Bone health in childhood and adolescence: an overview on dual-energy X-ray absorptiometry scanning, fracture surveillance and bisphosphonate therapy for low-middle-income countries

Bone accrual in childhood determines bone health in later life. Loss of bone strength in early life can lead to increased morbidity and reduced quality of life in childhood and adolescence. Increased availability of assessment tools and bisphosphonate therapy, together with increased awareness on the significance of fracture history and risk factors, have led to greater opportunities, to improve detection and optimize management of children and adolescents with bone fragility globally, including those in lower resource settings. Bone mineral density z-scores and bone mineral content are surrogate measures of bone strength, which can be measured by dual-energy X-ray absorptiometry (DXA), in growing individuals. DXA can aid in the diagnosis and management of primary and secondary bone fragility disorders in childhood. DXA helps evaluate children with clinically significant fractures, and monitor those with bone fragility disorders, or at high risk for compromised bone strength. Obtaining DXA images can however be challenging, especially in younger children, due to difficulty in positioning and movement artefacts, while paediatric DXA interpretation can be confounded by effects of growth and puberty. Furthermore, access to DXA facilities as well as appropriate paediatric reference norms and expertise for interpretation, may not be easily available especially in lower resource settings. Pediatric bone experts are now placing increasing emphasis on the fracture phenotype and clinical context to diagnose osteoporosis over bone mineral density (BMD) by DXA. Low trauma vertebral fractures are now recognized as a hallmark of bone fragility, and spinal fracture surveillance by either conventional lateral thoracolumbar radiographs or vertebral fracture assessment by DXA is gaining increasing importance in diagnosing childhood osteoporosis, and initiating bone protective therapy. Furthermore, it is now understood that even a single, low-trauma long bone fracture can signal osteoporosis in those with risk factors for bone fragility. Intravenous bisphosphonate therapy is the mainstay of treatment for childhood bone fragility disorders. Other supportive measures to improve bone strength include optimizing nutrition, encouraging weight bearing physical activity within the limits of the underlying condition, and treating any associated endocrinopathies. With this paradigm shift in childhood osteoporosis evaluation and management, lack of DXA facilities to assess BMD at baseline and/or provide serial monitoring is not a major barrier for initiating IV bisphosphonate therapy in children in whom it is clinically indicated and would benefit from its use. DXA is useful, however, to monitor treatment response and optimal timing for treatment discontinuation in children with transient risk factors for osteoporosis. Overall, there is lack of awareness and paucity of guidelines on utilizing and adopting available resources to manage paediatric bone disorders optimally in lower-resource settings. We provide an evidence-based approach to the assessment and management of bone fragility disorders in children and adolescents, with appropriate considerations for lower resource settings including LMIC countries

Health-related quality of life in children and adolescents with congenital adrenal hyperplasia: a systematic review and meta-analysis

Objective To conduct a systematic-review(SR) and meta-analysis(MA) on health-related quality-of-life (QoL) and associated factors among children/adolescents with congenital adrenal hyperplasia(CAH). Method Following registration in the PROSPERO International-prospective-register-of-systematic-reviews(reg no:CRD42022313389), Google-scholar, PubMed, LILACS, Cochrane and Scopus databases were searched up to 03/05/2022, using pre-defined search strategy/MESH terms, to identify original studies describing/assessing self-reported/parent-reported health-related QoL in patients with CAH ≤21 years. Methodological quality was assessed by Newcastle-Ottawa quality-assessment-scale (NOS), and heterogeneity by I2 statistics. MA assessed mean difference (MD) in QoL between children/adolescents with CAH and healthy children/adolescents. Results Among 1308 publications, the 12 studies eligible for the SR (CAH n=781), showed NOS scales of 3-7/9, and the six eligible for MA (CAH n=227) showed moderate-considerable heterogeneity. MA showed that parent-reported psychosocial QoL (MD-9.9[-12.6,7.3], P=<0.001)) {consisting of school ((MD-7.4[-12.2, -2.5], P=0.003), emotional (MD-5.6[-10.2, -0.9], P=0.02) and social domains (MD-4.3[-8.1, -0.5], P =0.03)}, and self-reported school domain QoL (MD-8.5[-15.9, -1.2], p=0.02) was lower in children/adolescents with CAH while parent-reported and self-reported physical QoL were similar to controls. Factors associated with lower QoL among children/adolescents with CAH included: poor disease control, poor medication compliance, and complications including hyper-pigmentation, virilization, hypertension, hospital admission and urinary incontinence. Conclusion Based on available data, children/adolescents with CAH had preserved physical QoL but impaired psychosocial QoL, especially in the school domain. Factors associated with lower QoL included poor disease-control, and disease/treatment-related complications. There is a need for further high-quality research that investigates the relationship between disease-control, provision of psychosocial support and improvement in QoL in children/adolescents with CAH

Virilization and feminization in an adolescent boy with 45X/46XY DSD due to bilateral gonadoblastomas: A case report

Introduction: Children with 45X/46XY difference/disorder of sex development (DSD) have varying internal/external genitalia/gonads, Turner-like features, and increased risk of gonadal malignancy. We present a case of concomitant virilization and feminization as a unique feature of gonadoblastoma in a boy with 45X/46XY DSD. Case presentation: The patient was born with ambiguous genitalia (phallus of 2cm, perineal urethra) and a Turner-like phenotype. Ultrasound scan revealed horseshoe kidneys, intra-abdominal gonads, and Mullerian remnants. His karyotype was 45X/46XY with atypical Y chromosome. Initial gonadotrophin levels were very high. Biopsy of the bilateral gonads revealed testicular tissue. It was decided to raise the baby as a boy. Staged orchidopexy and hypospadias repair were done between 4 and 6 years of age. He remained under close clinical, biochemical and radiological follow-up for the potential development of gonadal malignancies. He developed penile enlargement at the age of11 years. Within a few months, he developed bilateral gynecomastia and rapid cystic enlargement of the gonads. Hormone quantification revealed elevated serum estrogen, a peri-pubertal testosterone level, and normal tumor marker levels. After a multidisciplinary team discussion, he underwent surgical exploration and removal of a bulky uterus and both gonads. Histology showed evidence of gonadoblastoma within the testicular and the ovarian stroma. Conclusion: Children with DSD are at high risk for developing gonadoblastomas, which can present as rapid concurrent isosexual and heterosexual pubertal development. It is critical that patients with DSD remain under close oncologic surveillance

Clinical and genetic characteristics of a large international cohort of individuals with rare NR5A1/SF-1 variants of sex developmentResearch in context

Summary: 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