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1.
Medicine (Baltimore) ; 98(17): e15349, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31027114

RESUMO

The purpose of this study was to estimate the rate of spontaneous improvement in tibial metaphyseal-diaphyseal angle (TMDA) in physiologic bowing in comparison to that in Blount disease and to provide reference values of TMDA for monitoring patients with highly suspected to have Blount disease.We retrospectively reviewed patients with physiologic bowing meeting the following criteria:(1) TMDA greater than 9° before 36 months of age at initial evaluation;(2) two or more standing long bone radiographs available; and(3) follow-up conducted up to resolution of deformity.Patients with Blount disease had(1) more than 2 standing long bone radiographs obtained before 36 months of age and(2) underwent no treatment during the period in which these images were obtained.TMDA measurements were obtained from 174 patients with physiologic bowing and 32 patients with Blount disease. Rates of TMDA improvement were adjusted by multiple factors using a linear mixed model, with sex and laterality as fixed effects and age and individual patients as the random effects.In the physiologic bowing group, TMDA improved significantly, by 3° per 6 months and by 6° per year. Changes in TMDA were not significant in the Blount disease group.Knowing the rate of TMDA change can be helpful for physicians seeking to monitor infants with suspected as having Blount disease with a high TMDA and to avoid unnecessary repeat radiographic evaluations.


Assuntos
Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Genu Varum/diagnóstico por imagem , Osteocondrose/congênito , Tíbia/diagnóstico por imagem , Doenças do Desenvolvimento Ósseo/fisiopatologia , Criança , Pré-Escolar , Diáfises/diagnóstico por imagem , Diáfises/crescimento & desenvolvimento , Diáfises/fisiopatologia , Progressão da Doença , Feminino , Seguimentos , Genu Varum/fisiopatologia , Humanos , Lactente , Masculino , Osteocondrose/diagnóstico por imagem , Osteocondrose/fisiopatologia , Estudos Retrospectivos , Tíbia/crescimento & desenvolvimento , Tíbia/fisiopatologia
2.
Orthop Clin North Am ; 50(2): 193-209, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30850078

RESUMO

Osteogenesis imperfecta is a genetically and phenotypically heterogeneous disorder related to a defect or deficiency in the production of type I collagen. It is characterized by brittle bones, fractures, spine and extremity deformity, and a host of extraskeletal manifestations. Type I collagen is present in bone, tendons, ligaments, skin, dentin, and the sclera of the eye and other connective tissues. Osteogenesis imperfecta includes a multitude of disease manifestations that may be present at birth or develop over time and vary depending on the severity of the disease. This article describes the disease presentation and management considerations from a pediatric orthopedic perspective.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Deformidades Congênitas dos Membros/diagnóstico , Osteogênese Imperfeita/diagnóstico , Osteogênese Imperfeita/genética , Adolescente , Doenças do Desenvolvimento Ósseo/patologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Cálcio/administração & dosagem , Cálcio/uso terapêutico , Criança , Pré-Escolar , Difosfonatos/administração & dosagem , Difosfonatos/uso terapêutico , Exercício/fisiologia , Feminino , Órtoses do Pé/normas , Fraturas Ósseas/complicações , Fraturas Ósseas/terapia , Humanos , Lactente , Comunicação Interdisciplinar , Deformidades Congênitas dos Membros/etiologia , Deformidades Congênitas dos Membros/cirurgia , Deformidades Congênitas dos Membros/terapia , Masculino , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/patologia , Escoliose/patologia , Escoliose/cirurgia , Coluna Vertebral/anormalidades , Coluna Vertebral/patologia , Vitamina D/uso terapêutico
3.
Genes Brain Behav ; 18(4): e12553, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30786142

RESUMO

KBG syndrome is a neurodevelopmental disorder, caused by dominant mutations in ANKRD11, that is characterized by developmental delay/intellectual disability, mild craniofacial dysmorphisms, and short stature. Behavior and cognition have hardly been studied, but anecdotal evidence suggests higher frequencies of ADHD-symptoms and social-emotional impairments. In this study, the behavioral and cognitive profile of KBG syndrome will be investigated in order to examine if and how cognitive deficits contribute to behavioral difficulties. A total of 18 patients with KBG syndrome and a control group consisting of 17 patients with other genetic disorders with comparable intelligence levels, completed neuropsychological assessment. Age-appropriate tasks were selected, covering overall intelligence, attention, memory, executive functioning, social cognition and visuoconstruction. Results were compared using Cohen's d effect sizes. As to behavior, fewer difficulties in social functioning and slightly more attentional problems, hyperactivity, oppositional defiant behavior and conduct problems were found in the KBG syndrome group. Regarding cognitive functioning, inspection of the observed differences shows that patients with KBG syndrome showed lower scores on sustained attention, cognitive flexibility, and visuoconstruction. In contrast, the KBG syndrome group demonstrated higher scores on visual memory, social cognition and emotion recognition. The cognitive profile of KBG syndrome in this sample indicates problems in attention and executive functioning that may underlie the behavior profile which primarily comprises impulsive behavior. Contrary to expectations based on previous (case) reports, no deficits were found in social cognitive functioning. These findings are important for counseling purposes, for tailored education planning, and for the development of personalized intervention.


Assuntos
Anormalidades Múltiplas/fisiopatologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Cognição , Deficiência Intelectual/fisiopatologia , Fenótipo , Anormalidades Dentárias/fisiopatologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/psicologia , Adolescente , Adulto , Idoso , Atenção , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/psicologia , Criança , Função Executiva , Facies , Feminino , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/psicologia , Inteligência , Masculino , Memória , Pessoa de Meia-Idade , Proteínas Repressoras/genética , Comportamento Social , Anormalidades Dentárias/genética , Anormalidades Dentárias/psicologia , Percepção Visual
4.
BMC Med Genet ; 20(1): 16, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642272

RESUMO

BACKGROUND: KBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. So far, there have been over 100 cases of KBG syndrome reported. CASE PRESENTATION: Here, we describe two sisters of a non-consanguineous family, both presenting generalized epilepsy with febrile seizures (GEFS+), and one with a more complex phenotype associated with mild intellectual disability, skeletal and dental anomalies. Whole exome sequencing (WES) analysis in all the family members revealed a heterozygous SCN9A mutation, p.(Lys655Arg), shared among the father and the two probands, and a novel de novo loss of function mutation in the ANKRD11 gene, p.(Tyr1715*), in the proband with the more complex phenotype. The reassessment of the phenotypic features confirmed that the patient fulfilled the proposed diagnostic criteria for KBG syndrome, although complicated by early-onset isolated febrile seizures. EEG abnormalities with or without seizures have been reported previously in some KBG cases. The shared variant, occurring in SCN9A, has been previously found in several individuals with GEFS+ and Dravet syndrome. CONCLUSIONS: This report describe a novel de novo variant in ANKRD11 causing a mild phenotype of KGB syndrome and further supports the association of monogenic pattern of SCN9A mutations with GEFS+. Our data expand the allelic spectrum of ANKRD11 mutations, providing the first Brazilian case of KBG syndrome. Furthermore, this study offers an example of how WES has been instrumental allowing us to better dissect the clinical phenotype under study, which is a multilocus variation aggregating in one proband, rather than a phenotypic expansion associated with a single genomic locus, underscoring the role of multiple rare variants at different loci in the etiology of clinical phenotypes making problematic the diagnostic path. The successful identification of the causal variant in a gene may not be sufficient, making it necessary to identify other variants that fully explain the clinical picture. The prevalence of blended phenotypes from multiple monogenic disorders is currently unknown and will require a systematic re-analysis of large WES datasets for proper diagnosis in daily practice.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Epilepsia Generalizada/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Mutação , Fenótipo , Proteínas Repressoras/genética , Convulsões Febris/genética , Anormalidades Dentárias/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Alelos , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Doenças do Desenvolvimento Ósseo/etiologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Brasil , Eletroencefalografia , Epilepsia Generalizada/fisiopatologia , Facies , Feminino , Loci Gênicos , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/etiologia , Deficiência Intelectual/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Linhagem , Convulsões Febris/fisiopatologia , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/etiologia , Anormalidades Dentárias/fisiopatologia , Sequenciamento Completo do Exoma
5.
Hum Mol Genet ; 28(7): 1183-1198, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30544148

RESUMO

Natriuretic peptide receptor B (NPRB) produces cyclic guanosine monophosphate (cGMP) when bound by C-type natriuretic peptide (CNP). Activating mutations in NPRB cause a skeletal overgrowth disorder, which has been named epiphyseal chondrodysplasia, Miura type (ECDM; OMIM #615923). Here we explored the cellular and molecular mechanisms for the skeletal overgrowth in ECDM using a mouse model in which an activating mutant NPRB is specifically expressed in chondrocytes. The mutant mice (NPRB[p.V883M]-Tg) exhibited postnatal skeletal overgrowth and increased cGMP in cartilage. Both endogenous and transgene-derived NPRB proteins were localized at the plasma membrane of hypertrophic chondrocytes. The hypertrophic zone of growth plate was thickened in NPRB[p.V883M]-Tg. An in vivo BrdU-labeling assay suggested that some of the hypertrophic chondrocytes in NPRB[p.V883M]-Tg mice continued to proliferate, although wild-type (WT) chondrocytes stopped proliferating after they became hypertrophic. In vitro cell studies revealed that NPRB activation increased the phosphorylation of cyclic AMP-responsive element binding protein (CREB) and expression of cyclin D1 in matured chondrocytes. Treatment with cell-permeable cGMP also enhanced the CREB phosphorylation. Inhibition of cyclic adenosine monophosphate (cAMP)/protein kinase A pathway had no effects on the CREB phosphorylation induced by NPRB activation. In immunostaining of the growth plates for the proliferation marker Ki67, phosphorylated CREB and cyclin D1, most signals were similarly observed in the proliferating zone in both genotypes, but some cells in the hypertrophic zone of NPRB[p.V883M]-Tg were also positively stained. These results suggest that NPRB activation evokes its signal in hypertrophic chondrocytes to induce CREB phosphorylation and make them continue to proliferate, leading to the skeletal overgrowth in ECDM.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Receptores do Fator Natriurético Atrial/genética , Animais , Doenças do Desenvolvimento Ósseo/fisiopatologia , Cartilagem/crescimento & desenvolvimento , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Condrócitos/fisiologia , Condrogênese/genética , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Mutação com Ganho de Função/genética , Lâmina de Crescimento/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosforilação
7.
J Pediatr Orthop ; 38(2): 100-104, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27203823

RESUMO

BACKGROUND: Guided growth has long been used in the lower extremities but has not been applied to varus or valgus deformity in the hip, as may occur in children with cerebral palsy or developmental dysplasia of the hip. The purpose of this study was to determine if screw, plate, or drilling techniques decreased the femoral neck-shaft angle (NSA) and articular trochanteric disease (ATD), as well as describe growth plate structural changes with each method. METHODS: Twelve 8-week-old lambs underwent proximal femoral hemiepiphysiodesis (IACUC approved) using either a screw (n=4), plate (n=4), or drilling procedure (n=4). Postoperative time was 6 months. Radiographs taken after limb harvest were used to measure NSA and ATD. Differences between treated and control sides were determined by 1-tailed paired t tests and Bonferroni (α=0.05/3). Histology was obtained for 1 limb pair per group. Proximal femurs were cut in midcoronal plane and the longitudinal growth plates were examined for structural changes. RESULTS: The mean NSA measured 7 degrees less than controls in this model using the screw technique, and this difference was statistically significant. Differences between the control and the treated groups did not reach statistical significance for either the plate or the drill group. Differences in ATD were not statistically significant, although there was a trend for larger ATD measurements using the screw technique. Histologically, physeal changes were observed on the operative sides in screw and plate specimens, but not drill specimens, compared with contralateral sham control. The screw specimen exhibited the most severe changes, with growth plate closure over half the section. The plate specimen showed focal loss of the physis across the section, but with no evidence of closure. CONCLUSIONS: This study builds on previous work that indicates screw hemiepiphysiodesis can effectively alter the shape of the proximal femur, and result in a lower neck-shaft ankle (or lesser valgus). This study suggests that implantation of a screw is likely to be more effective than a plate or drilling procedure in decreasing the NSA in skeletally immature hips. CLINICAL SIGNIFICANCE: If further preclinical, and later clinical, studies demonstrate reproducible efficacy, guided growth of the proximal femur may eventually become a viable option for treatment or prevention of hip deformity in select patients.


Assuntos
Placas Ósseas , Parafusos Ósseos/efeitos adversos , Colo do Fêmur/cirurgia , Lâmina de Crescimento/cirurgia , Animais , Doenças do Desenvolvimento Ósseo/fisiopatologia , Criança , Feminino , Colo do Fêmur/diagnóstico por imagem , Colo do Fêmur/crescimento & desenvolvimento , Colo do Fêmur/patologia , Lâmina de Crescimento/patologia , Humanos , Masculino , Modelos Animais , Osteotomia , Radiografia , Ovinos
8.
Respir Med ; 131: 18-26, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28947027

RESUMO

BACKGROUND: Skeletal dysplasia encompasses a variety of developmental disorders of the bone and cartilage that manifest as disproportionate shortening of limbs and trunk in the neonate. Many types of skeletal dysplasia are complicated by respiratory failure at or soon after birth and require intensive care and prolonged hospitalization. Respiratory complications in these infants are complex and are characterized by airway anomalies, restrictive lung disease due to a narrow and abnormally compliant chest wall, pulmonary hypoplasia, and central apnea. Appropriate management of these unique patients requires a clear understanding of the pathophysiology and use of pulmonary function tests for early recognition and management of complications. CONCLUSION: This review provides an overview of the underlying respiratory pathology and a practical guide to the newborn care provider for the diagnosis and management of respiratory complications in infants with skeletal dysplasia.


Assuntos
Doenças do Desenvolvimento Ósseo/fisiopatologia , Pneumopatias/terapia , Doenças do Desenvolvimento Ósseo/complicações , Gerenciamento Clínico , Humanos , Lactente , Recém-Nascido , Pulmão/anormalidades , Pneumopatias/etiologia , Pneumopatias/fisiopatologia , Testes de Função Respiratória , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/fisiopatologia , Insuficiência Respiratória/terapia , Apneia do Sono Tipo Central/etiologia , Apneia do Sono Tipo Central/fisiopatologia , Apneia do Sono Tipo Central/terapia , Parede Torácica
9.
Arch Oral Biol ; 80: 10-17, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28363114

RESUMO

OBJECTIVE: In order to provide a better understanding of the sympathetic nervous system as a negative regulator of bone status, the aim of the study was to establish the biomechanical mandible response to different doses of a ß-adrenergic antagonist such as propranolol (P) in a stress-induced food restriction model of growth retardation. METHODS: Rats were assigned to eight groups: Control (C), C+P3.5 (CP3.5), C+P7 (CP7), C+P14 (CP14), NGR, NGR+P3.5 (NGRP3.5), NGR+P7 (NGRP7) and NGR+P14 (NGRP14). C, CP3.5, CP7 and CP14 rats were freely fed with the standard diet. NGR, NGRP3.5, NGRP7 and NGRP14 rats received, for 4 weeks (W4), 80% of the amount of controls food consumed. Propranolol 3.5, 7 and 14mg/kg/day was injected ip 5days per week in CP3.5 and NGRP3.5, CP7 and NGRP7, CP14 and NGRP14, respectively. At W4, zoometry, mandible morphometry, static histomorphometric and biomechanical competence were performed. RESULTS: A dose of Propranolol 7mg/kg/day induced interradicular bone volume accretion reaching a mandible stiffness according to chronological age. CONCLUSION: These findings evidenced that sympathetic nervous system activity is a negative regulator of mandible mechanical competence in the nutritional growth retardation model. Propranolol 7mg/kg/day, under the regimen usage, seems to be appropriate to blockade SNS activity on mandible mechanical performance in NGR rats, probably associated to an effect on bone mechanostat system ability to detect disuse mode as an error.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Privação de Alimentos/fisiologia , Mandíbula/efeitos dos fármacos , Mandíbula/crescimento & desenvolvimento , Propranolol/farmacologia , Sistema Nervoso Simpático/fisiopatologia , Animais , Biomarcadores , Fenômenos Biomecânicos , Peso Corporal , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Elasticidade , Masculino , Mandíbula/fisiopatologia , Tamanho do Órgão/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Wistar
10.
Am J Med Genet A ; 173(5): 1152-1158, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28371255

RESUMO

Delta phalanx is a rare abnormality typically associated with additional features. We describe a patient with a phenotype resembling Catel-Manzke syndrome, but with delta phalanx and abnormal vertebrae and ribs. The patient was the only child of half siblings born with a marked prenatal growth deficiency. At 10 years of age, she had a short stature, long face, long and tubular nose with small alae nasi, high palate, short and broad thorax, and short index fingers with radial deviation. There were hyperpigmentations following Blaschko's lines. Radiology showed a proximal delta phalanx in the index finger of hands, abnormal vertebrae, and fused and small ribs. GTG-Banding karyotype and microarray analysis yielded normal results. Exome sequencing identified 25 genes that harbored homozygous variants, but none of these is assumed to be a good candidate to explain (part of) the phenotype. The here described patient may have a new condition, possibly following an autosomal recessive pattern of inheritance, although due to the high degree of consanguinity a compound etiology of the phenotype by variants in various genes may be present as well.


Assuntos
Anormalidades Múltiplas/fisiopatologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Nanismo/fisiopatologia , Deformidades Congênitas da Mão/fisiopatologia , Síndrome de Pierre Robin/fisiopatologia , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Criança , Consanguinidade , Nanismo/diagnóstico por imagem , Nanismo/genética , Feminino , Deformidades Congênitas da Mão/diagnóstico por imagem , Deformidades Congênitas da Mão/genética , Humanos , Cariótipo , Linhagem , Fenótipo , Síndrome de Pierre Robin/diagnóstico por imagem , Síndrome de Pierre Robin/genética , Costelas/diagnóstico por imagem , Costelas/patologia , Costelas/fisiopatologia , Irmãos
11.
Methods Cell Biol ; 138: 321-346, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28129851

RESUMO

Small teleost fish such as zebrafish and medaka are increasingly studied as models for human skeletal diseases. Efficient new genome editing tools combined with advances in the analysis of skeletal phenotypes provide new insights into fundamental processes of skeletal development. The skeleton among vertebrates is a highly conserved organ system, but teleost fish and mammals have evolved unique traits or have lost particular skeletal elements in each lineage. Several unique features of the skeleton relate to the extremely small size of early fish embryos and the small size of adult fish used as models. A detailed analysis of the plethora of interesting skeletal phenotypes in zebrafish and medaka pushes available skeletal imaging techniques to their respective limits and promotes the development of new imaging techniques. Impressive numbers of zebrafish and medaka mutants with interesting skeletal phenotypes have been characterized, complemented by transgenic zebrafish and medaka lines. The advent of efficient genome editing tools, such as TALEN and CRISPR/Cas9, allows to introduce targeted deficiencies in genes of model teleosts to generate skeletal phenotypes that resemble human skeletal diseases. This review will also discuss other attractive aspects of the teleost skeleton. This includes the capacity for lifelong tooth replacement and for the regeneration of dermal skeletal elements, such as scales and fin rays, which further increases the value of zebrafish and medaka models for skeletal research.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Biologia Molecular/métodos , Oryzias/genética , Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/crescimento & desenvolvimento , Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/fisiopatologia , Sistemas CRISPR-Cas/genética , Modelos Animais de Doenças , Humanos , Oryzias/crescimento & desenvolvimento , Regeneração/genética , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição/genética , Peixe-Zebra/crescimento & desenvolvimento
12.
J Pediatr Orthop ; 37(1): e37-e42, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26523701

RESUMO

BACKGROUND: Guided growth is often used to correct limb deformity and yet implant screw failure in modular systems has been reported. There have been no reports of plate failure and we do not know the exact mode of failure when screws do break. METHODS: We report the first published case of a fractured plate in a modular plate and screw construct that was used to correct Blount disease in a child through guided growth. The implants were removed and analyzed for method of failure using scanning electron microscopy. RESULTS: Scanning electron microscopy of the explant confirms that the mode of failure was not a result of static tension from growth. Rather, analysis confirms cyclic fatigue that led to crack propagation across the anterior side of the plate until overload caused complete plate failure. CONCLUSIONS: This analysis confirms an in vivo cyclic compression-relaxation of the growth plate presumably to weight-bearing, and that when excessive may lead to implant failure as seen here in this case. LEVEL OF EVIDENCE: Level V.


Assuntos
Doenças do Desenvolvimento Ósseo , Alongamento Ósseo , Placas Ósseas/efeitos adversos , Desigualdade de Membros Inferiores , Microscopia Eletrônica de Varredura/métodos , Osteocondrose/congênito , Complicações Pós-Operatórias , Falha de Prótese , Doenças do Desenvolvimento Ósseo/complicações , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/fisiopatologia , Alongamento Ósseo/efeitos adversos , Alongamento Ósseo/instrumentação , Alongamento Ósseo/métodos , Criança , Humanos , Desigualdade de Membros Inferiores/diagnóstico , Desigualdade de Membros Inferiores/etiologia , Desigualdade de Membros Inferiores/cirurgia , Masculino , Osteocondrose/complicações , Osteocondrose/diagnóstico , Osteocondrose/fisiopatologia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/fisiopatologia , Complicações Pós-Operatórias/cirurgia , Falha de Prótese/efeitos adversos , Falha de Prótese/etiologia , Reoperação/métodos , Tíbia/diagnóstico por imagem , Resultado do Tratamento , Suporte de Carga
13.
Eur J Med Genet ; 59(11): 577-583, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27667191

RESUMO

Raine syndrome is a rare autosomal recessive bone dysplasia characterized by characteristic facial features with exophthalmos and generalized osteosclerosis. Amelogenesis imperfecta, hearing loss, seizures, and intracerebral calcification are apparent in some affected individuals. Originally, Raine syndrome was originally reported as a lethal syndrome. However, recently a milder phenotype, compatible with life, has been described. Biallelic variants inFAM20C, encoding aGolgi casein kinase involved in biomineralisation, have been identified in affected individuals. We report here a consanguineous Moroccan family with two affected siblingsa girl aged 18 and a boy of 15years. Clinical features, including learning disability, seizures and amelogenesis imperfecta, initially suggested a diagnosis of Kohlschutter-Tonz syndrome. However,a novel homozygous FAM20Cvariantc.676T > A, p.(Trp226Arg) was identified in the affected siblings. Our report reinforces that Raine syndrome is compatible with life, and that mild hypophosphatemia and amelogenesis imperfecta are key features of the attenuated form.


Assuntos
Anormalidades Múltiplas/genética , Amelogênese Imperfeita/genética , Caseína Quinase I/genética , Fissura Palatina/genética , Demência/genética , Diagnóstico Diferencial , Epilepsia/genética , Exoftalmia/genética , Proteínas da Matriz Extracelular/genética , Microcefalia/genética , Osteosclerose/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/fisiopatologia , Adolescente , Amelogênese Imperfeita/diagnóstico , Amelogênese Imperfeita/mortalidade , Amelogênese Imperfeita/fisiopatologia , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/mortalidade , Doenças do Desenvolvimento Ósseo/fisiopatologia , Fissura Palatina/diagnóstico , Fissura Palatina/mortalidade , Fissura Palatina/fisiopatologia , Demência/diagnóstico , Demência/mortalidade , Demência/fisiopatologia , Epilepsia/diagnóstico , Epilepsia/mortalidade , Epilepsia/fisiopatologia , Exoftalmia/diagnóstico , Exoftalmia/mortalidade , Exoftalmia/fisiopatologia , Feminino , Humanos , Transtornos de Aprendizagem/genética , Transtornos de Aprendizagem/fisiopatologia , Masculino , Microcefalia/diagnóstico , Microcefalia/mortalidade , Microcefalia/fisiopatologia , Osteosclerose/diagnóstico , Osteosclerose/mortalidade , Osteosclerose/fisiopatologia , Fenótipo , Convulsões/genética , Convulsões/fisiopatologia
14.
Eur J Med Genet ; 59(6-7): 330-6, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27182040

RESUMO

"Disorganized Development of Skeletal Component" (DDSC) is a group of genetic skeletal dysplasia, caused by mutations in 9 genes including ACVR1. The most known ACVR1-related disorder is fibrodysplasia ossificans progressiva (FOP). FOP variants are frequently encountered with diagnostic challenges due to overlapping clinical manifestations and variable severity. Application of high throughput sequencing methods can overcome these limitations by simultaneous investigation of the entire ACVR1 gene together with other genes involved in disorders with similar manifestations. A 33-year-old man with an unusual skeletal dysplasia and no previous clinical diagnosis is presented in this study. Whole exome sequencing detected a novel c.737T>A (p.Phe246Tyr) mutation in ACVR1 gene. Detailed targeted variant analysis in 226 known genes associated with genetic skeletal disorders together with more specific targeted analysis in 9 genes associated with DDSC ruled out the involvement of other investigated genes. Proband's phenotypically normal father and brother had the same mutation in whom subsequent investigations showed subclinical radiographic findings. The clinical manifestations, the disease course, and the molecular findings of involvement of ACVR1 gene in this family are suggestive of "FOP variant" or an unusual ACVR1-related skeletal dysplasia. Moreover, this report has demonstrated the critical role of the next generation sequencing technique in characterizing such a rare disorder with variable and even no clinical manifestations, providing the opportunity for effective preventive measures such as preimplantation genetic diagnosis.


Assuntos
Receptores de Ativinas Tipo I/genética , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Musculoesqueléticas/genética , Adulto , Doenças do Desenvolvimento Ósseo/fisiopatologia , Exoma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Anormalidades Musculoesqueléticas/fisiopatologia , Mutação , Fenótipo
15.
Am J Med Genet A ; 170(7): 1908-11, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27139183

RESUMO

Here we describe the second reported family with the CATSHL syndrome, a condition resulting from a unique mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. Our family confirms the consistent and unique phenotype of this condition, and the specificity of the mutation in FGFR3. The CATSHL syndrome appears to be an autosomal dominant disorder with full penetrance. © 2016 Wiley Periodicals, Inc.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Deformidades Congênitas da Mão/genética , Perda Auditiva Neurossensorial/genética , Perda Auditiva/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Adolescente , Sequência de Aminoácidos/genética , Doenças do Desenvolvimento Ósseo/fisiopatologia , Feminino , Deformidades Congênitas da Mão/fisiopatologia , Perda Auditiva/fisiopatologia , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Masculino , Mutação , Linhagem , Penetrância , Fenótipo
16.
Eur J Hum Genet ; 24(2): 198-207, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25966638

RESUMO

A rare lethal autosomal recessive syndrome with skeletal dysplasia, polycystic kidneys and multiple malformations was first described by Gillessen-Kaesbach et al and subsequently by Nishimura et al. The skeletal features uniformly comprise a round pelvis, mesomelic shortening of the upper limbs and defective ossification of the cervical spine. We studied two unrelated families including three affected fetuses with Gillessen-Kaesbach-Nishimura syndrome using whole-exome and Sanger sequencing, comparative genome hybridization and homozygosity mapping. All affected patients were shown to have a novel homozygous splice variant NM_024740.2: c.1173+2T>A in the ALG9 gene, encoding alpha-1,2-mannosyltransferase, involved in the formation of the lipid-linked oligosaccharide precursor of N-glycosylation. RNA analysis demonstrated skipping of exon 10, leading to shorter RNA. Mass spectrometric analysis showed an increase in monoglycosylated transferrin as compared with control tissues, confirming that this is a congenital disorder of glycosylation (CDG). Only three liveborn children with ALG9-CDG have been previously reported, all with missense variants. All three suffered from intellectual disability, muscular hypotonia, microcephaly and renal cysts, but none had skeletal dysplasia. Our study shows that some pathogenic variants in ALG9 can present as a lethal skeletal dysplasia with visceral malformations as the most severe phenotype. The skeletal features overlap with that previously reported for ALG3- and ALG12-CDG, suggesting that this subset of glycosylation disorders constitutes a new diagnostic group of skeletal dysplasias.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Doenças do Sistema Nervoso Central/genética , Exoma/genética , Manosiltransferases/genética , Proteínas de Membrana/genética , Degeneração Neural/genética , Osteocondrodisplasias/genética , Anormalidades Múltiplas/patologia , Processamento Alternativo/genética , Sequência de Aminoácidos , Doenças do Desenvolvimento Ósseo/fisiopatologia , Doenças do Sistema Nervoso Central/fisiopatologia , Criança , Hibridização Genômica Comparativa , Feminino , Glicosilação , Humanos , Masculino , Mutação de Sentido Incorreto , Degeneração Neural/fisiopatologia , Osteocondrodisplasias/patologia , Fenótipo , Isoformas de Proteínas/genética , Análise de Sequência de RNA
17.
J Pediatr Orthop ; 36(8): 877-883, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26090984

RESUMO

BACKGROUND: Slipped capital femoral epiphysis (SCFE) and tibia vara (Blount disease) are associated with childhood obesity. However, the majority of obese children do not develop SCFE or tibia vara. Therefore, it is hypothesized that other obesity-related biological changes to the physis, in addition to increased biomechanical stress, potentiate the occurrence of SCFE and tibia vara. Considering that hypertension can impose pathologic changes in the physis similar to those observed in these obesity-related diseases we set out to determine the prevalence of hypertension in patients with SCFE and tibia vara. METHODS: Blood pressure measurements were obtained in 44 patients with tibia vara and 127 patients with SCFE. Body mass index and blood pressure were adjusted for age, sex, and height percentiles utilizing normative distribution data from the CDC. These cohorts were compared with age-matched and sex-matched cohorts derived from an obesity clinic who did not have either bone disease. A multivariable proportional odds model was used to determine association. RESULTS: The prevalence of prehypertension/hypertension was significantly higher in the tibia vara (64%) and SCFE cohort (64%) compared with respective controls (43%). Patients diagnosed with either SCFE or tibia vara had 2.5-fold higher odds of having high blood pressure compared with age-matched and sex-matched obese patients without bone disease. Sex, age, and race did not have a significant effect on a patient's blood pressure. CONCLUSIONS: This is the first study to establish that the obesity-related bone diseases, SCFE and tibia vara, are significantly associated with high blood pressure. These data have immediate clinical impact as they demonstrate that children with obesity-related developmental bone disease have increased prevalence of undiagnosed and untreated hypertension. Furthermore, this prevalence study supports the hypothesis that hypertension in conjunction with increased biomechanical forces together potentiate the occurrence of SCFE and tibia vara. If proven true, it is plausible that hypertension may represent a modifiable risk factor for obesity-related bone disease. LEVEL OF EVIDENCE: Level III-case-control study.


Assuntos
Pressão Sanguínea , Doenças do Desenvolvimento Ósseo/complicações , Hipertensão/epidemiologia , Osteocondrose/congênito , Escorregamento das Epífises Proximais do Fêmur/complicações , Adolescente , Doenças do Desenvolvimento Ósseo/fisiopatologia , Criança , Pré-Escolar , Feminino , Humanos , Hipertensão/etiologia , Hipertensão/fisiopatologia , Masculino , Osteocondrose/complicações , Osteocondrose/fisiopatologia , Prevalência , Fatores de Risco , Escorregamento das Epífises Proximais do Fêmur/fisiopatologia , Estados Unidos/epidemiologia
18.
Ann Hum Genet ; 79(4): 238-44, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25959430

RESUMO

Acromesomelic dysplasia Maroteaux type (AMDM) is an autosomal recessive skeletal disorder characterized by disproportionate short stature with shortening of the acromesomelic sections of the limbs. AMDM is caused by mutations in the NPR2 gene located on chromosome 9p21-p12. The gene encodes the natriuretic peptide receptor B (NPR-B) that acts as an endogenous receptor for C-type natriuretic peptide (CNP). Both CNP and NPR-B are considered as important regulators of longitudinal growth. The study presented here investigated three consanguineous families (A, B, C) segregating AMDM in an autosomal recessive manner. Linkage in the families was established to the NPR2 gene on chromosome 9p12-21. Sequence analysis of the gene revealed two novel missense variants (p.Arg601Ser; p.Arg749Trp) in two families and a previously reported splice site variant (c.2986+2T>G) in the third family.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Consanguinidade , Análise Mutacional de DNA , Receptores do Fator Natriurético Atrial/genética , Doenças do Desenvolvimento Ósseo/patologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Feminino , Humanos , Masculino , Mutação , Mutação de Sentido Incorreto , Linhagem , Processamento de RNA
19.
Cell Mol Life Sci ; 72(7): 1347-61, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25487608

RESUMO

Several metabolic, genetic and oncogenic bone diseases are characterized by defective or excessive bone formation. These abnormalities are caused by dysfunctions in the commitment, differentiation or survival of cells of the osteoblast lineage. During the recent years, significant advances have been made in our understanding of the cellular and molecular mechanisms underlying the osteoblast dysfunctions in osteoporosis, skeletal dysplasias and primary bone tumors. This led to suggest novel therapeutic approaches to correct these abnormalities such as the modulation of WNT signaling, the pharmacological modulation of proteasome-mediated protein degradation, the induction of osteoprogenitor cell differentiation, the repression of cancer cell proliferation and the manipulation of epigenetic mechanisms. This article reviews our current understanding of the major cellular and molecular mechanisms inducing osteoblastic cell abnormalities in age-related bone loss, genetic skeletal dysplasias and primary bone tumors, and discusses emerging therapeutic strategies to counteract the osteoblast abnormalities in these disorders of bone formation.


Assuntos
Doenças do Desenvolvimento Ósseo/fisiopatologia , Neoplasias Ósseas/fisiopatologia , Osteoblastos/fisiologia , Osteoporose/fisiopatologia , Transdução de Sinais , Apoptose , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Diferenciação Celular , Humanos , Modelos Biológicos , Osteoblastos/metabolismo , Osteoporose/genética , Osteoporose/metabolismo
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