.org/10.1002/ajmg.c.32145","url":null,"abstract":"<p><p>This research review of Myhre syndrome is a summary of published articles which provide a valuable resource for readers, researchers, and future authors. It traces the evolution of the Laryngotracheal-Arthropathy-Prognathism-Short Stature (LAPS) syndrome to the current eponym of Myhre syndrome. These allelic disorders are caused by pathogenic variants in SMAD4. After the initial report over 40 years ago, the steady publication of case reports and small series was accelerated following the discovery of the pathogenic variants in SMAD4. The articles in this review include numerous case reports and small series, reports about basic science, the discovery of the causative gene, the emergence of the natural history in larger studies, and articles about specific features, especially the cardiovascular system and airways. We hope this analysis provides a foundation for future research that may extend symptom-based treatment to genetic-based therapy.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":"e32145"},"PeriodicalIF":2.8,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kirstine Stochholm, Astrid Bruun Rasmussen, Anne Skakkebæk
{"title":"Visualizing Turner Syndrome.","authors":"Kirstine Stochholm, Astrid Bruun Rasmussen, Anne Skakkebæk","doi":"10.1002/ajmg.c.32144","DOIUrl":"https://doi.org/10.1002/ajmg.c.32144","url":null,"abstract":"<p><p>Turner syndrome (TS) continues to present a diagnostic challenge to healthcare professionals. The diagnostic challenges associated with TS result in delayed treatment and clinical care. Here we provide an update of the physical appearance of girls and women with TS by presenting clinical photographs and detailed clinical descriptions of 25 Danish girls and women with TS. Our data highlight the wide variation in physical appearance and clinical phenotype seen in girls and women with TS.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":"e32144"},"PeriodicalIF":2.8,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144197992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Table of Contents, Volume 199, Number 1, March 2025","authors":"","doi":"10.1002/ajmg.c.32091","DOIUrl":"https://doi.org/10.1002/ajmg.c.32091","url":null,"abstract":"","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"199 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.32091","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144108978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cover Image, Volume 199, Number 1, March 2025","authors":"","doi":"10.1002/ajmg.c.32143","DOIUrl":"https://doi.org/10.1002/ajmg.c.32143","url":null,"abstract":"<p>From Stochholm et al. 2025. “Vizualizing Turner Syndrome.” <i>American Journal of Medical Genetics Part C: Seminars in Medical Genetics</i>: e32144. doi:10.1002/ajmg.c.32144. Photographs of individuals with Turner syndrome. Reproduced with permission from the patients and, where applicable, their legal guardians.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"199 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.c.32143","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144108763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Comment From the Guest Editors","authors":"Melissa L. Crenshaw, Anne Skakkebæk","doi":"10.1002/ajmg.c.32141","DOIUrl":"10.1002/ajmg.c.32141","url":null,"abstract":"","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":"199 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shelby E Redfield, Stephanie A Mauriac, Gwenaëlle S Géléoc, A Eliot Shearer
{"title":"A Genomic Analysis of Usher Syndrome: Population-Scale Prevalence and Therapeutic Targets.","authors":"Shelby E Redfield, Stephanie A Mauriac, Gwenaëlle S Géléoc, A Eliot Shearer","doi":"10.1002/ajmg.c.32142","DOIUrl":"https://doi.org/10.1002/ajmg.c.32142","url":null,"abstract":"<p><p>Usher syndrome, the most common form of deaf-blindness, displays extensive genetic, allelic, and phenotypic heterogeneity. The dual sensory impairment associated with this autosomal recessive disorder makes Usher syndrome an important target for gene therapy, with dozens of published preclinical studies targeting multiple Usher syndrome genes and using multiple gene therapy strategies. Nine genes have been conclusively linked to Usher syndrome; however, data on the prevalence and contribution of specific genetic variants is lacking. Such information is essential to choosing a favorable target gene or therapeutic approach during clinical trial design. Here, we used large genomic databases to systematically evaluate the genomics of Usher syndrome. We ascertained pathogenic Usher syndrome variants from three clinical databases and determined the occurrence of these pathogenic Usher syndrome variants within: (1) a publicly available dataset including worldwide populations (GnomAD), (2) a cohort of 3888 children without hearing loss, and (3) 637 children with hearing loss. Results show significant variability in the frequency of Usher syndrome variants by gene and genetic ancestry. 1% of control subjects carry a pathogenic USH variant. Pathogenic variants in USH2A are the most prevalent, at 1 in 150 individuals (0.0062). Calculated general population prevalence for all Usher syndrome subtypes is 1 in ~29,000, indicating that 30,405 individuals in the United States and 721,769 individuals worldwide are affected. We estimate that 324 babies in the United States and 12,090 worldwide are born with Usher syndrome each year. We identify key targets for genetic therapy based on population-level prevalence including a focus on alternatives to gene replacement therapies, specifically for USH2A.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":"e32142"},"PeriodicalIF":2.8,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Parental Decision-Making Following a Prenatal Diagnosis of Turner Syndrome: A Systematic Review.","authors":"Inger Lily Hjuler Dorf, Stina Lou, Anne Skakkebæk","doi":"10.1002/ajmg.c.32140","DOIUrl":"https://doi.org/10.1002/ajmg.c.32140","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":7445,"journal":{"name":"American Journal of Medical Genetics Part C: Seminars in Medical Genetics","volume":" ","pages":"e32140"},"PeriodicalIF":2.8,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}