Genomic newborn screening as a paradigm shift in rare disease management, with emphasis on endocrine conditions.

Genomic newborn screening as a paradigm shift in rare disease management, with emphasis on endocrine conditions.

The International Society for Neonatal Screening (ISNS) recognises six different geographical regions [...]

Rare endocrine diseases are complex conditions that require lifelong specialized care due to their chronic nature and associated long-term complications. In Korea, a lack of nationwide data on clinical practice and outcomes has limited progress in patient care. Therefore, the Multicenter Networks for Ideal Outcomes of Pediatric Rare Endocrine and Metabolic Disease (OUTSPREAD) study was initiated. This study involves 30 centers across Korea. The study aims to improve the long-term prognosis of Korean patients with rare endocrine diseases by collecting comprehensive clinical data, biospecimens, and patient-reported outcomes to identify complications and unmet needs in patient care. Patients with childhood-onset pituitary, adrenal, or gonadal disorders, such as craniopharyngioma, congenital adrenal hyperplasia (CAH), and Turner syndrome were prioritized. The planned enrollment is 1,300 patients during the first study phase (2022-2024). Clinical, biochemical, and imaging data from diagnosis, treatment, and follow-up during 1980-2023 were retrospectively reviewed. For patients who agreed to participate in the prospective cohort, clinical data and biospecimens will be prospectively collected to discover ideal biomarkers that predict the effectiveness of disease control measures and prognosis. Patient-reported outcomes, including quality of life and depression scales, will be evaluated to assess psychosocial outcomes. Additionally, a substudy on CAH patients will develop a steroid hormone profiling method using liquid chromatography-tandem mass spectrometry to improve diagnosis and monitoring of treatment outcomes. This study will address unmet clinical needs by discovering ideal biomarkers, introducing evidence-based treatment guidelines, and ultimately improving long-term outcomes in the areas of rare endocrine and metabolic diseases.

New ethical challenges in the management of rare pediatric diseases with innovative therapies

Diagnosis, treatment and management of rare diseases (RD) pose unique challenges due to their complex nature, significantly impacting the daily experiences of researchers and healthcare professionals working in this field. Despite increasing awareness and progress in the field of RD worldwide in recent years, a significant gap remains in our understanding of the specific barriers that these professionals face in their work with RD. This study provides a detailed survey analysis that sheds light on the challenges that researchers and healthcare professionals face in diagnosing, treating, managing and conducting research on RD. We developed a national online survey with three RD stakeholder groups (Researchers, Healthcare professionals and researcher-healthcare professionals) to identify the main challenges and needs in Türkiye for the diagnosis, treatment and follow-up processes of rare and undiagnosed diseases. The survey was completed by 363 participants, revealing that participants face key challenges such as the need to refer patients to specialized centers, financial burdens, limited access to necessary tests, inadequate support for rare disease research and a lack of interdisciplinary collaboration. Participants also noted that RD are inherently difficult to conduct research on with small cohorts. Survey results also suggest a number of policy improvements to accelerate research on RD: increased funding, establishment of robust surveillance systems, and development of comprehensive national action plans and guidelines on RD. To the best of our knowledge, this is the first study to be conducted in Türkiye. This study contributes to the understanding of the needs of professionals in rare disease research and highlights the urgent need for system improvements to support them.

For more than fifty years, screening United States newborns has been a federal public health mandate designed to test infants within forty-eight hours of birth for a set of genetic diseases or conditions that are treatable—such as cystic fibrosis, sickle cell disease, and congenital adrenal hyperplasia. Since the 1960s, newborn babies have been screened by newborn dried bloodspot screening (“NDBS”), an assay developed by microbiologist Robert Guthrie, which involves pricking the heel of a newborn and placing several bloodspots on a collection card made of special filter paper.[1] The bloodspot card is then sent to a state laboratory for testing, usually within forty-eight hours of collection. If the newborn’s screening suggests a disorder, a lab technician immediately contacts the healthcare provider to coordinate clinical care. Early detection and treatment is critical because it helps prevent lifelong disabilities or death.[2] Since their inception, the state screening programs have allowed for the release of bloodspots for public health research. Until recently, in all but a few states,[3] parental consent to use NDBS samples has been presumed, unless parents actively opt out. Research projects involving the use of residual bloodspots require review by institutional review boards—a body of scientific and legal experts charged with protecting the privacy rights of the persons from whom the samples came. To ensure the privacy and identity of the newborn samples, the genomic data is protected. Only public health related projects that are approved may go forward, and those that do must adhere to the approved research protocol.[4] A recently enacted[5] newborn screening law, the Newborn Screening Saves Lives Reauthorization Act of 2014 (“NSSLRA”), reauthorizes $20 million to continue funding for the state-based newborn screening programs described above. However, the law is deeply troubling to the biomedical research community and public health officials due to one of its provisions, which changes the scope of human subjects protection in connection with NDBS.[6] Section 12 of the NSSLRA (the “provision”) (i) reclassifies newborn dried bloodspot screening (NDBS) as research on human subjects, thereby requiring state health departments to obtain parental informed consent for deidentified newborn screening samples[7] and (ii) eliminates the ability of an institutional review board to waive informed consent requirements for research on newborn dried bloodspots.[8] In a recent JAMA viewpoint, biomedical researchers and policy experts from the National Institutes of Health and the National Human Genome Research Institute warn that the provision on parental research consent can damage public health investigations. As such, these experts believe that more discussion is necessary before modifying the consent policies. They assert that requiring parental consent could reduce the number of samples available for research and therefore adversely impact newborn screening participation rates. This could produce long-term consequences, such as a dearth of biomedical research relating to certain rare diseases, such as leukemia, thereby disadvantaging affected populations.[9] Given the potential of screening samples to benefit public health research—the CDC has even stated that NDBS “is one of the nation’s most successful public health programs”—it is unsurprising that the NSSLRA provision has alarmed public health officials.[10] While it is true that the provision may hamper important research outcomes, it remains important not to lose sight of autonomy, a core principle of research ethics. As the experts note, “the issue over whether and how to obtain parental consent for health research on residual dried bloodspots represents a tension between respecting individual liberties and ensuring public health,” acknowledging the possibility for technicians to reidentify the samples. Ultimately, the viewpoint concludes that “the importance of biomedical research for public health purposes is too great…to risk seriously adversely affecting the number of samples available for research.”[11] All things considered, since research using bloodspots has been a tremendous public health success and is likely to increase, it may be worth considering a bifurcation of consent processes (e.g., making screening opt-out and research opt-in), thereby providing comprehensive information to parents in order for them to make a considered decision. Another proposal that has gained traction among some bioethicists is to educate parents earlier—e.g., well before the pre-partum period.[12] At this point, there remains considerable cross-state variability in the administration of newborn screening. While there have been some recent efforts to standardize state screening processes, such as the Advisory Committee on Heritable Disorders in Newborns and Children,[13] newborn screening laws, including NSSLRA, must work toward developing a regulatory framework that is more palatable to both public health officials and concerned parents.

The experience of diagnosis announcement in rare endocrine diseases: A survey of the French FIRENDO network

Whole genome sequencing for newborns—The devil is in the details

Patient advocacy organizations have a forefront role in ensuring that patients’ voices and needs are embedded as a constitutive basis in drug development, diagnosis, and policy recommendations in the healthcare ecosystem. Their sustained involvement in accelerating the policy changes for inclusion of additional diseases in the newborn screening (NBS) programs, supporting harmonization in terms of number of screened diseases across the European Union, constitutes a driving force for advancing the quality of care and the management of rare diseases by aligning NBS policies and practices internationally. In the current European landscape, NBS varies significantly across regions and countries. Patient advocacy organizations are acting to alert healthcare authorities of the existing inequity in NBS and recommending that additional diseases be added to the national NBS programs. Here, we describe the state of play for Spinal Muscular Atrophy (SMA) as a model for advancing NBS for rare diseases where a treatment regime is available. Ultimately, a broad understanding of NBS for SMA will additionally serve as a means to understand the financial impact of early therapeutic intervention for a rare disease.

PurposeRare diseases affect <1 in 2000 people. Despite their rarity, they collectively affect ~30 million people across Europe. The aim of this article is to present the view of our European endocrine societies on the care of patients with rare endocrine conditions.MethodsWe evaluated the current situation of patients with rare endocrine disease and present the joint views of the European Society for Endocrinology (ESE) and the European Society for Pediatric Endocrinology (ESPE) on how the endocrine disciplines can support and contribute to a better health of patients with rare endocrine conditions in Europe.ResultsRare diseases pose many challenges, including early diagnosis and innovative treatment options. Rare endocrine diseases can be found among inherited disorders, cancers, and conditions associated with metabolic disorders such as diabetes, calcium and bone metabolism, lipid metabolism, hypogonadism, and adrenal, pituitary, and thyroid dysfunction. According to the European Registries for Rare Endocrine conditions, there are over 440 distinct rare diseases that affect the endocrine system. Rare endocrine diseases are often chronic and life-threatening.ConclusionsESE and ESPE support a strategic plan to address unmet needs in the area of rare endocrine conditions. The EU should continue to evolve and expand its plans for funding European Reference Networks so that they can expand their activities.

Although neurologists are frequently faced with the management of rare diseases, there is little generic guidance for the approach to management. There are complexities with respect to diagnosis, counselling, treatment...

Home to a culturally heterogeneous population, India is also a melting pot of genetic diversity. The population architecture characterized by multiple endogamous groups with specific marriage patterns, including the widely prevalent practice of consanguinity, not only makes the Indian population distinct from rest of the world but also provides a unique advantage and niche to understand genetic diseases. Centuries of genetic isolation of population groups have amplified the founder effects, contributing to high prevalence of recessive alleles, which translates into genetic diseases, including rare genetic diseases in India.Rare genetic diseases are becoming a public health concern in India because a large population size of close to a billion people would essentially translate to a huge disease burden for even the rarest of the rare diseases. Genomics-based approaches have been demonstrated to accelerate the diagnosis of rare genetic diseases and reduce the socio-economic burden. The Genomics for Understanding Rare Diseases: India Alliance Network (GUaRDIAN) stands for providing genomic solutions for rare diseases in India. The consortium aims to establish a unique collaborative framework in health care planning, implementation, and delivery in the specific area of rare genetic diseases. It is a nation-wide collaborative research initiative catering to rare diseases across multiple cohorts, with over 240 clinician/scientist collaborators across 70 major medical/research centers. Within the GUaRDIAN framework, clinicians refer rare disease patients, generate whole genome or exome datasets followed by computational analysis of the data for identifying the causal pathogenic variations. The outcomes of GUaRDIAN are being translated as community services through a suitable platform providing low-cost diagnostic assays in India. In addition to GUaRDIAN, several genomic investigations for diseased and healthy population are being undertaken in the country to solve the rare disease dilemma.In summary, rare diseases contribute to a significant disease burden in India. Genomics-based solutions can enable accelerated diagnosis and management of rare diseases. We discuss how a collaborative research initiative such as GUaRDIAN can provide a nation-wide framework to cater to the rare disease community of India.

Rare diseases occur in <50 per 100000 people and require lifelong management. However, essential epidemiological data on such diseases are lacking, and a consecutive monitoring system across time and regions remains to be established. Standardized digital phenotypes are required to leverage an international data network for research on rare endocrine diseases. We developed digital phenotypes for rare endocrine diseases using the observational medical outcome partnership common data model. Digital phenotypes of three rare endocrine diseases (medullary thyroid cancer, hypoparathyroidism, pheochromocytoma/paraganglioma) were validated across three databases that use different vocabularies: Severance Hospital's electronic health record from South Korea; IQVIA's United Kingdom (UK) database for general practitioners; and IQVIA's United States (US) hospital database for general hospitals. We estimated the performance of different digital phenotyping methods based on International Classification of Diseases (ICD)-10 in the UK and the US or systematized nomenclature of medicine clinical terms (SNOMED CT) in Korea. The positive predictive value of digital phenotyping was higher using SNOMED CT-based phenotyping than ICD-10-based phenotyping for all three diseases in Korea (e.g., pheochromocytoma/paraganglioma: ICD-10, 58%-62%; SNOMED CT, 89%). Estimated incidence rates by digital phenotyping were as follows: medullary thyroid cancer, 0.34-2.07 (Korea), 0.13-0.30 (US); hypoparathyroidism, 0.40-1.20 (Korea), 0.59-1.01 (US), 0.00-1.78 (UK); and pheochromocytoma/paraganglioma, 0.95-1.67 (Korea), 0.35-0.77 (US), 0.00-0.49 (UK). Our findings demonstrate the feasibility of developing digital phenotyping of rare endocrine diseases and highlight the importance of implementing SNOMED CT in routine clinical practice to provide granularity for research.

Long-awaited action on rare diseases.

Many pediatric patients with rare diseases use drugs off-label due to limited data in pediatric patients. Off-label treatment remains an important public health issue for neonates, infants, children, and adolescents, especially for pediatric patients with rare diseases. For patients with rare diseases, the majority of medications have no or limited information in labelling for pediatric use. Children present unique considerations in clinical trials due to ethical and clinical concerns, which have limited and even discouraged testing of drugs in the pediatric population. Numerous legislative measures have been enacted to address barriers in pediatric drug testing. This research reviewed off-label medication use in rare pediatric diseases, evaluated recent medication uses in pediatric clinical practice, discussed key regulations for rare pediatric diseases, and summarized recent drug approvals for rare pediatric diseases. This study demonstrates the ongoing medical need for newly approved medications to treat pediatric rare diseases and revealed the positive impact of regulations from the Orphan Drug Act of 1983 to the Research to Accelerate Cures and Equity (RACE) for Children Act on drug development and off-label medication practice in rare pediatric disease management. This article provides informative historical background and current considerations of off-label use of medications in neonates, infants, children, and adolescents with rare diseases.