Aris Siafarikas

Accurate and transparent information regarding pediatric gender service processes is vital for trans young people and their families. Parents of children seeking gender-affirming treatment have des...

Introduction: Mitochondrial diabetes is rare and typically treated with dietary intervention and oral hypoglycaemic agents. Most require insulin. Novel treatments are available but are not well characterised. Case Presentation: A 16-year-old adolescent girl with a genetically confirmed diagnosis of MELAS due to an m.3243A>G variant presented with clinical and biochemical features of diabetes. She was successfully transitioned from subcutaneous insulin therapy to weekly GLP-1RA monotherapy shortly after diagnosis of diabetes. Treatment with 0.25 mg semaglutide SC weekly led to a reduction in HbA1c from 13.7% (126 mmol/mol) to 5.6% (38 mmol/mol) over a 7-month period. Insulin was completely ceased within 5 days of starting semaglutide. CGM data from a 11 months follow-up period are presented, which demonstrate CGM data meeting glycaemic targets. Conclusion: Low-dose semaglutide 0.25 mg sc weekly was efficacious and well tolerated without lactic acidosis. Use of GLP-1RA could be considered a novel and effective treatment in the pharmacological management of paediatric mitochondrial diabetes.

Although hearing impairment is often listed as a nonskeletal complication of X-linked hypophosphatemia (XLH), the prevalence, etiology, pathology, and natural history are poorly described. This review aims to summarize existing literature with a view to guide the clinical management of hearing impairment in XLH. The review was conducted by 2 researchers independently. Four databases (PubMed/Medline, EMBASE, Web of Science, and Cochrane Library) were searched between January 1, 2000 and July 31, 2024, with keywords related to “X-linked hypophosphataemic rickets” and “hearing loss” including synonyms. Identified records were screened for inclusion and exclusion criteria. Human and animal studies were included. Out of 82 records found excluding duplicates, 12 studies met the final criteria and were reviewed. Studies described both conductive and sensorineural hearing loss in 13%-76% of adults with XLH, with sensorineural hearing loss more commonly reported, with impairment developing in adulthood, affecting high and low frequencies, and may be fluctuating. Evidence suggests that endolymphatic hydrops (ELH) may be a major underlying cause of hearing loss in XLH. Individuals with XLH have generalized osteosclerosis with petrous bone thickening and narrowing of the auditory meatus. No studies have looked at burosumab, a monoclonal antibody that inhibits FGF23, and its effect on the development of hearing loss in individuals with XLH. Animal studies of XLH mouse models (Hyp and Gy) describe both conductive and sensorineural hearing impairment. Mouse models demonstrate high Auditory Brainstem Response (ABR) thresholds and signs of osteomalacia of auditory ossicles and ELH. In conclusion, there is an association between hearing loss in XLH and, most commonly, adult-onset sensorineural hearing loss. Pathogenesis of hearing loss in XLH is incompletely understood, but possible contributing factors include thickening of the temporal bones, osteomalacia of the auditory ossicles, and development of ELH. There is currently no evidence that treatment with conventional therapy or burosumab reduces the risk or severity of hearing impairment.

X-linked hypophosphatemia (XLH) is an X-linked dominant condition where fibroblast growth factor-23 (FGF23) excess leads to hypophosphatemic rickets, lower limb bowing, and musculoskeletal pain. Burosumab, a monoclonal antibody against FGF23, has been shown to ameliorate the clinical phenotype of XLH and has recently been approved for use in many countries. This study aimed to evaluate patient and parental/caregiver perception of burosumab therapy and the acceptability of current management practices in Australia. Children with XLH and parents/carers were invited to respond to a survey on clinical and management information including use of telehealth, access to multidisciplinary team members, and perceptions and experience regarding burosumab therapy. This was a multi-centre, cross-sectional survey-based study involving 4 tertiary Australian children’s hospitals. A total of 21 survey responses from parents/carers were received between December 2022 and October 2023. Mean (SD) age at time of survey was 12.7 (4.1) yr and median time on burosumab was 42 mo (range 2-100). Reported side effects of burosumab were limited to local skin reactions (38%, n = 8) and injection site pain (5%, n = 1), with the majority (62%, n = 13) reporting no side effects. Logistical issues (availability from the pharmacy or medical centre holiday closure) led to most instances of missed or delayed doses, which were reported by 24% (n = 5). Most participants reported seeing their specialist both face-to-face and via telehealth (64%, n = 14). The majority saw an endocrinologist (100%, n = 21) and orthopaedic surgeon (67%, n = 14), but only a small minority saw a psychologist (10%, n = 2). Answers to Likert scale questions revealed that most parents/carers and children reported a perceived improvement in physical and psychological symptoms and function with burosumab therapy. This study supports the use of recently published local guidelines to manage children with XLH on burosumab due to high satisfaction expressed by children and parents/carers. However, logistical issues leading to delayed or missed doses should be addressed.

This study aims to describe the risk factors and trends in birth prevalence of septo-optic dysplasia (SOD) and gastroschisis between 1980 and 2023. This descriptive, population-based study of SOD and gastroschisis used Western Australian Register of Developmental Anomalies data from 1980 to 2023. Birth prevalence was calculated using Midwives Notification System data for all births after 20 weeks gestation. Relative risk (RR) for SOD and gastroschisis showed risk by maternal age. SOD and gastroschisis occurred in 99 and 391 cases respectively (no dual diagnoses), with a birth prevalence of 1.41 and 3.71 per 10,000 respectively (from 2010 to 2019), and have been stable since 2010. For the study period, younger maternal age (under 25 years old) increased the risk of SOD and gastroschisis (RR, 3.28 [95% confidence interval (CI) 2.13–5.00]; RR, 4.50 [95% CI 3.68–5.49] respectively). From 2010 to 2023, median maternal age increased for SOD and gastroschisis by 4.8 years (p = 0.044) to 27.0 and by 2.8 years (p < 0.001) to 25.5, respectively. Mothers living in areas of greater socioeconomic disadvantage had higher risk (RR, 1.81 [95% CI 1.14–2.88] in SOD and RR, 1.41 [95% CI 1.06–1.86] in gastroschisis), independent of maternal age. Premature birth was more common in children with SOD and gastroschisis. Conclusion: While younger mothers are more likely to have a child with either SOD or gastroschisis, maternal age at birth is higher than reported in the literature and is rising. This is probably attributable to the rising age of mothers at delivery, and further research into risk factors beyond maternal age is recommended. What is Known: • Septo-optic dysplasia and gastroschisis are both rare diseases, known to occur more commonly in younger mothers. • Maternal age at birth is increasing in high income countries. What is New: • Despite mean maternal age rising in both conditions, in-line with rising population maternal age, birth prevalence is stable. •  Mothers living in areas of greater socioeconomic disadvantage had a higher relative risk of SOD and gastroschisis.

X linked hypophosphataemia (XLH) is a systemic, chronic condition that significantly impairs quality of life. In XLH, a phosphate regulating endopeptidase homologue X‐linked (PHEX) gene mutation leads to excess fibroblast growth factor 23 (FGF23), causing hypophosphataemia and subsequent rickets, lower limb deformity, pain and other sequelae, however there are likely other non‐FGF23 mediated mechanisms contributing to disease. Burosumab is an FGF23 inhibiting monoclonal antibody that has been shown to be significantly more effective in treating X linked hypophosphataemia than previously available treatment (“conventional therapy” with oral phosphate and active vitamin D). Clinical trials and real‐world studies have shown that burosumab can improve lower limb deformity, growth, pain, exercise capacity, biochemistry, rickets, and quality of life. However, the full effect of burosumab on the lives of individuals with X linked hypophosphataemia is yet to be determined. How burosumab may impact some of the lesser understood clinical features, including dental abscesses, craniosynostosis, enthesopathy, and osteoarthritis, is unclear. Whether burosumab mitigates the risk of complications associated with conventional therapy (nephrocalcinosis and hyperparathyroidism) has also not been established. There are conflicting recommendations on who should receive burosumab, when they should start it, and for how long they should continue taking it. This review summarises what is known, and more importantly what is unknown, about burosumab use in X linked hypophosphataemia. We highlight important areas for future research to better understand the impact of burosumab in XLH, improve management of XLH, assess cost benefit of, and advocate for fair and equitable access to burosumab.

Context: Septo-optic dysplasia (SOD) is a major cause of congenital hypopituitarism and is known to be associated with overweight and obesity in up to 44% of children. Given the role of the hypothalamus in hormonal regulation, we sought to assess the association of resting energy expenditure (REE), appetite and physical activity with SOD. Objective: To characterize REE and other metabolic features in patients with SOD and evaluate relationships with elevated body mass index (BMI). Methods: Children with SOD above 5 years of age attending Perth Children's Hospital participated. A CosMED Q-NRG indirect calorimeter was used to calculate mean measure REE (mREE). This was compared with predictive REE (pREE) based on the Schofield equation to determine mREE/pREE quotient. A BMI z-score >1 was considered elevated. Parents/carers completed a questionnaire about pituitary function, the Hyperphagia Questionnaire and the Sleep Disturbances Scale for Children (SDSC). Results: Twenty-six participants underwent testing (9 female, mean age 12.1 years) with 11 having elevated BMI and 15 with pituitary hormone deficiencies. Mean mREE was 1309 kcal/day (838-1732), mREE/pREE quotient was 88.8% ± 10.1. mREE/pREE quotient was similar in those with elevated BMI compared with normal BMI (83.3% ± 12.5 vs 92.1% ± 7.2, P = .068). Those with midline defects had a higher mREE/pREE quotient (91.8% ± 8.1 vs 80.4% ± 11.3, P = .026). Hyperphagia and SDSC scores were similar between BMI groups. Hyperphagia domain scores were higher in children with multiple hypopituitarism, pituitary structural defects, and normal septum pellucidum (P = .044, .042, and .033, respectively). Conclusion: Children with SOD had lower mREE than predicted and hyperphagia scores were higher in those with biochemical or structural pituitary changes, suggesting that hypothalamic dysfunction could drive BMI elevation in SOD. Indirect calorimetry may be used to guide the management of overweight and obesity in SOD.

Objective: Determine if exercise interventions, beyond what is already provided to children and preschool children, improve bone health and reduce fracture incidence. Design: Systematic review and meta-analysis reported using the PRISMA guidelines. Certainty of evidence was assessed using GRADE recommendations. Data sources: Five electronic databases were searched for records: PUBMED; CINAHL; CENTRAL; SPORTDiscus; Web of Science. Eligibility criteria for selecting studies: Randomised, quasi-randomised and non-randomised controlled trials (including cluster-randomised) assessing the impact of additional exercise interventions (e.g., increased physical education classes or specific jumping programs) on bone health in children (6–12 years) and pre-school children (2–5 years) without dietary intervention. Results: Thirty-one records representing 16 distinct clinical trials were included. Dual-energy X-ray Absorptiometry (DXA) and/or peripheral Quantitative Computed Tomography (pQCT) were used to quantify bone health. Increased femoral neck bone mineral content in children with additional exercise interventions (n = 790, SMD = 0.55, 95% CI = 0.01 to 1.09) was reported, however this was not significant following sensitivity analysis. Other DXA and pQCT measures, as well as fracture incidence, did not appear to significantly differ over time between intervention and control groups. No studies reported adverse events. Studies failed to report all domains within the TIDieR checklist. All studies were at high risk of bias using the Cochrane RoB Tool 2.0. The certainty of the evidence was very low. Conclusions: The addition of exercise interventions, beyond what is provided to children, does not appear to improve DXA and pQCT measures of bone health. The effect of additional exercise interventions on bone health in pre-school children is largely unknown. Future trials should ensure adherence is clearly reported and controlled for within analysis as well as including reports of adverse events (e.g., apophysitis) that occur due to increased exercise interventions.