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RATIONALE: Pathogenic (P)/likely pathogenic (LP) SMAD3 variants cause Loeys-Dietz syndrome type 3 (LDS3), which is characterized by arterial aneurysms, dissections and tortuosity throughout the vascular system combined with osteoarthritis. OBJECTIVES: Investigate the impact of P/LP SMAD3 variants with functional tests on patient-derived fibroblasts and vascular smooth muscle cells (VSMCs), to optimize interpretation of SMAD3 variants. METHODS: A retrospective analysis on clinical data from individuals with a P/LP SMAD3 variant and functional analyses on SMAD3 patient-derived VSMCs and SMAD3 patient-derived fibroblasts, differentiated into myofibroblasts. RESULTS: Individuals with dominant negative (DN) SMAD3 variant in the MH2 domain exhibited more major events (66.7% vs. 44.0%, P = 0.054), occurring at a younger age compared to those with haploinsufficient (HI) variants. The age at first major event was 35.0 years [IQR 29.0-47.0] in individuals with DN variants in MH2, compared to 46.0 years [IQR 40.0-54.0] in those with HI variants (P = 0.065). Fibroblasts carrying DN SMAD3 variants displayed reduced differentiation potential, contrasting with increased differentiation potential in HI SMAD3 variant fibroblasts. HI SMAD3 variant VSMCs showed elevated SMA expression and altered expression of alternative MYH11 isoforms. DN SMAD3 variant myofibroblasts demonstrated reduced extracellular matrix formation compared to control cell lines. CONCLUSION: Distinguishing between P/LP HI and DN SMAD3 variants can be achieved by assessing differentiation potential, and SMA and MYH11 expression. The differences between DN and HI SMAD3 variant fibroblasts and VSMCs potentially contribute to the differences in disease manifestation. Notably, myofibroblast differentiation seems a suitable alternative in vitro test system compared to VSMCs.
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Fibroblastos , Estudios de Asociación Genética , Síndrome de Loeys-Dietz , Músculo Liso Vascular , Proteína smad3 , Humanos , Proteína smad3/genética , Proteína smad3/metabolismo , Síndrome de Loeys-Dietz/genética , Síndrome de Loeys-Dietz/patología , Masculino , Femenino , Fibroblastos/metabolismo , Adulto , Persona de Mediana Edad , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Diferenciación Celular/genética , Línea Celular , Miocitos del Músculo Liso/metabolismo , Estudios Retrospectivos , Fenotipo , Miofibroblastos/metabolismo , Miofibroblastos/patología , MutaciónRESUMEN
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.
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Dysregulated transforming growth factor TGF-ß signaling underlies the pathogenesis of genetic disorders affecting the connective tissue such as Loeys-Dietz syndrome. Here, we report 12 individuals with bi-allelic loss-of-function variants in IPO8 who presented with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation; the individuals were from nine unrelated families. Importin 8 belongs to the karyopherin family of nuclear transport receptors and was previously shown to mediate TGF-ß-dependent SMADs trafficking to the nucleus in vitro. The important in vivo role of IPO8 in pSMAD nuclear translocation was demonstrated by CRISPR/Cas9-mediated inactivation in zebrafish. Consistent with IPO8's role in BMP/TGF-ß signaling, ipo8-/- zebrafish presented mild to severe dorso-ventral patterning defects during early embryonic development. Moreover, ipo8-/- zebrafish displayed severe cardiovascular and skeletal defects that mirrored the human phenotype. Our work thus provides evidence that IPO8 plays a critical and non-redundant role in TGF-ß signaling during development and reinforces the existing link between TGF-ß signaling and connective tissue defects.
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Enfermedades Óseas/etiología , Enfermedades Cardiovasculares/etiología , Enfermedades del Tejido Conjuntivo/etiología , Inmunidad Celular/inmunología , Mutación con Pérdida de Función , Pérdida de Heterocigocidad , beta Carioferinas/genética , Adolescente , Adulto , Animales , Enfermedades Óseas/patología , Enfermedades Cardiovasculares/patología , Niño , Enfermedades del Tejido Conjuntivo/patología , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Transducción de Señal , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Adulto Joven , Pez Cebra , beta Carioferinas/metabolismoRESUMEN
Importin 8, encoded by IPO8, is a ubiquitously expressed member of the importin-ß protein family that translocates cargo molecules such as proteins, RNAs, and ribonucleoprotein complexes into the nucleus in a RanGTP-dependent manner. Current knowledge of the cargoes of importin 8 is limited, but TGF-ß signaling components such as SMAD1-4 have been suggested to be among them. Here, we report that bi-allelic loss-of-function variants in IPO8 cause a syndromic form of thoracic aortic aneurysm (TAA) with clinical overlap with Loeys-Dietz and Shprintzen-Goldberg syndromes. Seven individuals from six unrelated families showed a consistent phenotype with early-onset TAA, motor developmental delay, connective tissue findings, and craniofacial dysmorphic features. A C57BL/6N Ipo8 knockout mouse model recapitulates TAA development from 8-12 weeks onward in both sexes but most prominently shows ascending aorta dilatation with a propensity for dissection in males. Compliance assays suggest augmented passive stiffness of the ascending aorta in male Ipo8-/- mice throughout life. Immunohistological investigation of mutant aortic walls reveals elastic fiber disorganization and fragmentation along with a signature of increased TGF-ß signaling, as evidenced by nuclear pSmad2 accumulation. RT-qPCR assays of the aortic wall in male Ipo8-/- mice demonstrate decreased Smad6/7 and increased Mmp2 and Ccn2 (Ctgf) expression, reinforcing a role for dysregulation of the TGF-ß signaling pathway in TAA development. Because importin 8 is the most downstream TGF-ß-related effector implicated in TAA pathogenesis so far, it offers opportunities for future mechanistic studies and represents a candidate drug target for TAA.
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Aneurisma de la Aorta Torácica/etiología , Mutación con Pérdida de Función , Pérdida de Heterocigocidad , Fenotipo , beta Carioferinas/genética , Adulto , Animales , Aneurisma de la Aorta Torácica/metabolismo , Aneurisma de la Aorta Torácica/patología , Niño , Preescolar , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Linaje , Transducción de Señal , Síndrome , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , Adulto Joven , beta Carioferinas/metabolismoRESUMEN
OBJECTIVE: Thoracic endovascular aortic repair (TEVAR) in patients with genetic aortopathies (GA) is controversial, given concerns of durability. We describe characteristics and outcomes after TEVAR in patients with GA. METHODS: All patients undergoing TEVAR between 2010 and 2023 in the Vascular Quality Iniatitive were identified and categorized as having a GA or not. Demographics, baseline, and procedural characteristics were compared among groups. Multivariable logistic regression was used to evaluate the independent association of GA with postoperative outcomes. Kaplan-Meier methods and multivariable Cox regression analyses were used to evaluate 5-year survival and 2-year reinterventions. RESULTS: Of 19,340 patients, 304 (1.6%) had GA (87% Marfan syndrome, 9% Loeys-Dietz syndrome, and 4% vascular Ehlers-Danlos syndrome). Compared with patients without GA, patients with GA were younger (50 years [interquartile range, 37-72 years] vs 70 years [interquartile range, 61-77 years]), more often presented with acute dissection (28% vs 18%), postdissection aneurysm (48% vs 17%), had a symptomatic presentation (50% vs 39%), and were less likely to have degenerative aneurysms (18% vs 47%) or penetrating aortic ulcer (and intramural hematoma) (3% vs 13%) (all P < .001). Patients with GA were more likely to have prior repair of the ascending aorta/arch (open, 56% vs 11% [P < .001]; endovascular, 5.6% vs 2.1% [P = .017]) or the descending thoracic aorta (open, 12% vs 2% [P = .007]; endovascular, 8.2% vs 3.6% [P = .011]). No significant differences were found in prior abdominal suprarenal repairs; however, patients with GA had more prior open infrarenal repairs (5.3% vs 3.2%), but fewer prior endovascular infrarenal repairs (3.3% vs 5.5%) (all P < .05). After adjusting for demographics, comorbidities, and disease characteristics, patients with GA had similar odds of perioperative mortality (4.6% vs 7.0%; adjusted odds ratio [aOR], 1.1; 95% confidence interval [CI], 0.57-1.9; P = .75), any in-hospital complication (26% vs 23%; aOR, 1.24; 95% CI, 0.92-1.6; P = .14), or in-hospital reintervention (13% vs 8.3%; aOR, 1.25; 95% CI, 0.84-1.80; P = .25) compared with patients without GA. However, patients with GA had a higher likelihood of postoperative vasopressors (33% vs 27%; aOR, 1.44; 95% CI, 1.1-1.9; P = .006) and transfusion (25% vs 23%; aOR, 1.39; 95% CI, 1.03-1.9; P = .006). The 2-year reintervention rates were higher in patients with GA (25% vs 13%; adjusted hazard ratio, 1.99; 95% CI, 1.4-2.9; P < .001), but 5-year survival was similar (81% vs 74%; adjusted hazard ratio, 1.02; 95% CI, 0.70-1.50; P = .1). CONCLUSIONS: TEVAR for patients with GA seemed to be safe initially, with similar odds for in-hospital complications, in-hospital reinterventions, and perioperative mortality, as well as similar hazards for 5-year mortality compared with patients without GA. However, patients with GA had higher 2-year reintervention rates. Future studies should assess long-term durability after TEVAR compared with the recommended open repair to appropriately weigh the risks and benefits of endovascular treatment in patients with GA.
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Loeys-Dietz syndrome (LDS) is an autosomal connective tissue disorder commonly presenting with hypertelorism, bifid uvula, aortic aneurysms, and arterial tortuosity. The aim of the present study was to investigate differences in tortuosity index (TI) between genotypes of LDS, possible progression over time and its use as an adjunctive prognostic tool alongside aortic dimensions to aid timely surgical planning in pediatric patients. A retrospective observational study of pediatric LDS patients referred to our center (November 2012-February 2021) was conducted. Using magnetic resonance angiography (MRA) with 3D maximum intensity projection volume-rendered angiogram, arterial TI was measured. Twenty three patients had genetically confirmed LDS with at least one head and neck MRA and 19 had no less than one follow-up MRA available. All patients presented arterial tortuosity. Patients with TGFBR2 variants had greater values of TI compared to patients with TGFB2 variants (p = 0.041). For patients who did not undergo surgery (n = 18), z-scores at the level of the sinus of Valsalva showed a significant correlation with vertebral TI (rs = 0.547). There was one death during follow-up. This study demonstrates that patients with LDS and TGFBR2 variants have greater values of TI than patients with TGFB2 variants and that greatest values of TI are associated with increased aortic root z-scores. Furthermore, as TI decreases over time, less frequent neuroimaging follow-up can be considered. Nevertheless, additional studies are needed to better define more accurate risk stratification and long-term surveillance in these patients.
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Arterias/anomalías , Inestabilidad de la Articulación , Síndrome de Loeys-Dietz , Enfermedades Cutáneas Genéticas , Malformaciones Vasculares , Niño , Humanos , Receptor Tipo II de Factor de Crecimiento Transformador beta/genética , Síndrome de Loeys-Dietz/diagnóstico , Síndrome de Loeys-Dietz/genética , Síndrome de Loeys-Dietz/complicaciones , Enfermedades Cutáneas Genéticas/complicaciones , Aorta/patologíaRESUMEN
Children with Marfan (MFS) and Loeys-Dietz syndrome (LDS) report limitations in physical activities, sports, school, leisure, and work participation in daily life. This observational, cross-sectional, multicenter study explores associations between physical fitness and cardiovascular parameters, systemic manifestations, fatigue, and pain in children with MFS and LDS. Forty-two participants, aged 6-18 years (mean (SD) 11.5(3.7)), diagnosed with MFS (n = 36) or LDS (n = 6), were enrolled. Physical fitness was evaluated using the Fitkids Treadmill Test's time to exhaustion (TTE) outcome measure. Cardiovascular parameters (e.g., echocardiographic parameters, aortic surgery, cardiovascular medication) and systemic manifestations (systemic score of the revised Ghent criteria) were collected. Pain was obtained by visual analog scale. Fatigue was evaluated by PROMIS® Fatigue-10a-Pediatric-v2.0-short-form and PROMIS® Fatigue-10a-Parent-Proxy-v2.0-short-form. Multivariate linear regression analyses explored associations between physical fitness (dependent variable) and independent variables that emerged from the univariate linear regression analyses (criterion p < .05). The total group (MFS and LDS) and the MFS subgroup scored below norms on physical fitness TTE Z-score (mean (SD) -3.1 (2.9); -3.0 (3.0), respectively). Univariate analyses showed associations between TTE Z-score aortic surgery, fatigue, and pain (criterion p < .05). Multivariate analyses showed an association between physical fitness and pediatric self-reported fatigue that explained 48%; 49%, respectively, of TTE Z-score variance (F (1,18) = 18.6, p ≤ .001, r2 = .48; F (1,15) = 16,3, p = .01, r2 = .49, respectively). Conclusions: Physical fitness is low in children with MFS or LDS and associated with self-reported fatigue. Our findings emphasize the potential of standardized and tailored exercise programs to improve physical fitness and reduce fatigue, ultimately enhancing the physical activity and sports, school, leisure, and work participation of children with MFS and LDS. What is Known: ⢠Marfan and Loeys-Dietz syndrome are heritable connective tissue disorders and share cardiovascular and systemic manifestations. ⢠Children with Marfan and Loeys-Dietz syndrome report increased levels of disability, fatigue and pain, as well as reduced levels of physical activity, overall health and health-related quality of life. What is New: ⢠Physical fitness is low in children with Marfan and Loeys-Dietz syndrome and associated with self-reported fatigue. ⢠Our findings emphasize the potential of standardized and tailored exercise programs to improve physical fitness and reduce fatigue, ultimately enhancing the physical activity and sports, school, leisure, and work participation of children with Marfan and Loeys-Dietz syndrome.
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Fatiga , Síndrome de Loeys-Dietz , Síndrome de Marfan , Dolor , Aptitud Física , Humanos , Síndrome de Loeys-Dietz/fisiopatología , Síndrome de Loeys-Dietz/complicaciones , Adolescente , Síndrome de Marfan/fisiopatología , Síndrome de Marfan/complicaciones , Niño , Masculino , Estudios Transversales , Femenino , Aptitud Física/fisiología , Fatiga/etiología , Fatiga/fisiopatología , Dolor/etiología , Dolor/fisiopatología , Prueba de EsfuerzoRESUMEN
Loeys-Dietz syndrome (LDS) is an autosomal-dominant connective tissue disorder associated with mutations in the transforming growth factor ß receptor. It is characterized by distinctive craniofacial changes, skeletal features, and cardiovascular complications. We present a case of a 24-year-old male with development delay and a one-year history of progressively worsening dyspnea on moderate exertion and orthopnea. Echocardiography revealed right atrial and right ventricle dilation, right ventricle hypertrophy, atrial septal defect, and aneurysmal dilation of the pulmonary artery trunk. This case underscores the importance of early detection and comprehensive imaging in patients suspected of having LDS, particularly considering the potential for atypical vascular manifestations.
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Diagnóstico Tardío , Ecocardiografía , Defectos del Tabique Interatrial , Síndrome de Loeys-Dietz , Arteria Pulmonar , Humanos , Masculino , Síndrome de Loeys-Dietz/complicaciones , Síndrome de Loeys-Dietz/diagnóstico , Defectos del Tabique Interatrial/complicaciones , Defectos del Tabique Interatrial/diagnóstico , Arteria Pulmonar/diagnóstico por imagen , Arteria Pulmonar/anomalías , Adulto Joven , Ecocardiografía/métodos , Dilatación Patológica , Diagnóstico DiferencialRESUMEN
PURPOSE OF REVIEW: The aim of this article is to review the current echocardiographic considerations in the diagnosis and monitoring of patients with inherited aortopathies. RECENT FINDINGS: Aortic dilation is a key feature in heritable aortopathies, and dissection is a leading cause of morbidity and mortality. New genetic and histopathologic findings are helpful in better understanding these conditions. Non-invasive imaging modalities, including echocardiogram, computerized tomography, and magnetic resonance imaging, are essential in monitoring these patients, as well as providing new prognostic factors of arterial stiffness that may help with risk stratification in the future. Diagnosis of heritable aortopathies should be considered with identification of aortic root dilation, particularly in children and young adults, or when there is a family history of aortic disease. Recent adult consensus guidelines highlight the importance of underlying genotype and phenotypic features when considering prophylactic surgical intervention. There are currently no consensus pediatric guidelines.
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Ecocardiografía , Tomografía Computarizada por Rayos X , Adulto Joven , Humanos , Niño , Imagen por Resonancia Magnética , GenotipoRESUMEN
AIM: The "2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease" provides recommendations to guide clinicians in the diagnosis, genetic evaluation and family screening, medical therapy, endovascular and surgical treatment, and long-term surveillance of patients with aortic disease across its multiple clinical presentation subsets (ie, asymptomatic, stable symptomatic, and acute aortic syndromes). METHODS: A comprehensive literature search was conducted from January 2021 to April 2021, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through June 2022 during the guideline writing process, were also considered by the writing committee, where appropriate. Structure: Recommendations from previously published AHA/ACC guidelines on thoracic aortic disease, peripheral artery disease, and bicuspid aortic valve disease have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with aortic disease have been developed. There is added emphasis on the role of shared decision making, especially in the management of patients with aortic disease both before and during pregnancy. The is also an increased emphasis on the importance of institutional interventional volume and multidisciplinary aortic team expertise in the care of patients with aortic disease.
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Enfermedades de la Aorta , Enfermedad de la Válvula Aórtica Bicúspide , Cardiología , Femenino , Humanos , Embarazo , American Heart Association , Enfermedades de la Aorta/diagnóstico , Enfermedades de la Aorta/terapia , Informe de Investigación , Estados UnidosRESUMEN
Loeys-Dietz syndrome (LDS) is an autosomal-dominant connective-tissue disorder with vascular and musculoskeletal abnormalities similar to Marfan syndrome. However, unlike Marfan, retinal detachment (RD) is rarely reported, and screening protocols do not currently feature ophthalmic assessment or RD counseling. We report a 5-generation family affected by LDS, where RD occurred in six eyes of four individuals. The proband was an 84-year-old male recently diagnosed with type-V LDS (TGFß3 pathogenic variant c.899G>A, p.(Arg300Gln)). Further investigation was undertaken into the family's medical history. The proband experienced bilateral rhegmatogenous RD at age 60, requiring emergency surgical repair. Other notable ophthalmic features include unusual keratometry, abnormal biometry, and severe hayfever requiring long-term sodium cromoglycate treatment. The proband's sister, father, and uncle had also experienced RDs, all prior to LDS diagnosis. This series demonstrates that RD risk may be significant in LDS, and on occasion the presenting clinical feature. We suggest ophthalmic examination should be added to the initial assessment LDS patients, and patients informed of the early warning symptoms of retinal detachment. As in Marfan syndrome, LDS patients may exhibit cornea plana and abnormal corneal topography, producing atypical biometry. They may also present with allergic conjunctivitis, and awareness of these signs might facilitate earlier diagnosis.
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Enfermedades del Tejido Conjuntivo , Síndrome de Loeys-Dietz , Síndrome de Marfan , Desprendimiento de Retina , Masculino , Humanos , Persona de Mediana Edad , Anciano de 80 o más Años , Síndrome de Loeys-Dietz/complicaciones , Síndrome de Loeys-Dietz/diagnóstico , Síndrome de Loeys-Dietz/genética , Desprendimiento de Retina/diagnóstico , Desprendimiento de Retina/etiología , Síndrome de Marfan/complicaciones , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , OjoRESUMEN
Heterozygous missense variants in TGFBR1, encoding one subunit of the transforming growth factor-beta receptor, are a well-established cause of Loeys-Dietz syndrome (LDS)-an autosomal dominant disorder with variable phenotypic expression. Patients with LDS have compromised connective tissues that can result in life-threatening arterial aneurysms, craniosynostosis, characteristic craniofacial and skeletal anomalies, skin translucency, and abnormal wound healing. We report a full sibship with a biallelic type of TGFBR1-related disease. Each born at 38 weeks had aortic root dilation, congenital diaphragmatic hernia (CDH), skin translucency, and profound joint laxity at birth. Both had progressive dilation of the aorta and recurrence of a diaphragmatic defect after plication early in infancy. Patient 1 died at 66 days of age and Patient 2 is alive at 4 years and 4 months of age with multiple morbidities including cystic lung disease complicated by recurrent pneumothoraces and ventilator dependence, craniosynostosis, cervical spine instability, progressive dilation of the aorta, worsening pectus excavatum, large lateral abdominal wall hernia, and diffuse aortic ectasia. Fibroblasts cultured from Patient 2 showed decreased TGF-ß responsiveness when compared to control fibroblasts, consistent with previous observations in cells from individuals with autosomal dominant LDS. Whole genome copy number evaluation and sequencing for both patients including their parents as reference revealed compound heterozygous variants of uncertain clinical significance in exon 2 of TGFBR1 (c.239G>A; p.Arg80Gln paternal and c.313C>G; p.His105Asp maternal) in both siblings in trans. Each parent with their respective variant has no apparent medical issues and specifically no LDS characteristics. Neither of these variants have been previously reported. Thousands of patients have been diagnosed with LDS-an established autosomal dominant disease. These siblings represent the first reports of biallelic TGFBR1-related LDS and expand the differential diagnosis of CDH.
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Enfermedades del Tejido Conjuntivo , Craneosinostosis , Síndrome de Loeys-Dietz , Recién Nacido , Humanos , Receptor Tipo I de Factor de Crecimiento Transformador beta/genética , Síndrome de Loeys-Dietz/diagnóstico , Síndrome de Loeys-Dietz/genética , Hermanos , Receptores de Factores de Crecimiento Transformadores beta/genética , Dilatación Patológica , Craneosinostosis/diagnóstico , Craneosinostosis/genéticaRESUMEN
CLINICAL IMPACT: Large thoracoabdominal aortic aneurysms due to chronic aortic dissection in patients with connective tissue disorders such as Loeys-Dietz syndrome present a challenging scenario, particularly in cases of variant anatomy and when patients are not candidates for conventional open repair. We demonstrate how by combining and modifying off-the-shelf devices during a hybrid procedure, one can create an endovascular solution tailored to the patient's complex anatomy, making use of an aberrant right subclavian artery, and allow for good clinical outcomes.
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OBJECTIVE: To investigate bone fragility in patients with hereditary connective tissue disorders (HCTD), including Ehlers-Danlos syndrome (EDS), Marfan's syndrome (MFS) and Loeys-Dietz syndrome (LDS). METHODS: From inception to June 2022, potentially eligible studies were identified in the Medline and EMBASE databases using search strategy that included terms for "HCTD", "Fracture" and "Osteoporosis". Eligible studies must consist of a group of patients with HCTD and report prevalence/incidence of fracture/osteoporosis in their participants, with or without comparison with healthy individuals. Point estimates with standard errors were obtained from each study and combined using the generic inverse variance method. RESULTS: Among the 4206 articles identified, 19 studies were included. The pooled prevalence of fracture in EDS, MFS, and LDS were 44% (95% confidence interval [CI], 25% to 65%, I2 88%), 17% (95% CI, 11% to 26%, I2 68%), 69% (95% CI, 47% to 85%, I2 83%), respectively. The pooled prevalence of osteoporosis in EDS was 17% (95% CI, 8% to 34%, I2 96%). EDS was associated with fracture [pooled odds ratio {OR} 4.90 (95% CI, 1.49 - 16.08, I2 86%)], but not osteoporosis [pooled OR 1.34 (95% CI, 0.28 - 6.36, I2 87%). One study reported a 5% (95% CI, 3% to 8%) prevalence of osteoporosis in MFS, which was associated with fracture [incidence rate ratio 1.35 (95% CI, 1.18 - 1.55)] and osteoporosis [subhazard ratio 3.97 (95% CI, 2.53 - 6.25)]. CONCLUSION: EDS was associated with fracture, which could be independent of osteoporosis status. MFS had a milder degree of increased risk of fracture and osteoporosis. Despite no data from cohort studies, there was a significantly higher rate of fracture in LDS.
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Enfermedades del Tejido Conjuntivo , Síndrome de Ehlers-Danlos , Síndrome de Loeys-Dietz , Síndrome de Marfan , Osteoporosis , Fracturas Osteoporóticas , Humanos , Enfermedades del Tejido Conjuntivo/complicaciones , Enfermedades del Tejido Conjuntivo/epidemiología , Síndrome de Ehlers-Danlos/complicaciones , Síndrome de Ehlers-Danlos/epidemiología , Síndrome de Marfan/complicaciones , Síndrome de Marfan/epidemiología , Síndrome de Loeys-Dietz/complicaciones , Osteoporosis/etiología , Osteoporosis/complicaciones , Fracturas Osteoporóticas/epidemiología , Fracturas Osteoporóticas/etiología , Tejido ConectivoRESUMEN
Craniofacial development is a complex process involving several signaling pathways, including the one regulated by the TGF-beta (TGF-ß) superfamily of growth factors. Isoforms of TGF-ß play a vital part in embryonic development, notably in craniofacial patterning. Consequently, pathogenic variants in their coding genes may result in a variety of orofacial and craniofacial malformations. Here, we review the impact of genetic variability of TGF-ß signaling biomarkers in major disorders, including palatal and lip clefts, dental anomalies, and craniofacial syndromes, such as the Loeys-Dietz syndrome (LDS) and Camurati-Engelmann disease. Cleft lip and cleft palate are associated with missense mutations in the TGFB1 and TGFB3 genes, while mutations in the LTBP3 gene encoding TGF-ß binding protein 3 may cause selective tooth agenesis. Oligodontia may also be caused by TGFB1-inactivating mutations and/or by variations in the GREM2 gene, which disrupt the activity of gremlin 2, a TGF-ß/bone morphogenetic protein (BMP4) signaling antagonist. CED may be caused by mutations in the TGFB1 gene, while the TGF-ß-related genetic background of LDS consists mostly of TGFBR1 and TGFBR2 mutations, which may also impact the above syndromes' vascular manifestations. The potential utility of the TGF-ß signaling pathway factors as biomarkers that correlate genetics with clinical outcome of craniofacial malformations is discussed.
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Anomalías Craneofaciales , Síndrome de Loeys-Dietz , Humanos , Biomarcadores , Anomalías Craneofaciales/genética , Síndrome de Loeys-Dietz/genética , Síndrome de Loeys-Dietz/patología , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal/genética , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
For complex aortic root lesions, the flanged Bentall procedure has more advantages than the traditional one. Here, we report two patients with complex root lesions treated with the flanged Bentall and Cabrol procedure: one was a 25-year-old male with interventricular septal dissection with Behçet's disease, and the other was a 4-year-old female with a very large ascending aortic aneurysm with a small annulus and Loeys-Dietz syndrome. Both patients recovered uneventfully and obtained good short-term results.
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Enfermedades de la Aorta , Síndrome de Loeys-Dietz , Masculino , Femenino , Humanos , Preescolar , Adulto , Aorta Torácica , Resultado del Tratamiento , Aorta/diagnóstico por imagen , Aorta/cirugía , Válvula AórticaRESUMEN
BACKGROUND: Loeys-Dietz syndrome (LDS) is an inherited disorder predisposing individuals to thoracic aortic aneurysm and dissection. Currently, there are no medical treatments except surgical resection. Although the genetic basis of LDS is well-understood, molecular mechanisms underlying the disease remain elusive, impeding the development of a therapeutic strategy. In addition, aortic smooth muscle cells (SMCs) have heterogenous embryonic origins, depending on their spatial location, and lineage-specific effects of pathogenic variants on SMC function, likely causing regionally constrained LDS manifestations, have been unexplored. METHODS: We identified an LDS family with a dominant pathogenic variant in the TGFBR1 gene (TGFBR1A230T) causing aortic root aneurysm and dissection. To accurately model the molecular defects caused by this mutation, we used human induced pluripotent stem cells from a subject with normal aorta to generate human induced pluripotent stem cells carrying TGFBR1A230T, and corrected the mutation in patient-derived human induced pluripotent stem cells using CRISPR-Cas9 gene editing. After their lineage-specific SMC differentiation through cardiovascular progenitor cell (CPC) and neural crest stem cell lineages, we used conventional molecular techniques and single-cell RNA sequencing to characterize the molecular defects. The resulting data led to subsequent molecular and functional rescue experiments using activin A and rapamycin. RESULTS: Our results indicate the TGFBR1A230T mutation impairs contractile transcript and protein levels, and function in CPC-SMC, but not in neural crest stem cell-SMC. Single-cell RNA sequencing results implicate defective differentiation even in TGFBR1A230T/+ CPC-SMC including disruption of SMC contraction and extracellular matrix formation. Comparison of patient-derived and mutation-corrected cells supported the contractile phenotype observed in the mutant CPC-SMC. TGFBR1A230T selectively disrupted SMAD3 (SMAD family member 3) and AKT (AKT serine/threonine kinase) activation in CPC-SMC, and led to increased cell proliferation. Consistently, single-cell RNA sequencing revealed molecular similarities between a loss-of-function SMAD3 mutation (SMAD3c.652delA/+) and TGFBR1A230T/+. Last, combination treatment with activin A and rapamycin during or after SMC differentiation significantly improved the mutant CPC-SMC contractile gene expression and function, and rescued the mechanical properties of mutant CPC-SMC tissue constructs. CONCLUSIONS: This study reveals that a pathogenic TGFBR1 variant causes lineage-specific SMC defects informing the etiology of LDS-associated aortic root aneurysm. As a potential pharmacological strategy, our results highlight a combination treatment with activin A and rapamycin that can rescue the SMC defects caused by the variant.
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Células Madre Pluripotentes Inducidas/metabolismo , Síndrome de Loeys-Dietz/genética , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Humanos , Síndrome de Loeys-Dietz/patologíaRESUMEN
OBJECTIVE: Despite a shared degenerative vascular phenotype, Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and other genetically distinct connective tissue diseases (CTDs) have unique extravascular pathologies that impact the outcomes of aortic replacement. The aim of our study was to investigate the association of CTD genotype with postoperative outcomes and branch patency following open thoracoabdominal aortic replacement in a large institutional cohort. METHODS: All patients undergoing open branched thoracoabdominal aortic replacement at a single academic center from 2006 to 2020 were included and classified as CTD or non-CTD based on the presence of genotypic documentation. Outcomes were compared using analysis of variance and χ2 testing for continuous and discrete variables, respectively. Kaplan-Meier curves were utilized to examine patency of graft branches over time. RESULTS: Overall, 172 patients were included, with a mean follow-up of 30.5 ± 34.9 months. CTD was present in 45 patients (26%); specifically, 32 had MFS, five had LDS, and eight had another CTD. Patients with CTDs had more extent II thoracoabdominal aneurysms (40% vs 15%), more reconstructed branches (3.5 vs 1.8), more frequently reconstructed visceral branches (86.7% vs 22.7%), and higher intraoperative blood loss (13.3 vs 6.8 L; all P < .05) compared with non-CTD patients. Patients with MFS were more frequently systemically anticoagulated preoperatively (50% vs 5%) and demonstrated higher rates of postoperative deep vein thrombosis/pulmonary embolism compared with non-CTD patients (9% vs 2%; both P < .05). Five-year renal branch patency was decreased among all patients compared with visceral branches (87.3% vs 95.6%; P = .05), but there were no individual branch patency differences between patients with and without CTDs (P = .086). Overall branch patency at 1 and 5 years was significantly higher in patients with MFS than in non-CTD patients (98.9% vs 89.1% at 5 years); there were no significant patency differences between non-CTD patients and any other CTD subgroup, mostly due to early patency loss. CONCLUSIONS: Open thoracoabdominal reconstruction in patients with CTD is technically challenging and associated with increased transfusion and postoperative thromboembolic events when compared with non-CTD patients. Technical outcomes of the procedure are excellent and are differentially associated with genotype, with patients with MFS experiencing significantly improved branch patency over both non-CTD patients and patients with other CTDs, a finding which has multifactorial drivers.
Asunto(s)
Aneurisma de la Aorta Torácica/cirugía , Implantación de Prótesis Vascular/efectos adversos , Oclusión de Injerto Vascular/epidemiología , Síndrome de Loeys-Dietz/complicaciones , Síndrome de Marfan/complicaciones , Adolescente , Adulto , Anciano , Aneurisma de la Aorta Torácica/genética , Implantación de Prótesis Vascular/instrumentación , Estudios de Casos y Controles , Niño , Femenino , Oclusión de Injerto Vascular/etiología , Humanos , Síndrome de Loeys-Dietz/genética , Síndrome de Loeys-Dietz/cirugía , Masculino , Síndrome de Marfan/genética , Síndrome de Marfan/cirugía , Persona de Mediana Edad , Estudios Retrospectivos , Stents/efectos adversos , Grado de Desobstrucción Vascular/genética , Adulto JovenRESUMEN
Background: It is clinically widely overlooked that many patients with Marfan- (MFS) or Loeys-Dietz-Syndrome (LDS) are obese. While anthropometric routine parameters are not very suitable, the modern Bioelectrical Impedance Analysis (BIA) seems superior for the acquisition of reliable noninvasive assessment of body composition of patients. The aim of the study was to assess the body composition of patients with MFS/LDS by BIA in order to detect occult obesity, which may be a risk marker for aortic or vascular complications. Methods: In this exploratory cross-sectional study, 50 patients (66% female; mean age: 37.7 ± 11.7 [range: 17-64] years) with a molecular genetic (n = 45; 90%) or clinical (n = 5; 10%) proven diagnosis of MFS or LDS were enrolled between June 2020 and February 2022. All BIA-measurements were performed with the Multifrequence-Impedance-Analyzer Nutriguard-MS (Data Input, Poecking, Germany). Results: The MFS/LDS collective was significantly different from an age-, sex-, and BMI-adjusted control in terms of body fat, percent cellularity, body cell mass, extra cellular mass/body cell mass index, and phase angle (all p < 0.05). The mean BIA-measured bodyfat was 31.7 ± 8.7% [range: 9.5-53.5%], while the mean calculated BMI of the included patients was 23.0 ± 4.8 kg/ m 2 [range: 15.2-41.9 kg/ m 2 ]. Therefore, using the obesity cut-off values for the body fat percentage of 25% in men and 35% in women, the BIA classifies as many as 28 patients (56.0%) as obese. In contrast only 12 patients (24.0%) were pre-obese, respectively 3 (6.0%) obese by BMI. The significant difference (p < 0.001) had an accordance of 42.7%. Overall, 15 patients (13 MFS; 2 LDS) had previous aortic surgery (n = 14) and/or interventional treatment (n = 2) for aortic complications (aneurysm, aortic dissection). 11 out of these 15 (73.3%) were currently classified as obese by BIA. Conclusions: The fact that many patients with MFS or LDS are obese is widely unknown, although obesity may be associated with impaired vascular endothelial function and an increased risk of cardiovascular complications. Also, in patients with MFS/LDS, BIA allows a reliable assessment of the body composition beyond the normal anthropometric parameters, such as BMI. In the future, BIA-data possibly may be of particular importance for the assessment of the vascular risk of MFS/LDS patients, besides the aortic diameters.
RESUMEN
Loeys-Dietz syndrome (LDS) is a connective tissue disorder that commonly results in a dilated aorta, aneurysms, joint laxity, craniosynostosis, and soft skin that bruises easily. Neurodevelopmental abnormalities are uncommon in LDS. Two previous reports present a total of four patients with LDS due to pure 1q41 deletions involving TGFB2 (Gaspar et al., American Journal of Medical Genetics Part A, 2017, 173, 2289-2292; Lindsay et al., Nature Genetics, 2012, 44, 922-927). The current report describes an additional five patients with similar deletions. Seven of the nine patients present with some degree of hypotonia and gross motor delay, and three of the nine present with speech delay and/or intellectual disability (ID). The smallest deletion common to all patients is a 785 kb locus that contains two genes: RRP15 and TGFB2. Previous studies report that TGFB2 knockout mice exhibit severe perinatal anomalies (Sanford et al., Development, 1997, 124, 2659-2670) and TGFB2 is expressed in the embryonic mouse hindbrain floor (Chleilat et al., Frontiers in Cellular Neuroscience, 2019, 13). The deletion of TGFB2 may be associated with a neurodevelopmental phenotype with incomplete penetrance and variable expression.