Search

BACKGROUND: Hospital inpatient care is frequently mentioned by parents as unsatisfactory for children with diabetes. Ward staff are now less familiar with diabetes, as admissions are less common and diabetes management is more intensive. OBJECTIVE: To compare current practice with Department of Health Children's Diabetes Working Group care standards. METHODS: This audit surveyed the organisation of inpatient care for children with diabetes in three regional networks in southern England, and was funded by the Healthcare Quality Improvement Partnership. RESULTS: All 27 services completed the questionnaire. Protocols for diabetic ketoacidosis, surgery, new diagnosis and hypoglycaemia were generally available on wards (70% had all four protocols) but less available in emergency departments (EDs) (52%). Trained children's nurses worked on every shift in children's wards (100%) but not necessarily in EDs (33%). Diabetes link nurses were identified on 74% of wards and 61% of high-dependency units (HDUs), and diabetes specialist nurses have inpatient liaison in their job description (89%) and working role (93%). Standards achieved less often were access to dietetic advice on wards (37%), education sessions for ED and ward staff, and informing diabetes team (only 26% within 2 h of admission during the day, and only 11% would contact the diabetes consultant overnight for a child admitted to a paediatric intensive care unit/HDU). Half of centres reported insulin errors. CONCLUSIONS: This first audit of children's diabetes inpatient care organisation demonstrates that some standards can be achieved, but others, such as having children's nurses on every shift in EDs, lack of dietetic advice to ward staff, and liaison with the diabetes team quickly out of hours, are more challenging. Further planned audit outcomes are to produce patient and parent literature for children admitted to hospital and to refine the standards further. [ABSTRACT FROM AUTHOR]

The migration of Toxocara canis larvae in mices has been investigated. The organs and tissues in which the larvae may be found during various periods after infection are given together with pictorial evidence of their presence. After penetration of the small intestine, the larvae appear in the hepatic portal and mesenteric veins, and mesenteric lymph glands. From these sites they migrate to the liver, which they enter either by way of the portal tracts or directly through the capsule. The larvae enter the liver via the hepatic veins and pass to the lungs. The evidence suggests that they leave these organs by any one of three routes: 1. Via the bronchioles. 2. By way of the pulmonary veins. 3. Directly through the capsule. The larvae then appear in the brain and skeletal musculature. In the brain they do not promote a cellular response, but in the musculature each larva becomes enclosed in a fibrous tissue capsule. No evidence was obtained that once the larvae were established in the brain and musculature, they were capable of continuing their migration even though they remained alive for at least one year after infection. [ABSTRACT FROM AUTHOR]

This paper begins to define some concepts by detailing the IGF-1 and IGFBP-3 responses to low and standard doses biosynthetic human GH. The doses chosen have not been clearly defined and, as such, there is a pressing need for a full definition of the GH-IGF-1 dose response curve in normal individuals as near as possible, in order to begin to discern elements required for the definition of resetting, sensitivity and resistance. What is clear from this report is that the test can be conducted over relatively short periods of time, as maximum responses are observed within 36 hour of administration.

Background: Research on the effects of the COVID-19 pandemic on people with rare diseases is limited. Few studies compare healthcare throughout the progression of the ongoing pandemic., Aims: To assess the impact of the pandemic on individuals with osteogenesis imperfecta across two consecutive years, understand what challenges were encountered, and analyse the experience of remote consultation., Methods: An initial survey was distributed following the first lockdown in August 2020, and a second survey in April 2021. The surveys explored four themes- effects on therapy, alternatives to consultation, effect on mental health, and perceived risks of COVID-19., Results: In the 2020 survey, of the 110 respondents, 69 (63%) had at least one appointment delayed due to the lockdown, compared with 89 of the 124 respondents (72%) in 2021. Of the 110 respondents in 2020, 57 (52%) had a remote consultation, increasing to 92 of 124 (74%) in the follow-up survey. In the 2020 survey 63 of 91 respondents (69%) expressed anxiety due to lockdown, compared with 76 of 124 (61%) in 2021. The percentage of total respondents expressing a preference for remote consultation was 48% in 2020, increasing to 71% in 2021., Conclusions: The pandemic has had widespread effects on the mental and physical health of those with OI. These effects, alongside appointment delays, have increased as the pandemic progresses. Encouragingly, the increasing preference for remote consultation may indicate that this could be a viable long-lasting alternative to face-to-face appointments, especially for patients who previously traveled vast distances for specialist care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Smyth, Hytiris, Kelday, McDonnell, Burren, Gardner, Mills, Parekh, Semler, Stewart, Westerheim, Javaid, Osborne and Ahmed.)

Background/objectives: In England, children (0-18 years) with severe, complex and atypical osteogenesis imperfecta (OI) are managed by four centres (Birmingham, Bristol, London, Sheffield) in a 'Highly Specialised Service' (HSS OI); affected children with a genetic origin for their disease that is not in COL1A1 or COL1A2 form the majority of the 'atypical' group, which has set criteria for entry into the service. We have used the data from the service to assess the range and frequency of non-collagen pathogenic variants resulting in OI in a single country., Methods: Children with atypical OI were identified through the HSS OI service database. All genetic testing for children with OI in the service were undertaken at the Sheffield Diagnostic Genetics Service. Variant data were extracted and matched to individual patients. This study was done as part of a service evaluation project registered with the Sheffield Children's Hospital Clinical Governance Department., Results: One hundred of 337 children in the HSS met the 'atypical' criteria. Eighty have had genetic testing undertaken; 72 had genetic changes detected, 67 in 13 genes known to be causative for OI. The most frequently affected genes were IFITM5 (22), P3H1 (12), SERPINF1 (8) and BMP1 (6)., Conclusion: Among children with more severe forms of OI (approximately one-third of all children with OI), around 20% have pathogenic variants in non-collagen genes. IFITM5 was the most commonly affected gene, followed by genes within the P3H1 complex. These data provide additional information regarding the likelihood of different genetic origins of the disease in children with OI, which may influence clinical care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RS: reports grant support from Ascendis, BioMarin, QED and Theracon, received consulting fees from BioMarin and was a paid advisory board member for Ascendis, BioMarin, QED and Sanofi. JMDB: has nothing to disclose. PA: has nothing to disclose. HM: has nothing to declare. VC-D: was a paid advisory board member for BioMarin. VS: has nothing to disclose. MS: has nothing to disclose. BD: has nothing to disclose. AL-G: has nothing to disclose. FS-S: was a paid advisory board member for BioMarin. JPS: has nothing to disclose. MN: has nothing to disclose. MR: was a paid advisory board member for BioMarin. PK: has nothing to disclose. MB: reports grant support and paid consultancies from Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. JPIII: has nothing to disclose. HS: reports grant support from Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. PH: reports paid consutancies for Audentis, Aeglea, Homology, BioMarin, Shire, Genzyme, Ultragenyx, JCR, Denali, Orphazyme, Inventiva, Paradigm, REGENXBIO, Sangamo, QED, Ascendis Pharma, contracts for research from BioMarin and Inventiva and honoraria from BioMarin, Shire, Genzyme, Ultragenyx, and Ophazyme. CB: reports research support from Amgen, Pfizer, QED Therapeutics. GG: has nothing to disclose. TC, EM, RW, DR: report that they are employees of QED therapeutics. JH-F: reports paid consultancies from Pfizer/Therachon, BioMarin, QED Therapeutics, Sanofi, Ascendis Pharma, and grant support fromPfizer/Therachon, BioMarin, Ascendis Pharma. MI: was a paid advisory board member for Ascendis Pharma, BioMarin, QED Therapeutics, Sanofi, Therachon/Pfizer., (© The Author(s), 2022.)

Objectives: In the context of a lack of national consensus on the benefits of skull base imaging in children with osteogenesis imperfecta (OI), this study aims to analyse and correlate the clinical symptoms and radiological images of children with severe OI., Methods: A retrospective case notes and image analysis was carried out on children with complex OI between 2012 and 2018 at a specialist tertiary centre. Data were collected on patient demographic factors, clinical data, imaging findings (presence of Wormian bones, platybasia, basilar impression (McGregor's technique) and basilar invagination (McRae's technique)), and clinical features at the time of imaging., Results: Of the 127 patients in the OI database, 94 were included. A total of 321 radiographs, 21 CT scans and 39 MRI scans were analysed. Average frequency of radiographs was 8 per 10 years. Of the 94 patients, 58 (62%), 10 (11%), 1 (1%) demonstrated platybasia, basilar impression, and basilar invagination, respectively. Of the radiographs analysed, platybasia, basilar impression, basilar invagination, and the presence of Wormian bones, could not be evaluated in 71 (22.3%), 48 (15.2%), 61 (19.5%) and 28 (9.4%) radiographs respectively (due to poor positioning, anatomical abnormalities, and poor image quality). Of the 140 radiographs with platybasia, 17 (12%) also demonstrated basilar impression compared to only 3 (2.9%) out of the 99 without platybasia (p = 0.03). No significant associations were seen between the presence of Wormian bones and basilar impression. Of the 39 MRIs, additional information on CSF flow rate, spinal cord signal and cerebellar morphology was reported in 14 (36%). There was a lack of concordance between MRI and matched radiographs in 7.1% (1/14) and 36% (5/14) for platybasia and basilar impression respectively, with full concordance for basilar invagination. Fewer than 5% had positive clinical symptoms/signs at the time of imaging; 2% (7/321) had macrocephaly, 0.6% (2/321) headache, all other neurological features were absent). Clinical features were not documented in >85% of patients., Conclusion: The apparent low prevalence of clinical symptoms and signs and of radiologically identified cranio-cervical abnormalities, suggests that current levels of serial imaging may be excessive. Until larger prospective studies clarify these issues, we suggest a clinical pathway for base of skull imaging which proposes a risk stratification approach to radiographic frequency and suggests parameters for proceeding to MRI., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Brachyolmia is a skeletal dysplasia characterized by short spine-short stature, platyspondyly, and minor long bone abnormalities. We describe 18 patients, from different ethnic backgrounds and ages ranging from infancy to 19 years, with the autosomal recessive form, associated with PAPSS2. The main clinical features include disproportionate short stature with short spine associated with variable symptoms of pain, stiffness, and spinal deformity. Eight patients presented prenatally with short femora, whereas later in childhood their short-spine phenotype emerged. We observed the same pattern of changing skeletal proportion in other patients. The radiological findings included platyspondyly, irregular end plates of the elongated vertebral bodies, narrow disc spaces and short over-faced pedicles. In the limbs, there was mild shortening of femoral necks and tibiae in some patients, whereas others had minor epiphyseal or metaphyseal changes. In all patients, exome and Sanger sequencing identified homozygous or compound heterozygous PAPSS2 variants, including c.809G>A, common to white European patients. Bi-parental inheritance was established where possible. Low serum DHEAS, but not overt androgen excess was identified. Our study indicates that autosomal recessive brachyolmia occurs across continents and may be under-recognized in infancy. This condition should be considered in the differential diagnosis of short femora presenting in the second trimester., (© 2019 Wiley Periodicals, Inc.)

The authors present the case of a 6-year-old boy with a good neurological outcome from extreme hyponatraemia caused by autoimmune hypoadrenalism. He presented with 1 week of reduced appetite, lethargy, vomiting and one episode of diarrhoea. He was described as being slightly unsteady on his feet. Clinically he was alert, although intermittently confused, with dry mucous membranes and sunken eyes. Serum sodium was 96 mmol/l with normal serum potassium and renal function. He was initially treated with 3% saline intravenously, and his serum sodium increased to 128 mmol/l by day 3. He developed slurred speech and ataxia on day 4, although MRI brain showed no evidence of pontine myelinosis, and the symptoms resolved over 1 week. A Synacthen test on day 10 confirmed a diagnosis of Addison's disease and he was commenced on hydrocortisone and fludrocortisone replacement therapy. At 5 months follow-up there are no obvious neurological or developmental sequelae.

Mitochondrial dysfunction is associated with insulin resistance and type 2 diabetes. It has thus been suggested that primary and/or genetic abnormalities in mitochondrial function may lead to accumulation of toxic lipid species in muscle and elsewhere, impairing insulin action on glucose metabolism. Alternatively, however, defects in insulin signaling may be primary events that result in mitochondrial dysfunction, or there may be a bidirectional relationship between these phenomena. To investigate this, we examined mitochondrial function in patients with genetic defects in insulin receptor (INSR) signaling. We found that phosphocreatine recovery after exercise, a measure of skeletal muscle mitochondrial function in vivo, was significantly slowed in patients with INSR mutations compared with that in healthy age-, fitness-, and BMI-matched controls. These findings suggest that defective insulin signaling may promote mitochondrial dysfunction. Furthermore, consistent with previous studies of mouse models of mitochondrial dysfunction, basal and sleeping metabolic rates were both significantly increased in genetically insulin-resistant patients, perhaps because mitochondrial dysfunction necessitates increased nutrient oxidation in order to maintain cellular energy levels.

The effects of the calcimimetic drug Cinacalcet were assessed in six children with uncontrolled hyperparathyroidism secondary to stage 5 chronic kidney disease (CKD). Data were collected retrospectively regarding bone biochemistry and medications. Patients were between the ages of 11 months and 14 years on commencing Cinacalcet at initial doses of 0.4-1.4 mg/kg. Treatment, which was well tolerated in the majority and still on going in five patients, was for periods ranging between 3 months and 3 years. All six cases saw at least an 86% reduction in serum parathyroid hormone (PTH). Hypophosphataemia and/or hypocalcaemia were observed in three cases. Overall, achievement of UK Renal Association targets for corrected calcium (Ca), phosphate (P) and the calcium x phosphate product (Ca x P) were unaffected. We conclude that Cinacalcet is an effective treatment for correcting and sustaining correction of uncontrollable PTH levels seen in a difficult group of patients. Importantly, it has allowed the avoidance of parathyroidectomy for a significant time period in all cases. There remain questions about the effect of Cinacalcet on linear growth amongst paediatric dialysis patients, and future studies should aim to address this.

The melanocortin-4 receptor (MC4R) plays a critical role in the control of energy balance. Of its two pro-opiomelanocortin (POMC)-derived ligands, alpha- and beta-MSH, the majority of attention has focused on alpha-MSH, partly reflecting the absence of beta-MSH in rodents. We screened the POMC gene in 538 patients with severe, early-onset obesity and identified five unrelated probands who were heterozygous for a rare missense variant in the region encoding beta-MSH, Tyr221Cys. This frequency was significantly increased (p < 0.001) compared to the general UK Caucasian population and the variant cosegregated with obesity/overweight in affected family members. Compared to wild-type beta-MSH, the variant peptide was impaired in its ability to bind to and activate signaling from the MC4R. Obese children carrying the Tyr221Cys variant were hyperphagic and showed increased linear growth, both of which are features of MC4R deficiency. These studies support a role for beta-MSH in the control of human energy homeostasis.

The study of genetic growth hormone (GH) insensitivity is an evolving field. GH insensitivity syndrome (GHIS), otherwise known as Laron syndrome, is a heterogeneous disorder. Biochemical features consist of severe insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) deficiency and elevated GH secretion. In a heterogeneous 'European' cohort of GHIS patients, features varied from classical to moderate abnormalities of phenotype and endocrine disturbance. A study of facial features within this series showed that a mild subgroup existed with normal facies, mild short stature and moderate biochemical abnormalities. Overlap with idiopathic short stature (ISS) exists, with heterozygous mutations of the GH receptor demonstrated to cause impaired growth. This 'partial' GHIS has not yet been defined endocrinologically. GH sensitivity, measured by IGF-I and IGFBP-3 responses in the IGF-I generation test, may reveal abnormalities in ISS, although it is likely that the dose of recombinant human GH and frequency of sampling in the test need to be modified., (Copyright 2001 S. Karger AG, Basel)