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1.
J Med Case Rep ; 18(1): 240, 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38730409

RESUMO

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.


Assuntos
Acondroplasia , Fraturas do Fêmur , Patela , Humanos , Adulto , Masculino , Acondroplasia/complicações , Fraturas do Fêmur/cirurgia , Fraturas do Fêmur/diagnóstico por imagem , Patela/lesões , Patela/cirurgia , Patela/diagnóstico por imagem , Fraturas Intra-Articulares/cirurgia , Fraturas Intra-Articulares/diagnóstico por imagem , Fixação Interna de Fraturas/métodos
2.
Neurol India ; 72(2): 399-402, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38691484

RESUMO

Achondroplasia is an autosomal dominant disorder with defect in the ossification of the cartilage of long bones. Many bony abnormalities constitute its clinical features, with craniovertebral junction (CVJ) anomalies being one of most common issues which need to be addressed at the earliest. CVJ anomalies in individuals may cause neurovascular compression, which may warrant an early surgery to prevent catastrophic complications. Posterior circulation strokes secondary to CVJ anomalies are well known. We hereby present an unusual case of posterior circulation stroke in an achondroplastic dwarf who presented to our tertiary care centre. Prospective case study. The present case adds to the existing literature about one of the preventable causes of fatal posterior circulation strokes in the young. A high index of suspicion for neurovascular compression at the foramen magnum and early initiation of treatment in achondroplastic young individuals may have gratifying results.


Assuntos
Acondroplasia , Acidente Vascular Cerebral , Humanos , Acondroplasia/complicações , Acidente Vascular Cerebral/etiologia , Masculino , Fatores de Risco , Compressão da Medula Espinal/cirurgia , Compressão da Medula Espinal/etiologia , Feminino , Forame Magno/cirurgia , Adulto
3.
Clin Pharmacokinet ; 63(5): 707-719, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38649657

RESUMO

BACKGROUND AND OBJECTIVE: Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and effective in increasing linear growth. This study aimed to develop a population pharmacokinetic (PPK) model to characterize pharmacokinetics (PK) of vosoritide and establish a weight-band dosing regimen. METHODS: A PPK model was developed using data from five clinical trials in children with achondroplasia (aged 0.95-15 years) who received daily per-kg doses of vosoritide. The model was used to simulate expected exposures in children with a refined weight-band dosing regimen. Simulated exposure was compared with the observed exposure from the pivotal clinical trial to evaluate appropriateness of the weight-band dosing regimen. RESULTS: A one-compartment model with a change-point first-order absorption and first-order elimination accurately described PK of vosoritide in children with achondroplasia. Body weight was found to be a predictor of vosoritide's clearance and volume of distribution. Additionally, it was observed that dosing solution concentration and duration of treatment influenced bioavailability. The weight-band dosing regimen resulted in simulated exposures that were within the range demonstrated to be well tolerated and effective in the pivotal clinical trial and showed improved consistency in drug exposure across the achondroplasia population. CONCLUSIONS: The weight-band dosing regimen reduced the number of recommended dose levels by body weight and is expected to simplify dosing for children with achondroplasia and their caregivers. CLINICAL TRIAL REGISTRATION: NCT02055157, NCT02724228, NCT03197766, NCT03424018, and NCT03583697.


Assuntos
Acondroplasia , Peso Corporal , Modelos Biológicos , Humanos , Acondroplasia/tratamento farmacológico , Criança , Adolescente , Feminino , Pré-Escolar , Masculino , Lactente , Peptídeo Natriurético Tipo C/farmacocinética , Peptídeo Natriurético Tipo C/administração & dosagem , Peptídeo Natriurético Tipo C/análogos & derivados , Relação Dose-Resposta a Droga
4.
Obes Surg ; 34(5): 1949-1953, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38564174

RESUMO

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.


Assuntos
Acondroplasia , Cirurgia Bariátrica , Laparoscopia , Obesidade Mórbida , Adulto , Humanos , Feminino , Obesidade Mórbida/cirurgia , Estudos de Viabilidade , Estudos Retrospectivos , Obesidade/complicações , Obesidade/cirurgia , Gastrectomia/efeitos adversos , Redução de Peso , Acondroplasia/cirurgia , Acondroplasia/etiologia , Resultado do Tratamento
5.
Lancet Child Adolesc Health ; 8(4): 301-310, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38485412

RESUMO

Achondroplasia is the most common form of dwarfism in humans, caused by a common pathogenic variant in the gene encoding fibroblast growth factor receptor 3, FGFR3, which impairs the process of endochondral ossification of the growing skeleton. In this Review, we outline the clinical and genetic hallmarks of achondroplasia and related FGFR3 conditions, the natural history and impact of achondroplasia over a patient's lifespan, and diagnosis and management options. We then focus on the new and emerging drug therapies that target the underlying pathogenesis of this condition. These new options are changing the natural growth patterns of achondroplasia, with the prospect of better long-term health outcomes for patients.


Assuntos
Acondroplasia , Criança , Humanos , Acondroplasia/genética , Acondroplasia/terapia
6.
Eur J Med Genet ; 68: 104930, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38428804

RESUMO

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.


Assuntos
Acondroplasia , Instabilidade Articular , Osteocondrodisplasias , Masculino , Criança , Pré-Escolar , Feminino , Humanos , Adulto , Lactente , Prevalência , Qualidade de Vida , Instabilidade Articular/epidemiologia , Acondroplasia/epidemiologia , Acondroplasia/genética , Estudos Prospectivos
7.
Eur Spine J ; 33(4): 1385-1390, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38438586

RESUMO

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.


Assuntos
Acondroplasia , Cifose , Doenças Musculoesqueléticas , Estenose Espinal , Adulto , Humanos , Estenose Espinal/complicações , Estenose Espinal/cirurgia , Estudos Retrospectivos , Vértebras Torácicas/diagnóstico por imagem , Vértebras Torácicas/cirurgia , Descompressão Cirúrgica/efeitos adversos , Acondroplasia/complicações , Acondroplasia/cirurgia , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Cifose/cirurgia , Doenças Musculoesqueléticas/complicações , Doenças Musculoesqueléticas/cirurgia , Resultado do Tratamento
8.
Genes (Basel) ; 15(2)2024 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-38397181

RESUMO

Advanced paternal age increases the risk of transmitting de novo germline mutations, particularly missense mutations activating the receptor tyrosine kinase (RTK) signalling pathway, as exemplified by the FGFR3 mutation, which is linked to achondroplasia (ACH). This risk is attributed to the expansion of spermatogonial stem cells carrying the mutation, forming sub-clonal clusters in the ageing testis, thereby increasing the frequency of mutant sperm and the number of affected offspring from older fathers. While prior studies proposed a correlation between sub-clonal cluster expansion in the testis and elevated mutant sperm production in older donors, limited data exist on the universality of this phenomenon. Our study addresses this gap by examining the testis-expansion patterns, as well as the increases in mutations in sperm for two FGFR3 variants-c.1138G>A (p.G380R) and c.1948A>G (p.K650E)-which are associated with ACH or thanatophoric dysplasia (TDII), respectively. Unlike the ACH mutation, which showed sub-clonal expansion events in an aged testis and a significant increase in mutant sperm with the donor's age, as also reported in other studies, the TDII mutation showed focal mutation pockets in the testis but exhibited reduced transmission into sperm and no significant age-related increase. The mechanism behind this divergence remains unclear, suggesting potential pleiotropic effects of aberrant RTK signalling in the male germline, possibly hindering differentiation requiring meiosis. This study provides further insights into the transmission risks of micro-mosaics associated with advanced paternal age in the male germline.


Assuntos
Acondroplasia , Sêmen , Idoso , Humanos , Masculino , Acondroplasia/genética , Mutação , Receptores Proteína Tirosina Quinases/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Espermatozoides/metabolismo , Testículo/metabolismo , Senescência Celular
9.
Genes (Basel) ; 15(2)2024 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-38397214

RESUMO

Skeletal dysplasia, also called osteochondrodysplasia, is a category of disorders affecting bone development and children's growth. Up to 552 genes, including fibroblast growth factor receptor 3 (FGFR3), have been implicated by pathogenic variations in its genesis. Frequently identified causal mutations in osteochondrodysplasia arise in the coding sequences of the FGFR3 gene: c.1138G>A and c.1138G>C in achondroplasia and c.1620C>A and c.1620C>G in hypochondroplasia. However, in some cases, the diagnostic investigations undertaken thus far have failed to identify the causal anomaly, which strengthens the relevance of the diagnostic strategies being further refined. We observed a Caucasian adult with clinical and radiographic features of achondroplasia, with no common pathogenic variant. Exome sequencing detected an FGFR3(NM_000142.4):c.1075+95C>G heterozygous intronic variation. In vitro studies showed that this variant results in the aberrant exonization of a 90-nucleotide 5' segment of intron 8, resulting in the substitution of the alanine (Ala359) for a glycine (Gly) and the in-frame insertion of 30 amino acids. This change may alter FGFR3's function. Our report provides the first clinical description of an adult carrying this variant, which completes the phenotype description previously provided in children and confirms the recurrence, the autosomal-dominant pathogenicity, and the diagnostic relevance of this FGFR3 intronic variant. We support its inclusion in routinely used diagnostic tests for osteochondrodysplasia. This may increase the detection rate of causal variants and therefore could have a positive impact on patient management. Finally, FGFR3 alteration via non-coding sequence exonization should be considered a recurrent disease mechanism to be taken into account for new drug design and clinical trial strategies.


Assuntos
Acondroplasia , Osteocondrodisplasias , Criança , Adulto , Humanos , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Acondroplasia/diagnóstico , Acondroplasia/genética , Acondroplasia/patologia , Mutação , Éxons , Fenótipo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética
10.
Biomolecules ; 14(2)2024 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-38397390

RESUMO

Natural products with health benefits, nutraceuticals, have shown considerable promise in many studies; however, this potential has yet to translate into widespread clinical use for any condition. Notably, many drugs currently on the market, including the first analgesic aspirin, are derived from plant extracts, emphasizing the historical significance of natural products in drug development. Curcumin and resveratrol, well-studied nutraceuticals, have excellent safety profiles with relatively mild side effects. Their long history of safe use and the natural origins of numerous drugs contrast with the unfavorable reputation associated with nutraceuticals. This review aims to explore the nutraceutical potential for treating pseudoachondroplasia, a rare dwarfing condition, by relating the mechanisms of action of curcumin and resveratrol to molecular pathology. Specifically, we will examine the curcumin and resveratrol mechanisms of action related to endoplasmic reticulum stress, inflammation, oxidative stress, cartilage health, and pain. Additionally, the barriers to the effective use of nutraceuticals will be discussed. These challenges include poor bioavailability, variations in content and purity that lead to inconsistent results in clinical trials, as well as prevailing perceptions among both the public and medical professionals. Addressing these hurdles is crucial to realizing the full therapeutic potential of nutraceuticals in the context of pseudoachondroplasia and other health conditions that might benefit.


Assuntos
Acondroplasia , Produtos Biológicos , Curcumina , Curcumina/farmacologia , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Suplementos Nutricionais
11.
Acta Orthop ; 95: 47-54, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38287909

RESUMO

BACKGROUND AND PURPOSE: Bilateral femoral distraction osteogenesis in patients with achondroplasia is insufficiently reported. We aimed to perform the first study that exclusively analyzed simultaneous bilateral femoral distraction osteogenesis with motorized intramedullary lengthening nails via an antegrade approach in patients with achondroplasia focused on reliability, accuracy, precision, and the evolving complications. PATIENTS AND METHODS: In this retrospective singlecenter study we analyzed patients with achondroplasia who underwent simultaneous bilateral femoral lengthening with antegrade intramedullary lengthening nails between October 2014 and April 2019. 15 patients (30 femoral segments) of median age 14 years (interquartile range [IQR] 12-15) were available for analysis. The median follow-up was 29 months (IQR 27-37) after nail implantation. RESULTS: The median distraction length per segment was 49 mm (IQR 47-51) with a median distraction index of 1.0 mm/day (IQR 0.9-1.0), and a median consolidation index of 20 days/cm (IQR 17-23). Reliability of the lengthening nails was 97% and their calculated accuracy and precision were 96% and 95%, respectively. The most common complication was temporary restriction of knee range of motion during distraction in 10 of 30 of the lengthened segments. 1 patient was treated with 2 unplanned additional surgeries due to premature consolidation. CONCLUSION: The method is reliable and accurate with few complications.


Assuntos
Acondroplasia , Alongamento Ósseo , Fixação Intramedular de Fraturas , Osteogênese por Distração , Humanos , Adolescente , Osteogênese por Distração/efeitos adversos , Osteogênese por Distração/métodos , Estudos Retrospectivos , Fixação Intramedular de Fraturas/métodos , Seguimentos , Unhas , Reprodutibilidade dos Testes , Fêmur/cirurgia , Alongamento Ósseo/métodos , Acondroplasia/complicações , Acondroplasia/cirurgia , Pinos Ortopédicos/efeitos adversos , Resultado do Tratamento , Desigualdade de Membros Inferiores/cirurgia
12.
Orphanet J Rare Dis ; 19(1): 29, 2024 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-38281003

RESUMO

AIM: Achondroplasia is the most common of the skeletal dysplasias that cause fatal and disabling growth and developmental disorders in children, and is caused by a mutation in the fibroblast growth factor receptor, type 3 gene(FGFR3). This study aims to analyse the clinical characteristics and gene mutations of ACH to accurately determine whether a patient has ACH and to raise public awareness of the disease. METHODS: The database of Pubmed, Cochrane Library, Wanfang and CNKI were searched with terms of "Achondroplasias" or "Skeleton-Skin-Brain Syndrome" or "Skeleton Skin Brain Syndrome" or "ACH" and "Receptor, Fibroblast Growth Factor, Type 3" or "FGFR3". RESULTS: Finally, four hundred and sixty-seven patients with different FGFR3 mutations were enrolled. Of the 138 patients with available gender information, 55(55/138, 40%) were female and 83(83/138, 60%) were male. Among the patients with available family history, 47(47/385, 12%) had a family history and 338(338/385, 88%) patients were sporadic. The age of the patients ranged from newborn babies to 36 years old. The mean age of their fathers was 37 ± 7 years (range 31-53 years). Patients came from 12 countries and 2 continents, with the majority being Asian (383/432, 89%), followed by European (49/432, 11%). Short stature with shortened arms and legs was found in 112(112/112) patients, the abnormalities of macrocephaly in 94(94/112) patients, frontal bossing in 89(89/112) patients, genu valgum in 64(64/112) patients and trident hand were found in 51(51/112) patients. The most common mutation was p.Gly380Arg of the FGFR3 gene, which contained two different base changes, c.1138G > A and c.1138G > C. Ten rare pathogenic mutations were found, including c.831A > C, c.1031C > G, c.1043C > G, c.375G > T, c.1133A > G, c.1130T > G, c.833A > G, c.649A > T, c.1180A > T and c.970_971insTCTCCT. CONCLUSION: ACH was caused by FGFR3 gene mutation, and c.1138G > A was the most common mutation type. This study demonstrates the feasibility of molecular genetic testing for the early detection of ACH in adolescents with short stature, trident hand, frontal bossing, macrocephaly and genu valgum.


Assuntos
Acondroplasia , Geno Valgo , Megalencefalia , Osteocondrodisplasias , Criança , Recém-Nascido , Adolescente , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Acondroplasia/genética , Acondroplasia/patologia , Mutação/genética
13.
Am J Med Genet A ; 194(5): e63538, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38214061

RESUMO

Individuals with differing forms of skeletal dysplasias (SD) frequently report impaired mobility and symptoms. With the objetive to evaluate mobility and associated symptoms in people with SD at an Argentinian pediatric hospital, using an Argentinian version of the Screening Tool for Everyday Mobility and Symptoms (STEMS), a simple questionnaire that allows clinicians to quickly identify the presence of symptoms associated with mobility in people with SD, while considering different environmental settings and the use of assistive devices, an analytical study of a consecutive sample of patients older than 5 years with SD and their affected relatives was carried out.Diagnosis, comorbidities, socioenvironmental, therapeutic, auxological and mobility variables were recorded. The presence and intensity of symptoms was noted through use of both the STEMS and validated scales. Descriptive, association and correlation analyzes were performed. One hundred and nineteen individuals with SD were enrolled in the study and divided into groups: Osteogenesis Imperfecta (OI, n = 55), Achondroplasia (ACH, n = 36) and Other SD resulting in disproportionate short stature (n = 28). Mobility assistive devices were almost exclusively used by individuals with OI. They were more frequently used by individuals with overweight and obesity, more severe form of the disease and in the outdoor settings. Two thirds (66.4%) of the individuals assessed in this study reported pain, 87.4% reported fatigue, and 58.8% reported both pain and fatigue. The intensity of symptoms was similar between groups and correlated with age and auxological variables. The STEMS was clear, easy and quick to use for identifying presence of pain and fatigue in this population group. The STEMS proved to be a simple and useful tool for evaluating functional mobility and associated symptoms in our population of individuals with SD.


Assuntos
Acondroplasia , Osteogênese Imperfeita , Criança , Humanos , Osteogênese Imperfeita/diagnóstico , Acondroplasia/diagnóstico , Acondroplasia/epidemiologia , Acondroplasia/complicações , Inquéritos e Questionários , Dor , Fadiga/diagnóstico
14.
J Endocrinol Invest ; 47(2): 345-356, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37466810

RESUMO

PURPOSE: This study aimed to assess the real-world management of achondroplasia in Italy. METHODS: Two online surveys addressed to (1) parents/caregivers of individuals with achondroplasia and (2) Italian clinicians managing individuals with achondroplasia were conducted to assess real-world perspectives on achondroplasia management. Both surveys collected data on either patient or clinician demographics, details on diagnoses and referrals, disease complications, and views/experiences with limb lengthening surgery. RESULTS: In total, 42 parents/caregivers and 19 clinicians (from 18 hospitals) completed the surveys. According to parents/caregivers, achondroplasia diagnosis was most commonly made in the third trimester of gestation (55% of respondents), with a genetic test performed to confirm the diagnosis in all but one case. In contrast, the clinicians indicated that, while achondroplasia was typically suspected during the prenatal period (78%), diagnosis was more frequently confirmed postnatally (72%). Parents/caregivers reported that the greatest impact of achondroplasia-related complications occurred in their children between the ages of 2-5 years. The most significant complications were otitis, sleep apnoea, stenosis of the foramen magnum or pressure on the spinal cord, and hearing difficulties. Lengthening surgery had been presented as a treatment option to 92% of responding parents/caregivers, with 76% of clinicians viewing surgery favourably. Typically, clinicians' reasons for suggesting limb lengthening surgery were to improve patient quality of life, increase patient autonomy and self-acceptance, improve trunk-limb disproportion, short stature and walking, and ensure that all possible treatment options had been presented to the parents/caregivers. CONCLUSION: This survey provides insight into the real-world management of individuals with achondroplasia in Italy.


Assuntos
Acondroplasia , Qualidade de Vida , Criança , Humanos , Pré-Escolar , Cuidadores , Acondroplasia/diagnóstico , Acondroplasia/epidemiologia , Acondroplasia/terapia , Inquéritos e Questionários , Pais
15.
Childs Nerv Syst ; 40(3): 913-917, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38091071

RESUMO

Achondroplasia is the most common form of dwarfism, caused by a mutation in fibroblast growth factor receptor 3 gene, leading to multiple pathological conditions. Herein, we present a case of an infant with achondroplasia associated with hydrocephalus and severe foramen magnum stenosis. Computed tomography (CT) venography showed prominent suboccipital emissary veins comprising major venous drainage routes and hypoplastic transverse sinuses, which increased the risk of foramen magnum decompression. The infant was initially treated with ventriculo-peritoneal (VP) shunt. After 8 months, CT venography showed regression of suboccipital emissary veins and more prominent transverse sinuses. Subsequently, foramen magnum decompression was safely performed without sacrificing major venous drainage routes.


Assuntos
Acondroplasia , Derivação Ventriculoperitoneal , Lactente , Humanos , Derivação Ventriculoperitoneal/efeitos adversos , Crânio/cirurgia , Forame Magno/cirurgia , Acondroplasia/complicações , Acondroplasia/diagnóstico por imagem , Acondroplasia/cirurgia , Drenagem
16.
Eur J Med Genet ; 67: 104894, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38070826

RESUMO

Short stature or shortening of the limbs can be the result of a variety of genetic variants. Achondroplasia is the most common cause of disproportionate short stature and is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene (FGFR3). Short stature homeobox (SHOX) deficiency is caused by loss or defects of the SHOX gene or its enhancer region. It is associated with a spectrum of phenotypes ranging from normal stature to Léri-Weill dyschondrosteosis characterized by mesomelia and short stature or the more severe Langer mesomelic dysplasia in case of biallelic SHOX deficiency. Little is known about the interactions and phenotypic consequences of achondroplasia in combination with SHOX deficiency, as the literature on this subject is scarce, and no genetically confirmed clinical reports exist. We present the clinical findings in an infant girl with concurrent achondroplasia and SHOX deficiency. We conclude that the clinical findings in infancy are phenotypically compatible with achondroplasia, with no features of the SHOX deficiency evident. This may change over time, as some features of SHOX deficiency only become evident later in life.


Assuntos
Acondroplasia , Osteocondrodisplasias , Feminino , Humanos , Lactente , Acondroplasia/genética , Dinamarca , Deleção de Genes , Genes Homeobox , Transtornos do Crescimento/genética , Proteínas de Homeodomínio/genética , Osteocondrodisplasias/genética , Proteína de Homoeobox de Baixa Estatura/genética
17.
J Pediatr Orthop ; 44(3): e249-e254, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38084006

RESUMO

BACKGROUND: Femoral fracture after femoral lengthening in patients with achondroplasia and hypochondroplasia is a frequent complication, occurring in up to 30%. The purpose of this study is to demonstrate the effectiveness of prophylactic intramedullary rodding in preventing this complication. METHODS: Multicenter retrospective study involving 86 femoral lengthening procedures in 43 patients with achondroplasia or hypochondroplasia. Forty-two femora (21 patients) were prophylactically managed with intramedullary Rush rodding after external fixation removal (11 females and 10 males, mean age 14.6 years) compared with 44 femora (22 patients) without prophylactic intramedullary rodding (13 females and 9 males, mean age 15.2 years). The mean amount of lengthening in the rodding group was 13.3 cm (52.6%) with an External Fixation Index of 25.8 days/cm; in patients without rodding was 14.3 cm (61.5%) and 24.5 days/cm, respectively. RESULTS: Seven cases (15.9%) without rodding developed fractures. Four of them required surgical correction due to displacement or shortening. Only 1 patient (2.4%) had fracture of the femur after prophylactic rodding, and surgery was not required. The incidence of femur fracture was significantly lower in the prophylactic rodding group compared with the nonrodding group (2.4% vs. 15.9%, respectively; P =0.034). There were no cases of infection or avascular necrosis. CONCLUSIONS: Prophylactic intramedullary rodding is a safe and effective method for preventing femoral fractures after femoral lengthening in patients with achondroplasia or hypochondroplasia. LEVEL OF EVIDENCE: Level III-a retrospective comparative study.


Assuntos
Acondroplasia , Alongamento Ósseo , Osso e Ossos/anormalidades , Nanismo , Fraturas do Fêmur , Fixação Intramedular de Fraturas , Deformidades Congênitas dos Membros , Lordose , Masculino , Feminino , Humanos , Adolescente , Estudos Retrospectivos , Fêmur/cirurgia , Fixadores Internos/efeitos adversos , Acondroplasia/complicações , Fraturas do Fêmur/cirurgia , Alongamento Ósseo/métodos , Fixação Intramedular de Fraturas/métodos , Resultado do Tratamento
18.
Pediatr Radiol ; 54(1): 82-95, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37953411

RESUMO

BACKGROUND: Skeletal dysplasias collectively affect a large number of patients worldwide. Most of these disorders cause growth anomalies. Hence, evaluating skeletal maturity via the determination of bone age (BA) is a useful tool. Moreover, consecutive BA measurements are crucial for monitoring the growth of patients with such disorders, especially for timing hormonal treatment or orthopedic interventions. However, manual BA assessment is time-consuming and suffers from high intra- and inter-rater variability. This is further exacerbated by genetic disorders causing severe skeletal malformations. While numerous approaches to automate BA assessment have been proposed, few are validated for BA assessment on children with skeletal dysplasias. OBJECTIVE: We present Deeplasia, an open-source prior-free deep-learning approach designed for BA assessment specifically validated on patients with skeletal dysplasias. MATERIALS AND METHODS: We trained multiple convolutional neural network models under various conditions and selected three to build a precise model ensemble. We utilized the public BA dataset from the Radiological Society of North America (RSNA) consisting of training, validation, and test subsets containing 12,611, 1,425, and 200 hand and wrist radiographs, respectively. For testing the performance of our model ensemble on dysplastic hands, we retrospectively collected 568 radiographs from 189 patients with molecularly confirmed diagnoses of seven different genetic bone disorders including achondroplasia and hypochondroplasia. A subset of the dysplastic cohort (149 images) was used to estimate the test-retest precision of our model ensemble on longitudinal data. RESULTS: The mean absolute difference of Deeplasia for the RSNA test set (based on the average of six different reference ratings) and dysplastic set (based on the average of two different reference ratings) were 3.87 and 5.84 months, respectively. The test-retest precision of Deeplasia on longitudinal data (2.74 months) is estimated to be similar to a human expert. CONCLUSION: We demonstrated that Deeplasia is competent in assessing the age and monitoring the development of both normal and dysplastic bones.


Assuntos
Acondroplasia , Aprendizado Profundo , Osteocondrodisplasias , Criança , Humanos , Estudos Retrospectivos , Radiografia , Determinação da Idade pelo Esqueleto/métodos
19.
Adv Ther ; 41(1): 198-214, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37882884

RESUMO

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.


Assuntos
Acondroplasia , Peptídeo Natriurético Tipo C , Criança , Humanos , Peptídeo Natriurético Tipo C/uso terapêutico , Atenção à Saúde , Manejo da Dor , Acondroplasia/tratamento farmacológico
20.
Eur J Pediatr ; 183(3): 1121-1128, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37831302

RESUMO

As we continue to understand more about the complex mechanism of growth, a plethora of novel therapies have recently been developed that aim to address barriers and optimize efficacy. This review aims to explore these novel therapies and provide a succinct review based on the latest clinical studies in order to introduce clinicians to therapies that will soon constitute the future in the field of short stature.  Conclusion: The review focuses on long-acting growth hormone formulations, a novel growth hormone oral secretagogue, novel treatments for children with achondroplasia, and targeted therapies for rare forms of skeletal dysplasias. What is Known: • Recombinant human growth hormone has been the mainstay of treatment for children with short stature for years. • Such therapy is not always effective based on the underlying diagnosis (e.g achondroplasia, Turner syndrome). Compliance with daily injections is challenging and can directly affect efficacy. What is New: • Recent development of long-acting growth hormone regimens and oral secretagogues can overcome some of these barriers, however several limitations need to be taken into consideration. • Newer therapies for achondroplasia, and other rare forms of skeletal dysplasias introduce us to a new era of targeted therapies for children with short stature. Clinicians ought to be aware of pitfalls and caveats before introducing these novel therapies to every day practice.


Assuntos
Acondroplasia , Hormônio do Crescimento Humano , Síndrome de Turner , Criança , Humanos , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Hormônio do Crescimento/uso terapêutico , Acondroplasia/tratamento farmacológico
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