軟骨無形成症

BACKGROUND: The diagnostic odyssey of individuals with rare diseases is prolonged and associated with clinical, emotional, and financial burden. In Brazil, data on diagnostic delays and their determinants remain scarce. OBJECTIVE: This study aims to characterize the diagnostic odyssey of individuals with rare diseases using data from the Brazilian Rare Diseases Network (RARAS). METHODS: This descriptive cross-sectional study analyzed ambispective data collected from 2018-2025 across RARAS centers nationwide. Diagnostic odyssey was defined as the time between symptom onset and definitive diagnosis. Prenatal and newborn screening diagnoses were excluded. Sociodemographic, clinical and etiological data were collected through a standardized REDCap-based instrument. RESULTS: Among 18,625 unique participants, 12,048 had confirmed diagnoses and 5,984 met criteria for diagnostic odyssey analysis. The mean diagnostic interval was 6.21 years (± 8.41; median 2.94, IQR 0.80-8.13), indicating substantial heterogeneity. Longer delays were observed in individuals with symptom onset during adolescence. Patients referred during hospital admission experienced shorter diagnostic intervals. Regional differences were significant (p <0.001), with longer intervals in the Southeast region. Mean time to diagnosis ranged from 2.01 (± 2.89) years (achondroplasia) to 16.40 (± 12.59) years (hereditary angioedema). Patients consulted a mean of 5.32 (± 9.63) physicians and accessed 3.15 (± 4.96) healthcare services before diagnosis. Diagnostic intervals varied by race/ethnicity and etiological category, with longer delays among those with molecular diagnoses, while no association was observed with socioeconomic class. CONCLUSION: The diagnostic odyssey for rare diseases in Brazil remains prolonged and heterogeneous, reflecting structural disparities, healthcare fragmentation, and diagnostic complexity. These findings suggest that delays are not driven solely by limited access to advanced diagnostics, but also by barriers in early recognition, referral pathways, and care coordination, underscoring the need for integrated strategies across the health system.

Background: Premature consolidation of the regenerated bone is a relevant and underreported complication of limb lengthening in achondroplasia, with a reported incidence of 7-15% in the international literature. The gain-of-function fibroblast growth factor receptor 3 (FGFR3) mutation paradoxically enhances bone-healing capacity, predisposing patients to accelerated callus maturation during distraction osteogenesis and exposing patients to a risk of invasive procedures to treat this issue. This study reports the incidence and clinical features of premature consolidation in a cohort of achondroplastic patients treated with external fixation. Methods: A retrospective analysis was conducted on patients with achondroplasia who underwent lower limb lengthening (femur and/or tibia-fibula) between 2017 and 2024 at IRCCS Ospedale Galeazzi-Sant'Ambrogio (Milan, Italy). Inclusion criteria were ages 7-18 years, confirmed achondroplasia, and a clinical-radiological diagnosis of premature consolidation. Key parameters included the healing index (HI), length gained, proportional increase, and fixator duration. Results: Among 39 patients (112 segments: 46 femora and 66 tibia-fibula units), premature consolidation occurred in 7 patients (10 segments), yielding an overall incidence of 8.9%. The fibula was predominantly affected (6/10 segments). The mean HI was 33.47 days/cm for the tibia and 30.1 days/cm for the femur; the mean length gained was 8.1 cm and 8.2 cm, respectively. Conclusions: Premature consolidation affects approximately 9% of lengthened segments in achondroplastic patients, with a predilection for the fibula due to its passive indirect distraction mechanism. Early radiographic recognition and dynamic adjustment of the distraction protocol are essential to prevent surgical calloclasis and optimize outcomes, and further analyses of the FGFR3 mutation are fundamental to understand the biologic features of the bone during the lengthening and consolidation steps.

PURPOSE: Achondroplasia is a genetic syndrome characterized by short stature and rhizomelic shortening of the limbs. Many patients also exhibit craniocervical junction stenosis, which often progresses to spinal cord compression or hydrocephalus. Foramen magnum decompression (FMD) is performed to relieve stenosis at the craniovertebral junction. The purpose of this study was to analyze the clinical outcomes of FMD in achondroplasia patients and to discuss restenosis due to bone regrowth (bony restenosis), an important cause of postoperative worsening. METHODS: Medical records and brain imaging data of 89 pediatric achondroplasia patients who visited our institution between January 2012 and April 2022 were retrospectively analyzed. RESULTS: Among 89 achondroplasia patients, FMD was performed in 38 patients. During the median 60 months of follow-up after FMD, eleven patients developed warning changes at MRI. Warning changes consisted of four types: restenosis due to bone regrowth (bony restenosis), restenosis due to soft tissue thickening, de novo T2 HSI of the cervical spinal cord, and progression of ventriculomegaly. Patients with bony restenosis (3 of 38; 7.9%) required reoperation of FMD. The age of restenosis was 46, 48, and 98 months old, and the time interval after FMD was 38, 34, and 87 months, respectively. Removal of bony spur was performed and no recurrence of bony restenosis was found until the most recent follow-up. CONCLUSION: Bony restenosis was observed in 3 of 38 patients (7.9%) after FMD during the follow-up. Regular imaging studies and close observation until late childhood may be reasonable for early detection and management of bony restenosis.

In 2021, vosoritide became the first pharmaceutical approved to treat the pathophysiology of achondroplastic dwarfism. It has generated significant ethical debate. Proponents emphasize its potential to improve quality of life and functional independence, whereas critics raise concerns about pathologizing human variation, eroding cultural identity, and limiting children's autonomy. The drug has an extremely high cost (approximately $300,000 USD per year per patient) and is non-lifesaving, further provoking questions of distributive justice and public funding. This paper examines the key ethical issues surrounding vosoritide, including the distinction between its medical and social benefits, its potential impact on identity, the inclusion of disability communities in study design, the limits of parental decision-making, and the justification for public reimbursement. We argue that ethical evaluation requires robust empirical evidence on both medical and quality-of-life outcomes, inclusion of disability communities in the research process, and long-term psychosocial follow-up and mandated data sharing of treated children.

BACKGROUND: Hypochondroplasia, a fibroblast growth factor receptor 3 (FGFR3)-related skeletal condition characterized by disproportionate short stature and a spectrum of clinical features, has no available targeted therapies. Vosoritide, a C-type natriuretic peptide analogue approved for the treatment of achondroplasia, is being investigated for hypochondroplasia. METHODS: In this phase 3, multicenter trial, children with hypochondroplasia who were 3 to less than 18 years of age were randomly assigned to receive once-daily subcutaneous injections of vosoritide or placebo for 52 weeks per weight-band dosing regimen. The primary end point was change from baseline in annualized growth velocity at week 52 versus placebo. Confirmatory statistical testing using hierarchical procedures to control for type I error at the one-sided 0.025 significance level (equivalent to the two-sided 0.05 level) was performed for the primary and six key secondary efficacy end points. The safety and side effect profile of vosoritide versus placebo was assessed. RESULTS: A total of 81 participants were randomly assigned to receive vosoritide (n=41) or placebo (n=40). At week 52, the least squares mean (LSM) change from baseline in annualized growth velocity was 1.95 cm/year with vosoritide versus -0.39 cm/year with placebo (LSM difference of 2.33 cm/year; 95% confidence interval, 1.85-2.82 cm/year; two-sided P<0.0001). Most participants in the vosoritide group (87.8%) and the placebo group (72.5%) experienced at least one adverse event (AE). There were no reports of grade 3 or higher AEs, AEs leading to treatment discontinuation, or deaths. CONCLUSIONS: One year of vosoritide treatment significantly increased linear growth in children with hypochondroplasia. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT06455059.).