Editorial: Neonatal management of achondroplasia: one hospital's geosocial approach to improve patient outcomes No abstract available

Genetics of syndromic and nonsyndromic aortopathies Purpose of review To review the literature and provide a summary of management of syndromic and nonsyndromic aortopathies. Recent findings The number of newly identified genetic causes for aortopathies have continued to increase over the past 10 years. The number of reported individuals with most hereditary aneurysm genes is small but increasing with more publications focusing describing the natural history caused by each gene. Summary Aortopathy can present as an isolated finding or present as part of a larger genetic syndrome. Advances in genetic testing technology has shed light on the increasing importance of molecular diagnostics in the evaluation and management of patients with hereditary aortic disease. Molecular diagnostics and family phenotyping can aide in the diagnosis and management of pediatric patients with aortic disease.

Diversity and dysmorphology Purpose of review Dysmorphic features result from errors in morphogenesis frequently associated with genetic syndromes. Recognizing patterns of dysmorphic features is a critical step in the diagnosis and management of human congenital anomalies and genetic syndromes. This review presents recent developments in genetic syndromes and their related dysmorphology in diverse populations. Recent findings Clinical findings in patients with genetic syndromes differ in their heterogeneity across different population groups. Some genetic syndromes have variable features in different ethnicities, in part due to specific background exam characteristics such as flat facial profiles or nasal differences; however, other genetic syndromes are similar across different ethnicities. Facial analysis technology is accurate in diagnosing genetic syndromes in populations around the world and is a powerful adjunct to conventional clinical examination. This accuracy also reinforces the concept that genetic syndromes can and should be diagnosed in any ethnicity. Summary The increasing amount of data from studies on genetic syndromes in diverse populations is significantly improving our knowledge and approach to dysmorphic patients from various ethnic backgrounds. Optimal management of genetic syndromes requires early diagnosis, including in developing countries.

Osteogenesis imperfecta: advancements in genetics and treatment Purpose of review The purpose of this review is to outline the current understanding of the molecular mechanisms and natural history of osteogenesis imperfecta, and to describe the development of new treatments for this disorder. Recent findings The introduction of next-generation sequencing technology has led to better understanding of the genetic cause of osteogenesis imperfecta and enabled cost-effective and timely diagnosis via expanded gene panels and exome or genome sequencing. Clinically, despite genetic heterogeneity, different forms of osteogenesis imperfecta share similar features that include connective tissue and systemic manifestations in addition to bone fragility. Thus, the goals of treatment in osteogenesis imperfecta extend beyond decreasing the risk of fracture, to include the maximization of growth and mobility, and the management of extraskeletal complications. The standard of care in pediatric patients is bisphosphonates therapy. Ongoing preclinical studies in osteogenesis imperfecta mouse models and clinical studies in individuals with osteogenesis imperfecta have been instrumental in the development of new and targeted therapeutic approaches, such as sclerostin inhibition and transforming growth factor-β inhibition. Summary Osteogenesis imperfecta is a skeletal dysplasia characterized by bone fragility and extraskeletal manifestations. Better understanding of the mechanisms of osteogenesis imperfecta will enable the development of much needed targeted therapies to improve the outcome in affected individuals.

Fibrodysplasia ossificans progressiva: lessons learned from a rare disease Purpose of review Fibrodysplasia ossificans progressiva (FOP) is an extremely rare and severely disabling autosomal dominant disease that is yet to be clearly understood. The purpose of this review is to present recent literature on pathophysiology, clinical features, diagnosis and treatment of FOP. Recent findings FOP is characterized by congenital great toe deformity and progressive heterotopic ossifications in connective tissue. Heterotopic ossifications occur after painful flare-ups that can arise spontaneously or can be triggered by minor trauma. Each flare-up ultimately causes restriction of related-joint, and along with the others eventually leads to immobility. Death is usually caused by pulmonary complications because of chest wall involvement. The causative gene of FOP is activin A receptor type 1 (ACVR1), a bone morphogenetic protein-signalling component, which normally acts to inhibit osteoblastogenesis. The treatment of FOP is still preventive and supportive. Summary Although there are still gaps in the underlying mechanism of FOP, effective treatment options, such as potential pharmacologic targets and cell-based therapies are promising for the future. Some of these were tested without a clinical trial setting, and are currently in the process of evidence-based research.

At-home genetic testing in pediatrics Purpose of review This review discusses the state of at-home genetic testing, including both direct-to-consumer and consumer-directed genetic testing, for children. Recent findings At-home genetic testing continues to increase in popularity and laboratories are starting to offer tests geared towards newborns and children. Available at-home genetic tests for children address ancestral descent, supplement newborn screening, or provide risks for childhood and adult-onset disorders as well as pharmacogenomic data. However, there are aspects of at-home testing that are unique to children that both providers and parents need to be aware of before considering this type of testing; these include issues related to motivations for testing; privacy concerns; result interpretation; ethical, legal and social implications; and impact on family relationships, among others. Summary This review addresses the challenges associated with at-home genetic testing in children and provides guidance for pediatricians and other health care providers who field inquiries about this type of testing or who are presented with at-home genetic test results for interpretation.

Clinical utility of genomic sequencing Purpose of review Identifying pathogenic variation underlying pediatric developmental disease is critical for medical management, therapeutic development, and family planning. This review summarizes current genetic testing options along with their potential benefits and limitations. We also describe results from large-scale genomic sequencing projects in pediatric and neonatal populations with a focus on clinical utility. Recent findings Recent advances in DNA sequencing technology have made genomic sequencing a feasible and effective testing option in a variety of clinical settings. These cutting-edge tests offer much promise to both medical providers and patients as it has been demonstrated to detect causal genetic variation in ∼25% or more of previously unresolved cases. Efforts aimed at promoting data sharing across clinical genetics laboratories and systematic reanalysis of existing genomic sequencing data have further improved diagnostic rates and reduced the number of unsolved cases. Summary Genomic sequencing is a powerful and increasingly cost-effective alternative to current genetic tests and will continue to grow in clinical utility as more of the genome is understood and as analytical methods are improved. The evolution of genomic sequencing is changing the landscape of clinical testing and requires medical professionals who are adept at understanding and returning genomic results to patients.

The search for genetic determinants of human neural tube defects Purpose of review An update is presented regarding neural tube defects (NTDs) including spina bifida and anencephaly, which are among the most common serious birth defects world-wide. Decades of research suggest that no single factor is responsible for neurulation failure, but rather NTDs arise from a complex interplay of disrupted gene regulatory networks, environmental influences and epigenetic regulation. A comprehensive understanding of these dynamics is critical to advance NTD research and prevention. Recent findings Next-generation sequencing has ushered in a new era of genomic insight toward NTD pathophysiology, implicating novel gene associations with human NTD risk. Ongoing research is moving from a candidate gene approach toward genome-wide, systems-based investigations that are starting to uncover genetic and epigenetic complexities that underlie NTD manifestation. Summary Neural tube closure is critical for the formation of the human brain and spinal cord. Broader, more all-inclusive perspectives are emerging to identify the genetic determinants of human NTDs.

Vascular malformations syndromes: an update Purpose of review To provide an update of vascular malformation syndromes by reviewing the most recent articles on the topic and following the new International Society for the Study of Vascular Anomalies (ISSVA) 2018 classification. Recent findings This review discusses the main features and diagnostic approaches of the vascular malformation syndromes, the new genetic findings and the new therapeutic strategies developed in recent months. Summary Some vascular malformations can be associated with other anomalies, such as tissue overgrowth. PIK3CA-related overgrowth spectrum (PROS) is a group of rare genetic disorders with asymmetric overgrowth caused by somatic mosaic mutations in PI3K-AKT-mTOR pathway that encompass a heterogeneous group of rare disorder that are associated with the appearance of overgrowth. CLOVES syndrome and Klippel–Trénaunay syndrome are PROS disease. Proteus syndrome is an overgrowth syndrome caused by a somatic activating mutation in AKT1. CLOVES, Klippel–Trénaunay and Proteus syndromes are associated with high risk of thrombosis and pulmonary embolism. Hereditary hemorrhagic telangiectasia is an autosomic dominant disorder characterized by the presence of arteriovenous malformations. New therapeutic strategies with bevacizumab and thalidomide have been employed with promising results.