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.

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.

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.

Anesthetic dilemmas in an achondroplastic patient undergoing elective cesarean section.

Achondroplasia is a genetic condition characterized by skeletal dysplasia that results in characteristic craniofacial and spinal abnormalities. It is the most common form of short-limbed skeletal dysplasia. Additionally, a pregnant patient who is morbidly obese warrants specific anatomical and physiological considerations, such as a difficult airway with potential hypoxia, full stomach precautions, and a reduced functional residual capacity. Achondroplasia increases the risks of maternal and fetal complications. Although neuraxial techniques are generally preferred for cesarean sections, there is no consensus among patients with achondroplasia. We aimed to discuss the anesthetic challenges in an achondroplastic patient and report our regional anesthesia approach for an elective cesarean section.

Two Cases of Cardiovascular Adverse Events Following Subcutaneous Vosoritide Injection in Early Infancy.

Achondroplasia, characterized by short stature and skeletal abnormalities, is caused by a gain-of-function variant in the fibroblast growth factor receptor 3 gene. Vosoritide, a C-type natriuretic peptide analog, is an emerging treatment for achondroplasia that functions by promoting endochondral ossification. Vosoritide was approved for the treatment of achondroplasia in Europe and the United States in 2021, and in Japan, the following year. However, vosoritide is associated with a risk of hypotension and vomiting after subcutaneous injection due to its vasodilating effect. Herein, we present two cases of cardiovascular adverse events in infants following vosoritide injection. Case 1 involved a one-month-old female infant with achondroplasia who received the first subcutaneous injection of vosoritide 30 minutes after her last formula intake. Following injection, she developed transient symptomatic hypotension accompanied by vomiting. Although established guidelines recommend that injections be administered after approximately 30 minutes (Europe/Japan) or within one hour (USA) following the last feeding, an extended interval of 1.5 to two hours was required to prevent hypotension-associated vomiting. Case 2 involved a three-month-old female infant with achondroplasia. The first subcutaneous vosoritide injection was administered four hours after the last formula intake, and she subsequently developed prolonged compensated shock with marked tachycardia requiring intervention, including repetitive bolus saline injection. These cases indicate the need to monitor patients for cardiovascular adverse events following subcutaneous injection of vosoritide in early infancy.

Review of patients with achondroplasia: a single-center's experience with follow-up and associated morbidities.

Achondroplasia (ACH; MIM #100,800), caused by a heterozygous gain of function pathogenic variant in the fibroblast growth factor receptor 3 gene (FGFR3; MIM*134,934), is the most prevalent and most readily identifiable cause of disproportionate short stature that is compatible with life. In addition, individuals with achondroplasia face significant medical, functional, and psychosocial challenges throughout their lives. This study assessed associated morbidities in patients with achondroplasia at a single center in Turkey. In this study, the clinical findings and associated morbidities of a group of patients with achondroplasia (n = 68) with clinical multidisciplinary follow-up at a single center between the years 2005-2023 are evaluated retrospectively. A total of 68 patients, 30 male (44.1%) and 38 female (55.9%), were evaluated. In the majority (84.2%) of patients, shortness of extremities was detected in the prenatal period at an average of 28.7 gestational weeks (± 3.6 SDS) with the aid of ultrasonography. More than half (n = 34/63, 54%) of the patients had a father of advanced paternal age (≥ 35 years). Among the complications, respiratory system manifestations, including obstructive sleep apnea (70%), ear-nose-throat manifestations including adenoid hypertrophy (56.6%) and otitis media (54.7%), neurological manifestations due to foramen magnum stenosis (53.2%), and skeletal manifestations including scoliosis (28.8%), are represented among the most common. The mortality rate was 7.3% (n = 5/68).Conclusion: This study not only represents the first retrospective analysis of the associated morbidities of patients with achondroplasia from a single center in Turkey but also will provide a reference point for future studies.

Phosphorylation-Dependent Regulation of Guanylyl Cyclase (GC)-A and Other Membrane GC Receptors.

Receptor guanylyl cyclases (GCs) are single membrane spanning, multidomain enzymes, that synthesize cGMP in response to natriuretic peptides or other ligands. They are evolutionarily conserved from sea urchins to humans and regulate diverse physiologies. Most family members are phosphorylated on four to seven conserved serines or threonines at the beginning of their kinase homology domains. This review describes studies that demonstrate that phosphorylation and dephosphorylation are required for activation and inactivation of these enzymes, respectively. Phosphorylation sites in GC-A, GC-B, GC-E and sea urchin receptors are discussed as are mutant receptors that mimic the dephosphorylated, inactive or phosphorylated, active forms of GC-A and GC-B, respectively. A salt bridge model is described that explains why phosphorylation is required for enzyme activation. Potential kinases, phosphatases and ATP regulation of GC receptors are also discussed. Critically, knock-in mice with glutamate substitutions for receptor phosphorylation sites are described. The inability of opposing signaling pathways to inhibit cGMP synthesis in mice where GC-A or GC-B cannot be dephosphorylated demonstrates the necessity of receptor dephosphorylation in vivo. Cardiac hypertrophy, oocyte meiosis, long bone growth/achondroplasia, and bone density are regulated by GC phosphorylation, but additional processes are likely to be identified in the future.

Management of complete intra-articular distal femur and patellar fractures in an achondroplastic young adult; small is challenging' revisited: a case-report.

BACKGROUND: People with achondroplasia exhibit distinct physical characteristics, but their cognitive abilities remain within the normal range. The challenges encountered during surgical procedures and perioperative care for achondroplastic individuals, are underrepresented in the existing literature. CASE PRESENTATION: In this report, the management of a 26-year-old North-African achondroplastic male is highlighted. The patient suffered a complete intra-articular distal femur fracture (AO/OTA 33-C1) and an ipsilateral patella fracture (AO/OTA 34-C1). The patient's unusual anatomical variations and the lack of suitable orthopedic implants posed significant surgical challenges, particularly in the context of a resource-limited developing country. Facial and spinal deformities, which are common in patients with achondroplasia, further complicated the anesthetic approach. CONCLUSIONS: The limited information on operative management of fractures in achondroplastic patients necessitated independent decision-making and diverging from the convenient approach where clear guidance is available in the literature.

European Achondroplasia Forum Practical Considerations for Following Adults with Achondroplasia.

Achondroplasia is a lifelong condition requiring lifelong management. There is consensus that infants and children with achondroplasia should be managed by a multidisciplinary team experienced in the condition. However, many people are lost to follow-up after the transition from paediatric to adult care, and there is no standardised approach for management in adults, despite the recent availability of international consensus guidelines. To address this, the European Achondroplasia Forum has developed a patient-held checklist to support adults with achondroplasia in managing their health. The checklist highlights key symptoms of spinal stenosis and obstructive sleep apnoea, both among the most frequent and potentially severe medical complications in adults with achondroplasia. The checklist acts as a framework to support individuals and their primary care provider in completing a routine review. General advice on issues such as blood pressure, pain, hearing, weight, adaptive aids, and psychosocial aspects are also included. The checklist provides key symptoms to be aware of, in addition to action points so that people can approach their primary care provider and be directed to the appropriate specialist, if needed. Additionally, the European Achondroplasia Forum offers some ideas on implementing the checklist during the transition from paediatric to adult care, thus ensuring the existing multidisciplinary team model in place during childhood can support in engaging individuals and empowering them to take responsibility for their own care as they move into adulthood.

Sleep-Disordered Breathing in an Infant With Achondroplasia and Foramen Magnum Stenosis.

Sleep-disordered breathing (SDB) is a frequently recognized comorbidity in infants and children with achondroplasia due to alterations in craniofacial and upper airway anatomy. Foramen magnum stenosis and cervicomedullary compression can be associated with SDB in this population, requiring prompt evaluation by multidisciplinary teams. Untreated SDB is associated with adverse cardiovascular, metabolic, and behavioral effects in children, necessitating early screening and treatment of underlying causes. Cervicomedullary compression is also associated with increased mortality and sudden infant death in infants with achondroplasia. Management of SDB in children with achondroplasia may involve a combination of neurosurgical intervention, adenotonsillectomy, and/or continuous positive airway pressure (CPAP). We recognize a need for increased physician awareness of the recommended screening guidelines to optimize health outcomes for children with achondroplasia. In this report, we describe a case of a five-month-old infant with achondroplasia and severe SDB diagnosed by polysomnography and was found to have moderate-to-severe foramen magnum stenosis identified by MRI. Subsequently, this infant underwent foramen magnum decompression, which improved the severe SDB and was followed up for five years. Our case illustrates the importance of early screening in infants with achondroplasia for SDB to prevent further sequelae.

Spinal Postures and Mobility in Children with Achondroplasia vs. Age- and Sex-Matched Healthy Individuals: A Preliminary Report.

Background: Achondroplasia is a rare genetic disease, yet the most common form of dwarfism, characterized by limb shortening and disproportionate short stature along with musculoskeletal changes, such as postural deviations. Although postural changes in the spine in children with achondroplasia have been well investigated, little is known about the association of achondroplasia with spinal movements/mobility. Methods: This preliminary study aims to explore the association of achondroplasia with spinal mobility in children with achondroplasia compared to age- and sex-matched healthy individuals. Spinal posture and mobility were assessed using a radiation-free back scan, the Idiag M360 (Idiag, Fehraltorf, Switzerland). Between-group differences were determined using a two-way analysis of variance. Results: Children with achondroplasia had smaller thoracic lateral flexion [difference between groups (Δ) = 20.4°, 95% CI 0.1°-40.6°, p = 0.04], lumbar flexion (Δ = 17.4°, 95% CI 5.5°-29.4°, p = 0.006), lumbar extension (Δ = 14.2°, 95% CI 5.7°-22.8°, p = 0.002) and lumbar lateral flexion (Δ = 19.6°, 95% CI 10.7°-28.4°, p < 0.001) than age- and sex-matched healthy individuals, except for thoracic extension (Δ = 16.5°, 95% CI 4.4°-28.7°, p = 0.009) which was greater in children with achondroplasia. No differences were observed in global spinal postures between the two groups. Conclusions: Spinal mobility appears to be more influenced by achondroplasia than global spinal postures in childhood. These results also highlight the importance of considering the musculoskeletal assessment of segmental spinal postures and rehabilitative interventions aimed at promoting spinal flexibility in children with achondroplasia.

Bariatric Surgery in Patients with Achondroplasia, a Feasibility Study of Two Case Studies.

BACKGROUND: Achondroplasia is a common skeletal dysplasia with a high prevalence of obesity in adulthood. Bariatric surgery has been shown to be effective in treating obesity and related comorbidities, but its feasibility and effectiveness in patients with achondroplasia have not been clearly established. OBJECTIVES: The objective of this study was to evaluate the feasibility and effectiveness of bariatric surgery in patients with achondroplasia. SETTING: This study was performed in France, and bariatric surgeons from the Société Française et Francophone de Chirurgie de l'Obésité et des Maladies Métaboliques (French Francophone Society of Surgery for Obesity or Metabolic Diseases) were asked to participate. METHODS: Two adult women with confirmed achondroplasia and a high BMI were selected for laparoscopic sleeve gastrectomy. Preoperative data were collected, including demographic information, comorbidities, and follow-up at 1, 3, and 6 months and 1 year after surgery. Complications were monitored and recorded. RESULTS: Both patients had good excess weight loss outcomes, with an average excess weight loss of 60.5% 1 year after surgery. One patient had a follow-up of 3 years and an excess weight loss of 44%. The surgery was well-tolerated, and no major complications were observed. CONCLUSIONS: Bariatric surgery is feasible and effective in patients with achondroplasia, with good outcomes for excess weight loss and related comorbidities. These findings suggest that bariatric surgery should be considered a treatment option for patients with achondroplasia and obesity.

Low-dose infigratinib increases bone growth and corrects growth plate abnormalities in an achondroplasia mouse model.

Achondroplasia (ACH), the most common form of disproportionate short stature, is caused by gain-of-function point mutations in fibroblast growth factor receptor 3 (FGFR3). Abnormally elevated activation of FGFR3 modulates chondrocyte proliferation and differentiation via multiple signaling pathways, such as the MAPK pathway. Using a mouse model mimicking ACH (Fgfr3Y367C/+), we have previously shown that daily treatment with infigratinib (BGJ398), a selective and orally bioavailable FGFR1-3 inhibitor, at a dose of 2 mg/kg, significantly increased bone growth. In this study, we investigated the activity of infigratinib administered at substantially lower doses (0.2 and 0.5 mg/kg, given once daily) and using an intermittent dosing regimen (1 mg/kg every 3 days). Following a 15-day treatment period, these low dosages were sufficient to observe significant improvement of clinical hallmarks of ACH such as growth of the axial and appendicular skeleton and skull development. Immunohistological labeling demonstrated the positive impact of infigratinib on chondrocyte differentiation in the cartilage growth plate and the cartilage end plate of the vertebrae. Macroscopic and microcomputed analyses showed enlargement of the foramen magnum area at the skull base, thus improving foramen magnum stenosis, a well-recognized complication in ACH. No changes in FGF23 or phosphorus levels were observed, indicating that the treatment did not modify phosphate homeostasis. This proof-of-concept study demonstrates that infigratinib administered at low doses has the potential to be a safe and effective therapeutic option for children with ACH.

Traqueobroncopatía osteocondroplástica: reporte de cuatro casos clínicos / Osteochondroplastic tracheobronchopathy: Four case reports

Introducción La traqueobroncopatía osteocondroplástica es una rara enfermedad crónica benigna de etiología desconocida. La broncoscopía sigue siendo el estándar de oro para el reconocimiento de traqueopatía osteocondroplástica. Sus hallazgos típicos se describen como un empedrado, un jardín de rocas, una apariencia de paisaje montañoso o de una cueva con estalactitas. El objetivo del presente trabajo es mostrar las principales características clínicas de una patología poco conocida. Casos clínicos Se analizaron los datos clínicos de cuatro pacientes de mediana edad, tres fueron hombres y una mujer. Los principales síntomas clínicos fueron tos crónica, disnea, disfonía. Los pacientes tuvieron un diagnóstico preliminar mediante tomografía axial computarizada de tórax, confirmado por examen video broncoscópico e histopatológico. El tratamiento incluyó medicamentos para los síntomas y en un solo caso criocirugía y coagulación con argón plasma. Discusión El diagnóstico de traqueobroncopatía osteocondroplástica no fue sencillo por ser una entidad rara, cuyos síntomas son inespecíficos y muy frecuentes en otras patologías. En Perú no se han publicado artículos de serie de casos sobre esta patología. Por lo tanto, tomamos como referencia artículos originales publicados en otros países para compararlos con nuestros hallazgos. Conclusión La traqueopatía osteocondroplástica es una enfermedad benigna que predispone a los adultos, los hombres tienen más probabilidades de verse afectados. Sus manifestaciones clínicas son inespecíficas; frecuentemente de origen faríngeo y la causa no está aún definida. La tomografía axial computarizada de tórax combinada con video broncoscopía son los principales procedimientos para el diagnóstico. No existe un estándar de tratamiento con efectos terapéuticos consistentes.

Introduction Osteochondroplastic tracheobronchopathy is a rare benign chronic disease of unknown etiology. Bronchoscopy remains the gold standard for diagnosing osteochondroplastic tracheobronchopathy. Its typical findings are described as a cobblestone, rock garden, mountainscape, or stalactite cave appearance. The present work aims to show the main clinical features of this rare pathology. Clinical cases The clinical data of four middle-aged patients, three men and one woman, were analyzed. The main clinical symptoms were chronic cough, dyspnea, and dysphonia. The patient's preliminary diagnosis was made by computed axial tomography of the chest, confirmed by bronchoscopy and histopathological examination. Treatment included medication for symptoms and, in one case, cryosurgery and argon plasma coagulation. Discussion Diagnosing osteochondroplastic tracheobronchopathy was not easy, given its uncommon nature and non-specific symptoms often found in other pathologies. No case series articles on this pathology have been published in Peru. Therefore, we used the original articles published in other countries to reference our findings. Conclusion Osteochondroplastic tracheopathy is a benign disease that typically affects adults. Men are more likely to be affected. Its clinical manifestations are non-specific and frequently of pharyngeal origin, and the cause is not yet defined. Chest computed axial tomography combined with bronchoscopy are the main diagnostic procedures. There is no standard treatment with consistent therapeutic effects.

Long-term oral meclozine administration improves survival rate and spinal canal stenosis during postnatal growth in a mouse model of achondroplasia in both sexes.

Achondroplasia (ACH) is a skeletal dysplasia characterized by short-limbed short stature caused by the gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Activated FGFR3, which is a negative regulator of bone elongation, impairs the growth of long bones and the spinal arch by inhibiting chondrocyte proliferation and differentiation. Most patients with ACH have spinal canal stenosis in addition to short stature. Meclozine has been found to inhibit FGFR3 via drug repurposing. A 10-d treatment with meclozine promoted long-bone growth in a mouse model of ACH (Fgfr3ach mice). This study aimed to evaluate the effects of long-term meclozine administration on promoting bone growth and the spinal canal in Fgfr3ach mice. Meclozine (2 mg/kg/d) was orally administered to Fgfr3ach mice for 5 d per wk from the age of 7 d to 56 d. Meclozine (2 mg/kg/d) significantly reduced the rate of death or paralysis and improved the length of the body, cranium, and long bones in male and female Fgfr3ach mice. Micro-computed tomography analysis revealed that meclozine ameliorated kyphotic deformities and trabecular parameters, including BMD, bone volume/tissue volume, trabecular thickness, and trabecular number at distal femur of Fgfr3ach mice in both sexes. Histological analyses revealed that the hypertrophic zone in the growth plate was restored in Fgfr3ach mice following meclozine treatment, suggesting upregulation of endochondral ossification. Skeletal preparations demonstrated that meclozine restored the spinal canal diameter in Fgfr3ach mice in addition to improving the length of each bone. The 2 mg/kg/d dose of meclozine reduced the rate of spinal paralysis caused by spinal canal stenosis, maintained the growth plate structure, and recovered the bone quality and growth of axial and appendicular skeletons of Fgfr3ach mice in both sexes. Long-term meclozine administration has the potential to ameliorate spinal paralysis and bone growth in patients with ACH.

Surgical outcome after treatment of thoracolumbar spinal stenosis in adults with achondroplasia.

PURPOSE: To describe the complications and the outcome of patients with achondroplasia undergoing thoracolumbar spinal surgery. METHODS: Retrospective analysis of prospectively collected data of all patients with achondroplasia undergoing surgery within the years 1992-2021 at the thoracic and/or lumbar spine. The outcome was measured by analyzing the surgical complications and revisions. The patient-rated outcome was assessed with the COMI score from 2005 onwards. RESULTS: A total of 15 patients were included in this study undergoing a total of 31 surgeries at 79 thoracolumbar levels. 12/31 surgeries had intraoperative complications consisting of 11 dural tears and one excessive intraoperative bleeding. 4/18 revision surgeries were conducted due to post-decompression hyperkyphosis. The COMI score decreased from 7.5 IQR 1.4 (range 7.1-9.8) preoperatively to 5.3 IQR 4.1 (2.5-7.5) after 2 years (p = 0.046). CONCLUSION: Patients with achondroplasia, the most common skeletal dysplasia condition with short-limb dwarfism, are burdened with a congenitally narrow spinal canal and are commonly in need of spinal surgery. However, surgery in these patients is often associated with complications, namely dural tears and post-decompression kyphosis. Despite these complications, patients benefit from surgical treatment at a follow-up of 2 years after surgery.

Ligamentous laxity in children with achondroplasia: Prevalence, joint involvement, and implications for early intervention strategies.

Achondroplasia (ACH), the most common form of skeletal dysplasia, is characterized by severe disproportionate short stature, rhizomelia, exaggerated lumbar lordosis, brachydactyly, macrocephaly with frontal bossing and midface hypoplasia. Ligamentous laxity has been reported as a striking feature of ACH, but its prevalence and characteristics have not been systematically evaluated yet. There is growing evidence that ligamentous laxity can be associated with chronic musculoskeletal problems and may affect motor development leading to abnormal developmental trajectories. This study aimed to assess the prevalence of ligamentous laxity in children with ACH through standardized tools, the Beighton scale and its modified version for preschool-age children. A total of 33 children (mean age 6.4 ± 3.2 years; age range 1-12.5 years) diagnosed with ACH by the demonstration of a pathogenic variant in the FGFR3 gene and 33 age- and sex-matched healthy controls were included in the study. Both ligamentous laxity assessment and neurological examinations were performed; medical history was also collected from caregivers. Children with ACH showed a 2 times higher risk of ligamentous laxity than the group without skeletal dysplasia (OR = 2.2; 95% CI = 1.0 to 4.7), with 55% of children meeting the diagnostic criteria for hypermobility. No significant difference in ligamentous laxity was observed between males and females. Joint involvement analysis revealed characteristic patterns, with knee hypermobility observed in 67% of patients, while rare was elbow hypermobility. Longitudinal assessments indicated a decreasing trend in ligamentous laxity scores over time, suggesting a potential decrease in hypermobility issues during adulthood. The findings of this study provide valuable insights into the prevalence and characteristics of ligamentous laxity in ACH. Implementation of standardized ligamentous laxity assessments might guide patients' follow-up and facilitate early interventions, helping to prevent pain and improve outcomes and quality of life for such patients. Further prospective studies are needed to explore the natural history of ligamentous laxity in ACH and investigate the potential impact of emerging pharmacological treatments upon hypermobility.

Acondroplasia severa con retraso del desarrollo y acantosis nigricans (SADDAN) / Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN)

RESUMEN La acondroplasia severa con retraso del desarrollo y acantosis nigricans (SADDAN) es una rara y letal displasia esquelética. Presentamos el primer caso detectado en Perú, en un infante de 13 meses con características fenotípicas de macrocefalia relativa, tórax estrecho, extremidades micromélicas y piel en acordeón; asimismo, un marcado retraso del desarrollo psicomotor en todos los hitos (prueba peruana) y acantosis nigricans. El paciente tuvo mala evolución clínica caracterizada por crisis convulsivas recurrentes, dificultad respiratoria progresiva, y falleció por insuficiencia respiratoria concomitante a neumonía. Esta entidad requiere del acceso a exámenes específicos como el panel de displasias esqueléticas, la cual no es parte de la oferta en la mayoría de los hospitales del Perú. Se requiere una mayor atención las enfermedades raras, a fin de proveer diagnósticos e información oportuna a los involucrados.

ABSTRACT Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) is a rare and lethal skeletal dysplasia. We present the first case detected in Peru, in a 13-month-old infant with phenotypic characteristics of relative macrocephaly, narrow thorax, micromelic extremities and accordion skin; likewise, a marked delay in psychomotor development in all milestones (Peruvian test), and acanthosis nigricans. The patient had a poor clinical evolution characterized by recurrent seizures, progressive respiratory difficulty, dying from respiratory failure concomitant to pneumonia. This entity requires access to specific exams such as the skeletal dysplasia panel, which is not part of the offering in most hospitals in Peru. Greater attention is required for rare diseases, to provide timely diagnoses and information to those involved.

Clinical outcomes and medical management of achondroplasia in Japanese children: A retrospective medical record review of clinical data.

Achondroplasia (ACH) is a rare, autosomal dominant skeletal dysplasia characterized by short stature, characteristic facial configuration, and trident hands. Before vosoritide approval in Japan, patients with ACH could start growth hormone (GH) treatment at age 3 years. However, ACH and its treatment in young Japanese children have not been studied. This retrospective, longitudinal, medical records-based cohort study (before vosoritide approval) summarized symptoms, complications, monitoring, surgery/interventions, and height with/without GH in Japanese patients with ACH <5 years. Complications were observed in 89.2% of all 37 patients; 75.7% required surgery or intervention. All patients were monitored by magnetic resonance imaging; 73.0% had foramen magnum stenosis, while 54.1% had Achondroplasia Foramen Magnum Score 3 or 4. Of 28 GH-treated patients, 22 initiating at age 3 years were generally taller after 12 months versus 9 non-GH-treated patients. Mean annual growth velocity significantly increased from age 2 to 3 versus 3 to 4 years in GH-treated patients (4.37 vs. 7.23 cm/year; p = 0.0014), but not in non-GH-treated patients (4.94 vs. 4.20 cm/year). The mean height at age 4 years with/without GH was 83.6/79.8 cm. These results improve our understanding of young patients with ACH in Japan and confirm that early diagnosis of ACH and monitoring of complications help facilitate appropriate interventions.