The Children's Hospital at Westmead (formally Royal Alexandra Hospital for Children) is a children's hospital in Western Sydney. The hospital was founded in 1880 as "The Sydney Hospital for Sick Children". Its name was changed to the "Royal Alexandra Hospital for Children" on 4 January 1904 when King Edward VII granted use of the appellation ‘Royal’ and his consort, Queen Alexandra, consented to the use of her name.It is one of three children's hospitals in New South Wales. It is currently located on Hawkesbury Road in Westmead and is affiliated with the University of Sydney.On 1 July 2010, it became part of the newly formed The Sydney Children's Hospitals Network (Randwick and Westmead) incorporating the Royal Alexandra Hospital for Children'.
Osteonecrosis, or avascular necrosis, of the femoral head (ONFH) results from an avascular insult of traumatic or non-traumatic origin and can lead to significant morbidity, including pain, arthritis and the need for joint replacement at a young age. Non-surgical management of ONFH focuses on preservation of femoral head shape to reduce the need for arthroplasty or delay the age at which it is performed. Thirty patients diagnosed with ONFH on bone scan were prospectively studied to determine the safety of alternating denosumab and zoledronic acid over a 66-week treatment period. Patients underwent 6-weekly scheduled biochemical monitoring and assessment of bone mineral density at baseline and after twelve months. Mild hypercalcaemia (range 2.65-2.85 mmol/L) was noted in 5 patients (16%) during the treatment period. One of these patients was subsequently diagnosed with familial hypocalciuric hypercalcaemia. Asymptomatic hypocalcaemia (range 1.79-2.00 mmol/L) was detected on routine biochemical testing in a total of 15 patients (48%). All episodes responded to an increase in oral calcium supplementation. Bone mineral density (BMD) increased in all patients following treatment, with maximum total body height-adjusted Z-score +2.4 and lumbar spine +3.3. There were no episodes of medication-related osteonecrosis of the jaw, atypical femoral fracture or hypophosphataemia. Our study demonstrates that, with regular monitoring and management of serum calcium, alternating doses of denosumab and zoledronic acid can be administered safely for ONFH in children.
We investigated the pathogenicity of a homozygous intronic variant in CDK5RAP3, a key UFMylation adapter, in three individuals from two unrelated families with a lethal neurodevelopmental disorder. CDK5RAP3 variants have not been linked to human disorders to date; however, murine Cdk5rap3 knockout is embryonic lethal and variants in five other UFMylation components cause severe neurodevelopmental conditions. A segregating homozygous variant, chr17(GRCh38):g.47974691G > A, CDK5RAP3 NM_176096.3:c.334 + 243G > A, was identified by trio whole-genome and proband RNA sequencing in Family A and by trio whole-exome sequencing data reanalysis in Family B. Variant pathogenicity investigations included RT-PCR, Western blot, co-immunoprecipitation and (phospho)proteomics to assess transcript, protein and UFMylation complex effects. Antisense oligonucleotide-mediated rescue of CDK5RAP3 expression combined with proteomics and phosphoproteomics defined the mechanistic impact of CDK5RAP3 deficiency and rescue in amniocytes from an affected individual. All three affected individuals showed foetal growth restriction, foetal akinesia, pontocerebellar hypoplasia, arthrogryposis and hepatic pathology. CDK5RAP3 c.334 + 243G > A activates a cryptic donor splice-site causing pseudoexon/intron inclusion triggering nonsense-mediated decay and deficiency of full-length CDK5RAP3 (NP_788276.1), while potentially allowing retained expression of C-terminal alternative isoforms. Co-immunoprecipitation revealed only full-length CDK5RAP3 binds UFL1, whereas C-terminal isoforms cannot. Primary amniocytes showed CDK5RAP3 deficiency was associated with impaired UFMylation of known substrates, RPL26 and UFBP1. Proteomic and phosphoproteomic analyses revealed dysregulation of extracellular matrix organisation, cell adhesion, mitotic/genome stability pathways, cytoskeletal networks and neuronal guidance, which were reversed by restoration of canonical CDK5RAP3 expression via splice-correcting antisense oligonucleotides. Phosphoproteomic data implicate CDK5RAP3 as an upstream regulator of UFL1 S462 phosphorylation, known to be regulated by Ataxia-telangiectasia mutated (ATM) signalling. Our findings provide strong evidence linking deficiency of full-length CDK5RAP3 to severe neurodevelopmental, liver and muscle dysfunction. This study further highlights the therapeutic potential of ASO-based deep-intronic splicing defect correction.
Objective: The current study tested (1) how ADHD symptoms and internalizing or externalizing problems covaried across ages 3-18 in children with neurofibromatosis type 1 (NF1), and (2) whether demographic and NF1-specific factors moderated the associations. Method: We analyzed integrated cross-sectional data of 685 observations from 455 children and adolescents with NF1 (Mage = 9.79 years, SD = 3.88; 43% female) across six institutions in the United States and Australia. ADHD symptoms (inattention and hyperactivity/impulsivity) and internalizing/externalizing problems were assessed via parent-report measures. Time-varying effect modeling was employed to examine the age-specific associations between ADHD symptoms and internalizing/externalizing problems. Moderation analyses tested effects of sex, parental education, and NF1 inheritance mode (familial vs. sporadic). Results: Inattention and hyperactivity/impulsivity symptoms were associated with greater internalizing and externalizing problems across ages 3-17. Inattention links were similar across ages, while the hyperactivity/impulsivity-externalizing link was stronger in early childhood than during adolescence. NF1 inheritance mode significantly moderated the inattention-externalizing link, with stronger associations observed among children with familial NF1. Other moderators were nonsignificant. Conclusions: ADHD symptoms are robustly linked to internalizing and externalizing problems from childhood to middle adolescence in children with NF1, with familial NF1 emerging as a potentially elevated risk factor. Future longitudinal and experimental research is needed to inform integrated intervention approaches, especially for those with familial NF1.
Background Bordetella pertussis continues to circulate globally despite widespread vaccination, with a notable epidemic in 2024. Its resurgence is confounded by the emergence of pertactin-deficient, macrolide-resistant B pertussis strains in Asia and Europe, which are under-recognised by conventional diagnostics. We aimed to apply targeted culture-independent next-generation sequencing (tNGS) of respiratory specimens to improve global B pertussis diagnostic capability and genomic surveillance. Methods We did a nationwide genomic epidemiology study of B pertussis RT-PCR-positive respiratory specimens that were retrospectively and prospectively collected by diagnostic and public health laboratories in six of seven states and territories of Australia. Specimens underwent tNGS and macrolide-resistant B pertussis-specific PCR, and an opportunistic subset from New South Wales and Queensland were cultured for confirmatory susceptibility testing and whole-genome sequencing. Sequencing data were analysed for genome recovery, virulence profiles, and macrolide resistance mutations, and were compared with international macrolide-resistant B pertussis genomes and ancestral Australian genomes. The performance of the tNGS approach was assessed with logistic regression relative to RT-PCR cycle threshold values, and sensitivity and specificity values were calculated. Findings 255 respiratory specimens positive for B pertussis were included in the study. 64 (25%) were retrospectively collected between Jan 12, 2012, and Dec 31, 2023, and 191 (75%) were prospectively collected between Jan 1 and Oct 28, 2024. Of these 255 specimens, 148 (58%) yielded near-complete B pertussis genomes through tNGS. Seven co-circulating lineages of B pertussis were documented, including two associated with macrolide-resistance. Eight epidemiologically unrelated and geographically dispersed cases of macrolide-resistant B pertussis with a 23S rRNA 2037A→G mutation were identified by tNGS and confirmed by whole-genome sequencing. Three of these were further validated by phenotypic testing. The estimated prevalence of macrolide resistance among Australian cases positive for B pertussis was 4% (eight of 188). Interpretation tNGS can recover near-complete B pertussis genomes directly from clinical specimens, enabling identification of macrolide resistance mutations and high-resolution phylogenetic analysis. These findings show that tNGS complements PCR-based surveillance by providing genome-wide assessment of resistance, virulence, and genomic diversity in a single workflow. Funding NSW Health Prevention Research Support Program.
Purpose: Children with neurofibromatosis type 1 (NF1) frequently experience internalizing and externalizing problems, but their developmental patterns and predictors remain unclear. This study examined age trends and subgroup differences to inform individualized intervention efforts. Methods: Data from 1,841 children with NF1 (ages 3-18) were combined from nine institutions using integrative data analysis. Internalizing and externalizing problems were assessed with parent-rated Child Behavior Checklist (CBCL; N = 1,087) and Behavior Assessment System for Children (BASC; N = 754), which were analyzed separately. Time-varying effect modeling was used to delineate the age trends of internalizing and externalizing problems for the total samples and for subgroups based on sex, NF1 heritability (familial vs. sporadic), the presence (vs. absence) of plexiform neurofibromas, and attention-deficit/hyperactivity disorder (ADHD) diagnosis. Results: Across CBCL and BASC assessments, children with NF1 consistently exhibited elevated internalizing and externalizing problems compared to the normative means. The between-group gap in internalizing problems significantly widened with age, whereas the gap in externalizing problems remained relatively stable across ages. Age patterns for both types of problems were consistent across sex, NF1 heritability, and status of plexiform neurofibromas. Children with ADHD exhibited significantly higher levels of internalizing and externalizing problems compared to those without ADHD, with the age trends of both problems also differing between the two groups. Conclusions: Internalizing and externalizing problems in NF1 persist during childhood and adolescence and are particularly elevated among children with ADHD. Findings highlight the need for early, sustained, and developmentally tailored interventions, with attention to co-occurring ADHD.
