Service evaluation suggests variation in clinical care provision in adults with congenital adrenal hyperplasia in the UK and Ireland.

BACKGROUND: Congenital adrenal hyperplasia (CAH) encompasses a rare group of autosomal recessive disorders, characterised by enzymatic defects in steroidogenesis. Heterogeneity in management practices has been observed internationally. The International Congenital Adrenal Hyperplasia registry (I-CAH, https://sdmregistries.org/) was established to enable insights into CAH management and outcomes, yet its global adoption by endocrine centres remains unclear. DESIGN: We sought (1) to assess current practices amongst clinicians managing patients with CAH in the United Kingdom and Ireland, with a focus on choice of glucocorticoid, monitoring practices and screening for associated co-morbidities, and (2) to assess use of the I-CAH registry. MEASUREMENTS: We designed and distributed an anonymised online survey disseminated to members of the Society for Endocrinology and Irish Endocrine Society to capture management practices in the care of patients with CAH. RESULTS: Marked variability was found in CAH management, with differences between general endocrinology and subspecialist settings, particularly in glucocorticoid use, biochemical monitoring and comorbidity screening, with significant disparities in reproductive health monitoring, notably in testicular adrenal rest tumours (TARTs) screening (p = .002), sperm banking (p = .0004) and partner testing for CAH (p < .0001). Adoption of the I-CAH registry was universally low. CONCLUSIONS: Differences in current management of CAH continue to exist. It appears crucial to objectify if different approaches result in different long-term outcomes. New studies such as CaHASE2, incorporating standardised minimum datasets including replacement therapies and monitoring strategies as well as longitudinal data collection, are now needed to define best-practice and standardise care.

The Role of the European Reference Network for Rare Bone Diseases (ERN BOND) and European Registries for Rare Bone and Mineral Conditions (EuRR-Bone) in the Governance of the Management of Rare Bone and Mineral Diseases.

Rare diseases (RDs) bear a significant challenge to individuals, healthcare systems, and societies. The European reference network on Rare BONe diseases (ERN BOND) is committed to improving multidisciplinary, patient-centred care for individuals with rare bone and mineral diseases (RBMDs). Its affiliated project, the European registries for rare bone and mineral conditions (EuRR-Bone) collects data using two different platforms, an electronic surveillance system (e-REC) that captures the occurrence of RBMDs and the Core Registry, a platform with the infrastructure for collecting Core data fields and longitudinal generic and condition-specific information. With emerging registries and the overlap with other ERNs, it is key to maintain the capability of the platforms to adapt to the needs of the network and the community whilst adhering to quality and FAIR (findable, accessible, interoperable, and reusable) principles. This binomial ensures long-term sustainability and potential advances in the care pathway of RBMDs whilst promoting good practice standards within Europe and beyond.

Vascular dysfunction and increased cardiovascular risk in hypospadias.

AIMS: Hypogonadism is associated with cardiovascular disease. However, the cardiovascular impact of hypogonadism during development is unknown. Using hypospadias as a surrogate of hypogonadism, we investigated whether hypospadias is associated with vascular dysfunction and is a risk factor for cardiovascular disease. METHODS AND RESULTS: Our human study spanned molecular mechanistic to epidemiological investigations. Clinical vascular phenotyping was performed in adolescents with hypospadias and controls. Small subcutaneous arteries from penile skin from boys undergoing hypospadias repair and controls were isolated and functional studies were assessed by myography. Vascular smooth muscle cells were used to assess: Rho kinase, reactive oxygen species (ROS), nitric oxide synthase/nitric oxide, and DNA damage. Systemic oxidative stress was assessed in plasma and urine. Hospital episode data compared men with a history of hypospadias vs. controls. In adolescents with hypospadias, systolic blood pressure (P = 0.005), pulse pressure (P = 0.03), and carotid intima-media thickness standard deviation scores (P = 0.01) were increased. Arteries from boys with hypospadias demonstrated increased U46619-induced vasoconstriction (P = 0.009) and reduced acetylcholine-induced endothelium-dependent (P < 0.0001) and sodium nitroprusside-induced endothelium-independent vasorelaxation (P < 0.0001). Men born with hypospadias were at increased risk of arrhythmia [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.4-5.6, P = 0.003]; hypertension (OR 4.2, 95% CI 1.5-11.9, P = 0.04); and heart failure (OR 1.9, 95% CI 1.7-114.3, P = 0.02). CONCLUSION: Hypospadias is associated with vascular dysfunction and predisposes to hypertension and cardiovascular disease in adulthood. Underlying mechanisms involve perturbed Rho kinase- and Nox5/ROS-dependent signalling. Our novel findings delineate molecular mechanisms of vascular injury in hypogonadism, and identify hypospadias as a cardiovascular risk factor in males.

Society for Endocrinology UK Guidance on the initial evaluation of a suspected difference or disorder of sex development (Revised 2021).

It is paramount that any child or adolescent with a suspected difference or disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD and is discussed with the regional DSD service. In most cases, the paediatric endocrinologist within this service acts as the first point of contact but involvement of the regional multidisciplinary service will also ensure prompt access to specialist psychology and nursing care. The underlying pathophysiology of DSD and the process of delineating this should be discussed with the parents and affected young person with all diagnostic tests undertaken in a timely fashion. Finally, for rare conditions such as these, it is imperative that clinical experience is shared through national and international clinical and research collaborations.

Observer Agreement of Vertebral Fracture Grading Using Dual Energy Absorptiometry Vertebral Fracture Assessment in Duchenne Muscular Dystrophy.

Routine screening of the spine for vertebral fracture is recommended in the recent international standards of care for boys with Duchenne muscular dystrophy (DMD). Recent international consensus endorses the use of dual energy absorptiometry vertebral fracture assessment for identification of vertebral fractures in children, which could be used instead of spine radiographs. This study aims to evaluate the inter-observer agreement for vertebral fracture classification in boys with DMD, and the impact on clinical management. Dual energy absorptiometry vertebral fracture assessment and morphometric analysis in 39 boys was performed by a reader with no prior experience (R1) and 2 readers with experience (R2 and R3). Inter-observer concordance of vertebral fracture grading comparing R1 with R2 and R3 was substantial (Kappa 0.66, 95% CI 0.56, 0.76). Concordance between R2 and R3 was almost perfect (Kappa 0.93, 95% CI 0.89, 0.97) which did not lead to differences in clinical management. Grading by R1 in comparison to R2 and R3 would have led to change in management of 5/39 boys (13%), according to recent standards of care guidance. Structured education programme on identification of vertebral fractures should be explored to ensure consistency of reporting of this important health outcome measure in DMD.

Persistence of Muscle-bone Deficits Following Anti-tumour Necrosis Factor Therapy in Adolescents With Crohn Disease.

OBJECTIVES: The aim of the study is to assess change in the muscle-bone unit in adolescents with Crohn disease (CD) on anti-tumour necrosis factor (anti-TNFα). METHODS: Prospective study following anti-TNFα in 19 adolescents with CD with a median age (range) of 15.1 years (11.2, 17.2). At baseline, 6 and 12 months, subjects had a biochemical assessment of insulin growth factor axis, bone turnover and muscle-bone health by dual energy absorptiometry (DXA), peripheral quantitative computed tomography (pQCT), and dynamic isometry. RESULTS: Significant clinical improvement in disease activity was observed by 2 weeks (P = 0.004 vs baseline) and maintained at 12 months (P = 0.038 vs baseline). Median bone specific alkaline phosphatase standard deviation score (SDS) increased from -1.7 (-3.6 to -1.0) to -1.2 (-3.6 to -0.5) by 6 weeks (P = 0.01). At baseline, DXA total body and lumbar spine bone mineral density (BMD) SDS was -0.9 (-2.3 to 0.5) and -1.1 (-2.9 to 0.4), respectively. At baseline, pQCT trabecular BMD SDS at 4% tibia and muscle cross-sectional area SDS at 66% radius was -1.6 (-3.2 to 1.1) and -2.4 (-4.3 to -0.3), respectively. At baseline, maximal isometric grip force (MIGF) of the non-dominant hand adjusted for height was -1.5 (-4.5 to 0.49). All these deficits in muscle-bone persisted at 6 and 12 months. CONCLUSIONS: Despite improvement in disease and osteoblast activity, bone and muscle deficits, as assessed by DXA, pQCT, and grip strength in adolescents with CD did not improve following twelve months of anti-TNFα.

Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications.

The principle steroidal androgens are testosterone and its metabolite 5α-dihydrotestosterone (DHT), which is converted from testosterone by the enzyme 5α-reductase. Through the classic pathway with androgens crossing the plasma membrane and binding to the androgen receptor (AR) or via mechanisms independent of the ligand-dependent transactivation function of nuclear receptors, testosterone induces genomic and non-genomic effects respectively. AR is widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Androgens are essential for many developmental and physiological processes, especially in male reproductive tissues. It is now clear that androgens have multiple actions besides sex differentiation and sexual maturation and that many physiological systems are influenced by androgens, including regulation of cardiovascular function [nitric oxide (NO) release, Ca2+ mobilization, vascular apoptosis, hypertrophy, calcification, senescence and reactive oxygen species (ROS) generation]. This review focuses on evidence indicating that interplay between genomic and non-genomic actions of testosterone may influence cardiovascular function.

Prevalence of Vertebral Fractures in Children with Suspected Osteoporosis.

OBJECTIVES: To explore the prevalence and anatomic distribution of vertebral fractures in disease groups investigated for primary and secondary osteoporosis, using vertebral fracture assessment (VFA). STUDY DESIGN: VFA was performed independently by 2 nonradiologists, in 165 children (77 males, 88 females) as part of their investigation for osteoporosis. Vertebral bodies from T6 to L4 were assessed for vertebral fractures using the Genant scoring system. The common readings for the presence of vertebral fractures were used for evaluating the prevalence and anatomic distribution of vertebral fractures. RESULTS: The median age of the subjects was 13.4 years (range, 3.6, 18). Of the 165 children, 24 (15%) were being investigated for primary bone disease, and the remainder had a range of chronic diseases known to affect bone health. Vertebral fractures were identified in 38 (23%) children. The distribution of the vertebral fractures was bimodal, with vertebral fractures peaks centered at T9 and L4. Conditions associated with increased odds for vertebral fractures were inflammatory bowel disease (OR, 3.3; 95% CI, 1.4, 8.0; P = .018) and osteogenesis imperfecta (OR, 2.3; 95% CI, 1.04, 5.8; P = .022). Among children with vertebral fractures, those with Duchenne muscular dystrophy (P = .015) and osteogenesis imperfecta (P = .023) demonstrated higher number of vertebral fractures than the other disease groups. CONCLUSIONS: VFA identified the presence of vertebral fractures, in a bimodal distribution, in both primary bone disease and chronic disease groups. VFA is a practical screening tool for identification of vertebral fractures in children and adolescents at risk of fragility fractures.

Society for Endocrinology UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development (Revised 2015).

It is paramount that any child or adolescent with a suspected disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD. If there is any doubt, the case should be discussed with the regional DSD team. In most cases, particularly in the case of the newborn, the paediatric endocrinologist within the regional team acts commonly as the first point of contact. This clinician should be part of a multidisciplinary team experienced in management of DSD and should ensure that the affected person and parents have access to specialist psychological support and that their information needs are comprehensively addressed. The underlying pathophysiology of DSD and the strengths and weaknesses of the tests that can be performed should be discussed with the parents and affected young person and tests undertaken in a timely fashion. Finally, in the field of rare conditions, it is imperative that the clinician shares the experience with others through national and international clinical and research collaboration.

Turner syndrome--issues to consider for transition to adulthood.

BACKGROUND: Turner syndrome (TS) is associated with a spectrum of health problems across the age span, which requires particular attention during the transition period in these adolescents. AREAS OF AGREEMENT: The majority of girls with TS require oestrogen replacement from puberty onwards, which is important for adequate feminization, uterine development and maintenance of bone health. There is a lifetime increased risk from autoimmune conditions like hypothyroidism, coeliac disease, hearing loss and aortic dilatation with the potential to lead to aortic dissection. A systematic and holistic approach to provision of health care in TS is needed. AREAS OF CONTROVERSY: Several unanswered questions remain, including the choice of hormone replacement therapy in the young person with TS and in adulthood; the optimal mode of cardiovascular assessment; the best management and assessment prior to and during pregnancy. AREAS TIMELY FOR DEVELOPING RESEARCH: The optimal model of care and transition to adult services in TS requires attention. Further research is needed in relation to cardiovascular risk assessment, pregnancy management and hormone replacement therapy in TS.

Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Children with osteogenesis imperfecta are often treated with intravenous bisphosphonates. We aimed to assess the safety and efficacy of risedronate, an orally administered third-generation bisphosphonate, in children with the disease. METHODS: In this multicentre, randomised, parallel, double-blind, placebo-controlled trial, children aged 4-15 years with osteogenesis imperfecta and increased fracture risk were randomly assigned by telephone randomisation system in a 2:1 ratio to receive either daily risedronate (2·5 or 5 mg) or placebo for 1 year. Study treatment was masked from patients, investigators, and study centre personnel. Thereafter, all children received risedronate for 2 additional years in an open-label extension. The primary efficacy endpoint was percentage change in lumbar spine areal bone mineral density (BMD) at 1 year. The primary efficacy analysis was done by ANCOVA, with treatment, age group, and pooled centre as fixed effects, and baseline as covariate. Analyses were based on the intention-to-treat population, which included all patients who were randomly assigned and took at least one dose of assigned study treatment. The trial is registered with ClinicalTrials.gov, number NCT00106028. FINDINGS: Of 147 patients, 97 were randomly assigned to the risedronate group and 50 to the placebo group. Three patients from the risedronate group and one from the placebo group did not receive study treatment, leaving 94 and 49 in the intention-to-treat population, respectively. The mean increase in lumbar spine areal BMD after 1 year was 16·3% in the risedronate group and 7·6% in the placebo group (difference 8·7%, 95% CI 5·7-11·7; p<0·0001). After 1 year, clinical fractures had occurred in 29 (31%) of 94 patients in the risedronate group and 24 (49%) of 49 patients in the placebo group (p=0·0446). During years 2 and 3 (open-label phase), clinical fractures were reported in 46 (53%) of 87 patients in the group that had received risedronate since the start of the study, and 32 (65%) of 49 patients in the group that had been given placebo during the first year. Adverse event profiles were otherwise similar between the two groups, including frequencies of reported upper-gastrointestinal and selected musculoskeletal adverse events. INTERPRETATION: Oral risedronate increased areal BMD and reduced the risk of first and recurrent clinical fractures in children with osteogenesis imperfecta, and the drug was generally well tolerated. Risedronate should be regarded as a treatment option for children with osteogenesis imperfecta. FUNDING: Alliance for Better Bone Health (Warner Chilcott and Sanofi).

Development and validation of a short version of the quality of life-DSD questionnaire for parents of young children with conditions affecting sex development.

BACKGROUND: There is a paucity of information on health-related quality of life (HRQoL) outcomes in parents and children with conditions affecting sex development. The objective of this study was to develop short forms of HRQoL questionnaires which consist of a 63-item and 25-item parent self-report (PSR) and parent proxy-report (PPR), respectively, optimising use in routine clinic settings. METHODS: Short questionnaires were developed following exploratory factor analysis using raw data from 132 parents. Long and short PSRs were completed by 24 parents of children with conditions affecting sex development with median age of 3.6 years (range 0.1, 6.6); 21 (88%) were boys and 11 (46%) had proximal hypospadias. A subset of 19 parents completed long and short PPRs. RESULTS: Item selection based on factor loadings of >0.8 and expert consultation, produced short PSR and PPRs containing 16 and 7 items, respectively. There was no statistically significant difference in 11 out of 12 (92%) scales on the PSR and 4 out of 5 (80%) scales on the PPR when comparing short and long questionnaire scores. Short and long questionnaires took <1 minute and 5 minutes for completion, respectively. Eighteen parents (75%) reported that the time taken to complete short questionnaires was acceptable; 10 (42%) preferred short questionnaires. Ten (42%) versus 6 (25%) stated a preference for completing short versus long questionnaires. CONCLUSION: Short versions were largely representative of the long questionnaires and are acceptable to evaluate psychosocial distress in young children and their caregivers. Further psychometric validation of short forms is warranted.

Clinical and genetic characteristics of a large international cohort of individuals with rare NR5A1/SF-1 variants of sex development.

BACKGROUND: Steroidogenic factor 1 (SF-1/NR5A1) is essential for human sex development. Heterozygous NR5A1/SF-1 variants manifest with a broad range of phenotypes of differences of sex development (DSD), which remain unexplained. METHODS: We conducted a retrospective analysis on the so far largest international cohort of individuals with NR5A1/SF-1 variants, identified through the I-DSD registry and a research network. FINDINGS: Among 197 individuals with NR5A1/SF-1 variants, we confirmed diverse phenotypes. Over 70% of 46, XY individuals had a severe DSD phenotype, while 90% of 46, XX individuals had female-typical sex development. Close to 100 different novel and known NR5A1/SF-1 variants were identified, without specific hot spots. Additionally, likely disease-associated variants in other genes were reported in 32 individuals out of 128 tested (25%), particularly in those with severe or opposite sex DSD phenotypes. Interestingly, 48% of these variants were found in known DSD or SF-1 interacting genes, but no frequent gene-clusters were identified. Sex registration at birth varied, with <10% undergoing reassignment. Gonadectomy was performed in 30% and genital surgery in 58%. Associated organ anomalies were observed in 27% of individuals with a DSD, mainly concerning the spleen. Intrafamilial phenotypes also varied considerably. INTERPRETATION: The observed phenotypic variability in individuals and families with NR5A1/SF-1 variants is large and remains unpredictable. It may often not be solely explained by the monogenic pathogenicity of the NR5A1/SF-1 variants but is likely influenced by additional genetic variants and as-yet-unknown factors. FUNDING: Swiss National Science Foundation (320030-197725) and Boveri Foundation Zürich, Switzerland.

Effects of Sex Hormones on Vascular Reactivity in Boys With Hypospadias.

BACKGROUND: Arteries from boys with hypospadias demonstrate hypercontractility and impaired vasorelaxation. The role of sex hormones in these responses in unclear. AIMS: We compared effects of sex steroids on vascular reactivity in healthy boys and boys with hypospadias. METHODS: Excess foreskin tissue was obtained from 11 boys undergoing hypospadias repair (cases) and 12 undergoing routine circumcision (controls) (median age [range], 1.5 [1.2-2.7] years) and small resistance arteries were isolated. Vessels were mounted on wire myographs and vascular reactivity was assessed in the absence/presence of 17ß-estradiol, dihydrotestosterone (DHT), and testosterone. RESULTS: In controls, testosterone and 17ß-estradiol increased contraction (percent of maximum contraction [Emax]: 83.74 basal vs 125.4 after testosterone, P < .0002; and 83.74 vs 110.2 after estradiol, P = .02). 17ß-estradiol reduced vasorelaxation in arteries from controls (Emax: 10.6 vs 15.6 to acetylcholine, P < .0001; and Emax: 14.6 vs 20.5 to sodium nitroprusside, P < .0001). In hypospadias, testosterone (Emax: 137.9 vs 107.2, P = .01) and 17ß-estradiol (Emax: 156.9 vs 23.6, P < .0001) reduced contraction. Androgens, but not 17ß-estradiol, increased endothelium-dependent and endothelium-independent vasorelaxation in cases (Emax: 77.3 vs 51.7 with testosterone, P = .02; and vs 48.2 with DHT to acetylcholine, P = .0001; Emax: 43.0 vs 39.5 with testosterone, P = .02; and 39.6 vs 37.5 with DHT to sodium nitroprusside, P = .04). CONCLUSION: In healthy boys, testosterone and 17ß-estradiol promote a vasoconstrictor phenotype, whereas in boys with hypospadias, these sex hormones reduce vasoconstriction, with androgens promoting vasorelaxation. Differences in baseline artery function may therefore be sex hormone-independent and the impact of early-life variations in androgen exposure on vascular function needs further study.

SEC31A may be associated with pituitary hormone deficiency and gonadal dysgenesis.

PURPOSE: Disorders/differences of sex development (DSD) result from variants in many different human genes but, frequently, have no detectable molecular cause. METHODS: Detailed clinical and genetic phenotyping was conducted on a family with three children. A Sec31a animal model and functional studies were used to investigate the significance of the findings. RESULTS: By trio whole-exome DNA sequencing we detected a heterozygous de novo nonsense SEC31A variant, in three children of healthy non-consanguineous parents. The children had different combinations of disorders that included complete gonadal dysgenesis and multiple pituitary hormone deficiency. SEC31A encodes a component of the COPII coat protein complex, necessary for intracellular anterograde vesicle-mediated transport between the endoplasmic reticulum (ER) and Golgi. CRISPR-Cas9 targeted knockout of the orthologous Sec31a gene region resulted in early embryonic lethality in homozygous mice. mRNA expression of ER-stress genes ATF4 and CHOP was increased in the children, suggesting defective protein transport. The pLI score of the gene, from gnomAD data, is 0.02. CONCLUSIONS: SEC31A might underlie a previously unrecognised clinical syndrome comprising gonadal dysgenesis, multiple pituitary hormone deficiencies, dysmorphic features and developmental delay. However, a variant that remains undetected, in a different gene, may alternatively be causal in this family.

Gynecomastia and Its Management In Boys With Partial Androgen Insensitivity Syndrome.

INTRODUCTION: Partial androgen insensitivity syndrome (PAIS) is a rare condition that is reported to be commonly associated with gynecomastia in males. OBJECTIVES: To assess the management of gynecomastia in male PAIS. MATERIALS AND METHODS: Retrospective review of males with PAIS over the age of 10 years in the I-DSD registry. RESULTS: Of the 205 eligible cases, information was available for 57 from 13 centers. An androgen receptor gene variant was confirmed in 45 (79%) with a median age at first presentation of 1.0 year (range 0.1, 26.0). Of the 45 genetically confirmed cases, gynecomastia was present in 41 (91%) with a median age at the time of gynecomastia development of 13.5 years (11.0, 29.0). In the other 4 (9%) with no gynecomastia, the median age at last assessment was 15.7 years (10.6, 17.0). In 30 cases with information available, micropenis was present at the time of gynecomastia development in 23 (77%). Of the 35 with information available, 2 (6%) exhibited spontaneous resolution between the ages of 15 and 21 years and 25 (71%) had breast surgery at a median age of 15.7 years (14.0, 23.0). Of these 25, 9 (26%) had previously received medical therapy. The median clinician score of effectiveness for medical therapy was 3 (1, 8) compared to 10 (3, 10) for surgery (P < .0001). In 31 with information available, 13 (42%) had received psychology support. CONCLUSION: Gynecomastia is common in PAIS but not universal. Surgical management may be more effective than medical therapy, but there is a need for further standardized and systematic studies.

National service evaluation of the quality of care for children and young people with congenital adrenal hyperplasia in the United Kingdom: survey responses from patients and clinicians.

INTRODUCTION: Quantifying differences in service provision for children and young people (CYP) living with Congenital Adrenal Hyperplasia (CAH) across the United Kingdom. METHODS: A national service evaluation using online questionnaires circulated to patients and clinicians from secondary and tertiary UK centres managing CYP with CAH, and via the "Living with CAH" support group mailing list. RESULTS: Total of 195 responses relating to patients aged 0-20 years attending 33 clinics (43 patients, 152 carers), as well as 34 clinicians from 18 trusts working across the 33 clinics. Only 12% of clinicians were 'completely satisfied' with the service provided, compared to 68% of carers and 76% of patients. Whilst 94% of clinicians reported providing formal training to families with CAH, over 80% of both patients and carers reported not attending what they considered formal training. Appetite for further training was higher in carers (86%) than patients (55%), although further 'unsure' responses suggested formal training sessions would likely be well attended. Access to psychological services was difficult for 44% of clinicians. Biochemical monitoring of treatment was broadly in keeping with international guidelines, with 67% of clinicians reporting regular use of dried blood spots, and 12% regular urinary steroid metabolites. CONCLUSION: While there is overall good satisfaction with care provision among patients and carers with CAH in the UK, extra resources addressing the psychological and educational needs about the disease and its management would benefit patients and carers. Improved access to allied health professionals and psychologists will help support families and improve patient outcomes.

Temporal Trends in Acute Adrenal Insufficiency Events in Children With Congenital Adrenal Hyperplasia During 2019-2022.

Background: It is unclear whether targeted monitoring of acute adrenal insufficiency (AI) related adverse events (AE) such as sick day episodes (SDEs) and hospitalization rate in congenital adrenal hyperplasia (CAH) is associated with a change in the occurrence of these events. Aim: Study temporal trends of AI related AE in the I-CAH Registry. Methods: In 2022, data on the occurrence of AI-related AE in children aged <18 years with 21-hydroxylase deficiency CAH were compared to data collected in 2019. Results: In 2022, a total of 513 children from 38 centers in 21 countries with a median of 8 children (range 1-58) per center had 2470 visits evaluated over a 3-year period (2019-2022). The median SDE per patient year in 2022 was 0 (0-2.5) compared to 0.3 (0-6) in 2019 (P = .01). Despite adjustment for age, CAH phenotype and duration of study period, a difference in SDE rate was still apparent between the 2 cohorts. Of the 38 centers in the 2022 cohort, 21 had also participated in 2019 and a reduction in SDE rate was noted in 13 (62%), an increase was noted in 3 (14%), and in 5 (24%) the rate remained the same. Of the 474 SDEs reported in the 2022 cohort, 103 (22%) led to hospitalization compared to 299 of 1099 SDEs (27%) in the 2019 cohort (P = .02). Conclusion: The I-CAH Registry can be used for targeted monitoring of important clinical benchmarks in CAH. However, changes in reported benchmarks need careful interpretation and longer-term monitoring.

Inflammation and linear bone growth: the inhibitory role of SOCS2 on GH/IGF-1 signaling.

Linear bone growth is widely recognized to be adversely affected in children with chronic kidney disease (CKD) and other chronic inflammatory disorders. The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) pathway is anabolic to the skeleton and inflammatory cytokines compromise bone growth through a number of different mechanisms, which include interference with the systemic as well as the tissue-level GH/IGF-1 axis. Despite attempts to promote growth and control disease, there are an increasing number of reports of the persistence of poor growth in a substantial proportion of patients receiving rhGH and/or drugs that block cytokine action. Thus, there is an urgent need to consider better and alternative forms of therapy that are directed specifically at the mechanism of the insult which leads to abnormal bone health. Suppressor of cytokine signaling 2 (SOCS2) expression is increased in inflammatory conditions including CKD, and is a recognized inhibitor of GH signaling. Therefore, in this review, we will focus on the premise that SOCS2 signaling represents a critical pathway in growth plate chondrocytes through which pro-inflammatory cytokines alter both GH/IGF-1 signaling and cellular function.

Preventative interventions that target cardiovascular dysfunction in children and young people: a systematic review of their effectiveness and an investigation of sexual dimorphism.

Given that cardiovascular diseases remain a primary cause of mortality and morbidity, there is a need to consider preventative strategies to improve vascular function from early in life. The aims of this study were therefore to investigate which interventions may improve endothelial function, intima media thickness and arterial stiffness in children and young people and to assess whether these interventions differ in boys and girls. A systematic literature search of Science Direct, Pubmed, Google Scholar and the Cochrane Library by two independent reviewers was performed to source articles. Inclusion criteria were any studies including any child ≤18 years of age receiving an intervention, which measured vascular function other than blood pressure. Exclusion criteria were studies assessing children with chronic medical conditions. A total of 72 studies were identified, which met the inclusion criteria. A measurable change in outcome was more likely to be reported in studies investigating endothelial function (p = 0.03). Interventions which improved vascular function included physical activity and dietary programmes. Under 10% of studies considered sex differences. In conclusion, school-based physical activity interventions are most likely to result in improvements in vascular function. Endothelial function may be the first variable of vascular function to change secondary to an intervention. Standardisation of reporting of differences between the sexes is essential to be able to ensure interventions are equally effective for boys and girls.