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Background: Achondroplasia is the most common short-limbed skeletal dysplasia resulting from gain-of-function pathogenic variants in fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone formation. Most treatment options are symptomatic, targeting medical complications. Infigratinib is an orally bioavailable, FGFR1–3 selective tyrosine kinase inhibitor being investigated as a direct therapeutic strategy to counteract FGFR3 overactivity in achondroplasia. Objectives: The main objective of PROPEL is to collect baseline data of children with achondroplasia being considered for future enrollment in interventional studies sponsored by QED Therapeutics. The objectives of PROPEL 2 are to obtain preliminary evidence of safety and efficacy of oral infigratinib in children with achondroplasia, to identify the infigratinib dose to be explored in future studies, and to characterize the pharmacokinetic (PK) profile of infigratinib and major metabolites. Design: PROPEL (NCT04035811) is a prospective, noninterventional clinical study designed to characterize the natural history and collect baseline data of children with achondroplasia over 6−24 months. PROPEL 2 (NCT04265651), a prospective, phase II, open-label study of infigratinib in children with achondroplasia, consists of a dose-escalation, dose-finding, and dose-expansion phase to confirm the selected dose, and a PK substudy. Methods and analysis: Children aged 3−11 years with achondroplasia who completed ⩾6 months in PROPEL are eligible for PROPEL 2. Primary endpoints include treatment-emergent adverse events and change from baseline in annualized height velocity. Four cohorts at ascending dose levels are planned for dose escalation. The selected dose will be confirmed in the dose-expansion phase. Ethics: PROPEL and PROPEL 2 are being conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, principles of the Declaration of Helsinki, and relevant human clinical research and data privacy regulations. Protocols have been approved by local health authorities, ethics committees, and institutions as applicable. Parents/legally authorized representatives are required to provide signed informed consent; signed informed assent by the child is also required, where applicable. Discussion: PROPEL and PROPEL 2 will provide preliminary evidence of the safety and efficacy of infigratinib as precision treatment of children with achondroplasia and will inform the design of future studies of FGFR-targeted agents in achondroplasia. Registration: ClinicalTrials.gov: NCT04035811; NCT04265651.

ObjectivesVitamin D deficiency in the UK is more commonly seen in breast fed children of ethnic minority origin, but it is not clear whether this reflects differences in diet, or sunlight exposure.MethodAll new cases of vitamin D deficiency presenting to a large Children’s hospital for the periods March 2019—March 2020 and November 2021 – April 2022 were identified via active surveillance of biochemical results. Families were interviewed by a research dietician using a structured interview schedule including questions on the intake of vitamin-D-containing foods, usual clothing and time spent outdoors.A parallel web survey parents of healthy children was undertaken using the same survey instrument, targeted particularly at non-white UK residents.ResultsOf 41 children identified with Vitamin D deficiency with symptoms, or other biochemical indicators, 27 mothers of children median age (range) 23 (6–132) months completed an interview. All had non white ethnicity: (African 44% (12), South Asian 41% (11). Arab 15% (4).They were compared to 255 web-survey responses, for 121 white British (WB) children, and 234 of other ethnicities (OE); 73 S Asian, 63 African and 99 Arab; 217 of these reported themselves to be Muslim.The clinical group were no less likely to report eating vitamin D containing foods or to report ever taking vitamin drops, compared to both web groups, and the great majority of all 3 groups had breastfed their children. However, solids were started beyond age 7m in 40% of the clinical group compared to 6% of the WB and 13% of the OE group (p<0.001). The clinical group were 5.2 times more likely to eat 2 or fewer meals than WB (p<0.001) and 2.1 more likely than OE (p=0.002).All three groups of children had similar skin exposure, but 63% clinical children spent <5 hrs/week outside, compared to 17% WB (p<0.001) and 51% OE (p=0.23); 40% Clinical mothers spent <5 hrs/week outside, compared to 7% WB (p<0.001) and 46% OE (p=0.56). Clinical group mothers had similar skin exposure to the OE group, but much lower than the WB.ConclusionsChildren with vitamin D deficiency and their mothers spend very little time outside, in common with healthy families of similar ethnicity. They showed no obvious differences from healthy children in the vitamin D content of their diet, but they started solids later and ate fewer meals compared to healthy children in similar ethnic groups.

ObjectivesTo describe the sociodemographic and dietary characteristics of cases of vitamin D deficiency presenting to one large centre.MethodAll new cases of vitamin D deficiency presenting to a large Children’s hospital were identified via clinical report and active surveillance of biochemical results for the periods March 2019—March 2020 and November 2021 – April 2022. Their notes were reviewed and families interviewed by a dietician to gather sociodemographic and feeding data. These were compared to 2011 census data, Scottish breastfeeding statistics and the 2018 Scottish Maternal and Infant Nutrition survey (SMINS).ResultsThere were 41 children with both serum vitamin D <25 and physical symptoms or signs (N=37) or biochemical abnormality (N=4); 9 (22%) presented aged <1m, 9 (22%) 1–12m, 15 (37%) 1 – 5 years and 8 (20%) 5–11 years.Eight mothers (19%) were of white European origin, but only one of their infants presented beyond age 1m; 37% were of South Asian origin, 32% African and 12% Arab; South Asians were 5 times over-represented, and other ethnicities 13 times over-represented, compared to census data for the city.1 Mothers were aged median ((QR) 33 (28–38) years and 54% (22) lived in the most deprived SIMD quintile, similar to the city as whole (44%).2 At interview (N=27) 70% (23) mothers had received higher education.Most (82%, 27) children had been breast fed at some time compared to 65% for Scotland as a whole.3 Most (79%) mothers reported giving vitamin drops to their infants, and 76% (25) had taken them in pregnancy, compared to only 33% and 86% respectively in the Scottish Infant feeding survey.4 of those aged over 6 months with interviews, 10 (40%) started solids at ages 7–12m, compared to only 2% in the 2018 Scottish Infant feeding survey. Most (72%, 18) children ate a vitamin D containing food at least weekly.ConclusionsChildren presenting with significant Vitamin D deficiency were mainly of South Asian, African, or Arab origin. They were slightly more likely to be breastfed and were more likely to start complementary feeding late. They seemed more, not less, likely to have been given supplementary vitamins than the general population and regularly ate at least some vitamin D containing foods. More detailed information on diet and sunlight exposure in healthy children in these ethnic groups is required to understand why they are at so much greater risk of Vitamin D deficiency.Referenceshttps://www.scotlandscensus.gov.uk/search-the-census#/explore/snapshothttps://www.understandingglasgow.com/indicators/poverty/deprivation#:~:text=SIMD%20%E2%80%93%20Scottish%20Index%20of%20Multiple,(data%20zones)%20across%20Scotland.https://publichealthscotland.scot/publications/infant-feeding-statistics/infant-feeding-statistics-financial-year-2021-to-2022/#:~:text=Main%20points,of%20age%20in%202021%2F22.https://www.gov.scot/publications/scottish-maternal-infant-nutrition-survey-2017/

ObjectiveTo determine the incidence, demography and prognosis of vitamin D deficiency dilated cardiomyopathy (DCM) in Scotland over the last decade.Study designA retrospective review of cases of vitamin D deficiency DCM presenting to a national paediatric cardiac centre between 1 January 2008 and 1 January 2018. The departmental database and electronic and paper case notes were used to identify patients and extract data.ResultsSix patients were identified (three male), three of whom were Caucasian. Median age at presentation was 206 days (range 2–268.) All six patients had high serum parathyroid hormone levels (median 45 pmol/L, range 27–120 pmol/L), a sensitive marker of total body calcium deprivation secondary to vitamin D deficiency. All patients demonstrated clinical and echocardiographic improvement following high dose vitamin D treatment. No patients required cardiac transplant, and only one patient required extracorporeal life support as a bridge to recovery. One patient failed to comply with medical management and died 5 months after initial diagnosis. Three patients lived within some of the most deprived areas in Scotland.ConclusionsThis case series demonstrates a previously unreported demographic in Scotland, as 50% of cases presented in Caucasian children. Although vitamin D deficiency DCM is relatively rare, it is wholly preventable. Our study confirms that vitamin D deficiency cardiomyopathy is reversible with prompt identification and supplementation. The current implementation of public health policy in the UK is failing to prevent children from developing the most severe manifestation of vitamin D deficiency.

Why did you do this work?Congenital Hyperinsulinism (CHI) is a rare condition leading to inappropriate insulin release in the context of low blood sugars.1 2 Due to the inhibitory effect of insulin on lipolysis and ketogenesis, there is suppressed ketone body formation in the context of hypoglycaemia, and thus an increased risk of hypoglycaemic brain injury and subsequent severe neurodisability.1 2 Despite being a rare condition, CHI is the commonest cause of severe and persistent hypoglycaemia in the neonatal period,1 3 and is associated with significant mortality and morbidity without appropriate identification and treatment.We aim to investigate the incidence of CHI over a 10-year period in a neonatal unit and analyse whether the yearly number of cases has changed through this period; we also hypothesise on potential reasons for this. We aim to identify the proportion of patients who had delayed diagnoses of CHI (i.e. diagnosed after discharge home from the neonatal unit) and whether this has an impact on secondary adverse outcomes (such as ongoing seizures, developmental delay and speech delay). Finally, we aim to evaluate the appropriateness of the current model of genetic testing.What did you do?Using electronic hospital records, we retrospectively analyse data from 69 patients with CHI, born from 2015–2024. These patients were identified by their registration to a multidisciplinary CHI follow-up clinic in a tertiary paediatric hospital in Glasgow, Scotland. 2 patients, for whom neonatal care records were incomplete, were excluded.What did you find?We identified 67 patients referred from 8 separate NHS Health Boards. We found an overall increasing trend of the number of patients diagnosed each year, particularly from 2020 onwards. We also identified that a delayed diagnosis was given in 12 patients (18%), and of these, 7 had subsequent adverse secondary outcomes (58%). Of interest, there were only 3 years in which all patients were diagnosed during their initial stay. Of 45 patients (67%) who had genetic testing, 12 patients (18%) had positive findings related to their CHI.What does it mean?We found an increasing trend in the yearly number of patients diagnosed with CHI. Through researching historical CHI guidelines for the West of Scotland, we identified a key change in the threshold for further investigation of neonatal hypoglycaemia in an update in 2020. Moreover, as more patients are seen in the tertiary centre, clinicians’ general awareness of CHI would improve, and thus more effective diagnosis may arise from increased familiarity. This shows the value of having a centralised service and of effective teaching. We show that delayed diagnoses may lead to various adverse secondary outcomes, and so demonstrate the importance of early identification and appropriate management. Finally, we illustrate how the current model of testing for 16 genes related to CHI allows for rare genetic causes to be identified and helps guide further management.ReferencesGiri D, Hawton K, Senniappan S. Congenital hyperinsulinism: recent updates on molecular mechanisms, diagnosis and management. 2021.Demirbilek H, Hussain K. Congenital hyperinsulinism: diagnosis and treatment update. 2017.Zenker M, Mohnike K, Palm K. Syndromic forms of congenital hyperinsulinism. 2023.

BackgroundAchondroplasia is the most common form of disproportionate short stature and is associated with reduced life expectancy. It is not clear to what extent cardiovascular disease (CVD) is responsible for this. The primary aim of this systematic review was to identify the prevalence of CVD in individuals with achondroplasia.MethodsA systematic review of the literature was conducted in accordance with PRISMA guidelines by two independent reviewers using two databases. There were no language or date restrictions. The search strategy consisted of the terms: “achondroplasia” AND “vascular” OR “cardiovascular” OR “metabolic”. Quality assessment was undertaken using the Critical Appraisal Skills Programme checklists.ResultsIn total, 300 articles which met the inclusion criteria were screened. Of these, 33 (11%) were included for analysis published between 1972 and 2023, encompassing >5000 individuals with achondroplasia. Techniques of cardiovascular assessment included measures of adiposity in 20 (61% of included studies), metabolic parameters in 9 (27%), blood pressure in 6 (18%), physical activity in 6 (18%) and morbidity and mortality secondary to CVD in 5 (15%). People with achondroplasia were found to be at increased risk of obesity, impaired glucose regulation and hypertension.DiscussionThere is significant heterogeneity in the outcomes measured to assess CVD risk in people with achondroplasia. As a result, there remain significant gaps in the literature regarding the development of CVD in individuals with this condition. Longitudinal studies offering detailed cardiovascular phenotyping should be considered in people with achondroplasia to mitigate the risks of CVD-related morbidity and mortality.

Commentary Acute LRTIs, predominantly pneumonia, are the most common cause of childhood mortality worldwide. 8 Poor nutritional status is a well-recognised cause of susceptibility to acute LRTIs in children. 9 10 Vitamin D deficiency has been strongly associated with an increased susceptibility to acute LRTIs in a number of settings. 11-15 Furthermore, studies have shown that acute LRTIs are more frequent during winter months when vitamin D synthesis is naturally reduced due to decreasing hours of sunlight. 25 There are also concerns associated with the use of large bolus doses of vitamin D. Studies have shown that serum 25(OH)D concentrations of >56 ng/mL (140 nmol/L) have been linked with compromised immune responses 26 and this may reflect the role of vitamin D in modulating innate and adaptive immune responses. A major limitation of this study, like many others, was lack of serum 25(OH)D data. [...]the exact threshold of serum concentrations needed to decrease the incidence of pathogens such as influenza A is unknown.

ObjectiveThe UK national incidence of nutritional rickets is unknown. We aimed to describe the incidence, presentation and clinical management of children under 16 years with nutritional rickets in the UK presenting to secondary care.MethodsProspective data were collected monthly between March 2015 and March 2017 from 3500 consultant paediatricians using British Paediatric Surveillance Unit methodology. Clinicians completed online clinical questionnaires for cases fitting the surveillance case definition.Results125 cases met the case definition, an annual incidence of 0.48 (95% CI 0.37 to 0.62) per 100 000 children under 16 years. 116 children were under 5 years (annual incidence of 1.39 (95% CI 1.05 to 1.81) per 100 000. Boys (70%) were significantly more affected than girls (30%) (OR 2.17, 95% CI 1.25 to 3.78). The majority were of Black (43%) or South Asian (38%) ethnicity. 77.6% of children were not taking vitamin D supplements despite being eligible. Complications included delayed gross motor development (26.4%), fractures (9.6%), hypocalcaemic seizures (8%) and dilated cardiomyopathy (3%). Two children died (1.6%). In eight cases, rickets was confirmed radiologically and biochemically [raised serum alkaline phosphatase (ALP) and parathyroid hormone (PTH) levels ] but were excluded from the incidence analysis for not meeting the case definition of 25-hydroxyvitamin D of <25 nmol/L.ConclusionThe incidence of nutritional rickets in the UK is lower than expected. Serious complications and unexpected deaths, particularly in Black and South Asian children under 5 years, occurred. Both vitamin D deficiency and dietary calcium deficiency are role players in pathogenesis. Uptake of vitamin D supplementation remains low.

Achondroplasia is a genetic skeletal condition that results in disproportionately short stature and medical complications throughout life. Infigratinib is an orally bioavailable FGFR1-3 selective tyrosine kinase inhibitor in development for achondroplasia. In this phase 2 dose-finding study, we evaluated the safety and efficacy of oral infigratinib in children with achondroplasia between the ages of 3 and 11 years. A total of 72 children were enrolled in five sequential cohorts to receive daily infigratinib at doses of 0.016 mg per kilogram of body weight (cohort 1), 0.032 mg per kilogram (cohort 2), 0.064 mg per kilogram (cohort 3), 0.128 mg per kilogram (cohort 4), and 0.25 mg per kilogram (cohort 5) for 6 months, followed by 12 months of extended treatment in which the dose in cohorts 1 and 2 could be escalated to the next ascending level at months 6 and 12. The primary safety outcome was the incidence of adverse events that led to a decrease in the dose or discontinuation of infigratinib. The primary efficacy outcome was the change from baseline in the annualized height velocity. During treatment, all the children had at least one adverse event, most of which were mild or moderate in severity; none resulted in treatment discontinuation. In cohort 5, an increased annualized height velocity was observed, which persisted throughout the duration of the study, with a mean change from baseline at 18 months of 2.50 cm per year (95% confidence interval [CI], 1.22 to 3.79; P = 0.001). The mean change from baseline in height z score was 0.54 (95% CI, 0.35 to 0.72) relative to an untreated achondroplasia reference population at 18 months; the mean change from baseline in the upper-to-lower body segment ratio was -0.12 (95% CI, -0.18 to -0.06). The administration of oral infigratinib did not result in any apparent major safety signal and increased the annualized height velocity and z score and decreased the upper-to-lower body segment ratio at 18 months of treatment in cohort 5. (Funded by BridgeBio Pharma; PROPEL2 ClinicalTrials.gov number, NCT04265651.).

BackgroundAchondroplasia (ACH), the most common skeletal dysplasia, arises from gain-of-function variants in the fibroblast growth factor receptor 3 gene. Children with ACH experience lifelong medical, functional and psychosocial challenges requiring coordinated and anticipatory care. Although international guidance exists, the UK lacks national clinical care recommendations specific to its healthcare systems.ObjectiveTo develop UK-specific, multidisciplinary clinical recommendations for the care of children and young people (CYP) with ACH.MethodsThe UK Achondroplasia Network developed guidance in stages: stakeholder mapping of the care pathway, integration of contemporary literature with clinical expertise to draft age-specific guidance and Delphi statements, and a modified Delphi process with 25 multidisciplinary experts. The Delphi process involved two voting rounds and an in-person meeting, with consensus defined as ≥80% agreement.ResultsIn the first Delphi round, all 20 statements achieved consensus; nine achieved 100% agreement. To strengthen consensus, after meeting in person, 17 statements were refined (four were divided into two statements), one created and one removed, resulting in 24 statements for Round 2; all achieved consensus, with 21 reaching 100% agreement. The guidance outlines age-specific monitoring and referral from infancy to adolescence. Recommendations address medical management of complications, psychosocial support, educational planning and transfer to adult care.ConclusionThese are the first UK-specific multidisciplinary recommendations for the care of CYP with ACH. Aligned with international best practices and tailored to UK healthcare systems, they support anticipatory care, promote independence and enhance health and psychosocial outcomes. The guidelines offer a foundation for service planning, standardisation and equitable care.