Early closure of cranial base synchondroses in infants with Vosoritide-treated achondroplasia

Highlights

● Early SOS closure was observed in infants with achondroplasia.

● Closure sequence was reversed from the typical developmental pattern.

● Early vosoritide treatment did not normalize the closure sequence.

Introduction

Vosoritide, a C-type natriuretic peptide analog that promotes endochondral ossification by downregulating FGFR3 signaling, was approved in 2021 as the first disease-modifying therapy for achondroplasia (ACH) (1). In children aged 3–59 mo with ACH, treatment with vosoritide, versus placebo, improved height velocity as well as facial and paranasal sinus volumes (2). In Japan and Australia, its use from birth has been permitted (1); in addition to improving linear growth, a preventive effect on foramen magnum stenosis (FMS), a life-threatening complication in infancy, has been anticipated (3). Because FMS develops and progresses predominantly during infancy (2), the early initiation of disease-modifying therapy is considered particularly important. Moreover, given that vosoritide suppresses excessive FGFR3 signaling, treatment starting in early infancy or the neonatal period may mitigate the premature closure of cranial base synchondroses, thereby preventing or attenuating FMS development (4). However, evidence in humans of the effects of early vosoritide treatment of cranial base synchondrosis closure timing and sequence and FMS severity remains limited.

In ACH, gain-of-function variants in FGFR3 impair endochondral ossification, resulting in disproportionately short stature and characteristic craniofacial features. Growth at the cranial base depends on multiple synchondroses, including the spheno-occipital synchondrosis (SOS), anterior intraoccipital synchondrosis (AIOS), and posterior intraoccipital synchondrosis (PIOS) (5). Premature closure of these synchondroses is believed to contribute to cranial base hypoplasia and subsequent FMS (6), a major cause of morbidity and mortality in infancy. Among them, the SOS plays a pivotal role in postnatal cranial base and facial growth and is normally the last synchondrosis to close, typically remaining open until late childhood or adolescence, whereas the PIOS and AIOS close much earlier (4). However, whether this physiological closure sequence is preserved or altered in infants with ACH, particularly during early vosoritide treatment, remains unclear. Premature closure of the SOS, which normally closes last, in early infancy could indicate a fundamental disruption of cranial base growth and contribute critically to FMS development.

Patients and Methods

Study design and patients

This single-center retrospective observational study was conducted at Nihon University Itabashi Hospital. It included infants who were genetically diagnosed with ACH, who had initiated vosoritide treatment at 1–3 mo of age in 2021–2025, and were continuously followed at our institution.

Assessment of FMS severity

FMS severity was evaluated using the Achondroplasia Foramen Magnum Score (AFMS) based on the magnetic resonance imaging (MRI) findings (7). The AFMS classifies findings into five grades (0–4) according to degree of stenosis and spinal cord compression. An AFMS ≥ 3 was considered clinically severe, and the indication for foramen magnum decompression was determined based on comprehensive neurological and imaging assessments.

Assessment of cranial base synchondroses

CT imaging was performed to evaluate cranial base synchondroses as part of the clinical assessment of cranial base development in infants with ACH treated with vosoritide. Because of concerns regarding radiation exposure, serial CT examinations were not routinely performed. Therefore, only the earliest available CT study was used for synchondrosis evaluation in this study. The AIOS, PIOS, and SOS were assessed and classified as “open,” “partially closed,” or “completely closed” based on the presence or absence of low-density cartilage across the entire synchondrosis. The closure sequence was inferred from each patient’s age and closure degree at imaging.

Outcome measures

The primary outcomes were cranial base synchondrosis closure status and sequence during infancy. The secondary outcomes included the clinical course of FMS and need for foramen magnum decompression.

Ethics Statement

This retrospective study was approved by the Institutional Review Board of Nihon University Itabashi Hospital (approval no. RK-260414-5). Because of the retrospective study design, informed consent was obtained using an opt-out procedure in accordance with institutional guidelines. Outside the submitted work, Ichiro Morioka and Nobuhiko Nagano have received lecture fees from BioMarin Pharmaceutical Japan K.K.

Results

Patient characteristics

Five patients (two boys, three girls) carrying the heterozygous FGFR3 p.Gly380Arg variants were included (Table 1). The age at the last follow-up ranged from 1 yr, 1 mo to 3 yr, 10 mo. Vosoritide was initiated at 1–3 mo of age, and the treatment duration ranged from 11 mo to 2 yr, 10 mo. One patient experienced an approximate 1-yr treatment interruption. All patients underwent periodic MRI for the FMS assessment and CT for the cranial base synchondrosis evaluations.

Table 1. Clinical characteristics, treatment course, and imaging findings of infants with achondroplasia treated early with vosoritide.

Status of cranial base synchondroses

The cranial base synchondrosis closure status and timing for each patient are summarized in Table 1 and Supplementary Table 1; representative CT images are shown in Fig. 1. The CT scans were performed at ages ranging from 2 mo to 1 yr, 4 mo. In all patients, the SOS was completely closed in early infancy, with the earliest confirmed closure occurring at 2 mo of age. The AIOS remained open in four patients and partially closed in the patient with the treatment interruption. The PIOS partially closed in two younger infants and completely closed in the remaining three patients.

Fig. 1.

Representative computed tomography (CT) findings of cranial base synchondroses in infants with achondroplasia. Representative CT images showing cranial base synchondrosis closure status. (A) Case 5: 1 yr of age, showing complete closure of the spheno-occipital synchondrosis (SOS). (B) Case 5: 1 yr of age, showing complete closure of the posterior intraoccipital synchondrosis (PIOS) and an open anterior intraoccipital synchondrosis (AIOS). (C) Case 1: 3 yr of age, showing partial closure of the AIOS. (D) Case 2: 3 yr of age, showing partial closure of the PIOS. The arrows indicate open synchondroses, arrowheads indicate partial closure, and dashed circles indicate complete closure.

When the patients were arranged by age at CT, the inferred sequence of closure in ACH was SOS → PIOS → AIOS, a disruption of the normal developmental sequence (PIOS → AIOS → SOS).

FMS severity and surgical treatment

The longitudinal changes in AFMS are shown in Supplementary Table 2. Based on the MRI findings, three of the five patients progressed to AFMS grade 3 or 4 during follow-up and underwent foramen magnum decompression at ages 8 mo to 1 yr, 6 mo. In the remaining two patients, the AFMS remained at ≤ 1; thus, surgical intervention was not required.

Discussion

This study provided a longitudinal imaging assessment of cranial base synchondroses in infants with heterozygous ACH treated with early vosoritide. Its principal finding was that the SOS, which normally represents the last synchondrosis to close during cranial base development, was completely closed in all cases at the earliest available imaging time point. Physiological studies indicate that PIOS typically becomes partially fused around 1.5–2 yr of age and fully fuses by approximately 4 yr, followed by AIOS, which partially fuses by approximately 4 yr and completely fuses by approximately 10 yr. In contrast, the SOS remains open much longer, partially fusing around 9 yr and completely fusing as late as approximately 17 yr (4). Therefore, our findings indicate not merely premature closure but rather a striking disruption of the normal sequence of synchondrosis closure in ACH, with the SOS closing first (SOS → PIOS → AIOS). Notably, in some cases, the SOS completely closed as early as 2 mo of age, representing an extreme deviation from the normal developmental timeline. This inversion of the closure sequence strongly suggests that cranial base growth in the ACH is fundamentally altered from a very early stage, likely during fetal life. Despite early vosoritide treatment, this abnormal pattern did not normalize, indicating that the intrinsic disturbance of endochondral ossification driven by FGFR3 signaling may be established before or shortly after birth. This inversion of the closure sequence may represent a key imaging hallmark of early cranial base dysregulation in ACH.

Human data on SOS closure timing in patients with untreated ACH are extremely limited. Recent imaging studies have demonstrated premature fusion of cranial base synchondroses in children with ACH, supporting the concept that abnormal synchondrosis biology contributes to cranial base hypoplasia and FMS. For example, Ando et al. reported accelerated fusion of the SOS, AIOS, and PIOS in ACH compared with age-matched controls (8). However, longitudinal imaging data specifically evaluating the timing and sequence of synchondrosis closure during infancy remain limited. In particular, little is known regarding the earliest timing of SOS closure or whether the physiological closure sequence is altered in infants treated with vosoritide. In this context, the present study provides novel observations at different ages demonstrating that the SOS may already be completely fused in early infancy and that the closure sequence appears reversed (SOS → PIOS → AIOS). These findings underscore the need for larger cohorts and longitudinal studies to better clarify the treatment-related effects on cranial base development. Given that vosoritide is administered postnatally, it may be unable to reverse developmental changes that were established in utero, highlighting a potential “window of opportunity” for disease-modifying interventions.

Importantly, despite early SOS closure, some patients (Cases 1 and 5) remained clinically mild with an AFMS ≤ 1. This finding suggests that SOS closure alone does not determine FMS severity. The morphology of the foramen magnum is influenced by multiple synchondroses, including the AIOS and PIOS, and abnormal closure patterns may contribute to disease severity. Moreover, vosoritide reportedly induces various morphological changes, including improvements in long bone growth (9, 10), craniofacial structures and the foramen magnum area (2), and spinal and lower limb alignment (10). Therefore, even if treatment cannot reverse synchondrotic closure, it may still modify the growth environment within the limited anatomical spaces and potentially mitigate FMS severity. Although vosoritide may influence skeletal growth in ACH, the present findings suggest that early treatment does not necessarily normalize the sequence of cranial base synchondrosis closure or prevent the development of clinically significant FMS. These observations support the possibility that at least some aspects of cranial base dysplasia may originate prenatally, before initiation of postnatal therapy. Taken together, these findings support a multifactorial model of FMS.

The only patient who showed partial AIOS closure was the one (Case 1) who experienced an approximately 1-yr interruption of treatment. Although treatment discontinuation may have contributed to progression of synchondrosis closure, causal inference is not possible in this small cohort. Alternatively, closure progression despite treatment interruption may reflect the strong intrinsic effect of FGFR3 signaling on cranial base development. Notably, despite complete SOS and PIOS closure and partial AIOS closure, this patient remained clinically mild and did not require decompression, further supporting the multifactorial nature of FMS.

Despite treatment initiation during early infancy (1–3 mo of age), three of the five patients in our cohort ultimately required foramen magnum decompression. These findings suggest that early vosoritide treatment may be insufficient to fully prevent craniovertebral junction pathology once the developmental processes leading to cranial base abnormalities have already been established. Further longitudinal studies with larger cohorts will be required to clarify the extent to which vosoritide influences cranial base development and the risk of FMS.

Limitations

This study had several limitations. First, the sample size was small (n = 5), and the study was retrospective and single-center. Second, repeat CT examinations are limited because of radiation exposure, making it difficult to determine the exact timing of synchondrosis closure. Third, as the SOS was already closed at the earliest imaging time point, prenatal closure could not be excluded. Fourth, a direct comparison with an untreated control group was not feasible, and because human data on SOS closure timing in untreated heterozygous ACH cases are scarce, the effect of vosoritide on synchondrosis closure timing could not be quantitatively determined. Finally, quantitative measurements such as those of the foramen magnum area were not performed and should be addressed in future studies.

Conclusion

In infants with ACH, the sequence of cranial base synchondrosis closure is fundamentally altered, with the SOS normally closing last instead of first in early infancy. This marked inversion of the physiological closure sequence suggests a profound disruption of the cranial base development that likely begins in fetal life. Despite the early initiation of vosoritide, this abnormal pattern was not normalized, indicating that the pathogenesis of FMS is multifactorial and may not be fully prevented by postnatal treatment alone. Further longitudinal and quantitative imaging studies are required to clarify optimal strategies for early intervention.

Conflict of interests

The authors have nothing to declare.

Funding Statement

This work was supported by a research grant from Nihon University.