RESUMO
On average, Peruvian individuals are among the shortest in the world1. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvian individuals, and identify a population-specific, missense variant in the FBN1 gene (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency of 4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). To our knowledge, this is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin 1, which is a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals who were homozygous for G1297 compared with individuals who were homozygous for E1297. Moreover, we show that the E1297G locus is under positive selection in non-African populations, and that the E1297 variant shows subtle evidence of positive selection specifically within the Peruvian population. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, which suggests that short stature might be the result of adaptation to factors that are associated with the coastal environment in Peru.
Assuntos
Estatura/genética , Fibrilina-1/genética , Mutação de Sentido Incorreto , Seleção Genética , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Hereditariedade , Humanos , Indígenas Sul-Americanos/genética , Masculino , Microfibrilas/química , Microfibrilas/genética , PeruRESUMO
Aortopathy encompasses a spectrum of conditions predisposing to dilation, aneurysm, dissection, or rupture of the aorta and other blood vessels. Aortopathy is diagnosed commonly in children, from infancy through adolescence, primarily affecting the thoracic aorta, with variable involvement of the peripheral vasculature. Pathogeneses include connective tissue disorders, smooth muscle contraction disorders, and congenital heart disease, including bicuspid aortic valve, among others. The American Heart Association has published guidelines for diagnosis and management of thoracic aortic disease. However, these guidelines are predominantly focused on adults and cannot be applied adeptly to growing children with emerging features, growth and developmental changes, including puberty, and different risk profiles compared with adults. Management to reduce risk of progressive aortic dilation and dissection or rupture in children is complex and involves genetic testing, cardiovascular imaging, medical therapy, lifestyle modifications, and surgical guidance that differ in many ways from adult management. Pediatric practice varies widely, likely because aortopathy is pathogenically heterogeneous, including genetic and nongenetic conditions, and there is limited published evidence to guide care in children. To optimize care and reduce variation in management, experts in pediatric aortopathy convened to generate this scientific statement regarding the cardiovascular care of children with aortopathy. Available evidence and expert consensus were combined to create this scientific statement. The most common causes of pediatric aortopathy are reviewed. This document provides a general framework for cardiovascular management of aortopathy in children, while allowing for modification based on the personal and familial characteristics of each child and family.
RESUMO
PURPOSE: Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting multiple organ systems, including bone. METHODS: We defined the bone phenotype and clinical predictors of low bone density and fracture risk in 77 patients with LDS type 1 to type 5. RESULTS: Patients with LDS had dual-energy x-ray absorptiometry (DXA) Z-scores significantly < 0, and 50% of children and 9% of adults had Z-scores < -2. Sixty percent of patients had ≥1 fracture, and 24% of patients with spinal x-rays scans showed spinal compression fractures. Lower body mass index, asthma, male sex and eosinophilic gastrointestinal disease were correlated with lower DXA Z-scores. The count of 5 LDS-associated skeletal features (scoliosis, pes planus, arachnodactyly, spondylolisthesis, and camptodactyly) in patients with LDS was correlated with DXA Z-score. Adults with ≥1 skeletal features had DXA Z-scores significantly < 0, and children with >2 features had DXA Z-score significantly < -2. Bone turnover markers suggest accelerated bone resorption. Data from 5 patients treated with bisphosphonates suggest a beneficial effect. CONCLUSION: All LDS types are associated with reduced bone density and increased risk of fracture, which may be due to increased bone resorption. Clinical features can predict a subgroup of patients at highest risk of low bone density and fracture risk.
Assuntos
Doenças Ósseas Metabólicas , Fraturas Ósseas , Síndrome de Loeys-Dietz , Absorciometria de Fóton , Densidade Óssea , Fraturas Ósseas/diagnóstico por imagem , Fraturas Ósseas/epidemiologia , Humanos , Síndrome de Loeys-Dietz/complicações , Síndrome de Loeys-Dietz/genética , MasculinoRESUMO
PURPOSE: The growing size of public variant repositories prompted us to test the accuracy of pathogenicity prediction of DNA variants using population data alone. METHODS: Under the a priori assumption that the ratio of the prevalence of variants in healthy population vs that in affected populations form 2 distinct distributions (pathogenic and benign), we used a Bayesian method to assign probability to a variant belonging to either distribution. RESULTS: The approach, termed Bayesian prevalence ratio (BayPR), accurately parsed 300 of 313 expertly curated CFTR variants: 284 of 296 pathogenic/likely pathogenic variants in 1 distribution and 16 of 17 benign/likely benign variants in another. BayPR produced an area under the receiver operating characteristic curve of 0.99 for 103 functionally confirmed missense CFTR variants, which is equal to or exceeds 10 commonly used algorithms (area under the receiver operating characteristic curve range = 0.54-0.99). Application of BayPR to expertly curated variants in 8 genes associated with 7 Mendelian conditions led to the assignment of a disease-causing probability of ≥80% to 1350 of 1374 (98.3%) pathogenic/likely pathogenic variants and of ≤20% to 22 of 23 (95.7%) benign/likely benign variants. CONCLUSION: Irrespective of the variant type or functional effect, the BayPR approach provides probabilities of pathogenicity for DNA variants responsible for Mendelian disorders using only the variant counts in affected and unaffected population samples.
Assuntos
Algoritmos , Mutação de Sentido Incorreto , Teorema de Bayes , Humanos , Curva ROCRESUMO
PURPOSE: In a large cohort of 373 pediatric patients with Marfan syndrome (MFS) with a severe cardiovascular phenotype, we explored the proportion of patients with MFS with a pathogenic FBN1 variant and analyzed whether the type/location of FBN1 variants was associated with specific clinical characteristics and response to treatment. Patients were recruited on the basis of the following criteria: aortic root z-score > 3, age 6 months to 25 years, no prior or planned surgery, and aortic root diameter < 5 cm. METHODS: Targeted resequencing and deletion/duplication testing of FBN1 and related genes were performed. RESULTS: We identified (likely) pathogenic FBN1 variants in 91% of patients. Ectopia lentis was more frequent in patients with dominant-negative (DN) variants (61%) than in those with haploinsufficient variants (27%). For DN FBN1 variants, the prevalence of ectopia lentis was highest in the N-terminal region (84%) and lowest in the C-terminal region (17%). The association with a more severe cardiovascular phenotype was not restricted to DN variants in the neonatal FBN1 region (exon 25-33) but was also seen in the variants in exons 26 to 49. No difference in the therapeutic response was detected between genotypes. CONCLUSION: Important novel genotype-phenotype associations involving both cardiovascular and extra-cardiovascular manifestations were identified, and existing ones were confirmed. These findings have implications for prognostic counseling of families with MFS.
Assuntos
Ectopia do Cristalino , Síndrome de Marfan , Variação Biológica da População , Criança , Ectopia do Cristalino/complicações , Ectopia do Cristalino/genética , Fibrilina-1/genética , Fibrilinas/genética , Genótipo , Humanos , Síndrome de Marfan/genética , Mutação , FenótipoRESUMO
Despite significant research efforts, clinical practice for arterial bypass surgery has been stagnant, and engineered grafts continue to face postimplantation challenges. Here, we describe the development and application of a durable small-diameter vascular graft with tailored regenerative capacity. We fabricated small-diameter vascular grafts by electrospinning fibrin tubes and poly(ε-caprolactone) fibrous sheaths, which improved suture retention strength and enabled long-term survival. Using surface topography in a hollow fibrin microfiber tube, we enable immediate, controlled perfusion and formation of a confluent endothelium within 3-4 days in vitro with human endothelial colony-forming cells, but a stable endothelium is noticeable at 4 weeks in vivo. Implantation of acellular or endothelialized fibrin grafts with an external ultrathin poly(ε-caprolactone) sheath as an interposition graft in the abdominal aorta of a severe combined immunodeficient Beige mouse model supports normal blood flow and vessel patency for 24 weeks. Mechanical properties of the implanted grafts closely approximate the native abdominal aorta properties after just 1 week in vivo. Fibrin mediated cellular remodeling, stable tunica intima and media formation, and abundant matrix deposition with organized collagen layers and wavy elastin lamellae. Endothelialized grafts evidenced controlled healthy remodeling with delayed and reduced macrophage infiltration alongside neo vasa vasorum-like structure formation, reduced calcification, and accelerated tunica media formation. Our studies establish a small-diameter graft that is fabricated in less than 1 week, mediates neotissue formation and incorporation into the native tissue, and matches the native vessel size and mechanical properties, overcoming main challenges in arterial bypass surgery.
Assuntos
Materiais Biocompatíveis/química , Endotélio Vascular/fisiologia , Regeneração , Enxerto Vascular/métodos , Animais , Artérias/fisiologia , Artérias/cirurgia , Feminino , Fibrina/química , Camundongos , Poliésteres/química , Fluxo Sanguíneo Regional , Engenharia Tecidual/métodosRESUMO
BACKGROUND: Loeys-Dietz syndrome (LDS) commonly presents with foot deformities, such as talipes equinovarus (TEV), also known as "clubfoot." Although much is known about the treatment of idiopathic TEV, very little is known about the treatment of TEV in LDS. Here, we summarize the clinical characteristics of patients with LDS and TEV and compare clinical and patient-reported outcomes of operative versus nonoperative treatment. METHODS: We identified 47 patients with TEV from a cohort of 252 patients with LDS who presented to our academic tertiary care hospital from 2010 to 2016. A questionnaire, electronic health records, clinical photos and radiographs, and telephone calls were used to collect baseline, treatment, and outcome data. The validated disease-specific instrument was used to determine patient-reported foot/ankle functional limitations after treatment. Patients were categorized into nonoperative and operative groups, with the operative group subcategorized according to whether the posteromedial release was performed. RESULTS: Within our TEV cohort, bilateral TEV was present in 40 patients (85%). Thirty-seven patients underwent surgery (14 involving posteromedial release), and 10 were treated nonoperatively. The operative group had a higher incidence of posttreatment foot/ankle functional limitation (71%) than the nonoperative group (25%) ( P =0.04). The pain was the most common functional limitation (54%). The posteromedial release was associated with a higher incidence of developing hindfoot valgus compared with surgery not involving posteromedial release (43% vs. 8.7%, P =0.04) and compared with nonoperative treatment (43% vs. 0.0%, P =0.02). CONCLUSIONS: We found that patients with LDS have a high incidence of bilateral TEV. Operative treatment was associated with posttreatment foot/ankle functional limitations, and posteromedial release was associated with hindfoot valgus overcorrection deformity. These findings could have implications for the planning of surgery for TEV in LDS patients. LEVEL OF EVIDENCE: Level III-retrospective comparative study.
Assuntos
Pé Torto Equinovaro , Pé Equino , Síndrome de Loeys-Dietz , Pé Torto Equinovaro/cirurgia , Estudos de Coortes , Pé , Humanos , Síndrome de Loeys-Dietz/complicações , Síndrome de Loeys-Dietz/cirurgia , Estudos RetrospectivosRESUMO
BACKGROUND: Loeys-Dietz syndrome (LDS) is a rare autosomal-dominant connective tissue disorder caused by genetic mutations in the transforming growth factor-ß (TGFß) signaling pathway. In addition to vascular malformations, patients with LDS commonly present with bone and tendon abnormalities, including joint laxity. While TGFß signaling dysregulation has been implicated in many of these clinical manifestations, the degree to which it influences the tendinopathy and tendon healing issues in LDS has not been determined. METHODS: Wound healing after patellar tendon transection was compared between wild-type (WT) and Tgfbr2-mutant (LDS) mice (7 mice per group). In all mice, the right patellar tendon was transected at midsubstance, while the left was untouched to serve as a control. Mice were euthanized 6 weeks after surgery. Tendon specimens were harvested for histopathologic grading according to a previously validated scoring metric, and gene expression levels of Mmp2, Tgfb2, and other TGFß-signaling genes were assayed. Between-group comparisons were made using 1-way analysis of variance with post hoc Tukey honestly significant difference testing. RESULTS: Expression levels of assayed genes were similar between LDS and WT tendons at baseline; however, at 6 weeks after patellar tendon transection, LDS tendons showed sustained elevations in Mmp2 and Tgfb2 compared with baseline values; these elevations were not seen in normal tendons undergoing the same treatments. Histologically, untreated LDS tendons had significantly greater cellularity and cell rounding compared with untreated WT tendons, and both WT and LDS tendons had significantly worse histologic scores after surgery. CONCLUSION: We present the first mechanistic insight into the effect of LDS on tendons and tendon healing. The morphologic differences between LDS and WT tendons at baseline may help explain the increased risk of tendon/ligament dysfunction in patients with LDS, and the differential healing response to injury in LDS may account for the delayed healing and weaker repair tissue. LEVEL OF EVIDENCE: Level V.
Assuntos
Síndrome de Loeys-Dietz , Ligamento Patelar , Fator de Crescimento Transformador beta2 , Animais , Modelos Animais de Doenças , Síndrome de Loeys-Dietz/genética , Metaloproteinase 2 da Matriz , Camundongos , Ligamento Patelar/fisiopatologia , Ligamento Patelar/cirurgia , Tendões/fisiopatologia , Tendões/cirurgia , Fator de Crescimento Transformador beta2/genética , Fator de Crescimento Transformador beta2/fisiologia , CicatrizaçãoRESUMO
Tremendous progress has been made in understanding the etiology, pathogenesis, and treatment of inherited vascular connective tissue disorders. While new insights regarding disease etiology and pathogenesis have informed patient counseling and care, there are numerous obstacles that need to be overcome in order to achieve the full promise of precision medicine. In this review, these issues will be discussed in the context of Marfan syndrome and Loeys-Dietz syndrome, with additional emphasis on the pioneering contributions made by Victor McKusick.
Assuntos
Doenças do Tecido Conjuntivo/genética , Síndrome de Loeys-Dietz/genética , Síndrome de Marfan/genética , Doenças Vasculares/genética , Tecido Conjuntivo/patologia , Doenças do Tecido Conjuntivo/patologia , Humanos , Síndrome de Loeys-Dietz/patologia , Síndrome de Marfan/patologia , Medicina de Precisão , Doenças Vasculares/patologiaRESUMO
Loeys-Dietz syndrome is an autosomal dominant aortic aneurysm syndrome characterized by multisystemic involvement. The most typical clinical triad includes hypertelorism, bifid uvula or cleft palate and aortic aneurysm with tortuosity. Natural history is significant for aortic dissection at smaller aortic diameter and arterial aneurysms throughout the arterial tree. The genetic cause is heterogeneous and includes mutations in genes encoding for components of the transforming growth factor beta (TGFß) signalling pathway: TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 and TGFB3. Despite the loss of function nature of these mutations, the patient-derived aortic tissues show evidence of increased (rather than decreased) TGFß signalling. These insights offer new options for therapeutic interventions.
Assuntos
Dissecção Aórtica , Síndrome de Loeys-Dietz , Humanos , Síndrome de Loeys-Dietz/diagnóstico , Síndrome de Loeys-Dietz/genética , Mutação , Receptores de Fatores de Crescimento Transformadores beta/genéticaRESUMO
OBJECTIVE: To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial. STUDY DESIGN: In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models. RESULTS: Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status. CONCLUSIONS: In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.
Assuntos
Atenolol/uso terapêutico , Citocromo P-450 CYP2C9/genética , Regulação da Expressão Gênica , Losartan/uso terapêutico , Síndrome de Marfan/tratamento farmacológico , Receptores Adrenérgicos beta 1/genética , Adolescente , Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Adulto , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Criança , Pré-Escolar , Citocromo P-450 CYP2C9/biossíntese , DNA/genética , Feminino , Seguimentos , Genótipo , Humanos , Lactente , Masculino , Síndrome de Marfan/genética , Síndrome de Marfan/metabolismo , Receptores Adrenérgicos beta 1/biossíntese , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Loeys-Dietz syndrome (LDS) is a systemic connective tissue disease (CTD) associated with a predisposition for intestinal inflammation, food allergy, and failure to thrive, often necessitating nutritional supplementation via gastrostomy tube. Poor wound healing has also been observed in in some patients with CTD, potentially increasing the risk of surgical interventions. We undertook to determine the safety and efficacy of gastrostomy tube placement in this population. METHODS: We performed a retrospective cohort study of 10 LDS patients who had a total of 12 gastrostomy tubes placed. RESULTS: No procedural complications occurred, although one patient developed buried bumper syndrome in the near post-procedural time period and one patient had a small abscess at a surgical stitch. Most patients exhibited improvements in growth, with a median immediate improvement in BMI Z-score of 0.2 per month following the institution of gastrostomy tube feedings. Those with uncontrolled inflammation due to inflammatory bowel disease or eosinophilic gastrointestinal disease showed the least benefit and in some cases failed to demonstrate significant weight gain despite nutritional supplementation. CONCLUSIONS: Gastrostomy tube placement (surgical or endoscopic) is a generally safe and a reasonable therapeutic option for patients with LDS despite their underlying CTD.
Assuntos
Nutrição Enteral/métodos , Gastrostomia , Síndrome de Loeys-Dietz/cirurgia , Adolescente , Índice de Massa Corporal , Criança , Pré-Escolar , Nutrição Enteral/efeitos adversos , Seguimentos , Gastrostomia/efeitos adversos , Humanos , Lactente , Complicações Pós-Operatórias , Estudos Retrospectivos , Resultado do Tratamento , Aumento de PesoRESUMO
In the published version of this paper the author Neus Baena's name was incorrectly given as Neus Baena Diez. This has now been corrected in both the HTML and PDF versions of the paper.
RESUMO
In systemic sclerosis (SSc), a common and aetiologically mysterious form of scleroderma (defined as pathological fibrosis of the skin), previously healthy adults acquire fibrosis of the skin and viscera in association with autoantibodies. Familial recurrence is extremely rare and causal genes have not been identified. Although the onset of fibrosis in SSc typically correlates with the production of autoantibodies, whether they contribute to disease pathogenesis or simply serve as a marker of disease remains controversial and the mechanism for their induction is largely unknown. The study of SSc is hindered by a lack of animal models that recapitulate the aetiology of this complex disease. To gain a foothold in the pathogenesis of pathological skin fibrosis, we studied stiff skin syndrome (SSS), a rare but tractable Mendelian disorder leading to childhood onset of diffuse skin fibrosis with autosomal dominant inheritance and complete penetrance. We showed previously that SSS is caused by heterozygous missense mutations in the gene (FBN1) encoding fibrillin-1, the main constituent of extracellular microfibrils. SSS mutations all localize to the only domain in fibrillin-1 that harbours an Arg-Gly-Asp (RGD) motif needed to mediate cell-matrix interactions by binding to cell-surface integrins. Here we show that mouse lines harbouring analogous amino acid substitutions in fibrillin-1 recapitulate aggressive skin fibrosis that is prevented by integrin-modulating therapies and reversed by antagonism of the pro-fibrotic cytokine transforming growth factor ß (TGF-ß). Mutant mice show skin infiltration of pro-inflammatory immune cells including plasmacytoid dendritic cells, T helper cells and plasma cells, and also autoantibody production; these findings are normalized by integrin-modulating therapies or TGF-ß antagonism. These results show that alterations in cell-matrix interactions are sufficient to initiate and sustain inflammatory and pro-fibrotic programmes and highlight new therapeutic strategies.
Assuntos
Autoimunidade/efeitos dos fármacos , Contratura/tratamento farmacológico , Contratura/patologia , Integrinas/efeitos dos fármacos , Integrinas/metabolismo , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/patologia , Dermatopatias Genéticas/tratamento farmacológico , Dermatopatias Genéticas/patologia , Motivos de Aminoácidos/genética , Substituição de Aminoácidos/genética , Animais , Anticorpos Antinucleares/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/farmacologia , Anticorpos Neutralizantes/uso terapêutico , Autoimunidade/imunologia , Contratura/imunologia , Contratura/prevenção & controle , Células Dendríticas/efeitos dos fármacos , Feminino , Fibrilina-1 , Fibrilinas , Fibrose/tratamento farmacológico , Fibrose/patologia , Fibrose/prevenção & controle , Masculino , Camundongos , Proteínas dos Microfilamentos/química , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Mutação de Sentido Incorreto/genética , Plasmócitos/efeitos dos fármacos , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/prevenção & controle , Dermatopatias Genéticas/imunologia , Dermatopatias Genéticas/prevenção & controle , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/imunologiaRESUMO
The objective of the present study was to 1) analyze the ascending aortic proteome within a mouse model of Marfan syndrome (MFS; Fbn1C1041G/+) at early and late stages of aneurysm and 2) subsequently test a novel hypothesis formulated on the basis of this unbiased proteomic screen that links changes in integrin composition to transforming growth factor (TGF)-ß-dependent activation of the rapamycin-independent component of mammalian target of rapamycin (Rictor) signaling pathway. Ingenuity Pathway Analysis of over 1,000 proteins quantified from the in vivo MFS mouse aorta by data-independent acquisition mass spectrometry revealed a predicted upstream regulator, Rictor, that was selectively activated in aged MFS mice. We validated this pattern of Rictor activation in vivo by Western blot analysis for phosphorylation on Thr1135 in a separate cohort of mice and showed in vitro that TGF-ß activates Rictor in an integrin-linked kinase-dependent manner in cultured aortic vascular smooth muscle cells. Expression of ß3-integrin was upregulated in the aged MFS aorta relative to young MFS mice and wild-type mice. We showed that ß3-integrin expression and activation modulated TGF-ß-induced Rictor phosphorylation in vitro, and this signaling effect was associated with an altered vascular smooth muscle cell proliferative-migratory and metabolic in vitro phenotype that parallels the in vivo aneurysm phenotype in MFS. These results reveal that Rictor is a novel, context-dependent, noncanonical TGF-ß signaling effector with potential pathogenic implications in aortic aneurysm. NEW & NOTEWORTHY We present the most comprehensive quantitative analysis of the ascending aortic aneurysm proteome in Marfan syndrome to date resulting in novel and potentially wide-reaching findings that expression and signaling by ß3-integrin constitute a modulator of transforming growth factor-ß-induced rapamycin-independent component of mammalian target of rapamycin (Rictor) signaling and physiology in aortic vascular smooth muscle cells.
Assuntos
Aneurisma Aórtico/metabolismo , Síndrome de Marfan/complicações , Músculo Liso Vascular/metabolismo , Proteômica/métodos , Proteína Companheira de mTOR Insensível à Rapamicina/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Aorta/metabolismo , Aorta/patologia , Aneurisma Aórtico/etiologia , Aneurisma Aórtico/patologia , Movimento Celular , Proliferação de Células , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Dilatação Patológica , Modelos Animais de Doenças , Progressão da Doença , Fibrilina-1/genética , Predisposição Genética para Doença , Integrina beta3/metabolismo , Masculino , Síndrome de Marfan/genética , Espectrometria de Massas , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculo Liso Vascular/patologia , Mutação , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Fenótipo , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Fatores de TempoRESUMO
PURPOSE: We delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10. METHODS: We retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-ß signaling with immunohistochemistry for pSMAD2 and CTGF. RESULTS: Stenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Thus far, no reports unequivocally document vascular dissections or ruptures. Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed. Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition. EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality. Skin and end-stage diseased vascular tissue do not indicate increased TGF-ß signaling. CONCLUSION: Our findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards. EM on skin biopsies shows disease-specific abnormalities.
Assuntos
Artérias/anormalidades , Proteínas Facilitadoras de Transporte de Glucose/genética , Hérnia Diafragmática/genética , Instabilidade Articular/genética , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Dermatopatias Genéticas/genética , Malformações Vasculares/genética , Adolescente , Adulto , Aorta/diagnóstico por imagem , Aorta/fisiopatologia , Artérias/diagnóstico por imagem , Artérias/fisiopatologia , Biópsia , Criança , Pré-Escolar , Fator de Crescimento do Tecido Conjuntivo/genética , Feminino , Hérnia Diafragmática/fisiopatologia , Humanos , Lactente , Instabilidade Articular/epidemiologia , Instabilidade Articular/fisiopatologia , Masculino , Mutação , Linhagem , Síndrome do Desconforto Respiratório do Recém-Nascido/fisiopatologia , Pele/patologia , Dermatopatias Genéticas/epidemiologia , Dermatopatias Genéticas/fisiopatologia , Proteína Smad2/genética , Fator de Crescimento Transformador beta/genética , Malformações Vasculares/epidemiologia , Malformações Vasculares/fisiopatologiaRESUMO
BACKGROUND: Loeys-Dietz syndrome (LDS) is a rare multisystemic disorder characterized by vascular and skeletal abnormalities, with considerable intra- and interfamilial variability. CASE PRESENTATION: We report the case of an 8-year-old male with clinical features of two distinct genetic disorders, namely LDS, manifesting in the first months by progressive aortic root dilatation, arterial tortuosity, bifid uvula, and inguinal hernias and oculocutaneous albinism (OCA) manifesting by white hair and skin that does not tan, nystagmus, reduced iris pigment with iris translucency, and reduced retinal pigment). We identified previously reported, homozygous mutations of TYR, c.1A > G (p.Met1Val) and heterozygous, missense mutation of TGFBR1, c.1460G > A (p.Arg487Gln). Family history revealed that his mother underwent multiple surgical repairs for recurrent hemorrhage originating from the buccal artery. Molecular studies confirmed a maternally inherited low grade TGFBR1 mutation somatic mosaicism (18% in peripheral blood leukocytes, 18% in buccal cells and 10% in hair root cells). Maternal cardiac investigations revealed peculiar cardiovascular features: mild tortuosity at the aortic arch, dilatation of the proximal abdominal aorta, multiple deep left ventricular myocardial crypts, and dysplastic mitral valve. TGFBR2 germline mosaicism has been described in three fathers of children carrying TGFBR2 mutations but, to the best of our knowledge, no case of maternally inherited TGFBR1 mutation mosaicism has been reported so far. CONCLUSIONS: This case report suggests that individuals with somatic mosaicism might be at risk for mild and unusual forms of LDS but germline mosaicism can lead to full blown picture of the disease in offspring.
Assuntos
Albinismo Oculocutâneo/genética , Dilatação Patológica/genética , Síndrome de Loeys-Dietz/genética , Herança Materna , Mosaicismo , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Adulto , Albinismo Oculocutâneo/diagnóstico por imagem , Albinismo Oculocutâneo/patologia , Aorta/diagnóstico por imagem , Aorta/metabolismo , Aorta/patologia , Criança , Dilatação Patológica/diagnóstico por imagem , Dilatação Patológica/patologia , Feminino , Expressão Gênica , Mutação em Linhagem Germinativa , Humanos , Síndrome de Loeys-Dietz/diagnóstico por imagem , Síndrome de Loeys-Dietz/patologia , Angiografia por Ressonância Magnética , Masculino , Mutação de Sentido Incorreto , Miocárdio/metabolismo , Miocárdio/patologia , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismoRESUMO
OBJECTIVE: This study aimed to determine if carotid arterial tortuosity represents a marker of disease severity in Loeys-Dietz syndrome (LDS). METHODS: Fifty-four 54 LDS patients (mean age, 17.0 years) who underwent computed tomogram angiography from January 2004 to December 2013 were retrospectively identified. Carotid artery tortuosity index (CATI) was calculated from computed tomogram angiography. Clinical variables were obtained from the medical records. Relationship between CATI and need for aortic root replacement was evaluated with Cox proportional hazard model and Kaplan-Meier analysis. RESULTS: Higher CATI was associated with the need for aortic root replacement (P < 0.001) in the univariate Cox proportional hazard model. Patients were stratified based on both CATI and aortic root size in Kaplan-Meier analysis, and patients with higher CATI were more likely to require aortic root replacement (P < 0.001) in both aortic root size strata. CONCLUSION: Increased carotid artery tortuosity is associated with the need for early aortic root replacement in patients with LDS.
Assuntos
Aorta/cirurgia , Artérias Carótidas/anormalidades , Artérias Carótidas/diagnóstico por imagem , Síndrome de Loeys-Dietz/complicações , Adolescente , Angiografia por Tomografia Computadorizada/métodos , Feminino , Humanos , Masculino , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
BACKGROUND: We studied the prevalence and treatment outcomes of spondylolisthesis in patients with Loeys-Dietz syndrome (LDS). METHODS: Clinical data and lumbosacral imaging of 138 patients with LDS were reviewed. Spondylolisthesis (L4-L5 or L5-S1) and spondylolysis were characterized by multimodal imaging and correlated with clinical data. Treatments and outcomes were characterized for patients with spondylolisthesis. Associations were determined using the Fisher exact, Mann-Whitney, and Student t tests (α=0.05). RESULTS: Twenty-four patients (17%) had spondylolysis and 23 (17%) had spondylolisthesis. Median age at spondylolisthesis diagnosis was 11 (interquartile range, 9.5) years. In patients in whom measurement was possible (n=20), mean (±SD) slip was 48% (±35%). Nineteen patients had L5-S1 slip and 4 had L4-L5 slip. Of the patients with spondylolisthesis, 5 had no evidence of spondylolysis; of those with spondylolysis, all but 6 had spondylolisthesis. Eleven patients with spondylolisthesis underwent posterior spinal fusion (PSF) to treat slip progression, pain, and/or neurological deficit. Spondylolisthesis recurred in 1 patient who underwent PSF with bone graft arthrodesis alone (no instrumentation). The other 10 patients underwent PSF with instrumentation and fusion. Three patients additionally underwent Bohlman interbody fusion. Two patients developed implant failure. S2 fixation was performed at revision to achieve fusion in these patients. Mean Meyerding grade improved in patients who underwent arthrodesis, from 3.9 (±1.2) to 1.9 (±1.3) (P=0.002). Complications were 2 cerebrospinal fluid leaks, 2 transient postoperative paresthesias, and 1 case each of pseudarthrosis at S1-S2, wound dehiscence, and transient urinary incontinence. No significant associations between LDS type and lumbosacral abnormalities were found. CONCLUSIONS: High-grade spondylolisthesis is common in LDS and usually associated with spondylolysis. Patients requiring surgery for spondylolisthesis present during childhood and do well after instrumented PSF. Interbody fusion and stabilization of S1 and S2 can prevent physeal deformation. LDS should be considered in patients with high-grade spondylolisthesis. Patients with LDS should be monitored for spondylolisthesis and spondylolysis starting when they are young. LEVEL OF EVIDENCE: Level IV-retrospective study.