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

The effect of estrogen deficiency on bone health in Turner syndrome (TS) may be a concern even before adulthood. Previous guidelines have discussed hormone replacement therapy (HRT) in children with TS. However, some practical issues related to puberty induction in TS require clarification, such as how to implement HRT to achieve adequate bone health. It is generally assumed that earlier initiation of HRT will result in better bone health in young adults with TS and estrogen deficiency. The present study reviews pubertal development, bone health, and current pubertal induction therapies in TS, with a particular focus on patients without endogenous estrogen production. Current guidelines recommend using transdermal estradiol patches starting at the age of 11–12 years if necessary to mimic the gradual increase in circulating, physiological estradiol. Theoretically, earlier therapy combined with forecasting estrogen deficiency on the basis of increased FSH may allow a closer approximation to endogenous estradiol secretion in patients with TS without spontaneous puberty. This approach may lead to better long-term outcomes, such as the acquisition of normal bone mineral density. Further research is needed to assess how the achievement of normal bone density and bone quality relates to the timing of HRT in children and young adults with TS. The resulting improvements in transdermal estradiol therapy may help patients with TS achieve optimal bone health.

Neurofibromatosis type 1 (NF1) is a progressive multisystem condition that is characterized by a wide range of clinical manifestations and clinical variability. Individuals with NF1 can be significantly impacted by NF1-related complications, and targeted therapies are emerging. Currently, MEK inhibitors selumetinib and mirdametinib are the only FDA-approved targeted therapies for NF1-related symptomatic or progressive, inoperable plexiform neurofibromas. Several additional MEK inhibitors are being investigated in clinical trials for the treatment of plexiform neurofibromas. Additional therapies are currently under investigation for the treatment of malignant peripheral nerve sheath tumors, low-grade gliomas, skeletal manifestations, cutaneous neurofibromas, and other NF1-related complications.

Myhre syndrome is a rare connective tissue disorder characterized by skeletal, cardiopulmonary, dermatologic, neurocognitive changes, and a predisposition to exaggerated fibrosis in response to mechanical stress. We report monozygotic male twins with Myhre syndrome caused by the recurrent SMAD4 gain-of-function variant c.1498A>G (p.Ile500Val), identified by targeted next-generation sequencing of peripheral blood. Proband 1 presented at age 37 years for evaluation of symptomatic aortic stenosis. Clinical recognition of Myhre syndrome prompted deferral of transesophageal echocardiography, and molecular diagnosis informed subsequent conservative management. His co-twin, Proband 2, underwent posterior pharyngeal flap surgery and right-heart catheterization with pulmonary artery stenting in childhood; later, he developed progressive pulmonary arterial hypertension and died at 31 years. We report on the differing outcomes of the twins and the possibility that invasive airway and cardiac procedures may have accelerated fibro-proliferative complications of Proband 2. Early recognition of Myhre syndrome allows selection of alternatives to high-risk procedures, longitudinal monitoring, and may reduce morbidity and mortality.

Myhre syndrome (MIM #139210) is a rare multisystem disorder first described in 1981, characterized by short stature, neurodevelopmental delay, joint contractures, and cardiopulmonary complications. Its molecular basis, recurrent pathogenic variants in SMAD4, was not discovered until 2011. This narrative is based on a review of medical records, personal experiences in the care of a remarkable patient, and family interviews. It traces the life of a young man from rural Montana whose diagnosis was delayed for over two decades, despite early evaluations by renowned specialists. The absence of a unifying diagnosis profoundly shaped his and his family's experience-emotionally, medically, and socially. When the diagnosis of Myhre syndrome was finally established via whole exome sequencing in adulthood, it brought both clarity and new uncertainties. Through his story, we examine the psychosocial toll of diagnostic delay, the transformative potential of genomic medicine, and the resilience of individuals and families living with complex, undiagnosed conditions. The narrative also underscores the ongoing systemic barriers to care and inclusion for individuals with lifelong rare disorders. Lastly, this account offers a reflection on the philosophical framework of Maurice Merleau-Ponty, whose phenomenology of the lived body versus the body-object provides a lens to understand the subjective and embodied dimensions of living with an undiagnosed condition.

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.

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.

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.

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.