Rare Pediatric Disease Research Articles

The economic impact of living with a rare disease for children and their families: a scoping review protocol.

Rare diseases are an often chronic, progressive and life-limiting group of conditions affecting more than 30 million people in Europe. These diseases are associated with significant direct and indirect costs to a spectrum of stakeholders, ranging from individuals and their families to society overall. Further quantitative research on the economic cost for children and their families living with a rare disease is required as there is little known on this topic. This scoping review aims to document the extent and type of evidence on the economic impacts of living with a rare disease for children and their families. This scoping review will follow the PRISMA-ScR and Joanna Briggs Institute guidelines and follow the six-stage methodology for scoping reviews: (1) identifying the research question, (2) identifying relevant studies, (3) study selection, (4) charting the data, (5) collating, summarising and reporting results and (6) knowledge user consultation. Key inclusion criteria have been developed according to the Population-Concept-Context (PCC) framework. The databases EconLit, ABI/Inform, MEDLINE, PubMed, CINAHL, and Scopus will be searched for possible articles for inclusion. Two independent reviewers will screen titles and abstracts of potential articles using a dual review process to ensure all relevant studies are included. All included articles will be assessed using a validated quality appraisal tool. A panel of patient and public involvement representatives experiencing rare diseases and knowledge users will validate the review results. This scoping review will map the current literature on the economic impact of paediatric rare diseases to understand how these impacts affect children living with rare diseases and their families. This evidence has the potential to influence policy and future research in this area and will support further research on the economic impact of rare diseases on families.

Preliminary Experience with 3-Dimensional-Exoscopic Untethering of a Type II Diastematomyelia: Technical Note and Review of the Literature

ObjectiveThe aim of this paper is to describe the use of high-definition 3D exoscope (VITOM 3D exoscope - Karl Storz GmbH, Tuttlingen, Germany) for the neurosurgical treatment of a rare pediatric disease, type II diastematomyelia with associated tethered cord. MethodsA 13-year-old girl suffering diastematomyelia type II with a tethered cord was surgically treated with the aid of a high-definition 3D exoscope, with a third operator moving and pivoting its arm. Intraoperative monitoring and mapping was arranged. The surgery required a bilateral access to address both the split cord malformation and the tethering of the filum terminale. The filum terminale was identified and cut, and the connective fibrovascular tissue separating the two medullary halves were unraveled. These steps were performed with no changes of intraoperative monitoring. Pertinent literature has been carefully addressed ResultsThe surgery was successful, and the patient was discharged home on the eleventh postoperative day without any complications. The 3-month postoperative MRI demonstrated regular surgical outcomes; no dynamic motor disturbances were reported. To our knowledge this is the first spinal congenital malformation treated with the use of a 3D exoscope. ConclusionsThe use of 3D exoscope is advancing in spinal surgery, as it provides magnification, stereopsis, lighting and definition comparable to the operating microscope; the addition of a third operator simplified the operations of moving around the arm, releasing these burdens for the surgeons. Our preliminary experience proved that the use of a 3D exoscope is feasible and safe for surgical management of a type II diastematomyelia with tethered cord.

Referent data for investigations of upper limb accelerometry: harmonized data from three cohorts of typically-developing children.

The rise of wearable sensing technology shows promise for addressing the challenges of measuring motor behavior in pediatric populations. The current pediatric wearable sensing literature is highly variable with respect to the number of sensors used, sensor placement, wearing time, and how data extracted from the sensors are analyzed. Many studies derive conceptually similar variables via different calculation methods, making it hard to compare across studies and clinical populations. In hopes of moving the field forward, this report provides referent upper limb wearable sensor data from accelerometers on 25 variables in typically-developing children, ages 3-17 years. This is a secondary analysis of data from three pediatric cohorts of children 3-17 years of age. Participants (n = 222) in the cohorts wore bilateral wrist accelerometers for 2-4 days for a total of 622 recording days. Accelerometer data were reprocessed to compute 25 variables that quantified upper limb movement duration, intensity, symmetry, and complexity. Analyses examined the influence of hand dominance, age, gender, reliability, day-to-day stability, and the relationships between variables. The majority of variables were similar on the dominant and non-dominant sides, declined slightly with age, and were not different between boys and girls. ICC values were moderate to excellent. Variation within individuals across days generally ranged from 3% to 32%. A web-based R shiny object is available for data viewing. With the use of wearable movement sensors increasing rapidly, these data provide key, referent information for researchers as they design studies, and analyze and interpret data from neurodevelopmental and other pediatric clinical populations. These data may be of particularly high value for pediatric rare diseases.

Contractile and Genetic Characterization of Cardiac Constructs Engineered from Human Induced Pluripotent Stem Cells: Modeling of Tuberous Sclerosis Complex and the Effects of Rapamycin.

The implementation of three-dimensional tissue engineering concurrently with stem cell technology holds great promise for in vitro research in pharmacology and toxicology and modeling cardiac diseases, particularly for rare genetic and pediatric diseases for which animal models, immortal cell lines, and biopsy samples are unavailable. It also allows for a rapid assessment of phenotype-genotype relationships and tissue response to pharmacological manipulation. Mutations in the TSC1 and TSC2 genes lead to dysfunctional mTOR signaling and cause tuberous sclerosis complex (TSC), a genetic disorder that affects multiple organ systems, principally the brain, heart, skin, and kidneys. Here we differentiated healthy (CC3) and tuberous sclerosis (TSP8-15) human induced pluripotent stem cells (hiPSCs) into cardiomyocytes to create engineered cardiac tissue constructs (ECTCs). We investigated and compared their mechano-elastic properties and gene expression and assessed the effects of rapamycin, a potent inhibitor of the mechanistic target of rapamycin (mTOR). The TSP8-15 ECTCs had increased chronotropy compared to healthy ECTCs. Rapamycin induced positive inotropic and chronotropic effects (i.e., increased contractility and beating frequency, respectively) in the CC3 ECTCs but did not cause significant changes in the TSP8-15 ECTCs. A differential gene expression analysis revealed 926 up- and 439 down-regulated genes in the TSP8-15 ECTCs compared to their healthy counterparts. The application of rapamycin initiated the differential expression of 101 and 31 genes in the CC3 and TSP8-15 ECTCs, respectively. A gene ontology analysis showed that in the CC3 ECTCs, the positive inotropic and chronotropic effects of rapamycin correlated with positively regulated biological processes, which were primarily related to the metabolism of lipids and fatty and amino acids, and with negatively regulated processes, which were predominantly associated with cell proliferation and muscle and tissue development. In conclusion, this study describes for the first time an in vitro TSC cardiac tissue model, illustrates the response of normal and TSC ECTCs to rapamycin, and provides new insights into the mechanisms of TSC.

Analysis of the first ten years of FDA’s rare pediatric disease priority review voucher program: designations, diseases, and drug development

BackgroundThe Rare Pediatric Disease (RPD) Priority Review Voucher (PRV) Program was enacted in 2012 to support the development of new products for children. Prior to requesting a voucher, applicants can request RPD designation, which confirms their product treats or prevents a rare disease in which the serious manifestations primarily affect children. This study describes the trends and characteristics of these designations. Details of RPD designations are not publicly disclosable; this research represents the first analysis of the RPD designation component of the program.ResultsWe used an internal US Food and Drug Administration database to analyze all RPD designations between 2013 and 2022. Multiple characteristics were analyzed, including the diseases targeted by RPD designation, whether the product targeted a neonatal disease, product type (drug/biologic), and the level of evidence (preclinical/clinical) to support designation. There were 569 RPD designations during the study period. The top therapeutic areas were neurology (26%, n = 149), metabolism (23%, n = 131), oncology (18%, n = 105). The top diseases targeted by RPD designation were Duchenne muscular dystrophy, neuroblastoma, and sickle cell disease. Neonatology products represented 6% (n = 33), over half were for drug products and 38% were supported by clinical data.ConclusionsThe RPD PRV program was created to encourage development of new products for children. The results of this study establish that a wide range of diseases have seen development—from rare pediatric cancers to rare genetic disorders. Continued support of product development for children with rare diseases is needed to find treatments for all children with unmet needs.

Developing a community-led rare disease ELSI research agenda.

Research priorities are best defined through engagement with communities who will be impacted by the research and have lived experience of the topics to be studied. We aimed to establish a pediatric rare disease community stakeholder group and empower them in (1) eliciting perspectives from affected families in the wider region and (2) synthesizing collective ideas into a research agenda focused on shared ethical, legal, and social implications (ELSI) across rare disease. This two-year project utilized a community-centered approach to engage rare disease community members as equal partners in developing a research agenda for ELSI in rare disease. We established "Rare Voices" (RV), a 22-member stakeholder group of patients, parents, clinicians and researchers. Following capacity-building trainings, RV designed and conducted listening sessions with teen patients and parents of children with rare diseases to explore challenges, positive experiences, and ethical concerns. Listening session findings were synthesized and contextualized into research topics, which RV members further refined and prioritized. We used established measures to assess RV member engagement and satisfaction. From 14 listening sessions with parents (n = 52) and teen patients (n = 13), RV identified eight core research topics as most important for future rare disease research: coordinating care, communication, accessing resources and care, impact on family unit, community and support in society, mental health and identity, ethical aspects of care, and uncertainty. RV members were highly engaged throughout the two-year project and reported high levels of satisfaction with the experience and research agenda. Through capacity-building and authentic engagement, this project resulted in a community-led rare disease research agenda to guide future rare disease ELSI research that aligns with patients' and families' priorities. An environment of equal partnership and respect created a space for mutual learning where community members were empowered to shape the research agenda based on their collective experiences. The agenda recognizes the shared psychosocial and healthcare experiences of rare disease and offers practical areas of research to address patient and family needs.

A Drug Discovery Perspective on FDA Expedited Development and Incentive Programs.

Expedited development and approval pathways at the Food and Drug Administration (FDA) such as Priority review, Fast Track Designation, Breakthrough Designation, and Accelerated Approval are programs available to drug sponsors that aim to incentivize and expedite the delivery of drugs to patients in need. In addition, other incentive programs such as Orphan Drug Designation (ODD), Qualified Infectious Disease Product Designation (QIDP), and Rare Pediatric Disease Designation (RPDD) are available to drug sponsors to help motivate development of drugs that may have lower economic incentive for commercialization. These programs have been largely effective, and many new innovative drugs since 2010 have accessed these programs. This Perspective highlights how these programs have been used in recent FDA drug approvals and discusses future ways sponsors and regulatory agencies may further enable development of these innovative drugs in the most expeditious fashion.

Use of Mexiletine in Children: A Minireview

AbstractMexiletine is well-established sodium channel blocker that acts on cardiac myocytes and neurons. It has recently been repositioned as an orphan drug in the treatment of rare neuromuscular diseases in adults with nondystrophic myotonia. It has also long been used in some rare pediatric diseases in the areas of cardiopathy, epilepsy, neuromuscular diseases, and pain disorders. Here, we review the different uses of mexiletine reported in pediatrics, stating indications, efficacy, and tolerance. Special attention by health authorities to maintain access to mexiletine in rare pediatric diseases and further pediatric research in these rare syndromes are required.

Diversity of kidney care referral pathways in national child health systems of 48 European countries.

Primary, secondary and tertiary healthcare services in Europe create complex networks covering pediatric subspecialties, sociology, economics and politics. Two surveys of the European Society for Paediatric Nephrology (ESPN) in 1998 and 2017 revealed substantial disparities of kidney care among European countries. The purpose of the third ESPN survey is to further identify national differences in the conceptualization and organization of European pediatric kidney health care pathways during and outside normal working hours. In 2020, a questionnaire was sent to one leading pediatric nephrologist from 48 of 53 European countries as defined by the World Health Organization. In order to exemplify care pathways in pediatric primary care nephrology, urinary tract infection (UTI) was chosen. Steroid sensitive nephrotic syndrome (SSNS) was chosen for pediatric rare disease nephrology and acute kidney injury (AKI) was analyzed for pediatric emergency nephrology. The care pathways for European children and young people with urinary tract infections were variable and differed during standard working hours and also during night-time and weekends. During daytime, UTI care pathways included six different types of care givers. There was a shift from primary care services outside standard working hours to general outpatient polyclinic and hospital services. Children with SNSS were followed up by pediatric nephrologists in hospitals in 69% of countries. Patients presenting with community acquired AKI were admitted during regular working hours to secondary or tertiary care hospitals. During nights and weekends, an immediate shift to University Children's Hospitals was observed where treatment was started by intensive care pediatricians and pediatric nephrologists. Gaps and fragmentation of pediatric health services may lead to the risk of delayed or inadequate referral of European children with kidney disease to pediatric nephrologists. The diversity of patient pathways outside of normal working hours was identified as one of the major weaknesses in the service chain.

"A very big challenge": a qualitative study to explore the early barriers and enablers to implementing a national genomic medicine service in England.

Background: The Genomic Medicine Service (GMS) was launched in 2018 in England to create a step-change in the use of genomics in the NHS, including offering whole genome sequencing (WGS) as part of routine care. In this qualitative study on pediatric rare disease diagnosis, we used an implementation science framework to identify enablers and barriers which have influenced rollout. Methods: Semi-structured interviews were conducted with seven participants tasked with designing the GMS and 14 tasked with leading the implementation across the seven Genomic Medicine Service Alliances (GMSAs) and/or Genomic Laboratory Hubs (GLHs) between October 2021 and February 2022. Results: Overall, those involved in delivering the service strongly support its aims and ambitions. Challenges include: 1) concerns around the lack of trained and available workforce (clinicians and scientists) to seek consent from patients, interpret findings and communicate results; 2) the lack of a digital, coordinated infrastructure in place to support and standardize delivery with knock-on effects including onerous administrative aspects required to consent patients and order WGS tests; 3) that the "mainstreaming agenda", whilst considered important, encountered reluctance to become engaged from those who did not see it as a priority or viewed it as being politically rather than clinically driven; 4) the timelines and targets set for the GMS were perceived by some as too ambitious. Interviewees discussed local adaptations and strategies employed to address the various challenges they had encountered, including 1) capacity-building, 2) employing genomic associates and other support staff to support the consent and test ordering process, 3) having "genomic champions" embedded in mainstream services to impart knowledge and best practice, 4) enhancing collaboration between genetic and mainstream specialties, 5) building evaluation into the service and 6) co-creating services with patients and the public. Conclusion: Our findings highlight the challenges of implementing system-wide change within a complex healthcare system. Local as well as national solutions can undoubtedly address many of these barriers over time.

Orphan Drug Label Expansions: Analysis Of Subsequent Rare And Common Indication Approvals.

The Orphan Drug Act of 1983 was enacted to provide financial incentives to stimulate drug development for rare diseases. In recent years, concerns have been raised regarding these orphan drugs, including how many are being approved for both rare and common diseases and the number of subsequent indication approvals. Policy makers have suggested modifications to the Orphan Drug Act's incentives to address these concerns. In this study we investigated the approval "family trees" of orphan drugs. We found that 491 novel orphan drugs were approved between 1990 and 2022. To date, 65percent have been approved for a single rare disease, 15percent have been approved for multiple rare diseases, and 20percent have been approved for both rare and common diseases. Ten percent of orphan drugs received a subsequent indication approval for a pediatric population of an orphan disease. Revenue estimates from 2021 show that one-third of the drugs approved for both rare and common indications and 6percent of rare-only drugs were among the 200 top-selling drugs worldwide. The results have implications for the possible externalities of modifying the incentives of the Orphan Drug Act, such as a potential decrease in the initiation of programs to develop pediatric rare disease drugs.

The Impact of Raising Children with Barth Syndrome on Parental Health-Related Quality of Life and Family Functioning: Preliminary Reliability and Validity of the PedsQL™ Family Impact Module.

This study examined the preliminary reliability and validity of the PedsQL™ Family Impact Module (PedsQL FIM) in families of children with Barth syndrome (BTHS). A total of 72 parents with children or youth between the ages of 5 and 19 participated in this study. Thirty-three parents of children with BTHS and 39 parents of unaffected children completed the PedsQL FIM and a demographic information form. Internal consistency reliability and item-total correlations were calculated to test the reliability of the PedsQL FIM. Construct validity was examined using the known-groups method. We estimated the mean score differences of the PedsQL FIM between the two groups using three different models, including unadjusted, multivariate regression, and propensity score matching with inverse probability of treatment weighting (PS-IPTW) models. The Cronbach's alpha coefficients were greater than 0.70 for all scales of the PedsQL FIM, except for the communication scale. The item-total correlations were significant for all scales with moderate to high correlations (p < .05). In construct validity, the mean scores of the PedsQL FIM between the two groups were significantly different (p < .05) for all scales and total score in the unadjusted and PS-IPTW models. However, in the multivariate regression model, the family relationships scale was not significant between the two groups. The PedsQL FIM demonstrated adequate measurement properties of preliminary reliability and validity in assessing the impact of children with BTHS on parental health-related quality of life (HRQoL) and family functioning. Further research needs to be conducted to examine the psychometric properties of the PedsQL FIM with a large sample of BTHS and with other pediatric rare diseases.

Development and validation of a computable phenotype for Turner syndrome utilizing electronic health records from a national pediatric network.

Turner syndrome (TS) is a genetic condition occurring in ~1 in 2000 females characterized by the complete or partial absence of the second sex chromosome. TS research faces similar challenges to many other pediatric rare disease conditions, with homogenous, single-center, underpowered studies. Secondary data analyses utilizing electronic health record (EHR) have the potential to address these limitations; however, an algorithm to accurately identify TS cases in EHR data is needed. We developed a computable phenotype to identify patients with TS using PEDSnet, a pediatric research network. This computable phenotype was validated through chart review; true positives and negatives and false positives and negatives were used to assess accuracy at both primary and external validation sites. The optimal algorithm consisted of the following criteria: female sex, ≥1 outpatient encounter, and ≥3 encounters with a diagnosis code that maps to TS, yielding an average sensitivity of 0.97, specificity of 0.88, and C-statistic of 0.93 across all sites. The accuracy of any estradiol prescriptions yielded an average C-statistic of 0.91 across sites and 0.80 for transdermal and oral formulations separately. PEDSnet and computable phenotyping are powerful tools in providing large, diverse samples to pragmatically study rare pediatric conditions like TS.

Vosoritide, a miracle drug, covering unmet need in achondroplasia: A regulatory update.

Dwarfism is a rare condition characterized by small stature. Achondroplasia is predominantly considered the leading cause of dwarfism. Although the condition is not life-threatening, it dramatically impacts the social life of the patient. The United States Food and Drug Administration (US FDA) first approved the drug Voxzogo (vosoritide) for achondroplasia. The drug also received approval from the European Medicines Agency (EMA) via the centralized procedure. The drug is associated with a decrease in blood pressure, a severe adverse event. However, this adverse event/risk has been overcome by benefits, i.e. fulfilling of unmet medical need. In the United States, the drug received accelerated approval as it satisfied the criteria of rare pediatric disease. This review includes a detailed orphan drug approval process with particular reference to vosoritide, which is considered a milestone for the treatment of achondroplasia.

Improving visual outcomes in patients with rare paediatric eye diseases.

Rare paediatric eye diseases (RPEDs) threaten both vision and life. Recently, rare diseases were recognised as a global public health agenda, with children specified as a priority in the World Health Organization's VISION 2020 against avoidable visual loss. We conducted a review through a query of online databases (PubMed, Embase and Cochrane Library). Articles related to RPEDs were selected based on relevance by 2 authors, with any disagreements adjudicated by the third author. We synthesise the current state of knowledge regarding RPEDs, barriers to their care, and recommendations for the future. RPEDs often result in significant visual loss, profoundly impacting the way children comprehend and participate in the world. These diseases may also reduce life expectancy and even be life-threatening. Barriers to the care of RPEDs include an unclear definition of "rare diseases", missed or delayed diagnosis, inadequate knowledge and expertise in management, and challenging research environments. Our findings provide an update on the diagnosis and management of RPEDs, which is of relevance to ophthalmologists, paediatricians, healthcare policymakers and social workers. We propose supportive policies and adequate resource allocation to these diseases, comprehensive and patient-centred care, alongside improved education and training, enhanced research capabilities and continued collaboration across institutions.

Mechanisms Underlying Rare Inherited Pediatric Retinal Vascular Diseases: FEVR, Norrie Disease, Persistent Fetal Vascular Syndrome.

Familial Exudative Vitreoretinopathy (FEVR), Norrie disease, and persistent fetal vascular syndrome (PFVS) are extremely rare retinopathies that are clinically distinct but are unified by abnormal retinal endothelial cell function, and subsequent irregular retinal vascular development and/or aberrant inner blood-retinal-barrier (iBRB) function. The early angiogenesis of the retina and its iBRB is a delicate process that is mediated by the canonical Norrin Wnt-signaling pathway in retinal endothelial cells. Pathogenic variants in genes that play key roles within this pathway, such as NDP, FZD4, TSPAN12, and LRP5, have been associated with the incidence of these retinal diseases. Recent efforts to further elucidate the etiology of these conditions have not only highlighted their multigenic nature but have also resulted in the discovery of pathological variants in additional genes such as CTNNB1, KIF11, and ZNF408, some of which operate outside of the Norrin Wnt-signaling pathway. Recent discoveries of FEVR-linked variants in two other Catenin genes (CTNND1, CTNNA1) and the Endoplasmic Reticulum Membrane Complex Subunit-1 gene (EMC1) suggest that we will continue to find additional genes that impact the neural retinal vasculature, especially in multi-syndromic conditions. The goal of this review is to briefly highlight the current understanding of the roles of their encoded proteins in retinal endothelial cells to understand the essential functional mechanisms that can be altered to cause these very rare pediatric retinal vascular diseases.

Basic notions about gene therapy from the nucleic acid perspective and applications in a pediatric disease: Duchenne muscular dystrophy

Gene therapy involves the introduction of genetic material into cells as a therapeutic molecule to cure a disease. Through the transfer of specific nucleic acid to the target tissue, gene expression can be downregulated, augmented, or corrected thanks to the nucleic acid sequence as a support of gene expression. This is achieved through molecular interactions according to the sequence arrangement or the secondary structure of the molecules or through their catalytic properties. Over the past two decades, the rapid advances of knowledge and technologies in gene therapy have led to the development of different strategies and to the extension of its use to numerous indications, including certain cancers. Major success has been achieved in clinical trials and the field of gene therapy is booming. Several gene therapy products are now on the market in Europe, the United States, and China. In this review, we cover the basic principles of gene therapy and the characteristics of the main vectors used to transfer genetic material into the cell. As an example of applications, we address the various strategies applied to a rare pediatric muscle disease: Duchenne muscular dystrophy. © 2023 Published by Elsevier Masson SAS on behalf of French Society of Pediatrics.

Current limitations of gene therapy for rare pediatric diseases: Lessons learned from clinical experience with AAV vectors

Gene therapy using adeno-associated viral (AAV) vectors is a promising therapeutic strategy for multiple inherited diseases. Following intravenous injection, AAV vectors carrying a copy of the missing gene or the genome-editing machinery reach their target cells and deliver the genetic material. Several clinical trials are currently ongoing and significant success has already been achieved with at least six AAV gene therapy products with market approval in Europe and the United States. Nonetheless, clinical trials and preclinical studies have uncovered several limitations of AAV gene transfer, which need to be addressed in order to improve the safety and enable the treatment of the largest patient population. Limitations include the occurrence of immune-mediated toxicities, the potential loss of correction in the long run, and the development of neutralizing antibodies against AAV vectors preventing re-administration. In this review, we summarize these limitations and discuss the potential technological developments to overcome them. © 2023 Published by Elsevier Masson SAS on behalf of French Society of Pediatrics.

FRI478 Pharmacometrics-based Computer Model Utilizing Heart Rate To Monitor Thyroid Function In Children With Graves' Disease

Abstract Disclosure: B. Steffens: None. G. Koch: None. F. Claude: None. F. Bachmann: None. J. Schropp: None. M. Janner: None. D. l'Allemand: None. D. Konrad: None. M. Pfister: None. G. Szinnai: None. Graves’ disease (GD) with onset in childhood or adolescence is a pediatric rare disease (ORPHA:525731) with a ten times lower incidence than in adults. Leading clinical signs of hyperthyroidism are sinus tachycardia, weight loss, tremor, and goiter. First-line treatment are anti-thyroid drugs in order to normalize thyroid function. However, dose finding in pediatric GD is complex due to a broad spectrum of disease severity at diagnosis, and highly variable disease activity during follow-up, especially during puberty. As thyroid hormones have a strong positive chronotropic effect, heart rate (HR) turns out to be a useful clinical marker to monitor thyroid activity under treatment. Our overall aim was to provide a practical pharmacometrics-based (PMX-based) computer model characterizing both, individual FT4 dynamics and the relation between FT4 and tachycardia in children with various disease severity of GD during the first 120 days of treatment. Development of the PMX computer model was based on the non-linear mixed effects approach (i) linking FT4 kinetics with HR dynamics, (ii) accounting for inter-individual variability, and (iii) incorporating individual patient characteristics. Retrospectively collected clinical (resting heart rate during consultation) and laboratory data (FT4) from 41 children and adolescents with GD at four pediatric hospitals in Switzerland (75% female, median age 11.2 [IQR 8.5, 13.5] years) with 187 FT4 measurements and 132 HR measurements, and 124 paired measurements, were available and used for model development. Pediatric patients showed median FT4 of 59.6 [IQR 44.5, 73.0] pmol/l and median HR of 112 [IQR 100, 128] bpm at diagnosis. GD severity groups were defined based on FT4 measurement at diagnosis, resulting in equal numbers of mild (13), moderate (14) and severe (14) GD. We observed a significant difference in HR at diagnosis (p &amp;lt; 0.01) between the three GD severity groups based on FT4 at diagnosis. The final PMX computer model accounted for inter-individual variability and clinically relevant covariate effects such as age, gender, and GD severity, and was able to accurately predict FT4 and HR dynamics for each individual patient during the first 120 days of treatment. A PMX-based computer model that leverages individual HR dynamics can be applied to facilitate personalized pharmacotherapy in pediatric GD and mitigate the risk for under- or overdosing of anti-thyroid drugs in these patients. Prospective randomized validation trials are warranted to further validate and fine-tune such computer-supported personalized dosing in children with Graves’ disease. Presentation: Friday, June 16, 2023

Treatment of aseptic facial granuloma as a manifestation of pediatric rosacea with oral macrolides.

Aseptic facial granuloma is a rare pediatric disease, presenting with asymptomatic facial nodules on the cheeks or the eyelids and may represent a form of granulomatous rosacea in children. In this retrospective case series, 12 children with aseptic facial granuloma were treated with oral macrolides (erythromycin or roxithromycin) resulting in a healing of the lesions within a mean treatment time of 5.25 months with no recurrences. The treatment was mainly well tolerated. Oral macrolides may be effective in the treatment of patients with aseptic facial granuloma.