Complicated Spinal Stenosis and Spinal Deformity in Patients with Achondroplasia: Case Series and Review of the Literature.

OBJECTIVE: Due to the low incidence of achondroplasia (Ach), there is a relative lack of research on the treatment and management of spinal complications of Ach. Characteristics and interventions for spinal complications in patients with Ach are in urgent need of investigation. This study aimed to summarize the common spinal complications in patients with Ach and the corresponding treatment strategies. METHODS: This study is a retrospective case series. We retrospectively collected and analyzed Ach cases who presented to our hospital with neurological symptoms due to skeletal anomalies between February 2003 and October 2023. A total of seven patients were included, four males (57.1%) and three females (42.9%) with a mean age of 38.57 years. Patient pain/numbness visual analog scale (VAS), preoperative Oswestry disability index (ODI), development of neurological complaints, and presentation of skeletal abnormalities were collected and followed up routinely at 3, 6, 12 and 24 months postoperatively. The relevant literature was reviewed. RESULTS: Seven patients were included in this series. The mean preoperative VAS was 4, and the mean preoperative ODI was 50.98%. All patients had concomitant spinal stenosis, four with thoracolumbar kyphosis (TLK), and one with scoliosis. Six of the seven patients underwent surgery, and one patient received conservative treatment. In the routine follow-ups, all patients experienced satisfactory relief of symptoms. Only one of the seven patients developed a new rare lesion adjacent to the primary segments. Six months after the first surgery, a follow-up visit revealed thoracic spinal stenosis caused by ossification of the ligamentum flavum, and his symptoms were relieved after thoracic decompression surgery. CONCLUSIONS: Ach seriously affects the skeletal development of patients and can lead to the development of spinal stenosis, spinal deformities, and other complications of the locomotor system. Surgery remains the primary treatment for complications of the musculoskeletal system. Specific surgical approaches and comprehensive, long-term management are critical to the treatment of patients with spinal complications.

Patients with achondroplasia have increased risk of 90-day adverse events following laminectomy: A matched comparison using a national database.

PURPOSE: Performing laminectomies in patients with achondroplasia-a common skeletal dysplasia-can present unique challenges. There are a limited number of studies that have reported on the adverse effects of laminectomies in patients with achondroplasia. To compare the 90-day postoperative adverse events following laminectomy in patients with and without achondroplasia. METHODS: Retrospective cohort study using the 2010-2020 PearlDiver Mariner 91 administrative database was used to identify patients who underwent thoracic, thoracolumbar, or lumbar laminectomy. Patients with achondroplasia were matched 1:4 to patients without achondroplasia based on age, sex, insurance, and ECI. Univariate and multivariate logistic regression analyses assessed and compared 90-day adverse events. Odds ratios (OR), 95% confidence intervals (CI), and p-values were reported with significance set at p < 0.05. RESULTS: A multivariate analysis revealed that when laminectomy was performed, patients with achondroplasia were 2.82 times more likely to have 90-day AE compared to those without achondroplasia (p < 0.001). When comparing individual subtypes of adverse events, patients with achondroplasia were found to have significantly greater odds of a transfusion (OR 6.40, p < 0.001), UTI (OR 3.79, p < 0.001), disruption of wound (OR 3.71, p < 0.001), and hematoma (OR 2.94, p = 0.032). Pneumonia, cardiac arrest, AKI, other perioperative events, durotomy, and VTE were not significantly different between the two cohorts. CONCLUSION: This study uses one of the largest cohorts to compare patients with and without achondroplasia undergoing laminectomy. Patients with achondroplasia were found to have a significantly greater risk of 90-day adverse events following laminectomy compared to their matched cohort of patients without achondroplasia.

Meeting report from the 3rd ISCBH-ERN BOND Achondroplasia Workshop on Long Bone Pathology in Children with Achondroplasia, Salzburg, Austria 22nd June 2024.

A pre-meeting workshop on Long Bone Pathology in Children with Achondroplasia was held in Salzburg, Austria at the 11th International Conference on Children's Bone Health (ICCBH) 22-25 June 2024. There remains poor understanding and awareness amongst physicians managing achondroplasia of the underlying pathophysiology, radiology, natural history and orthopaedic procedures available for long bone deformities and restrictions. The structure of the workshop consisted of presentation of the results of a multinational patient survey on views of leg lengthening in achondroplasia, lectures, a debate and an interactive round table discussion. In total 150 attendees from 71 different cities and 31 countries were in attendance.

Achondroplasia current concept of orthopaedic management.

Achondroplasia, the most common form of inherited disproportionate short stature, is caused by mutations in the fibroblast growth factor receptor 3 gene. The typical clinical features of achondroplasia include short stature, rhizomelic disproportion, joint hyperlaxity, spinal deformity and deformity of the upper and lower limbs. The latter are among the challenges of state-of-the-art orthopaedic treatment plans and significantly contribute to the burden of the disease in individuals with achondroplasia. Multidisciplinary preoperative individual decision-making concerning surgical interventions should be considered. New medical treatments for achondroplasia have been developed and (some) have been approved for clinical use in several countries. While the number of research articles on achondroplasia is increasing rapidly, many unknown or controversial orthopaedic topics remain. Furthermore, in view of new medical developments with improvements in growth and potentially other effects, the timing and algorithms of orthopaedic treatments (e.g. guided growth, limb lengthening and deformity correction) need to be re-evaluated. While standing height is the primary research focus in medical therapy, it is crucial to comprehensively assess orthopaedic parameters in this multifactorial disease. The current treatment of patients with achondroplasia requires specialised multidisciplinary centres with transitional care and individual orthopaedic counselling.

Achondroplasia: aligning mouse model with human clinical studies shows crucial importance of immediate postnatal start of the therapy.

Achondroplasia is the most common form of human dwarfism caused by mutations in the FGFR3 receptor tyrosine kinase. Current therapy begins at two years of age and improves longitudinal growth but does not address the cranial malformations including midface hypoplasia and foramen magnum stenosis, which lead to significant otolaryngeal and neurologic compromise. A recent clinical trial found partial restoration of cranial defects with therapy starting at 3 months of age, but results are still inconclusive. The benefits of achondroplasia therapy are therefore controversial, increasing skepticism among the medical community and patients. We used a mouse model of achondroplasia to test treatment protocols aligned with human studies. Early postnatal treatment (from day 1) was compared to late postnatal treatment (from day 4, equivalent to ~5 months in humans). Animals were treated with the FGFR3 inhibitor infigratinib and the effect on skeleton was thoroughly examined. We show that premature fusion of the skull base synchondroses occurs immediately after birth and leads to defective cranial development and foramen magnum stenosis in the mouse model to achondroplasia. This phenotype appears significantly restored by early infigratinib administration when compared to late treatment, which provides weak to no rescue. In contrast, the long bone growth is similarly improved by both early and late protocols. We provide clear evidence that immediate postnatal therapy is critical for normalization of skeletal growth in both the cranial base and long bones and the prevention of sequelae associated with achondroplasia. We also describe the limitations of early postnatal therapy, providing a paradigm-shifting argument for the development of prenatal therapy for achondroplasia.

The article provides clear evidence that achondroplasia should be treated immediately after birth, not only to increase height (appendicular growth), but more importantly to prevent defective cranial skeletogenesis and associated severe neurological complications. Although later treatment promotes growth of the long bones (achondroplasia patients grow taller), the defective head skeleton that forms before and/or early after birth cannot be restored if therapy is not started immediately after birth. We also describe the limitations of postnatal treatment and make a strong case for the development of prenatal therapy for achondroplasia, which appears necessary for a comprehensive treatment of this condition.

Reverse Total Shoulder Arthroplasty in an Adult With Achondroplasia.

Background: Achondroplasia can result in many skeletal manifestations, and degenerative osteoarthritis can develop in patients with achondroplasia. Morphologic changes to both the humerus and glenoid-short humeri with patulous metaphyses and a medialized glenoid-can cause challenges that must be overcome to achieve a successful surgical result in a patient with shoulder dysfunction. Because patients with achondroplasia have near-normal life expectancies, the operative shoulder must be functional as well as quite durable in the long term. In an achondroplastic dwarf with shoulder osteoarthritis and rotator cuff insufficiency, achieving functionality and durability requires the use of a reverse total shoulder arthroplasty (TSA). This procedure has its own set of issues, namely, baseplate fixation and correction of glenoid medialization, if present. Case Report: We present the case of an adult with achondroplastic dwarfism with shoulder osteoarthritis and rotator cuff insufficiency and report the 2-year clinical results for this patient after reverse TSA. Conclusion: Reverse TSA is a viable treatment option for adult achondroplastic patients with shoulder dysfunction. Careful preoperative planning is required to ensure a good clinical result in patients with potentially dysplastic anatomy.

Persistent growth-promoting effects of vosoritide in children with achondroplasia are accompanied by improvements in physical and social aspects of health-related quality of life.

PURPOSE: Evaluate the impact of vosoritide on health-related quality of life in children with achondroplasia. METHODS: Participants received vosoritide (15 µg/kg/day) in an extension trial (NCT03424018) after having participated in a placebo-controlled trial (NCT03197766). RESULTS: The population comprised 119 participants (mean [SD] age 9.7 [2.6] years). Mean treatment duration was 4 (0.78) years. At year 3, the largest mean (SD) changes were observed in the QoLISSY physical score (5.99 [19.41], caregiver-reported; 6.32 [20.15], self-reported) and social score (2.85 [8.29] and 6.76 (22.64), respectively). Changes were greatest in participants with ≥1 SD increase in height Z-score (physical: 11.36 [19.51], caregiver-reported [n=38]; 8.48 [21.83], self-reported [n=28]) (social: 5.84 [15.45] and 9.79 [22.80], respectively). To determine how domain scores may change with age in untreated persons, models were produced using observational/untreated-person data. A 1-year increase in age was associated with a change of 0.16 (SE, 0.55) and 0.16 (0.50), for caregiver-reported physical and social domain scores, respectively. Self-reported scores changed by 1.45 (0.71) and 1.92 (0.77), respectively. CONCLUSION: These data suggest that after 3 years of treatment vosoritide demonstrates a positive effect on physical and social functioning among children with achondroplasia, particularly in children with a more pronounced change in height Z-score.

Unusual Histopathological Challenges in Diagnosis of Giant Cell Tumor Cases Treated with Neoadjuvant Denosumab Chemotherapy: A Rare Case Report.

Introduction: Giant cell tumor of bone (GCTB) is a rare yet locally aggressive neoplasm primarily affecting young adults. Its hallmark features include multinucleated osteoclast-type giant cells and mononuclear tumor cells. Treatment with denosumab, an anti-RANK ligand antibody, has shown efficacy, but it alters histomorphology, posing diagnostic challenges. Co-occurrence with achondroplasia, though rare, warrants consideration in bone lesion evaluations. Case Report: A 30-year-old male with achondroplasia presented with a proximal femur GCT, a rare association. Neoadjuvant denosumab was administered due to thin tumor cortex and cortical breech. Surgical excision with bone cement filling and Philo's plate supplementation was performed. Histopathological examination post-treatment revealed the absence of osteoclast-type giant cells, extensive necrosis, hyalinization, and mononuclear infiltrates. Discussion: Denosumab induces a reduction in osteoclast numbers, causing tumor shrinkage and sclerosis, while altering typical GCT histology. Similar findings were noted in the literature, including stromal changes like spindle-shaped cells, inflammation, vascular proliferation, and hemosiderin-laden foamy macrophages. Recognition of these alterations is crucial for accurate diagnosis. Conclusion: GCT, though rare, presents distinct histopathological features aiding diagnosis. Denosumab treatment modifies tumor morphology, necessitating thorough clinical evaluation for accurate diagnosis post-treatment. Understanding, these challenges is essential for optimal management of GCT cases.

Dual diagnosis of achondroplasia and mandibulofacial dysostosis with microcephaly.

BACKGROUND: Achondroplasia and mandibulofacial dysostosis with microcephaly (MFDM) are rare monogenic, dominant disorders, caused by gain-of-function fibroblast growth factor receptor 3 (FGFR3) gene variants and loss-of-function elongation factor Tu GTP binding domain-containing 2 (EFTUD2) gene variants, respectively. The coexistence of two distinct Mendelian disorders in a single individual is uncommon and challenges the traditional paradigm of a single genetic disorder explaining a patient's symptoms, opening new avenues for diagnosis and management. CASE PRESENTATION: We present a case of a female patient initially diagnosed with achondroplasia due to a maternally inherited pathogenic FGFR3 variant. She was referred to our genetic department due to her unusually small head circumference and short stature, which were both significantly below the expected range for achondroplasia. Additional features included distinctive facial characteristics, significant speech delay, conductive hearing loss, and epilepsy. Given the complexity of her phenotype, she was recruited to the DDD (Deciphering Developmental Disorders) study and the 100,000 Genomes project for further investigation. Subsequent identification of a complex EFTUD2 intragenic rearrangement confirmed an additional diagnosis of mandibulofacial dysostosis with microcephaly (MFDM). CONCLUSION: This report presents the first case of a dual molecular diagnosis of achondroplasia and mandibulofacial dysostosis with microcephaly in the same patient. This case underscores the complexity of genetic diagnoses and the potential for coexistence of multiple genetic syndromes in a single patient. This case expands our understanding of the molecular basis of dual Mendelian disorders and highlights the importance of considering the possibility of dual molecular diagnoses in patients with phenotypic features that are not fully accounted for by their primary diagnosis.

International expert opinion on the considerations for combining vosoritide and limb surgery: a modified delphi study.

BACKGROUND: Achondroplasia is the most common form of skeletal disorder with disproportionate short stature. Vosoritide is the first disease-specific, precision pharmacotherapy to increase growth velocity in children with achondroplasia. Limb surgery is a standard approach to increase height and arm span, improve proportionality and functionality, as well as correcting deformities. The aim of this study was to gain expert opinion on the combined use of vosoritide and limb surgery in children and adolescents with achondroplasia. METHODS: An international expert panel of 17 clinicians and orthopaedic surgeons was convened, and a modified Delphi process undertaken. The panel reviewed 120 statements for wording, removed any unnecessary statements, and added any that they felt were missing. There were 26 statements identified as facts that were not included in subsequent rounds of voting. A total of 97 statements were rated on a ten-point scale where 1 was 'Completely disagree' and 10 'Completely agree'. A score of ≥ 7 was identified as agreement, and ≤ 4 as disagreement. All experts who scored a statement ≤ 4 were invited to provide comments. RESULTS: There was 100% agreement with several statements including, "Achieve a target height, arm span or upper limb length to improve daily activities" (mean level of agreement [LoA] 9.47, range 8-10), the "Involvement of a multidisciplinary team in a specialist centre to follow up the patient" (mean LoA 9.67, range 7-10), "Planning a treatment strategy based on age and pubertal stage" (mean LoA 9.60, range 8-10), and "Identification of short- and long-term goals, based on individualised treatment planning" (mean LoA 9.27, range 7-10), among others. The sequence of a combined approach and potential impact on the physes caused disagreement, largely due to a lack of available data. CONCLUSIONS: It is clear from the range of responses that this modified Delphi process is only the beginning of new considerations, now that a medical therapy for achondroplasia is available. Until data on a combined treatment approach are available, sharing expert opinion is a vital way of providing support and guidance to the clinical community.

Bilateral humeral lengthening and deformity correction with hexapod external fixator in an achondroplastic patient: A case report.

INTRODUCTION AND IMPORTANCE: Achondroplasia, a prevalent skeletal dysplasia, often results in limb asymmetry and functional limitations, typically managed surgically with bone lengthening techniques. CASE PRESENTATION: We present the case of a 10-year-old girl with achondroplasia who underwent bilateral humeral lengthening using hexapod external fixators. The patient, previously treated for lower limb lengthening, exhibited significant upper limb shortening affecting daily activities. Surgical intervention involved two stages, employing two hexapod external fixators for precise correction and lengthening. Symmetrical lengthening of 6 cm in both humeri was achieved without major complications. Follow-up assessments revealed improved functionality and satisfactory outcomes, emphasizing the importance of addressing upper limb deformities in achondroplasia patients. CLINICAL DISCUSSION: While humeral lengthening is less common than lower extremity lengthening due to historical concerns about neurovascular complications and functional implications, recent advancements highlight its potential benefits, particularly in achieving functional and aesthetic balance. CONCLUSION: This case highlights the efficacy and safety of hexapod fixators in achieving multiplanar correction and functional improvement in upper limb lengthening. Further investigation should be carried out to study broader application in similar cases.

Challenges in endoscopic third ventriculostomy for patients with achondroplasia: a focus on third ventricle floor anatomy.

OBJECTIVE: Hydrocephalus is one of the neurological risks occurring in patients with achondroplasia. Ventriculoperitoneal shunt (VPS) insertion is the most common treatment. However, reports of successful endoscopic third ventriculostomy (ETV) suggest that ETV may be a good alternative to VPS insertion in achondroplasia. However, it has been stated that ETV in achondroplasia patients is technically demanding to perform. The current study examined the anatomical variations of the third ventricle and the brainstem in achondroplasia patients and correlated the findings with the difficulty of performing ETV. METHODS: A retrospective analysis of 51 patients with achondroplasia and 138 hydrocephalus patients without achondroplasia (48 patients had tumor-related hydrocephalus and 90 patients had hydrocephalus of nontumorous origin) who have visited the authors' institution since 2012 was performed. Preoperative T2-weighted sagittal MR images were used to measure α (steepness of the third ventricle floor), ß (endoscopic angle of incidence), d1 (vertical distance between the dorsum sellae and basilar bifurcation), and d2 (horizontal distance between the dorsum sellae and basilar artery). Each value was compared using the Tukey multicomparison test. RESULTS: Achondroplasia patients showed significantly smaller α (p < 0.001) and ß (p < 0.001) angles, while there were no significant differences between the control groups (p = 0.947 for α, p = 0.836 for ß). The d1 value was significantly larger in achondroplasia patients (p < 0.001), and d2 was smaller (p < 0.001). The control groups showed similar d1 and d2 values (p = 0.415 for d1, p = 0.154 for d2). Smaller α and ß values meant that in achondroplasia patients the third ventricle floor stood more vertically than in other patients with hydrocephalus, and the endoscopic contact angles were small, increasing the risk of ventriculostomy devices slipping down into the infundibular recess. Additionally, a large d1 meant that the basilar artery was shifted upward and a small d2 indicated that the basilar artery was located closer to the dorsum sellae, potentially increasing the risk of basilar artery damage. CONCLUSIONS: Achondroplasia patients' skull and brain anatomies were significantly different from those of other hydrocephalus patients, with steeper third ventricle floors and basilar arteries closer to the dorsum sellae. Because these anatomical differences lead to difficulties in performing ETVs in achondroplasia patients, such differences should be considered when ETV is planned for the patients.

Management and outcomes of foramen magnum stenosis in children with achondroplasia at a single center over 15 years.

OBJECTIVE: Achondroplasia is associated with foramen magnum stenosis (FMS), which can lead to sudden unexpected death in infants. There is no wide consensus regarding the best management of FMS. This study aimed to analyze the prevalence of FMS in a cohort of children with achondroplasia and to evaluate screening and neurosurgical interventions of FMS regarding its effects and complications. METHODS: The authors conducted a retrospective cohort study including all children with achondroplasia assessed or treated at Karolinska University Hospital between September 2005 and June 2020. The severity of FMS was graded using the MRI Achondroplasia Foramen Magnum Score (AFMS). The AFMS was correlated with neurological examinations and polysomnography (PSG) results. RESULTS: Severe FMS (AFMS 3-4) was present in 35% of the 51 children included in the study. As many as 65% of the children in the cohort underwent foramen magnum decompression (FMD). Neurological examination had a high specificity (94%) but a low sensitivity (28%) for severe FMS. Signs of central apnea on PSG did not correlate with severity of FMS (p = 0.735). Surgery improved FMS (p < 0.001) with a nonsignificant trend of decreased central apnea (p = 0.070), but carried a 9% risk of severe surgery- and anesthesia-related complications. CONCLUSIONS: This study confirmed previous reports that severe FMS is common in children with achondroplasia, that neurological symptoms may be absent even in severe FMS, and that FMD improves FMS and may improve central apnea. The finding that neurological examination had a low sensitivity for severe FMS supports the recommendation that all children with achondroplasia should undergo early MRI.

Outcomes of Lower Extremity Total Joint Arthroplasty in Patients With Skeletal Dysplasia: A Systematic Review.

Background: Patients with genetic skeletal dysplasias often require lower extremity total joint arthroplasty (TJA) due to early joint degeneration; however, little data exists regarding the outcomes of TJA in this population. Our purpose was to review the literature to determine the complication rates, revision rates, implant survivorship, and patient-reported outcomes of total knee arthroplasty and total hip arthroplasty (THA) in those with genetic skeletal dysplasias. Methods: A systematic literature review of online databases (PubMed and Google Scholar) was conducted. Studies that reported the outcomes of THA or total knee arthroplasty in patients with genetically confirmed skeletal dysplasias were included. Case reports and studies that defined dysplasia based on height alone were excluded. Fourteen studies met the criteria for data extraction and analysis. Results: Our review yielded a sample of 596 skeletal dysplasia patients with a median follow-up of 6.01 years (1.7-15.9). Mean age was 54.04 years, and mean body mass index was 29.1 kg/m2. Cementless fixation was utilized in 65.7% of THAs, while all knees were cemented. Hip implant survivorship was 79% at 10 years and 56% at 20 years. Knee implant survivorship was 92% at 10 years and 46% at 20 years. Hip and knee revisions were 15.3% and 13.5%, respectively. The most common indication was aseptic loosening and polyethylene wear. Patient-reported outcomes improved across all domains. Conclusions: The literature regarding lower extremity TJA in those with genetic skeletal dysplasias demonstrates appropriate 10-year implant survivorship and improvement in patient-reported outcomes across all survey domains.

SIADH as a Rare Complication of Foramen Magnum Stenosis in an Infant With Achondroplasia.

Achondroplasia is the most common skeletal dysplasia and is associated with serious complications such as foramen magnum stenosis (FMS). This case report describes an infant with achondroplasia who presented with a syndrome of inappropriate antidiuretic hormone secretion (SIADH), secondary to significant FMS and myelocompression. A 2-month-old boy with prenatally diagnosed achondroplasia was referred due to disordered breathing and altered consciousness. On admission, apathy, hypotonus, and hypothermia with typical features of achondroplasia were noticed. Laboratory investigations revealed severe hyponatremia and hypochloridaemia with normal glucose and urea levels. The diagnosis of SIADH was made based on low serum osmolality in the presence of high urine osmolality, along with an elevated copeptin level. An emergency computerized tomography showed a high-grade stenosis at the cranio-cervical junction; subsequent magnetic resonance imaging demonstrated myelocompression. The patient underwent decompression surgery the next day; serum osmolality increased after the operation. Spontaneous breathing after extubation was sufficient whereas tetraplegia persisted despite intensive physiotherapy. Clinicians should be aware of SIADH as a presenting sign of FMS in children with achondroplasia. Further discussion is warranted regarding improving parental education and timing of screening recommendations.

Progress in managing children with achondroplasia.

INTRODUCTION: Achondroplasia is a heritable disorder of the skeleton that affects approximately 300,000 individuals worldwide. Until recently, treatment for this condition has been purely symptomatic. Efficacious treatment options for children are now approved or are in clinical trials. AREAS COVERED: This review discusses key advances in the therapeutic management of children with achondroplasia, including vosoritide, the first approved drug, and other emerging precision therapies. These include navepegritide, a long-acting form of C-type natriuretic peptide, and infigratinib, a tyrosine kinase receptor inhibitor, summarizing trial outcomes to date. EXPERT OPINION: The advent of the first approved precision therapy for achondroplasia in vosoritide has been a paradigm shifting advance for children affected by this condition. In addition to changing their natural growth history, it is hoped that it will decrease their medical complications and enhance functionality. These new treatment options highlight the importance of prompt prenatal identification and subsequent testing of a suspected fetus with achondroplasia and counseling of families. It is hoped that, in the near future, families will have the option to consider a range of effective targeted therapies that best suit their child with achondroplasia, starting from birth should they choose.

The Digital Atlas of Ancient Rare Diseases (DAARD) and its relevance for current research.

BACKGROUND: The history of rare diseases is largely unknown. Research on this topic has focused on individual cases of prominent (historical) individuals and artistic (e.g., iconographic) representations. Medical collections include large numbers of specimens that exhibit signs of rare diseases, but most of them date to relatively recent periods. However, cases of rare diseases detected in mummies and skeletal remains derived from archaeological excavations have also been recorded. Nevertheless, this direct evidence from historical and archaeological contexts is mainly absent from academic discourse and generally not consulted in medical research on rare diseases. RESULTS: This desideratum is addressed by the Digital Atlas of Ancient Rare Diseases (DAARD: https://daard.dainst.org ), which is an open access/open data database and web-based mapping tool that collects evidence of different rare diseases found in skeletons and mummies globally and throughout all historic and prehistoric time periods. This easily searchable database allows queries by diagnosis, the preservation level of human remains, research methodology, place of curation and publications. In this manuscript, the design and functionality of the DAARD are illustrated using examples of achondroplasia and other types of stunted growth. CONCLUSIONS: As an open, collaborative repository for collecting, mapping and querying well-structured medical data on individuals from ancient times, the DAARD opens new avenues of research. Over time, the number of rare diseases will increase through the addition of new cases from varied backgrounds such as museum collections and archaeological excavations. Depending on the research question, phenotypic or genetic information can be retrieved, as well as information on the general occurrence of a rare disease in selected space-time intervals. Furthermore, for individuals diagnosed with a rare disease, this approach can help them to build identity and reveal an aspect of their condition they might not have been aware of. Thus, the DAARD contributes to the understanding of rare diseases from a long-term perspective and adds to the latest medical research.

Consensus Guidelines for the Use of Vosoritide in Children with Achondroplasia in Australia.

BACKGROUND: Achondroplasia, the most prevalent skeletal dysplasia, stems from a functional mutation in the fibroblast growth factor receptor 3 gene, leading to growth impairment. This condition presents multifaceted medical, functional and psychosocial challenges throughout childhood, adolescence and adulthood. Current management strategies aim to minimise medical complications, optimise functional capabilities and provide comprehensive supportive care. Vosoritide (trade name: VOXZOGO®, BioMarin Pharmaceuticals) is the first disease-modifying pharmaceutical treatment approved for the management of patients with achondroplasia and became available in Australia in May 2023. METHODS: Standardised clinical guidelines for its optimal use are not yet widely available. To address this gap, a multidisciplinary Australian Vosoritide Working Group, comprising 12 experts with experience in achondroplasia management from across Australia, developed recommendations to guide the use of vosoritide in clinical practice. RESULTS: The recommendations, which are expert opinions of the Australian Vosoritide Working Group, aim to (i) standardise the use of vosoritide across Australia, (ii) support the safe clinical rollout of vosoritide and (iii) support universal access. CONCLUSIONS: These recommendations have been developed for healthcare professionals and institutions that are engaged in using vosoritide in the management of achondroplasia and will be revised using a formal framework for clinical guideline development once more evidence is available.