軟骨無形成症

Genetic bone diseases are a rare group of afflictions suffered by the general population. However, their rarity should not diminish research efforts to help patients understand and treat their diseases. This review summarizes the pathology, symptoms, diagnosis, and treatment insight into six well-known genetic bone diseases. Only six bone diseases are included due to the relatively low prevalence of them as whole limiting our scope to ensure accurate information and attention is provided for each disease individually. A literature search of PubMed is conducted, including studies published within the past five years (January 2020-December 2025). Thirty-six studies met inclusion criteria, and no significant risk of bias is identified among the selected articles. Study findings are synthesized into disease overview, clinical and radiographic features, and diagnostic and treatment approaches. Actively developing or novel therapies relevant to each disease are also included. These treatments include: fresolimumab for osteogenesis imperfecta, small interfering ribonucleic acid (RNA) therapy for Osteopetrosis, denosumab for Paget's disease of bone, vosoritide/recifercept/infigratinib for achondroplasia, mesenchymal stem cell therapy for craniosynostosis, and combination losartan and atenolol therapy for Marfan syndrome. These treatments are generally more recently acknowledged in literature and are either actively undergoing research or require further research to determine their efficacy.

Hypochondroplasia is a rare genetic condition that causes disproportionate short stature. This retrospective, real-world, matched-cohort study used electronic health records data from the Clinical Practice Research Datalink Aurum primary care database, linked to Hospital Episode Statistics and Office of National Statistics mortality records, to assess the natural history of hypochondroplasia in England from 1998 to 2019. A total of 549 participants with hypochondroplasia and 2196 matched controls were included. Mean follow-up time was 7.50 years for participants with hypochondroplasia and 11.68 years for controls. Approximately 60% of participants were aged >18 years at start of follow-up. Mean age (standard deviation) at first recorded hypochondroplasia code was 29.20 (20.2) years. The highest event rates for participants with hypochondroplasia involved cardiovascular, orthopaedic, respiratory, mental health, and ear, nose and throat (ENT) systems. Event rates for the selected comorbidities combined were higher in participants with hypochondroplasia versus controls (rate ratio [RR] 2.13, 95% confidence interval [CI] 1.98-2.28). Participants with hypochondroplasia had higher healthcare visit rates, including a median of 10.91 annual general practitioner visits versus 5.52 for controls (RR 1.63, 95% CI 1.48-1.80). Mortality rates were more than double for participants with hypochondroplasia versus controls (RR 2.64, 95% CI 1.33-5.26), mainly driven by cohorts aged ≥30 years and by cardiovascular and respiratory diseases. Rates for procedures, particularly orthopaedic and ENT, and medication use were also higher among participants with hypochondroplasia versus controls. These results highlight the medical burden of hypochondroplasia and need for coordinated, multidisciplinary management starting early in life.

Very few articles have investigated pregnancy in women with achondroplasia. A scoping review methodology was used to record and summarize the existing research evidence. The review process was conducted in accordance with the PRISMA-ScR guidelines. Original studies and case series mentioning achondroplasia with a minimum of 5 pregnancies were included. A total of 1527 articles were screened by title and abstract. Twenty-one full-text articles were reviewed for eligibility criteria. Seven studies were included. The reference details, study characteristics, topics of interest, and main findings are presented. The combination of short stature and a narrow pelvis led to a difficult antenatal and intrapartum period. Over the past decades, the number of publications on achondroplasia has increased overall, but pregnancy-related articles are still lacking. Multicentre studies should be initiated following methodological reference standards to strengthen the reliability and generalizability of the findings and to increase their relevance for implementation in clinical practice.

BACKGROUND: Achondroplasia is a genetic skeletal condition caused by FGFR3 pathogenic variants. Infigratinib, an oral FGFR1-3 tyrosine kinase inhibitor, down-regulates key pathways in the pathogenesis of achondroplasia. METHODS: In this phase 3, multicenter, double-blind, placebo-controlled trial, we randomly assigned children with achondroplasia (3 to 17 years of age) in a 2:1 ratio to receive infigratinib (at a dose of 0.25 mg per kilogram of body weight) or placebo once daily for 52 weeks. The primary end point was the change from baseline in the annualized height velocity in the infigratinib group as compared with the placebo group at week 52. Key secondary end points were the change from baseline in the height z score and in the upper-to-lower body segment ratio at week 52. The primary analysis evaluated the treatment effect at week 52 in the full analysis population, with missing data handled with a prespecified imputation approach. RESULTS: In all, 114 patients underwent randomization: 75 patients to receive infigratinib (with 1 withdrawal before treatment) and 39 patients to receive placebo. The difference between infigratinib and placebo in the least-squares mean change from baseline to week 52 was 1.74 cm per year (95% confidence interval [CI], 1.31 to 2.17; P<0.001) for the annualized height velocity, 0.32 (96% CI, 0.23 to 0.41; P<0.001) for the height z score, and -0.02 (96% CI, -0.06 to 0.01) for the upper-to-lower body segment ratio. Adverse events occurred in 71 of 74 patients (96%) in the infigratinib group and in 37 of 39 patients (95%) in the placebo group; serious adverse events occurred in 4 of 74 patients (5%) and 1 of 39 patients (3%), respectively. No serious adverse events or adverse events leading to treatment discontinuation were considered by the investigator to be related to infigratinib or placebo. CONCLUSIONS: In children with achondroplasia, treatment with once-daily oral infigratinib for 52 weeks resulted in a significantly greater increase from baseline in the annualized height velocity than placebo. (Funded by BridgeBio Pharma; PROPEL 3 ClinicalTrials.gov number, NCT06164951; EudraCT number, 2023-506130-67.).