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PURPOSE: Pregnancies affected by maternal or fetal achondroplasia present unique challenges. The optimal route of delivery in fetuses with achondroplasia has not been established. Our objective was to determine whether the route of delivery affects postnatal achondroplasia-related surgical burden. METHODS: We conducted a secondary analysis of Achondroplasia Natural History Study (CLARITY), which is a multicenter natural history cohort study of patients with achondroplasia. Achondroplasia-related surgical morbidity, which we defined as the need for one or more postnatal achondroplasia-related surgeries, was assessed in relation to the route of delivery and whether the mother also had achondroplasia. Rate of each individual surgery type (otolaryngology, brain, foramen magnum, spine, and extremity) was also assessed in relation to the route of delivery. RESULTS: Eight hundred fifty-seven patients with achondroplasia with known route of delivery and known maternal stature were included. Three hundred sixty (42%) patients were delivered vaginally, and 497 (58%) patients were delivered by a cesarean delivery. There was no difference in the odds of requiring any postnatal achondroplasia-related surgery in those with achondroplasia who were delivered vaginally compared with those delivered by cesarean birth (odds ratio 0.95, 95% CI = 0.68-1.34, P = .80). No difference was present in the odds of requiring any postnatal achondroplasia-related surgery when route of delivery was compared for fetuses born to 761 average stature mothers (odds ratio 1.05, 95% CI = 0.74-1.51, P = .78). There was also no difference in the odds of requiring each of the individual achondroplasia-related surgeries by route of delivery, including cervicomedullary decompression. CONCLUSION: Our study suggests that it is reasonable for average stature patients carrying a fetus with achondroplasia to undergo a trial of labor in the absence of routine obstetric contraindications.
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Acondroplasia , Cesárea , Gravidez , Feminino , Humanos , Estudos de Coortes , Acondroplasia/cirurgia , Acondroplasia/complicações , Feto , Morbidade , Estudos RetrospectivosRESUMO
PURPOSE: Achondroplasia is the most common short stature skeletal dysplasia (1:20,000-30,000), but the risk of adverse health outcomes from cardiovascular diseases, pain, poor function, excess weight, and sleep apnea is unclear. A multicenter retrospective natural history study was conducted to understand medical and surgical practices in achondroplasia. METHODS: Data from patients with achondroplasia evaluated by clinical geneticists at Johns Hopkins University, A.I. duPont Hospital for Children, McGovern Medical School UTHealth, and University of Wisconsin were populated into a REDCap database. All available retrospective medical records of anthropometry (length/height, weight, occipitofrontal circumference), surgery, polysomnography (PSG), and imaging (e.g., X-ray, magnetic resonance imaging) were included. RESULTS: Data from 1,374 patients (48.8% female; mean age 15.4 ± 13.9 years) constitute the primary achondroplasia cohort (PAC) with 496 subjects remaining clinically active and eligible for prospective studies. Within the PAC, 76.0% had a de novo FGFR3 pathologic variant and 1,094 (79.6%) had one or more achondroplasia-related surgeries. There are ≥37,000 anthropometry values, 1,631 PSGs and 10,727 imaging studies. CONCLUSION: This is the largest multicenter achondroplasia natural history study, providing a vast array of medical information for use in caring for these patients. This well-phenotyped cohort is a reference population against which future medical and surgical interventions can be compared.
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Acondroplasia , Osteocondrodisplasias , Acondroplasia/diagnóstico por imagem , Acondroplasia/epidemiologia , Acondroplasia/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Polissonografia , Estudos Prospectivos , Estudos Retrospectivos , Estados Unidos/epidemiologia , Adulto JovemRESUMO
More information is available concerning risks of craniocervical junction issues in infancy than at later ages. Therefore, we elected to quantify the risks at greater than 1 year of age through a retrospective analysis of 477 individuals with achondroplasia using a REDCap database. Evaluation of these 477 individuals revealed 77 (16.1%) who had pathologic neurologic manifestations after 1 year of age related to the craniocervical junction. Within this subpopulation of 77 individuals, 43 (55.8%) underwent craniocervical decompression surgery, or 9.0% of the total population. Whether decompressed or not, most individuals with craniocervical junction issues after infancy had a normal outcome, without long-term neurological sequelae (57/77, 74.0%). The remaining 20 had various long-term neurological issues. This is the first cohort based estimate of risks related to the upper cervical spine in individuals with achondroplasia specifically beyond infancy.
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Acondroplasia/diagnóstico , Compressão da Medula Espinal/diagnóstico , Doenças da Medula Espinal/diagnóstico , Acondroplasia/complicações , Acondroplasia/epidemiologia , Acondroplasia/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Compressão da Medula Espinal/complicações , Compressão da Medula Espinal/fisiopatologia , Doenças da Medula Espinal/complicações , Doenças da Medula Espinal/epidemiologia , Doenças da Medula Espinal/fisiopatologia , Adulto JovemRESUMO
Achondroplasia is the most common disproportionate short statured skeletal dysplasia with a prevalence of approximately 1:20,000-30,000. We created the largest database to date of a historical cohort of 1374 patients with achondroplasia (CLARITY-aChondropLasia nAtuRal hIsTory studY). This cohort was queried for the presence of unrecognized or under-recognized features associated with achondroplasia. Craniosynostosis was found to co-occur with achondroplasia in 9 (0.65%) patients in this cohort, which is much higher than the general population prevalence of 3.1-7.2 per 10,000. In addition, 27 patients had seizures (2.0%), an apparent excess as compared to the general population. Only two people had diabetes despite a high rate of adult obesity. This report documents for the first time an increased prevalence of craniosynostosis in persons with achondroplasia, and adds support to previous observations of an apparently higher than expected prevalence of seizures and lower prevalence of diabetes mellitus.
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Acondroplasia/epidemiologia , Craniossinostoses/epidemiologia , Osteocondrodisplasias/epidemiologia , Convulsões/epidemiologia , Acondroplasia/diagnóstico , Acondroplasia/patologia , Adulto , Craniossinostoses/diagnóstico , Craniossinostoses/patologia , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/genética , Diabetes Mellitus/patologia , Feminino , Humanos , Masculino , Mutação/genética , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/patologia , Fenótipo , Convulsões/diagnóstico , Convulsões/patologia , Adulto JovemRESUMO
AIM: To assess the clinical picture underlying apparent life-threatening events (ALTEs) occurring in infants with achondroplasia and provide guidance for evaluation after an event. METHODS: A population of 477 individuals with achondroplasia was retrospectively reviewed, and information regarding possible ALTEs was recorded in a REDCap database. RESULTS: ALTEs occurred in the first year of life in 18 of 477 individuals (3.8%). Most (14/18, 78%) occurred in the first 6 months of life and presented as episodes of apnoea and/or seizures. Of affected infants, 8/18 (44%) had more than one episode. Many of the initial ALTEs arose while infants were in car seats (11/18, 61%). Assessment following ALTEs most often demonstrated either craniocervical junction concerns and/or seizures, with 12/18 (67%) patients undergoing cervicomedullary decompression and 5/18 (28%) starting on anti-epileptic medications after the event. CONCLUSION: Although this study is limited in size and was retrospective, it shows that infants with achondroplasia appear to be at high risk for ALTEs. Evaluation after an event should include neuroimaging of the foramen magnum, inpatient hospital observation including respiratory monitoring and electroencephalography, and a car seat challenge.
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Acondroplasia , Evento Inexplicável Breve Resolvido , Acondroplasia/epidemiologia , Apneia/epidemiologia , Apneia/etiologia , Bases de Dados Factuais , Humanos , Lactente , Estudos RetrospectivosRESUMO
Two children with achondroplasia who developed an abnormal bony outgrowth at the distal radioulnar joint (DRUJ), indistinguishable from an osteochondroma on histology, but the radiographic appearance, location, and asymmetry suggested the rare diagnosis of dysplasia epiphysealis hemimelica (DEH or "Trevor's disease"). One child experienced symptomatic relief with surgical excision and one was observed clinically due to lack of significant symptoms. These are the first presented cases of DEH in achondroplasia, both affecting the DRUJ. Due to the infrequency of DEH, more research is needed to better understand the potential connection to achondroplasia. For management, we suggest shared surgical decision making based on symptoms.
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Acondroplasia/genética , Doenças do Desenvolvimento Ósseo/genética , Fêmur/anormalidades , Osteocondroma/genética , Tíbia/anormalidades , Acondroplasia/diagnóstico por imagem , Acondroplasia/fisiopatologia , Acondroplasia/cirurgia , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Doenças do Desenvolvimento Ósseo/fisiopatologia , Doenças do Desenvolvimento Ósseo/cirurgia , Criança , Epífises/diagnóstico por imagem , Epífises/fisiopatologia , Epífises/cirurgia , Feminino , Fêmur/diagnóstico por imagem , Fêmur/fisiopatologia , Fêmur/cirurgia , Humanos , Masculino , Osteocondroma/diagnóstico por imagem , Osteocondroma/fisiopatologia , Osteocondroma/cirurgia , Tíbia/diagnóstico por imagem , Tíbia/fisiopatologia , Tíbia/cirurgia , Articulação do Punho/diagnóstico por imagem , Articulação do Punho/fisiopatologia , Articulação do Punho/cirurgiaRESUMO
There are virtually no data regarding appropriate oral intake in infants with dwarfing disorders such as achondroplasia, nor is there clear information regarding appropriate weight gain velocity in this population. Yet, these individuals are at increased risk for both early failure to thrive and, later in life, for obesity. Having appropriate expectations regarding weight gain and reasonable goals in management is imperative. We sought to clarify the rate of weight gain in infants with achondroplasia during the first year of life through analysis of data from 60 infants with achondroplasia seen at least twice during the first year of life in the Midwest Regional Bone Dysplasia Clinic, University of Wisconsin-Madison between 1998 and 2018. The mean weight gain velocity during the first 3 months was 23 g/day which contrasts with 30 g/day in average statured infants. Mean weight gain from 0 to 12 months of age was 13 g/day. The 3% of weight gain velocity during the first year of life was 8 g/day, and this rate did not differ between 0-3 months and 0-12 months of age. Infants with achondroplasia slightly more than doubled their birth weights by 1 year of age in contrast to averaged statured infants who typically triple birth weights by 1 year. Infants with achondroplasia can be thriving but erroneously assessed as failing to thrive if the incorrect reference values are used. This article describes infant weight gain velocity reference data for this population.
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Acondroplasia/epidemiologia , Insuficiência de Crescimento/epidemiologia , Obesidade/epidemiologia , Aumento de Peso/fisiologia , Acondroplasia/fisiopatologia , Peso ao Nascer/fisiologia , Estatura/fisiologia , Aleitamento Materno , Insuficiência de Crescimento/fisiopatologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Obesidade/fisiopatologia , Valores de ReferênciaRESUMO
Human MITF is, by convention, called the "microphthalmia-associated transcription factor" because of previously published seminal mouse genetic studies; however, mutations in MITF have never been associated with microphthalmia in humans. Here, we describe a syndrome that we term COMMAD, characterized by coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness. COMMAD is associated with biallelic MITF mutant alleles and hence suggests a role for MITF in regulating processes such as optic-fissure closure and bone development or homeostasis, which go beyond what is usually seen in individuals carrying monoallelic MITF mutations.
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Albinismo/genética , Alelos , Coloboma/genética , Surdez/genética , Megalencefalia/genética , Fator de Transcrição Associado à Microftalmia/genética , Microftalmia/genética , Osteopetrose/genética , Animais , Pré-Escolar , Feminino , Homozigoto , Humanos , Lactente , Masculino , Linhagem , Síndrome , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genéticaRESUMO
Acanthosis nigricans (AN) in those with achondroplasia has been reported occasionally in the literature previously. Other disorders arising from constitutive activation of FGFR3 also manifest AN at various frequencies. We assessed the prevalence of AN in a sequential series of 477 individuals with achondroplasia. Using a REDCap database, we collected and analyzed what other features or medical issues may co-occur with AN in those with achondroplasia. AN arises in approximately 10% of individuals with achondroplasia. It usually first appears in preadolescence or adolescence, is more likely in the non-White population and in those who are obese. It is not severe and generally will need no treatment. It is not associated with any evident risk for neither hyperinsulinemic states nor malignancy, and therefore, no special investigations are warranted when it is recognized. Thus, clinicians should not be surprised or concerned upon discovering this finding in those with achondroplasia. In addition, the mechanisms and genetic causes of AN are detailed.
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Acantose Nigricans/complicações , Acondroplasia/complicações , Acantose Nigricans/diagnóstico , Acantose Nigricans/genética , Acondroplasia/diagnóstico , Acondroplasia/genética , Adolescente , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Fenótipo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Adulto JovemRESUMO
Geleophysic dysplasia is a rare skeletal dysplasia often complicated by progressive cardiac disease. Information about long-term outcomes is limited. A clinical update of the oldest surviving patient described with geleophysic dysplasia type 1 is provided. Special note is made in relation to the cardiac disease and interventions. Genetic testing of ADAMTSL2 revealed a previously reported missense mutation as well as a novel nonsense mutation, which can be added to the list of causative mutations in geleophysic dysplasia.
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Doenças do Desenvolvimento Ósseo/complicações , Cardiopatias/complicações , Deformidades Congênitas dos Membros/complicações , Adulto , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Pré-Escolar , Fácies , Feminino , Cardiopatias/diagnóstico por imagem , Humanos , Recém-Nascido , Deformidades Congênitas dos Membros/diagnóstico por imagem , Masculino , Tomografia Computadorizada por Raios XRESUMO
Diaphanospondylodysostosis (DSD) and ischiospinal dysostosis (ISD) are both rare skeletal dysplasias consisting of abnormal axial skeletal development but normal appendicular skeletal development. Both disorders recently have been found to result from mutations in the BMPER gene. We report a patient with one deletion and one mutation of the BMPER gene who has features most consistent with DSD but who has survived to age 9 years. Survival suggests that DSD and ISD reflect a spectrum of severity of one disease process.
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Proteínas de Transporte/genética , Anormalidades Craniofaciais/genética , Disostoses/genética , Ísquio/patologia , Mutação , Costelas/anormalidades , Coluna Vertebral/anormalidades , Criança , Anormalidades Craniofaciais/patologia , Disostoses/patologia , Humanos , Masculino , Prognóstico , Costelas/patologia , Coluna Vertebral/patologiaRESUMO
We describe five children with Hereditary Multiple Exostosis (HME) who also had syringomyelia. Of these, four had a tethered cord/fibrolipoma. No spinal osteochondromas were found in these patients. All had antecedent neurological signs or symptoms that prompted spinal imaging with MRI. Of all patients with HME seen in the Midwest Regional Bone Dysplasia Clinic from 1982 to present, 44% (17/39) of patients had signs or symptoms concerning for possible cord-related neurological findings. However, only 10 of 39 had spinal imaging. Assuming that all individuals with syringomyelia were identified, then 5/39 (13%) were in that way affected. This, of course, is a minimal estimate given that many were not imaged. The incidence of syringomyelia appears to be increased in this population, and seems to be unrelated to spinal osteochondromas. A low threshold for obtaining spinal MRI in patients with Hereditary Multiple Exostosis seems rational. © 2016 Wiley Periodicals, Inc.
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Exostose Múltipla Hereditária/complicações , Exostose Múltipla Hereditária/diagnóstico , Siringomielia/complicações , Siringomielia/diagnóstico , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Análise Mutacional de DNA , Exostose Múltipla Hereditária/genética , Exostose Múltipla Hereditária/cirurgia , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , N-Acetilglucosaminiltransferases/genética , Fenótipo , Estudos Retrospectivos , Siringomielia/genética , Siringomielia/cirurgia , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Vosoritide is the first precision medical therapy approved to increase growth velocity in children with achondroplasia. Sharing early prescribing experiences across different regions could provide a framework for developing practical guidance for the real-world use of vosoritide. METHODS: Two meetings were held to gather insight and early experience from experts in Europe, the Middle East, and the USA. The group comprised geneticists, pediatric endocrinologists, pediatricians, and orthopedic surgeons. Current practices and considerations for vosoritide were discussed, including administration practicalities, assessments, and how to manage expectations. RESULTS: A crucial step in the management of achondroplasia is to determine if adequate multidisciplinary support is in place. Training for families is essential, including practical information on administration of vosoritide, and how to recognize and manage injection-site reactions. Advocated techniques include establishing a routine, empowering patients by allowing them to choose injection sites, and managing pain. Patients may discontinue vosoritide if they cannot tolerate daily injections or are invited to participate in a clinical trial. Clinicians in Europe and the Middle East emphasized the importance of assessing adherence to daily injections, as non-adherence may impact response and reimbursement. Protocols for monitoring patients receiving vosoritide may be influenced by regional differences in reimbursement and healthcare systems. Core assessments may include pubertal staging, anthropometry, radiography to confirm open physes, the review of adverse events, and discussion of concomitant or new medications-but timing of these assessments may also differ regionally and vary across institutions. Patients and families should be informed that response to vosoritide can vary in both magnitude and timing. Keeping families informed regarding vosoritide clinical trial data is encouraged. CONCLUSION: The early real-world experience with vosoritide is generally positive. Sharing these insights is important to increase understanding of the practicalities of treatment with vosoritide in the clinical setting.
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Acondroplasia , Peptídeo Natriurético Tipo C , Criança , Humanos , Peptídeo Natriurético Tipo C/uso terapêutico , Atenção à Saúde , Manejo da Dor , Acondroplasia/tratamento farmacológicoRESUMO
Children with skeletal dysplasia are frequently referred to pediatric endocrinologists due to short stature. These children may present with disproportionate growth or medical histories that point to a skeletal dysplasia. This primer will discuss when to be concerned about skeletal dysplasia, the initial steps in evaluation for a skeletal dysplasia, and new therapies that are either recently approved or in development.
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Cervical and craniocervical instability are associated with catastrophic procedural outcomes. We discuss three individuals who required otolaryngologic surgical intervention: two with symptomatic spinal instability and one in whom spinal stability was unable to be assessed. Two cases were managed with procedural positioning precautions and evoked potential monitoring, and the other with procedural positioning precautions alone. Methods of monitoring and triggers for repositioning are discussed. This series is intended to discuss the approach and potential added value of evoked potential monitoring for risk mitigation in pediatric patients with concern for cervical spine instability.
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Potenciais Somatossensoriais Evocados , Monitorização Neurofisiológica Intraoperatória , Humanos , Criança , Potenciais Somatossensoriais Evocados/fisiologia , Potencial Evocado Motor/fisiologia , Pescoço/cirurgia , Procedimentos Neurocirúrgicos , Vértebras Cervicais/cirurgiaRESUMO
OBJECTIVE: The objective of this study was to describe the incidence and management of hydrocephalus in patients with achondroplasia over a 60-year period at four skeletal dysplasia centers. METHODS: The Achondroplasia Natural History Study (CLARITY) is a registry for clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the US from 1957 to 2017. Data were entered and stored in a REDCap database and included surgeries with indications and complications, medical diagnoses, and radiographic information. RESULTS: A total of 1374 patients with achondroplasia were included in this study. Of these, 123 (9%) patients underwent treatment of hydrocephalus at a median age of 14.4 months. There was considerable variation in the percentage of patients treated for hydrocephalus by center and decade of birth, ranging from 0% to 28%, although in the most recent decade, all centers treated less than 6% of their patients, with an average of 2.9% across all centers. Undergoing a cervicomedullary decompression (CMD) was a strong predictor for treatment of hydrocephalus (OR 5.8, 95% CI 3.9-8.4), although that association has disappeared in those born since 2010 (OR 1.1, 95% CI 0.2-5.7). In patients born since 1990, treatment of hydrocephalus with endoscopic third ventriculostomy (ETV) has become more common; it was used as the first line of treatment in 38% of patients in the most recent decade. Kaplan-Meier analysis suggests that a single ETV will treat hydrocephalus in roughly half of these patients. CONCLUSIONS: While many children with achondroplasia have features of hydrocephalus with enlarged intracranial CSF spaces and relative macrocephaly, treatment of hydrocephalus in achondroplasia patients has become relatively uncommon in the last 20 years. Historically, there was a significant association between symptomatic foramen magnum stenosis and treatment of hydrocephalus, although concurrent treatment of both has fallen out of favor with the recognition that CMD alone will treat hydrocephalus in some patients. Despite good experimental data demonstrating that hydrocephalus in achondroplasia is best understood as communicating in nature, ETV appears to be reasonably successful in certain patients and should be considered an option in selected patients.
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Acondroplasia , Hidrocefalia , Neuroendoscopia , Terceiro Ventrículo , Criança , Humanos , Lactente , Resultado do Tratamento , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/epidemiologia , Hidrocefalia/etiologia , Acondroplasia/complicações , Acondroplasia/epidemiologia , Ventriculostomia/efeitos adversos , Terceiro Ventrículo/diagnóstico por imagem , Terceiro Ventrículo/cirurgia , Neuroendoscopia/efeitos adversos , Estudos RetrospectivosRESUMO
BACKGROUND: The purpose of this study was to describe the frequency and risk factors for orthopedic surgery in patients with achondroplasia. CLARITY (The Achondroplasia Natural History Study) includes clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the United States from 1957 to 2018. Data were entered and stored in a Research Electronic Data Capture (REDCap) database. RESULTS: Information from one thousand three hundred and seventy-four patients with achondroplasia were included in this study. Four hundred and eight (29.7%) patients had at least one orthopedic surgery during their lifetime and 299 (21.8%) patients underwent multiple procedures. 12.7% (n = 175) of patients underwent spine surgery at a mean age at first surgery of 22.4 ± 15.3 years old. The median age was 16.7 years old (0.1-67.4). 21.2% (n = 291) of patients underwent lower extremity surgery at a mean age at first surgery of 9.9 ± 8.3 years old with a median age of 8.2 years (0.2-57.8). The most common spinal procedure was decompression (152 patients underwent 271 laminectomy procedures), while the most common lower extremity procedure was osteotomy (200 patients underwent 434 procedures). Fifty-eight (4.2%) patients had both a spine and lower extremity surgery. Specific risk factors increasing the likelihood of orthopedic surgery included: patients with hydrocephalus requiring shunt placement having higher odds of undergoing spine surgery (OR 1.97, 95% CI 1.14-3.26); patients having a cervicomedullary decompression also had higher odds of undergoing spine surgery (OR 1.85, 95% CI 1.30-2.63); and having lower extremity surgery increased the odds of spine surgery (OR 2.05, 95% CI 1.45-2.90). CONCLUSIONS: Orthopedic surgery was a common occurrence in achondroplasia with 29.7% of patients undergoing at least one orthopedic procedure. Spine surgery (12.7%) was less common and occurred at a later age than lower extremity surgery (21.2%). Cervicomedullary decompression and hydrocephalus with shunt placement were associated with an increased risk for spine surgery. The results from CLARITY, the largest natural history study of achondroplasia, should aid clinicians in counseling patients and families about orthopedic surgery.
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Acondroplasia , Hidrocefalia , Procedimentos Ortopédicos , Humanos , Adolescente , Criança , Adulto Jovem , Adulto , Lactente , Pré-Escolar , Descompressão Cirúrgica/métodos , Estudos Retrospectivos , Acondroplasia/cirurgia , Acondroplasia/complicações , Hidrocefalia/complicações , Hidrocefalia/cirurgiaRESUMO
Background: TransCon CNP (navepegritide) is an investigational prodrug of C-type natriuretic peptide (CNP) designed to allow for continuous CNP exposure with once-weekly dosing. This 52-week phase 2 (ACcomplisH) trial assessed the safety and efficacy of TransCon CNP in children with achondroplasia. Methods: ACcomplisH is a global, randomised, double-blind, placebo-controlled, dose-escalation trial. Study participants were recruited between June 10, 2020, and September 24, 2021. Eligible participants were prepubertal, aged 2-10 years, with genetically confirmed achondroplasia, and randomised 3:1 to once-weekly subcutaneous injections of TransCon CNP (6, 20, 50, or 100 µg CNP/kg/week) or placebo for 52 weeks. Primary objectives were safety and annualised growth velocity (AGV). ACcomplisH is registered with ClinicalTrials.gov (NCT04085523) and Eudra (CT 2019-002754-22). Findings: Forty-two participants received TransCon CNP at doses of 6 µg (n = 10; 7 female), 20 µg (n = 11; 3 female), 50 µg (n = 10; 3 female), or 100 µg (n = 11; 6 female) CNP/kg/week, with 15 receiving placebo (5 female). Treatment-emergent adverse events (TEAEs) were mild or moderate with no grade 3/4 events reported. There were 2 serious TEAEs that were assessed as not related to TransCon CNP. Eleven injection site reactions occurred in 8 participants receiving TransCon CNP and no symptomatic hypotension occurred. TransCon CNP demonstrated a dose-dependent improvement in AGV. At 52 weeks, TransCon CNP 100 µg CNP/kg/week significantly improved AGV vs placebo (least squares mean [95% CI] 5.42 [4.74-6.11] vs 4.35 [3.75-4.94] cm/year; p = 0.0218), and improved achondroplasia-specific height SDS from baseline (least squares mean [95% CI] 0.22 [0.02-0·41] vs -0·08 [-0.25 to 0.10]; p = 0.0283). All participants completed the randomised period and continued in the ongoing open-label extension period receiving TransCon CNP 100 µg CNP/kg/week. Interpretation: This phase 2 trial suggests that TransCon CNP is effective, safe, with low injection site reaction frequency, and may provide a novel, once-weekly treatment option for children with achondroplasia. These results support TransCon CNP at 100 µg CNP/kg/week in the ongoing pivotal trial. Funding: Ascendis Pharma, A/S.
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Neurosurgical patients with genetic syndromes often receive care from multidisciplinary teams. Successful models range from multiple providers in one clinic space seeing a patient together to specialists located at different institutions working together. Collaboration and bidirectional communication are key. Multidisciplinary care improves outcomes and patient satisfaction. Choosing the goal of the clinic, using ancillary staff, and obtaining institutional buy-in are important initial first steps to establishing a multidisciplinary team clinic. Multidisciplinary teams can leverage technology to expand care via telehealth in multidisciplinary clinics and more vitally communication between providers on the team.
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Equipe de Assistência ao Paciente , Satisfação do Paciente , Comunicação , Humanos , SíndromeRESUMO
OBJECTIVES/HYPOTHESIS: To quantify otolaryngologic surgery utilization in patients with achondroplasia, and to identify any changes in utilization over the past four decades. STUDY DESIGN: Retrospective cohort study. METHODS: A retrospective cohort study of 1,374 patients with achondroplasia enrolled in the CLARITY retrospective cohort study at four centers of multi-specialty care for patients with achondroplasia. Otolaryngologic surgeries are presented by birth cohort decade. The main outcomes were number of primary and additional otolaryngologic procedures; age at surgery; likelihood of repeated surgery; temporal trends in surgical utilization. RESULTS: In this cohort of 1,374 patients with achondroplasia, 620 (45.1%) had pharyngeal surgery at least once, 150 (10.9%) had pharyngeal surgery on more than one occasion, and patients who had adenoidectomy first were 2.68 times more likely to require a second pharyngeal surgery than those who had adenotonsillectomy. Seven hundred and seventy-nine (56.7%) had tympanostomy tubes placed at least once, and 447 (32.5%) had tympanostomy tubes placed more than one time. Age at first pharyngeal surgery decreased by 1.2 years per birth cohort decade, and age at tympanostomy tube placement decreased by 1.1 years per decade. CONCLUSIONS: Patients with achondroplasia often require otolaryngologic surgery, particularly adenoidectomy and/or tonsillectomy as well as tympanostomy tube placement. Such surgery is performed now more frequently and at younger ages than in earlier decades. While otolaryngologic disease associated with achondroplasia is now recognized earlier and treated more frequently, long-term outcome studies are needed. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:1548-1554, 2022.