Valérie Cormier-Daire

Background: Hypochondroplasia is a skeletal dysplasia characterized by disproportionate short stature that is caused by gain-of-function variants in the fibroblast growth factor receptor 3 gene ( FGFR3 ), which negatively regulates endochondral bone growth. Current treatments are based on symptom management; there are no treatments targeting the signaling pathways that underlie hypochondroplasia. Vosoritide, a C-type natriuretic peptide analog that counteracts overactive FGFR3 signaling to stimulate endochondral bone growth, is approved for the treatment of achondroplasia in children. A phase 1/2 clinical trial demonstrated that vosoritide treatment for 1 year increased growth in children with hypochondroplasia and was well-tolerated. Objectives: The objectives of CANOPY HCH-3 are to evaluate the efficacy and safety of vosoritide for the treatment of hypochondroplasia in children. Design: CANOPY HCH-3 was a phase 3, randomized, double-blind, placebo-controlled, multicenter study. Methods and Analysis: Children aged ≥3 to <18 years with confirmed hypochondroplasia who had ≥6 months of pre-treatment standing height from a prior observational study before randomization were enrolled. Participants were randomized to receive 52 weeks of daily treatment with vosoritide or placebo, followed by 2 weeks of safety follow-up. The primary endpoint is change from baseline in annualized growth velocity at week 52 versus placebo. Ethics: CANOPY HCH-3 was conducted in accordance with the Council for International Organizations of Medical Sciences International Ethical Guidelines, the principles of the Declaration of Helsinki and of Good Clinical Practice, and applicable laws and regulations. Protocols were approved by relevant local health authorities, ethics committees, and institutions. Written informed consent from the participant, or parent or legal guardian, was obtained prior to any study-related procedures being performed. Discussion: CANOPY HCH-3 will provide further evidence for the efficacy and safety of vosoritide in children with hypochondroplasia.

Hypochondroplasia is a skeletal dysplasia caused by pathogenic variants in FGFR3 and characterized by disproportionate short stature and relative macrocephaly. Diagnostic uncertainty remains common, particularly in early childhood and in individuals with mild or atypical presentations, leading to delayed diagnosis, inconsistent management, and challenges in counselling and care planning. Individuals can be affected by medical complications and psychosocial consequences and have unmet needs for multidisciplinary care. To address these unmet needs, an international, multidisciplinary panel of experts and patient representatives convened to develop consensus-based diagnostic recommendations using a modified two-stage Delphi approach, with a predefined consensus threshold of 70% of respondents rating statements ≥70 (on a scale of 0 to 100). The panel integrated clinical, anthropometric, radiographic, neuroimaging and genetic criteria to define diagnostic categories that can be applied across diverse health-care settings globally. Major and minor diagnostic criteria are proposed, alongside guidance on the appropriate use of molecular testing, radiographic evaluation and brain magnetic resonance imaging. These recommendations provide a practical framework to help standardize timely and accurate diagnosis of hypochondroplasia in clinical practice and research.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic bone disorder associated with considerable clinical, economic, and societal impacts on patients, their caregivers, and the healthcare system. The aim of this study was to update the estimated prevalence of FOP in France, characterize the FOP patient population and impact of the disease, assess associated mortality rates, and quantify healthcare resource utilization and socioeconomic costs for individuals with FOP. An observational, retrospective case-control study was conducted using linked data for individuals with FOP from the French National Rare Diseases Registry and the French National Healthcare System Database (SNDS). Results were compared with the SNDS for a control group of individuals with any disease other than FOP. Prevalence of FOP was estimated at 1.39 per million. Data were available for 77 individuals with FOP and 769 controls without FOP. Of 70 individuals with FOP and a social security number at the index date, 50.0% (n = 35/70) were female, and the mean (SD) age was 25.3 (15.7) yr. Comorbidities were consistently more prevalent in individuals with FOP than in people without FOP. Consultations with general practitioners and non-physician healthcare providers, hospitalizations, and use of medical devices and treatments were significantly greater in individuals with vs without FOP (p < .05 for all). Mean total annual healthcare expenditure was more than 10 times greater in individuals with FOP than those without FOP from a societal perspective (largely driven by outpatient costs) and 14 times greater from a payer perspective. Overall survival was significantly worse in individuals with FOP than in individuals without (p < .0001). Findings from this study reinforce the clinical, economic, and societal impacts associated with FOP. Improving disease awareness and developing new interventions to support a reduction in these impacts should be considered key priorities for the FOP community and healthcare providers.

Multiple epiphyseal dysplasia (MED) is a genetically diverse skeletal disorder characterized by abnormal and delayed epiphyseal ossification, early-onset osteoarthritis, joint pain and mild short stature. MED is primarily caused by pathogenic variants in genes involved in cartilage and bone development, including COMP, MATN, COL9A1-3, CANT1 and SLC26A2. FGFR1 was suggested as a cause of MED in a study published in 2020, which reported a frameshift variant in the last exon of this gene. We assembled an international cohort of 13 individuals with MED carrying C-terminal frameshift variants in FGFR1 (NM_023110.3: c.2424_2425del, c.2436_2440del, and c.2460dup). In all three families, the frameshift variants are predicted to result in the same 164-amino acid C-terminal elongation tail. The cohort includes two families (three affected individuals in one, nine in the other) and one previously reported individual. All affected individuals presented with MED without vertebral involvement. Age of symptom onset ranged from 3 to 13 years, with complete penetrance. Genu valgum was very frequent, and most affected patients required its surgical correction. Hypogonadotropic hypogonadism was present in approximately half of the cases. Adult height was mildly reduced, with an median of 164.0 cm in males (-1.7 SDS) and 153.1 cm in females (-1.6 SDS). Structural modeling for the novel C-terminal stretch as a result of the variants could acquire secondary structures, including an α-helix and a β-sheet domain, and could bring a potential antimorphic effect. Our findings confirm FGFR1 C-terminal frameshift variants as a cause of MED and provide further clinical characterization of this disorder.

Enamel–renal syndrome is a rare inherited disorder caused by mutations in FAM20A, characterized by severe dental defects and ectopic mineralization across multiple tissues. Although FAM20A is essential for mineralized tissue development, how its loss disrupts alveolar bone formation remains unclear. Here, we combined clinical, radiographic and patient-derived cell analyses to define the craniofacial and cellular consequences of FAM20A deficiency in a patient with a confirmed FAM20A mutation. Clinical and imaging evaluations revealed severe dental abnormalities and persistent impairment of craniofacial growth during adolescence. Patient-derived alveolar bone cells showed disrupted cellular organization, reduced proliferative capacity and defective osteogenic differentiation. These abnormalities were accompanied by reduced Wnt signaling activity, a central regulator of bone formation. Pharmacological activation of Wnt signaling partially restored osteogenic potential in patient-derived cells, supporting Wnt pathway dysfunction as a targetable mechanism. Together, our findings link FAM20A deficiency to impaired Wnt-dependent osteogenic signaling and provide mechanistic insight into alveolar bone pathology in enamel–renal syndrome.

Myhre syndrome is a rare genetic disorder caused by pathogenic variants in SMAD4 . The neurocognitive profile may include intellectual disability and developmental delay across a wide spectrum of domains. Four individuals with Myhre syndrome and psychosis and/or schizophrenia have been reported. We discuss three additional individuals (one briefly mentioned in a review of patients with Myhre syndrome) with SMAD4 pathogenic variants at codon Arg496Cys (two cases) and codon Ile500Val (one case). All had social challenges and variable developmental delays. They presented with acute‐onset psychosis and were diagnosed with either psychosis, not otherwise specified, or psychosis associated with bipolar disorder. The seven individuals (5 female, 2 male) ranged in age from 13 to 24 years (mean 18.7 years) and had variable responses to pharmacologic and behavioral interventions. The underlying mechanism of psychosis in Myhre syndrome may be due to disruptions in the TGF‐β signaling pathway, which involves the interactions of TGF‐β family members and SMAD proteins, including SMAD4. Although additional cases are needed to verify our observations, psychosis may be a component of the neurodevelopmental phenotype of Myhre syndrome, highlighting the importance of rapid psychiatric evaluation and intervention.

Myhre syndrome (MS) is a connective‐tissue disorder within the acromelic dysplasia spectrum. It is characterized by congenital craniofacial, skeletal, cutaneous anomalies, respiratory, cardiovascular along with intellectual disability, deafness, and progressive fibrosis. MS is caused by germline variants in the transcriptional co‐regulator SMAD4 (mothers against DPP homolog 4). SMAD4 is a key intracellular mediator of signal transduction and participates in several pathways, notably canonical TGFβ and BMP signaling. These pathways play central roles in developmental and homeostatic processes. As the number of reported MS cases continues to grow, clarifying its pathophysiology is becoming increasingly important. Current evidence suggests that dysregulation of TGFβ/BMP signaling contributes to extracellular matrix (ECM) disorganization and fibrosis in MS, a relationship that remains under active investigation. Here, we review the literature and summarize current knowledge on the clinical features and pathogenic mechanisms of MS. We also discuss emerging biological roles of molecular actors that appear to be compromised, and outline therapeutic strategies that may lead to promising interventions to improve patients' quality of life.

Recent advances in sequencing technologies have enhanced patient diagnosis; however, causal pathogenic variants remain unidentified for a significant numbe

Rare bone disease referral centers (RBDCs) were established to improve the diagnosis and management of rare diseases. The objective of this retrospective observational study was to characterize real-life care pathways of patients with osteogenesis imperfecta (OI) in the Paris region. Patient data were extracted from the Assistance Publique-Hôpitaux de Paris (AP-HP) health data warehouse (Entrepôt de Données de Santé). Patients were identified using the ICD-10 code for OI (Q78.0) and keyword searches. Inclusion criteria were age ≥15 yr and at least one hospital visit between January 1, 2016 and March 1, 2021. After exclusion of unconfirmed diagnoses and patients younger than 15 yr, 472 patients with OI were included (mean age 39.5 ± 16.2 yr; 64.6% women). Of these patients, 78% (N = 368) were cared for in one of Paris RBDC, the majority in a single center (76% (N = 280)), while 104 patients (22%) were not seen within RBDCs in AP-HP data. The most frequent specialties involved were rheumatology (74.9%, N = 326), orthopedics (17.6%, N = 76), and otorhinolaryngology (12.9%, N = 56). The proportion of patients seen in rheumatology increased after the transition age of 25 yr (81.8% before vs 90% after, p = .04), whereas consultations in orthopedics and genetics decreased (29.5% vs 17.8%, p = .02, and 22.7% vs 6.8%, p < .0001, respectively). Orthopedic surgery during follow-up was performed in 6.2% of patients followed in RBDCs and 8.6% of those not seen within RBDCs. Although 78% (N = 368) of patients with OI in the Paris region were followed within RBDCs, nearly one quarter were not (22%), suggesting persistent gaps in access to specialized care. These findings provide a real-life description of hospital-based care pathways for OI but do not allow assessment of the effectiveness of the referral center model.