First of all, the experts carried out a narrative review with the aim of compiling current guidelines and consensus documents on achondroplasia, and studies on the efficacy, safety or posology of vosoritide. The collected publications provided the necessary background to develop a preliminary report that included the main recommendations extracted from the literature.

Then, the experts held two meetings to reach a consensus regarding the recommendations found in the literature and their adaptation to the particular circumstances of Spain. These meetings were organised as round tables in which all experts presented their opinions, experiences and knowledge on the subject. A qualitative consensus was reached through structured and targeted questions on the recommendations proposed in the in the preliminary report.

The complexity of the disease and of its treatment clearly call for a coordinated and specialised multidisciplinary management approach (Table 1 presents the timeline for the routine follow-up of patients with achondroplasia, adapted by Leiva-Gea et al.20) that is not always implemented. Therefore, the introduction of vosoritide offers an opportunity to initiate adequate and comprehensive follow-up in these patients. This approach allows safer delivery of treatment and rigorous assessment of its outcomes. In addition, it can improve patient care as well as patient’s autonomy and adherence to treatment.8 Thus, this protocol is intended for multidisciplinary care teams with experience in achondroplasia, ideally located in a reference centre for skeletal dysplasias.1 The care team must have a main coordinator responsible for ensuring uniform care delivery and facilitate communication between team members. Care coordinators must have proven experience in the management of achondroplasia, independently of the field in which they are specialised.1,8,23 Ideally, the multidisciplinary care team would include a specialist in medical genetics and/or a paediatric endocrinologist and/or a paediatrician expert in skeletal dysplasias in addition to specialists in the fields of paediatric neurology, neurosurgery, paediatric pulmonology, otorhinolaryngology, paediatric orthopaedics and traumatology and rehabilitation. Other specialists involved in the care of these patients include anaesthesiologists, psychologists and social workers.24 It is important that patients as well as caregivers receive psychological support from the outset and throughout follow-up. In addition, involvement of a nurse case manager is recommended to provide continuous support the family and schedule the required appointments and tests. The case manager would also be responsible for ensuring continuity of care and assist the transition from paediatric to adult care. All these specialists must have clinical experience in the management of achondroplasia and the existing resources for supporting patients and families.24,25

Vosoritide is a C-type natriuretic peptide analogue indicated for use in patients with genetically confirmed achondroplasia from age 4 months25 (the indication has been authorised by the European Medicines Agency [EMA], and treatment in Spain is funded by the public health system26,27) and that can be administered until growth plates close and the growth velocity is less than 1.5 cm/year.

It is administered subcutaneously once a day. The currently available preparations are all in vials (vosoritide 0.4 mg, 0.56 mg and 12 mg powder) accompanied by a glass syringe prefilled with water for its reconstitution.25 The customary dose is of 15–30 μg/kg body weight,15 although it may vary based on the volume of distribution of the drug in relation to the weight.

Appendix B presents the recommendations regarding the presentation, injection and storage of the drug in greater detail.

Before starting vosoritide, the multidisciplinary care team should provide the necessary information to both patients and their caregivers so that they can make informed decisions about treatment. It may also be useful to have a separate conversation with the patient, adapting the language as appropriate, to establish the child’s views and understanding.24 During these conversations, it is important to discuss the motivation of the patient and caregivers for undertaking treatment with vosoritide,28 eligibility criteria, the timeframe and accepted measures of treatment response and the safety of treatment. Providers should also emphasise that vosoritide is an elective treatment and that its discontinuation would not harm the patient.24 It is important to allow sufficient time to patients and caregivers to process this information and make any relevant questions. Another aspect to consider is that patients and caregivers may have received information about vosoritide from various sources that may have elicited confusion or concern. These issues should also be addressed.24

Regarding treatment response, providers should inform that vosoritide increases linear growth (average of 1.57 cm/year, greater in male than in female patients: 1.98 vs 1.55 cm/year), and that this increase in final height may have functionally beneficial consequences.16,29 They should also clarify that the response to vosoritide may vary between patients, and that various factors may have an impact on height gain.29 Furthermore, they ought to explain that the response to treatment cannot be assessed immediately and requires repeated anthropometric evaluations for a minimum of 1–2 years after treatment initiation.16,24,29 It can be helpful to show patients specific achondroplasia growth curves so that they can discern the beneficial effect of treatment. Providers must explain that, at present, there is no evidence that vosoritide improves other areas other than linear growth,24 although it is associated with an improving trend in the disproportion between the upper and lower body segments.24,30 In terms of safety, providers must explain the type of adverse events observed in clinical trials and warn of the potential occurrence of serious adverse events that, while infrequent, have been reported in other studies.15,17,30

During the initial visit, the coordinator will reinforce previous guidance regarding treatment expectations and provide information to the patient and caregivers on the procedure to be performed or education on how to administer the drug. Training for subcutaneous administration of vosoritide consists of a practical workshop adapted to the psychosocial characteristics of the patient and caregivers.

In this visit, the coordinator will also carry out a comprehensive assessment of the patient, including history-taking, verification of eligibility criteria for vosoritide and additional recommended examinations and diagnostic tests, which are detailed in Table 2. This is also the time to check whether the follow-up of the patient to date has adhered to current guidelines (Table 1).

Treatment initiation (day 0) can take place on the day of the initial visit to the coordinator or on a different day, depending on the protocols of each facility.

Prior to vosoritide administration, the nurse case manager will educate caregivers on how to prepare and inject the drug (see instructions in Appendix B). The case manager should also propose downloading the myVOXZOGO app, which allows both health care providers and caregivers to monitor adherence. This app includes information on achondroplasia and the use of vosoritide.

The nurse will record the patient's vital signs before administering the drug and 1 h after, watch for local reactions and symptoms of hypotension, and inform caregivers about possible adverse events and how to act if they occur. Hospital contact details will also be provided for reporting of any adverse events. To ensure that caregivers have become competent in the injection of the drug, they can visit the hospital two or three more days to administer the drug under supervision.

In this and all other visits, the hospital pharmacy staff will dispense the medication. In this regard, is essential that caregivers have a portable fridge or cooler to transport the medication without breaking the cold chain.

We recommend scheduling a first remote visit a week or a month after treatment initiation, depending on the needs of the patient and the protocols of the centre. In this appointment, the nurse case manager will make an assessment to ensure that treatment is going well. The nurse will address any concerns that may have arisen for the patient and caregivers and monitor adherence and adverse events.

During the first year of treatment, patients will have visits every 3 months. At these visits, the specialist in charge of follow-up will perform a checkup and collect anthropometric measurements standardised using as reference the Neumeyer adapted growth charts for patients with achondroplasia.31,32 Changes in growth velocity and safety aspects should be rigorously monitored, and adherence and difficulties with injection technique also be considered, especially in the youngest patients.

After the first year, visits should be scheduled every 6 months. In these visits, the specialist will check whether the patient meets the growth velocity criterion and determine whether treatment should continue or not. Specifically, treatment should be discontinued if the growth velocity is less than 1.5 cm/year and/epiphyseal closure has taken place. These are indicators that the patient has no further growth potential.25

Table 3 summarises the assessments and tests performed at treatment initiation and during follow-up and their frequency. Table 4 presents the main assessments performed by the different specialists involved in the management of achondroplasia.

There is currently no consensus on the performance of annual radiographs to assess bone age throughout the follow-up. Moreover, there are limitations to their interpretation, as the available reference that is used (the Greulich and Pyle atlas) does not include subjects with achondroplasia, so the natural history in these patients is unknown. However, there is the possibility of conducting these assessments on a regular basis for research purposes, even if they do not have a direct impact on clinical decision-making.

In short, this consensus expert was motivated by the urgent need of developing a protocol for the management of achondroplasia after the introduction of a novel treatment, vosoritide, authorised in 202133 and funded by the Spanish public health system for patients starting from age 4 months.27 Thus, this is one of the first protocols, to our knowledge, developed in this new context.24,34

In addition, it addresses the need to establish optimised and standardised criteria to monitor treatment and assess outcomes of vosoritide therapy in clinical practice. This is crucial, as there are limitations to the evidence from clinical trials at the present time: followup duration of less than 10 years or lack of data on response-dependent variables.13,15–17,24,30 In addition, there is no knowledge of the potential impact of vosoritide on non-anthropometric outcomes or whether tachyphylaxis can develop in the long term.

Broadly speaking, this protocol stresses the importance of managing achondroplasia with a specialised and multidisciplinary approach, in line with the current international consensus.1,8,18 The management of achondroplasia should involve coordinated care delivery by specialists in different fields (medical genetics, paediatric endocrinology and/or paediatrics as well as paediatric neurology, paediatric pulmonology, neurosurgery, otorhinolaryngology, rehabilitation and orthopaedics, among others) taking into account recently published practical considerations for the use of vosoritide.1,8,18,24 In agreement with the current international consensus, this consensus document highlights the importance of patient and caregiver education by the multidisciplinary care team, with particular emphasis on discussing expectations regarding the effects of vosoritide and practical aspects of vosoritide administration and treatment monitoring. This was also emphasised in the article published recently by Semler et al.24

The initial assessment and follow-up of the patient must be comprehensive and requires a coordinated multidisciplinary care team. It must include an anthropometric evaluation, biochemical and functional tests and assessments of patient-reported variables. It also requires very close monitoring, with a higher frequency of visits and assessments in the first year of treatment, as specified in the international consensus.1 Follow-up must continue until the end of treatment.

In addition to the implementation of these recommendations, there are several initiatives that could advance our understanding of achondroplasia and of the impact of vosoritide on this disease. These include the establishment of registers for standardised collection of data on outcome variables, as well as the promotion of biomedical research with the creation and establishment of achondroplasia-specific biobanks for markers of bone metabolism in blood or urine specimens collected during followup.