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Selenophosphate synthetase (SEPHS) plays an essential role in selenium metabolism. Two mammalian SEPHS paralogues, SEPHS1 and SEPHS2, share high sequence identity and structural homology with SEPHS. Here, we report nine individuals from eight families with developmental delay, growth and feeding problems, hypotonia, and dysmorphic features, all with heterozygous missense variants in SEPHS1. Eight of these individuals had a recurrent variant at amino acid position 371 of SEPHS1 (p.Arg371Trp, p.Arg371Gln, and p.Arg371Gly); seven of these variants were known to be de novo. Structural modeling and biochemical assays were used to understand the effect of these variants on SEPHS1 function. We found that a variant at residue Trp352 results in local structural changes of the C-terminal region of SEPHS1 that decrease the overall thermal stability of the enzyme. In contrast, variants of a solvent-exposed residue Arg371 do not impact enzyme stability and folding but could modulate direct protein-protein interactions of SEPSH1 with cellular factors in promoting cell proliferation and development. In neuronal SH-SY5Y cells, we assessed the impact of SEPHS1 variants on cell proliferation and ROS production and investigated the mRNA expression levels of genes encoding stress-related selenoproteins. Our findings provided evidence that the identified SEPHS1 variants enhance cell proliferation by modulating ROS homeostasis. Our study supports the hypothesis that SEPHS1 plays a critical role during human development and provides a basis for further investigation into the molecular mechanisms employed by SEPHS1. Furthermore, our data suggest that variants in SEPHS1 are associated with a neurodevelopmental disorder.
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Deficiência Intelectual , Anormalidades Musculoesqueléticas , Transtornos do Neurodesenvolvimento , Animais , Criança , Humanos , Deficiências do Desenvolvimento/genética , Éxons , Deficiência Intelectual/genética , Mamíferos/genética , Hipotonia Muscular/genética , Anormalidades Musculoesqueléticas/genética , Neuroblastoma/genética , Transtornos do Neurodesenvolvimento/genética , Espécies Reativas de OxigênioRESUMO
Hypophosphatasia (HPP) is a rare inborn error of metabolism that presents variably in both age of onset and severity. HPP is caused by pathogenic variants in the ALPL gene, resulting in low activity of tissue nonspecific alkaline phosphatase (TNSALP). Patients with HPP tend have a similar pattern of elevation of natural substrates that can be used to aid in diagnosis. No formal diagnostic guidelines currently exist for the diagnosis of this condition in children, adolescents, or adults. The International HPP Working Group is a comprised of a multidisciplinary team of experts from Europe and North America who have expertise in the diagnosis and management of patients with HPP. This group reviewed 93 papers through a Medline, Medline In-Process, and Embase search for the terms "HPP" and "hypophosphatasia" between 2005 and 2020 and that explicitly address either the diagnosis of HPP in children, clinical manifestations of HPP in children, or both. Two reviewers independently evaluated each full-text publication for eligibility and studies were included if they were narrative reviews or case series/reports that concerned diagnosis of pediatric HPP or included clinical aspects of patients diagnosed with HPP. This review focused on 15 initial clinical manifestations that were selected by a group of clinical experts.The highest agreement in included literature was for pathogenic or likely pathogenic ALPL variant, elevation of natural substrates, and early loss of primary teeth. The highest prevalence was similar, including these same three parameters and including decreased bone mineral density. Additional parameters had less agreement and were less prevalent. These were organized into three major and six minor criteria, with diagnosis of HPP being made when two major or one major and two minor criteria are present.
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Hipofosfatasia , Adulto , Criança , Humanos , Adolescente , Hipofosfatasia/diagnóstico , Hipofosfatasia/genética , Fosfatase Alcalina/genética , Europa (Continente) , Prevalência , MutaçãoRESUMO
Hypophosphatasia (HPP) is an inborn error of metabolism caused by reduced or absent activity of the tissue non-specific alkaline phosphatase (TNSALP) enzyme, resulting from pathogenic variants in the ALPL gene. Clinical presentation of HPP is highly variable, including lethal and severe forms in neonates and infants, a benign perinatal form, mild forms manifesting in adulthood, and odonto-HPP. Diagnosis of HPP remains a challenge in adults, as signs and symptoms may be mild and non-specific. Disease presentation varies widely; there are no universal signs or symptoms, and the disease often remains underdiagnosed or misdiagnosed, particularly by clinicians who are not familiar with this rare disorder. The absence of diagnosis or a delayed diagnosis may prevent optimal management for patients with this condition. Formal guidelines for the diagnosis of adults with HPP do not exist, complicating efforts for consistent diagnosis. To address this issue, the HPP International Working Group selected 119 papers that explicitly address the diagnosis of HPP in adults through a Medline, Medline In-Process, and Embase search for the terms "hypophosphatasia" and "HPP," and evaluated the pooled prevalence of 17 diagnostic characteristics, initially selected by a group of HPP clinical experts, in eligible studies and in patients included in these studies. Six diagnostic findings showed a pooled prevalence value over 50% and were considered for inclusion as major diagnostic criteria. Based on these results and according to discussion and consideration among members of the Working Group, we finally defined four major diagnostic criteria and five minor diagnostic criteria for HPP in adults. Authors suggested the integrated use of the identified major and minor diagnostic criteria, which either includes two major criteria, or one major criterion and two minor criteria, for the diagnosis of HPP in adults.
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Hipofosfatasia , Lactente , Adulto , Recém-Nascido , Humanos , Hipofosfatasia/diagnóstico , Hipofosfatasia/epidemiologia , Hipofosfatasia/genética , Fosfatase Alcalina/genética , Mutação , PrevalênciaRESUMO
BACKGROUND: This manuscript provides a summary of the current evidence to support the criteria for diagnosing a child or adult with hypophosphatasia (HPP). The diagnosis of HPP is made on the basis of integrating clinical features, laboratory profile, radiographic features of the condition, and DNA analysis identifying the presence of a pathogenic variant of the tissue nonspecific alkaline phosphatase gene (ALPL). Often, the diagnosis of HPP is significantly delayed in both adults and children, and updated diagnostic criteria are required to keep pace with our evolving understanding regarding the relationship between ALPL genotype and associated HPP clinical features. METHODS: An International Working Group (IWG) on HPP was formed, comprised of a multidisciplinary team of experts from Europe and North America with expertise in the diagnosis and management of patients with HPP. Methodologists (Romina Brignardello-Petersen and Gordon Guyatt) and their team supported the IWG and conducted systematic reviews following the GRADE methodology, and this provided the basis for the recommendations. RESULTS: The IWG completed systematic reviews of the literature, including case reports and expert opinion papers describing the phenotype of patients with HPP. The published data are largely retrospective and include a relatively small number of patients with this rare condition. It is anticipated that further knowledge will lead to improvement in the quality of genotype-phenotype reporting in this condition. CONCLUSION: Following consensus meetings, agreement was reached regarding the major and minor criteria that can assist in establishing a clinical diagnosis of HPP in adults and children.
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Hipofosfatasia , Adulto , Criança , Humanos , Hipofosfatasia/diagnóstico , Hipofosfatasia/genética , Mutação , Estudos Retrospectivos , Fosfatase Alcalina/genética , Genótipo , FenótipoRESUMO
Editing services within academic health centers are uncommon, and few studies have reported on their impact. In this article, we describe our medical writing center's editing service for faculty and trainees at a pediatric teaching hospital and associated outcomes of scholarly products (e.g., manuscripts and grants) over an 8-year period. Data for manuscripts and grant proposals edited by the writing center from 2015 through 2022 were collected electronically from our service request database. Outcome data on publications and grant proposals were regularly collected up to 12 months post-submission. Users were also asked if the writing center edits were helpful, improved readability, and if they planned to use the service in the future. From 2015 through 2022, the writing center received 697 requests, 88.4% to edit a document. Of the documents edited, 81.3% of manuscripts and 44.4% of grant proposals were successfully published or funded. When rating their experience, 97.8% of respondents rated the edits "helpful," 96.7% indicated the edits "improved readability," and 99.3% stated they planned to use the writing center in the future. Our results showed steady use of the writing center and high satisfaction with services. A writing center can be an effective tool to support psychology faculty development.
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PURPOSE: This study aimed to assess the amount and types of clinical genetic testing denied by insurance and the rate of diagnostic and candidate genetic findings identified through research in patients who faced insurance denials. METHODS: Analysis consisted of review of insurance denials in 801 patients enrolled in a pediatric genomic research repository with either no previous genetic testing or previous negative genetic testing result identified through cross-referencing with insurance prior-authorizations in patient medical records. Patients and denials were also categorized by type of insurance coverage. Diagnostic findings and candidate genetic findings in these groups were determined through review of our internal variant database and patient charts. RESULTS: Of the 801 patients analyzed, 147 had insurance prior-authorization denials on record (18.3%). Exome sequencing and microarray were the most frequently denied genetic tests. Private insurance was significantly more likely to deny testing than public insurance (odds ratio = 2.03 [95% CI = 1.38-2.99] P = .0003). Of the 147 patients with insurance denials, 53.7% had at least 1 diagnostic or candidate finding and 10.9% specifically had a clinically diagnostic finding. Fifty percent of patients with clinically diagnostic results had immediate medical management changes (5.4% of all patients experiencing denials). CONCLUSION: Many patients face a major barrier to genetic testing in the form of lack of insurance coverage. A number of these patients have clinically diagnostic findings with medical management implications that would not have been identified without access to research testing. These findings support re-evaluation of insurance carriers' coverage policies.
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Genômica , Cobertura do Seguro , Criança , HumanosRESUMO
De novo variants in FOXP4 were recently associated with a neurodevelopmental disorder characterized by speech and language delay, growth abnormalities, hypotonia, and variable congenital abnormalities, including congenital diaphragmatic hernia, cervical spine abnormalities, strabismus, cryptorchidism, and ptosis. The variant spectrum in this small cohort was limited to de novo missense except for one frameshift, the inheritance of which was unknown. Variants tested in vitro exhibited reduced repressor transcriptional activity, indicating loss of function is the likely mechanism of disease, but only one frameshift variant was reported. Here, we report four affected individuals from two unrelated families heterozygous for a nonsense variant, c.1893C > G, p.Tyr631*, in FOXP4. The phenotype of the affected children includes developmental delay, feeding difficulties in infancy, and similar facial features. In both cases, the variant was inherited from a parent with mild or even subclinical features. Interestingly, one patient presented with congenital diaphragmatic hernia, as reported in two other FOXP4 patients. This report implicates FOXP4 truncating variants in human disease and highlights the wide phenotypic spectrum and variable expressivity.
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Fatores de Transcrição Forkhead , Hérnias Diafragmáticas Congênitas , Transtornos do Neurodesenvolvimento , Criança , Humanos , Masculino , Fatores de Transcrição Forkhead/genética , Mutação da Fase de Leitura , Hérnias Diafragmáticas Congênitas/genética , Deficiência Intelectual/genética , Hipotonia Muscular/genética , FenótipoRESUMO
Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-causing variants in PPM1D leading to JdVS. Clinical data were provided by treating physicians and/or families. Of the 37 individuals, 27 were male and 10 female, with median age 8.75 years (range 8 months to 62 years). Four families document autosomal dominant transmission, and 32/34 probands were diagnosed via exome sequencing. The facial gestalt, including a broad forehead and broad mouth with a thin and tented upper lip, was most recognizable between 18 and 48 months of age. Common manifestations included global developmental delay (35/36, 97%), hypotonia (25/34, 74%), short stature (14/33, 42%), constipation (22/31, 71%), and cyclic vomiting (6/35, 17%). Distinctive personality traits include a hypersocial affect (21/31, 68%) and moderate-to-severe anxiety (18/28, 64%). In conclusion, JdVS is a clinically recognizable neurodevelopmental syndrome with a characteristic personality and distinctive facial features. The association of pathogenic variants in PPM1D with cyclic vomiting bears not only medical attention but also further pathogenic and mechanistic evaluation.
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Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Adulto , Criança , Feminino , Humanos , Lactente , Masculino , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Proteína Fosfatase 2C/genética , Estudos Retrospectivos , Vômito , Pré-Escolar , Adolescente , Adulto Jovem , Pessoa de Meia-IdadeRESUMO
Notch signaling is an established developmental pathway for brain morphogenesis. Given that Delta-like 1 (DLL1) is a ligand for the Notch receptor and that a few individuals with developmental delay, intellectual disability, and brain malformations have microdeletions encompassing DLL1, we hypothesized that insufficiency of DLL1 causes a human neurodevelopmental disorder. We performed exome sequencing in individuals with neurodevelopmental disorders. The cohort was identified using known Matchmaker Exchange nodes such as GeneMatcher. This method identified 15 individuals from 12 unrelated families with heterozygous pathogenic DLL1 variants (nonsense, missense, splice site, and one whole gene deletion). The most common features in our cohort were intellectual disability, autism spectrum disorder, seizures, variable brain malformations, muscular hypotonia, and scoliosis. We did not identify an obvious genotype-phenotype correlation. Analysis of one splice site variant showed an in-frame insertion of 12 bp. In conclusion, heterozygous DLL1 pathogenic variants cause a variable neurodevelopmental phenotype and multi-systemic features. The clinical and molecular data support haploinsufficiency as a mechanism for the pathogenesis of this DLL1-related disorder and affirm the importance of DLL1 in human brain development.
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Proteínas de Ligação ao Cálcio/genética , Haploinsuficiência , Proteínas de Membrana/genética , Transtornos do Neurodesenvolvimento/genética , Estudos de Coortes , Feminino , Humanos , Ligantes , Masculino , Linhagem , Sequenciamento do ExomaRESUMO
BACKGROUND: Hypophosphatasia (HPP), a rare metabolic disease, can be inherited in an autosomal recessive (biallelic) or an autosomal dominant (monoallelic) manner. Most of the severe, early-onset, frequently lethal HPP in infants is acquired through recessive inheritance; less severe, later-onset, typically nonlethal HPP phenotypes are acquired through either dominant or recessive inheritance. HPP's variable clinical presentation arises from >400 identified ALPL pathogenic variants with likely variable penetrance, especially with autosomal dominant inheritance. This post hoc analysis investigated the relationship between ALPL variant state (biallelic and monoallelic) and clinical outcomes with asfotase alfa in HPP. METHODS: Data were pooled from two phase 2, randomized, open-label studies in adolescents and adults with HPP; one study evaluated the efficacy and safety of different doses of asfotase alfa (n = 25), and the other assessed the pharmacodynamics and safety of asfotase alfa (n = 19). Patients were grouped by ALPL variant state (biallelic or monoallelic). Available data from both studies included ALPL pathogenic variant state, Baseline characteristics, HPP-specific medical history, and Baseline TNSALP substrate levels (inorganic pyrophosphate [PPi] and pyridoxal 5'-phosphate [PLP]) concentrations). Clinical outcomes over 5 years of treatment were available from only the efficacy and safety study. RESULTS: In total, 44 patients with known variant status were included in the pooled analysis (biallelic, n = 30; monoallelic, n = 14). The most common pathogenic variant was c.571G > A (p.Glu191Lys) in biallelic patients (allele frequency: 19/60) and c.1133A > T (p.Asp378Val) in monoallelic patients (allele frequency: 7/28). Median (min, max) Baseline PPi concentrations were significantly higher in patients with a biallelic vs monoallelic variant state (5.3 [2.2, 12.1] vs 4.3 [3.5, 7.4] µM; P = 0.0113), as were Baseline PLP concentrations (221.4 [62.4, 1590.0] vs 75.1 [28.8, 577.0] ng/mL; P= 0.0022). HPP-specific medical history was generally similar between biallelic and monoallelic patients in terms of incidence and type of manifestations; notable exceptions included fractures, which were more common among monoallelic patients, and delayed walking and bone deformities such as abnormally shaped chest and head and bowing of arms or legs, which were more common among biallelic patients. Data from the efficacy and safety study (n = 19) showed that median PPi and PLP concentrations were normalized over 5 years of treatment in patients with both variant states. Median % predicted distance walked on the 6-Minute Walk Test remained within the normal range for monoallelic patients over 4 years of treatment, and improved from below normal (<84%) to normal in biallelic patients. CONCLUSIONS: Although patients with biallelic variants had significantly higher Baseline PPi and PLP levels than monoallelic variants, both groups generally showed similar pretreatment Baseline clinical characteristics. Treatment with asfotase alfa for up to 5 years normalized TNSALP substrate concentrations and improved functional outcomes, with no clear differences between biallelic and monoallelic variant states. This study suggests that patients with HPP have significant disease burden, regardless of ALPL variant state.
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Fosfatase Alcalina/administração & dosagem , Fosfatase Alcalina/genética , Hipofosfatasia/tratamento farmacológico , Imunoglobulina G/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Adolescente , Adulto , Ensaios Clínicos Fase II como Assunto , Feminino , Genes Recessivos/genética , Humanos , Hipofosfatasia/genética , Hipofosfatasia/patologia , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Adulto JovemRESUMO
Nager syndrome epitomizes the acrofacial dysostoses, which are characterized by craniofacial and limb defects. The craniofacial defects include midfacial retrusion, downslanting palpebral fissures, prominent nasal bridge, and micrognathia. Limb malformations typically include hypoplasia or aplasia of radial elements including the thumb. Nager syndrome is caused by haploinsufficiency of SF3B4, encoding a spliceosomal protein called SAP49. Here, we report a patient with a loss of function variant in SF3B4 without acrofacial dysostosis or limb defects, whose reason for referral was developmental and growth delay. This patient is evidence of a broader phenotypic spectrum associated with SF3B4 variants than previously appreciated.
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Predisposição Genética para Doença , Disostose Mandibulofacial/genética , Fatores de Processamento de RNA/genética , Spliceossomos/genética , Disostose Craniofacial/genética , Disostose Craniofacial/patologia , Haploinsuficiência/genética , Humanos , Lactente , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/patologia , Masculino , Disostose Mandibulofacial/patologia , Mutação/genética , Fenótipo , Spliceossomos/patologiaRESUMO
CDC42BPB encodes MRCKß (myotonic dystrophy-related Cdc42-binding kinase beta), a serine/threonine protein kinase, and a downstream effector of CDC42, which has recently been associated with Takenouchi-Kosaki syndrome, an autosomal dominant neurodevelopmental disorder. We identified 12 heterozygous predicted deleterious variants in CDC42BPB (9 missense, 2 frameshift, and 1 nonsense) in 14 unrelated individuals (confirmed de novo in 11/14) with neurodevelopmental disorders including developmental delay/intellectual disability, autism, hypotonia, and structural brain abnormalities including cerebellar vermis hypoplasia and agenesis/hypoplasia of the corpus callosum. The frameshift and nonsense variants in CDC42BPB are expected to be gene-disrupting and lead to haploinsufficiency via nonsense-mediated decay. All missense variants are located in highly conserved and functionally important protein domains/regions: 3 are found in the protein kinase domain, 2 are in the citron homology domain, and 4 in a 20-amino acid sequence between 2 coiled-coil regions, 2 of which are recurrent. Future studies will help to delineate the natural history and to elucidate the underlying biological mechanisms of the missense variants leading to the neurodevelopmental and behavioral phenotypes.
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Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Miotonina Proteína Quinase/genética , Transtornos do Neurodesenvolvimento/genética , Adolescente , Adulto , Sequência de Aminoácidos , Transtorno Autístico/epidemiologia , Transtorno Autístico/genética , Transtorno Autístico/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/patologia , Feminino , Mutação da Fase de Leitura , Haploinsuficiência , Heterozigoto , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/patologia , Mutação com Perda de Função/genética , Masculino , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/patologia , FenótipoRESUMO
The 20th annual Santa Fe Bone Symposium was held August 9-10, 2019, in Santa Fe, New Mexico, USA. This is an annual meeting devoted to clinical applications of recent advances in skeletal research that impact the care of patients with osteoporosis, metabolic bone diseases, and inherited bone diseases. Participants included practicing and academic physicians, fellows, advanced practice providers, fracture liaison service (FLS) coordinators, clinical researchers, and bone density technologists. The symposium consisted of lectures, case presentations, and panel discussions, with an emphasis on learning through interaction of all attendees. Topics included new approaches in the use of anabolic agents for the treatment osteoporosis, a review of important events in skeletal health over the past year, new and emerging treatments for rare bone diseases, the use of genetic testing for bone diseases in clinical practice, medication-associated causes of osteoporosis, new concepts in the use of estrogen therapy for osteoporosis, new Official Positions of the International Society for Clinical Densitometry, skeletal consequences of bariatric surgery, and update on the progress and potential of Bone Health TeleECHO, a virtual community of practice using videoconferencing technology to link healthcare professionals for advancing the care of osteoporosis worldwide. Sessions on rare bone diseases were developed in collaboration with the Rare Bone Disease Alliance. Symposium premeetings included an FLS workshop by the National Osteoporosis Foundation and others devoted to the use of new therapeutic agents for the care of osteoporosis and related disorders.
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Doenças Ósseas/terapia , Osteoporose/terapia , Animais , Densidade Óssea , Doenças Ósseas/genética , Doenças Ósseas/metabolismo , Humanos , Doenças Raras/terapiaRESUMO
PURPOSE: Osteogenesis imperfecta (OI) is a genetic connective tissue disorder that causes bone fragility. Phenotypic severity influences ability to walk, however, little is known about ambulatory characteristics of individuals with OI, especially in more severe forms. The purpose of this work was to characterize mobility in OI using standard clinical assessment tools and determine if patient characteristics could be used to predict mobility outcomes. METHODS: We collected mobility data at five clinical sites to analyze the largest cohort of individuals with OI (n = 491) to date. Linear mixed models were developed to explore relationships among subject demographics and mobility metrics. RESULTS: Results showed minor limitations in the mild group while the more severe types showed more significant limitations in all mobility metrics analyzed. Height and weight were shown to be the most significant predictors of mobility. Relationships with mobility and bisphosphonates varied with OI type and type used (oral/IV). CONCLUSION: These results are significant to understanding mobility limitations of specific types of OI and beneficial when developing rehabilitation protocols for this population. It is important for physicians, patients, and caregivers to gain insight into severity and classification of the disease and the influence of disease-related characteristics on prognosis for mobility.
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Limitação da Mobilidade , Osteogênese Imperfeita/fisiopatologia , Osteogênese Imperfeita/reabilitação , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte , Fenótipo , PrognósticoRESUMO
Pulmonary complications are a significant cause for morbidity and mortality in osteogenesis imperfecta (OI). However, to date, there have been few studies that have systematically evaluated pulmonary function in individuals with OI. We analyzed spirometry measurements, including forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1 ), in a large cohort of individuals with OI (n = 217) enrolled in a multicenter, observational study. We show that individuals with the more severe form of the disease, OI type III, have significantly reduced FVC and FEV1 which do not follow the expected trends of the normal population. We also show that "normalization" of FVC and FEV1 using general population data to generate percent predicted values underestimates the pulmonary involvement in OI. Within each subtype of OI, we used linear mixed models to find potential correlations between FEV1 and FVC with the clinical variables including mobility, bisphosphonate use, and scoliosis. Our results are an important step in understanding the extent of pulmonary involvement in individuals with OI and for developing pulmonary endpoints for use in the routine patient care as well as in the investigation of new therapies.
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Pulmão/fisiopatologia , Osteogênese Imperfeita/fisiopatologia , Adolescente , Adulto , Idoso , Criança , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Osteogênese Imperfeita/diagnóstico , Testes de Função Respiratória , Índice de Gravidade de Doença , Espirometria , Capacidade Vital , Adulto JovemRESUMO
BACKGROUND: To report a single-center surgical experience treating humeral deformity and fractures in children with osteogenesis imperfecta (OI) using the Fassier-Duval (FD) intramedullary elongating rods. METHODS: A retrospective review was conducted between December 2005 and July 2013 of all OI patients who underwent FD rodding with a minimum of 1-year follow-up. All patients were also being concurrently treated with bisphosphonates. RESULTS: Eighteen patients underwent internal fixation on a total of 35 humeri: 7 males and 11 females with an average age of 49 months. Thirty-five procedures were performed using FD rodding, with 5 utilizing only the male portion. Thirty procedures were primary FD implantation and 5 were revisions. Twelve patients had type III OI and 6 patients type IV OI. Indications for surgery included recurrent fracture, severe bowing deformity, and pain. Osteotomy methods included closed osteoclasis, percutaneous, or open osteotomies. Two patients required transfusions during their hospital stay. At our determined endpoint, 23 humeri (65.7%) had acceptable results with a mean follow-up time of 43 months (SD=27) with no revision. The remaining 12 humeri (34.3%) necessitated revision with a mean time to revision of 35 months (SD=29). Reasons for revision included: migration resulting in pain and functional difficulty (8.6%), migration with bowing (8.6%), and hardware failure secondary to trauma (8.6%). In addition, 2 revisions were required for nonunion (5.7%) and 1 for malunion (2.9%). To our knowledge, all other osteotomies performed during surgery resulted in bony union. CONCLUSIONS: The use of the FD system for correction of humeral deformity demonstrates a reasonable option to improve comfort and function in children with recurrent fractures and deformity secondary to OI. The FD system allows for decreased revision rates and less morbid instrumentation. LEVEL OF EVIDENCE: Level IV-retrospective case series.
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Fraturas Ósseas/cirurgia , Fixadores Internos/efeitos adversos , Osteogênese Imperfeita/cirurgia , Osteotomia/métodos , Adolescente , Criança , Pré-Escolar , Falha de Equipamento , Feminino , Fraturas Ósseas/etiologia , Humanos , Úmero/anormalidades , Úmero/lesões , Úmero/cirurgia , Masculino , Osteogênese Imperfeita/complicações , Estudos RetrospectivosRESUMO
BACKGROUND: Patients with osteogenesis imperfecta (OI) have significant burden of both fractures and bony deformities. The present approach to care in this disorder is a combination of surgical care with intramedullary rod fixation, cyclic bisphosphonate therapy, and rehabilitation with goal of maximizing patient function and quality of life. METHODS: Retrospective chart review identified 58 children with OI who had realignment osteotomies with Fassier-Duval (FD) intramedullary nailing of the lower extremity by a single surgeon. This is a consecutive series treated between 2003 and 2010. Postoperatively, patients were followed up clinically and radiologically. Motor function was assessed using the Brief Assessment of Motor Function score and the walking scale subset of the Gillette Functional Assessment Questionnaire. RESULTS: Fifty-eight patients had 179 lower extremity FD intramedullary rods placed. This technique allowed for intervention on multiple long bones, with 29% having bilateral femur and tibial rodding in the same procedure. Revisions were required in 53% of patients, which occurred at a mean time of 52 months after initial rodding surgery. In most cases, revision surgery was related to patient growth and subsequent fracture, although rod migration did occur in a minority of patients. Nonunion or incomplete union was 14.5% in this series. Bisphosphonate infusion was not postponed after surgical procedures. Patients had improvement in mobility status at the latest follow-up. CONCLUSIONS: This series lends evidence to the medium-term utility of FD intramedullary rods as an effective and less invasive platform for stabilization and correction of deformity in long bones of patients with OI. Relatively low blood loss and relatively short hospitalizations were noted. Nonunion rate was comparable with existing literature noting that our patients did not have postsurgical postponement of bisphosphonate therapy. LEVEL OF EVIDENCE: Therapeutic study to investigate the results of treatment with FD rods. Retrospective case series model of Level IV evidence quality.
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Fêmur/cirurgia , Fixação Intramedular de Fraturas/métodos , Osteogênese Imperfeita/cirurgia , Osteotomia/métodos , Tíbia/cirurgia , Adolescente , Conservadores da Densidade Óssea/uso terapêutico , Criança , Pré-Escolar , Difosfonatos/uso terapêutico , Feminino , Fraturas Ósseas/cirurgia , Humanos , Lactente , Fixadores Internos , Masculino , Osteogênese Imperfeita/tratamento farmacológico , Qualidade de Vida , Reoperação , Estudos RetrospectivosRESUMO
Hypophosphatasia (HPP) is a rare, inherited, systemic, metabolic disorder caused by autosomal recessive mutations or a single dominant-negative mutation in the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). The disease is associated with a broad range of signs, symptoms, and complications, including impaired skeletal mineralization, altered calcium and phosphate metabolism, recurrent fractures, pain, respiratory problems, impaired growth and mobility, premature tooth loss, developmental delay, and seizures. Asfotase alfa is a human, recombinant enzyme replacement therapy that is approved in many countries for the treatment of patients with HPP. To address the unmet need for guidance in the monitoring of patients receiving asfotase alfa, an international panel of physicians with experience in diagnosing and managing HPP convened in May 2016 to discuss treatment monitoring parameters. The panel discussions focused on recommendations for assessing and monitoring patients after the decision to treat with asfotase alfa had been made and did not include recommendations for whom to treat. Based on the consensus of panel members, this review provides guidance on the monitoring of patients with HPP during treatment with asfotase alfa, including recommendations for laboratory, efficacy, and safety assessments and the frequency with which these should be performed during the course of treatment. Recommended assessments are based on patient age and include regular monitoring of biochemistry, skeletal radiographs, respiratory function, growth, pain, mobility and motor function, and quality of life. Because of the systemic presentation of HPP, a coordinated, multidisciplinary, team-based, patient-focused approach is recommended in the management of patients receiving asfotase alfa. Monitoring of efficacy and safety outcomes must be tailored to the individual patient, depending on medical history, clinical manifestations, availability of resources in the clinical setting, and the clinician's professional judgment.