Impact of early diagnosis on surgical outcomes in patients with Loeys-Dietz syndrome.

Background: This study aimed to investigate the influence of early diagnosis (ED) on surgical outcomes in patients definitively diagnosed with Loeys-Dietz syndrome (LDS). Methods: A retrospective review was conducted on 38 patients with LDS who underwent aortic surgery at our institution between January 1995 and June 2022. The primary endpoint was freedom from aortic reoperation. Results: Among the patients, the median age at the initial surgery was 33 (range: 39-44) years, and 23 (60.5%) patients were male. Twenty-one (55.3%; aortic dissection or rupture (n = 2) and aneurysm (n = 19)) patients were diagnosed with LDS before the initial surgery (ED group). Meanwhile, the remaining 17 (44.7%; aortic dissection or rupture (n = 13) and aneurysm (n = 4)) patients were after surgery [delayed diagnosis (DD) group]. The ED group had significantly lower rates of emergency surgery and concomitant arch procedure (P < .001, respectively) but a higher rate of valve-sparing root surgery (P = .018) compared to the DD group. No in-hospital mortality was observed in either group. Nevertheless, the ED group had a shorter postoperative hospital stay (median difference: 3 days, P = .032) and a lower rate of aortic reoperation (P = .013). Conclusion: Early detection of LDS may help in preventing acute aortic syndrome, reducing the risk of aortic reoperation, and potentially shortening hospital stay. Careful medical management before surgery could contribute to better clinical outcomes and an improved quality of life for patients with LDS.

Like Father like Daughter: Surgical Redo Thoracoabdominal Aneurysm Repairs in a Family With Loeys-Dietz Syndrome.

Loeys Dietz Syndrome (LDS) is an autosomal dominant connective tissue disorder resulting from a mutation in the transforming growth factor beta receptor (TGFBR) family of genes. It is commonly associated with the development of aortic aneurysms and dissections. We report the successful open surgical management of thoracoabdominal aneurysms in a father and daughter with Loeys-Dietz Syndrome after failed endovascular repair. The daughter required stent graft explantation, while the stent graft remained in the father. These cases highlight the importance of early genetic testing of both patients and first-degree family members in those with a strong history of aortic disease, even when there is a lack of typical connective tissue disorder associated physical exam findings and open surgical index operations.

Cardiovascular Management of Aortopathy in Children: A Scientific Statement From the American Heart Association.

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.

Impact of valve-sparing aortic root replacement on aortic fluid dynamics and biomechanics in patients with syndromic heritable thoracic aortic disease.

OBJECTIVES: Patients with syndromic heritable thoracic aortic diseases (sHTAD) who underwent prophylactic aortic root replacement are at high risk of distal aortic events, but the underlying mechanisms are poorly understood. This prospective, longitudinal study aims to assess the impact of valve-sparing aortic root replacement (VSARR) on aortic fluid dynamics and biomechanics in these patients, and to examine whether they present altered haemodynamics or biomechanics prior to surgery compared to sHTAD patients with no indication for surgery (sHTAD-NSx) and healthy volunteers (HV). METHODS: Sixteen patients with Marfan or Loeys-Dietz syndrome underwent two 4D flow CMR studies before (sHTAD-preSx) and after VSARR (sHTAD-postSx). Two age, sex and BSA matched cohorts of 40 HV and 16 sHTAD-NSx patients with available 4D flow CMR, were selected for comparison. In-plane rotational flow (IRF), systolic flow reversal ratio (SFRR), wall shear stress (WSS), pulse wave velocity (PWV) and aortic strain were analysed in the ascending (AscAo) and descending aorta (DescAo). RESULTS: All patients with sHTAD presented altered haemodynamics and increased aortic stiffness (p<0.05) compared to HV, both in the AscAo (median PWV 7.4 in sHTAD-NSx; 6.8 in sHTAD-preSx; 4.9m/s in HV) and DescAo (median PWV 9.1 in sHTAD-NSx; 8.1 in sHTAD-preSx; 6.3m/s in HV). Patients awaiting VSARR had markedly reduced in-plane (median IRF -2.2 vs 10.4 cm2/s in HV, p=0.001), but increased through-plane flow rotation (median SFRR 7.8 vs 3.8% in HV, p=0.002), and decreased WSS (0.36 vs 0.47N/m2 in HV, p=0.004) in the proximal DescAo. After VSARR, proximal DescAo in-plane rotational flow (p=0.010) and circumferential WSS increased (p=0.011), no longer differing from HV, but through-plane rotational flow, axial WSS and stiffness remained altered. Patients in which aortic tortuosity was reduced after surgery showed greater post-surgical increase in IRF compared to those in which tortuosity increased (median IRF increase 18.1 vs 3.3cm²/s, p=0.047). Most AscAo flow alterations were restored to physiological values after VSARR. CONCLUSIONS: In patients with sHTAD, VSARR partially restores downstream fluid dynamics to physiological levels. However, some flow disturbances and increased stiffness persist in the proximal DescAo. Further longitudinal studies are needed to evaluate whether persistent alterations contribute to post-surgical risk.

Temporal Pattern Analysis of Ultrasound Surveillance Data in Vascular Connective Tissue Disorders.

BACKGROUND: Ehlers-Danlos syndrome (EDS), Marfan syndrome (MFS), and Loeys-Dietz syndrome (LDS) are connective tissue disorders frequently associated with vascular aneurysm formation, dissections, and subsequent major complications. Regular imaging surveillance is recommended for these conditions. However, no guidelines currently exist regarding imaging modality or surveillance intervals. METHODS: This retrospective single-center observational study analyzed clinical and imaging data of patients attending an outpatient clinic for vascular connective tissue disorders between August 2008 and January 2024. Imaging (1424 data points in total) and clinical data were extracted from electronic health records. Analysis primarily included a comparison of vessel diameter progression across imaging modalities, with an additional review of the clinical history of vascular events. RESULTS: In total, 19 patients with vascular connective tissue disorders (vCTDs) underwent consultations at our outpatient clinic. Nine (47.4%) patients experienced vascular events, while two (10.5%) passed away during the study period. Multimodal imaging surveillance revealed a tendency towards arterial diameter increase. Consistent ultrasound monitoring provided more reliable diameter progression data for the same arterial segment than a combination of imaging modalities. Temporal analysis indicated a tendency for the continuous growth of the abdominal aorta, the common and internal carotid artery, and the common femoral and popliteal artery. CONCLUSION: The study highlights the importance of standardized, modality-specific imaging protocols in monitoring patients with vCTDs. The variability in disease progression among these patients further complicates surveillance strategies, contemplating the need for individualized approaches. Further research and prospective multicenter studies are required to refine and improve monitoring protocols.

Acute Transverse Myelitis in a Patient With Type 2 Loeys-Dietz Syndrome: A Report of a Rare Case From India.

Loeys-Dietz syndrome (LDS) is a very rare connective tissue disorder with autosomal dominant inheritance, characterized by the involvement of the cardiovascular, musculoskeletal, and cutaneous systems, along with dysmorphic facial features. Currently, there are limited data regarding this disease. This case presents a clinical observation of a 17-year-old boy with acute onset of sensorimotor paraparesis and genetically confirmed LDS. The predominant symptoms of LDS include arterial aneurysms, arterial tortuosity, hypertelorism, and bifid uvula. However, this constellation of symptoms is not found in all patients with the disease. Genetic confirmation is essential for an accurate diagnosis. The prognosis for LDS differs from its mimics, such as Marfan syndrome, Beals syndrome, Ehlers-Danlos syndrome, and Shprintzen-Goldberg syndrome. Management of the disease warrants a multidisciplinary approach to address its various manifestations. Such an approach can help increase the life expectancy and improve the quality of life for these patients.

Management of an elderly patient with nonsyndromic TGFBR1-related aortopathy: A case report.

Key Clinical Message: Genetic variants associated with hereditary TAAD may contribute to nonsyndromic TAAD. We present the case of a 72-year-old man with nonsyndromic TAAD undergoing prophylactic surgery after a gene panel test revealed a pathogenic variant in TGFBR1, but the indication for genetic testing in such elderly-onset cases still warrants further discussion. Abstract: Hereditary thoracic aortic aneurysm and dissection (TAAD) is a serious clinical condition resulting in a fatal outcome. Recently, variants in causative genes for syndromic hereditary TAAD, such as Marfan syndrome and Loeys-Dietz syndrome (LDS), have been reported to predispose to the development of nonsyndromic TAAD; however, genetic testing for patients with elderly-onset nonsyndromic TAAD warrants further discussion. We present a 72-year-old nonsyndromic Japanese man with moderate-sized aortic annulus ectasia (AAE) with moderate aortic regurgitation and ascending to distal arch aortic dilatation (maximum diameter: 46 mm). He had been treated for hypertension and dyslipidemia for 7 years, and his eldest son had AAE at 33 years old and type A aortic dissection at 43 years old. Surgical repair was considered a treatment option because the patient potentially had a nonsyndromic hereditary aortic disease, and genetic panel testing for TAAD identified a pathogenic missense variant in TGFBR1 (c.934G > A, p.[Gly312Ser]), previously reported in patients with LDS type 1. He was diagnosed with nonsyndromic TGFBR1-related aortopathy and underwent prophylactic surgery using a modified Bentall operation and total arch replacement with open stent graft implantation. Genetic testing was useful in guiding the treatment strategy, but further analysis is warranted to establish the clinical value in the treatment plan for patients with elderly-onset nonsyndromic TAAD.

Endovascular fenestration and stenting for renovisceral malperfusion in a pediatric patient with type II Loeys-Dietz syndrome.

A 16-year-old girl with Loeys-Dietz syndrome presented with an acute, complicated type B aortic dissection (AD) with mesenteric and right renal malperfusion owing to a dynamic obstruction. The anatomy of her AD and her genetic aortography were suboptimal for thoracic endovascular aortic repair. Given the concern for anticipated late aortic degeneration and the need for open aortic repair, she underwent successful transfemoral endovascular septal fenestration with stenting of the fenestration into the superior mesenteric artery and additional stenting of the right renal artery. Her renal failure and mesenteric angina resolved, and she was discharged home. Endovascular fenestration provides an elegant solution for AD-associated dynamic malperfusion of aortic branch vessels without compromising future open aortic repairs.

Marfan and Loeys-Dietz aortic phenotype: A potential tool for diagnosis and management.

Objective: In heritable aortic diseases, different vascular involvement may occur with potential variable implications in aortic dilation/dissection risk. This study aimed to analyze the aortic anatomy of individuals with Marfan syndrome and Loeys-Dietz syndrome to identify possible morphological differences. Methods: Computed tomography and magnetic resonance imaging of the thoracoabdominal aorta from the proximal supra-aortic vessels to the femoral bifurcation level of 114 patients with Marfan and Loeys-Dietz syndromes and 20 matched control subjects were examined. Aortic diameters, areas, length, and tortuosity were measured in different aortic segments using specific vessel analysis software. Results: Patients with Marfan syndrome showed a higher prevalence of ascending aorta and aortic root dilation (P = .011), larger and longer aortic roots (P = .013) with pear-shaped phenotype, larger isthmus/descending aorta diameter ratio (P = .015), and larger suprarenal aorta and iliac arteries. Patients with Loeys-Dietz syndrome showed longer indexed segments and a significantly longer arch (P = .006) with type 2/3 arch prevalence (P = .097). Measurement ratios analysis provided cut-off values (aortic root to ascending aorta length/aortic root diameter, aortic root/sinotubular junction, aortic root/ascending aorta diameter) differentiating patients with Marfan syndrome from patients with Loeys-Dietz syndrome, even in the early stage of the disease. Conclusions: Both syndromes show peculiar anatomic patterns at different aortic levels irrespective of aortic dilation and disease severity. These features may represent the expression of different genetic mutations on aortic development, with a potential impact on prognosis and possibly contributing to better management of the diseases. The systematic adoption of whole body imaging with magnetic resonance or computed tomography should always be considered, because they allow a complete vascular assessment with practical indicators of differential diagnosis.

Acute Primary Small Bowel Volvulus in a Male With Loeys-Dietz Syndrome.

Loeys-Dietz syndrome (LDS) is a connective tissue disorder with features including, but not limited to, aortic dissections, skeletal abnormalities, and craniofacial defects. However, considering its relatively recent discovery, there are still many unknowns about LDS. The extent of a connective tissue disorder like LDS is yet to be defined throughout the various organ systems, including the gastrointestinal system. Connective tissue disorders have been found to have higher associations with certain conditions, like constipation. In a similar manner, LDS may increase the propensity for developing uncommon gastrointestinal manifestations, like primary small bowel volvulus. A volvulus is defined as an abnormal rotation of the small bowel segment along the axis of its mesentery. Primary small bowel volvulus is differentiated from secondary small bowel volvulus by its nature of origin: primary small bowel volvulus occurs as an independent spontaneous occurrence, whereas secondary small bowel volvulus is secondary to the presence of adhesions, diverticular disease, or abdominal masses. In this case report, we highlight a potential gastrointestinal manifestation of LDS with the occurrence of a primary small bowel volvulus in a young adult male diagnosed with LDS. The patient experienced acute primary small bowel volvulus 14 days into his stay, which may have been influenced by this newfound connective tissue disorder.

Giant Morgagni hernia and aorto-pulmonary collaterals in a Loeys-Dietz patient undergoing surgery for aortic root aneurysm and mitral valve prolapse.

The case of a Loeys-Dietz syndrome patient undergoing mitral valve repair and composite aortic root and valve replacement is here described: preoperative CT scan unravelled a previously misdiagnosed Morgagni hernia (anterior diaphragmatic), containing omentum only, compressing the right ventricle. Intraoperatively, an abnormal oxygenated blood backflow into the left ventricle was observed, postoperatively found to be caused by major aorto-pulmonary collateral arteries. This is the 1st case of Morgagni hernia and systemic-pulmonary shunt ever reported associated with Loeys-Dietz syndrome. These congenital features may be important in both phenotyping and surgical management.

Hereditary Aortic Aneurysms and Dissections: Clinical Diagnosis and Genetic Testing.

Hereditary aortic aneurysms and dissections, such as Marfan syndrome, differ in that they occur in younger patients without generally recognized risk factors, have a predilection for the thoracic rather than the abdominal aorta, and are at risk for dissection even at smaller aortic diameters. Early diagnosis, careful follow-up, and early intervention, such as medication to reduce aortic root growth and prophylactic aortic replacement to prevent fatal aortic dissection, are essential for a better prognosis. Molecular genetic testing is extremely useful for early diagnosis. However, in actual clinical practice, the question often arises as to when and to which patient genetic testing should be offered since the outcome of the tests can have important implications for the patient and the relatives. Pre- and post-test genetic counseling is essential for early intervention to be effective. (This article is a secondary translation of Jpn J Vasc Surg 2023; 32: 261-267.).

Delayed diagnosis of Loeys-Dietz syndrome revealed through atrial septal defect with pulmonary artery dilation.

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.

Unraveling the genetic collagen connection: clinical and therapeutic insights on genetic connective tissue disorders.

Hereditary connective tissue disorders include more than 200 conditions affecting different organs and tissues, compromising the biological role of the extracellular matrix through interference in the synthesis, development, or secretion of collagen and/or its associated proteins. The clinical phenotype includes multiple signs and symptoms, usually nonspecific but of interest to rheumatologists because of musculoskeletal involvement. The patient´s journey to diagnosis is long, and physicians should include these disorders in their differential diagnoses of diseases with systemic involvement. In this review, insights for the diagnosis and treatment of osteogenesis imperfecta, hypermobility spectrum disorder/Ehlers-Danlos syndrome, Marfan, Loeys-Dietz, and Stickler syndromes are presented.

Cardiovascular and obstetrical outcomes among delivering patients with Marfan or Loeys-Dietz syndrome: a retrospective analysis by hospital delivery setting.

BACKGROUND: Pregnancy is a high-risk time for patients with Marfan syndrome or Loeys-Dietz syndrome because of the risk for cardiovascular complications, including the risk for aortic dissection. Little is known about the differences in obstetrical and cardiac outcomes based on delivery hospital setting (academic or academic-affiliated vs community medical centers). OBJECTIVE: This study aimed to evaluate the obstetrical and cardiac outcomes of patients with Marfan syndrome or Loeys-Dietz syndrome based on delivery hospital setting. STUDY DESIGN: This was a secondary analysis of a retrospective, observational cohort study of singleton pregnancies among patients with a diagnosis of Marfan syndrome or Loeys-Dietz syndrome from 1990 to 2016. Patients were identified through the Marfan Foundation, the Loeys-Dietz Syndrome Foundation, or the Cardiovascular Connective Tissue Clinic at Johns Hopkins Hospital. Data were obtained via self-reported obstetrical history and verified by review of medical records. Nonparametric analyses were performed using Fisher's exact tests and Wilcoxon rank-sum tests. RESULTS: A total of 273 deliveries among patients with Marfan syndrome or Loeys-Dietz syndrome were included in this analysis (Table 1). More patients who had a known diagnosis before delivery of either Marfan syndrome or Loeys-Dietz syndrome delivered at an academic hospital as opposed to a community hospital (78.6% vs 59.9%; P=.001). Patients with Marfan syndrome or Loeys-Dietz syndrome who delivered at academic centers were more likely to have an operative vaginal delivery than those who delivered at community centers (23.7% vs 8.6%; P=.002). When the indications for cesarean delivery were assessed, connective tissue disease was the primary indication for the mode of delivery at community centers when compared with academic centers (55.6% vs 43.5%; P=.02). There were higher rates of cesarean delivery for arrest of labor and/or malpresentation at community hospitals than at academic centers (23.6% vs 5.3%; P=.01). There were no differences between groups in terms of the method of anesthesia used for delivery. Among those with a known diagnosis of Marfan syndrome or Loeys-Dietz syndrome before delivery, there were increased operative vaginal delivery rates at academic hospitals than at community hospitals (27.2% vs 15.1%; P=.03) (Table 2). More patients with an aortic root measuring ≥4 cm before or after pregnancy delivered at academic centers as opposed to community centers (33.0% vs 10.2%; P=.01), but there were no significant differences in the median size of the aortic root during pregnancy or during the postpartum assessment between delivery locations. Cardiovascular complications were rare; 8 patients who delivered at academic centers and 7 patients who delivered at community centers had an aortic dissection either in pregnancy or the postpartum period (P=.79). CONCLUSION: Patients with Marfan syndrome or Loeys-Dietz syndrome and more severe aortic phenotypes were more likely to deliver at academic hospitals. Those who delivered at academic hospitals had higher rates of operative vaginal delivery. Despite lower frequencies of aortic root diameter >4.0 cm, those who delivered at community hospitals had higher rates of cesarean delivery for the indication of Marfan syndrome or Loeys-Dietz syndrome. Optimal delivery management of these patients requires further prospective research.

Diameter and dissection of the abdominal aorta and the risk of distal aortic reoperation after surgery for type A aortic dissection.

BACKGROUND: Surgery for Stanford type A aortic dissection (TAAD) is associated with an increased risk of late aortic reoperations due to degeneration of the dissected aorta. METHODS: The subjects of this analysis were 990 TAAD patients who survived surgery for acute TAAD and had complete data on the diameter and dissection status of all aortic segments. RESULTS: After a mean follow-up of 4.2 ± 3.6 years, 60 patients underwent 85 distal aortic reoperations. Ten-year cumulative incidence of distal aortic reoperation was 9.6%. Multivariable competing risk analysis showed that the maximum preoperative diameter of the abdominal aorta (SHR 1.041, 95%CI 1.008-1.075), abdominal aorta dissection (SHR 2.133, 95%CI 1.156-3.937) and genetic syndromes (SHR 2.840, 95%CI 1.001-8.060) were independent predictors of distal aortic reoperation. Patients with a maximum diameter of the abdominal aorta >30 mm and/or abdominal aortic dissection had a cumulative incidence of 10-year distal aortic reoperation of 12.0% compared to 5.7% in those without these risk factors (adjusted SHR 2.076, 95%CI 1.062-4.060). CONCLUSION: TAAD patients with genetic syndromes, and increased size and dissection of the abdominal aorta have an increased the risk of distal aortic reoperations. A policy of extensive surgical or hybrid primary aortic repair, completion endovascular procedures for aortic remodeling and tight surveillance may be justified in these patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04831073.

Endovascular aortic repair in patients with Marfan and Loeys-Dietz syndrome is safe and durable when employed by a multi-disciplinary aortic team.

OBJECTIVES: The aim of this study was to report on mid-term outcomes after endovascular aortic repair (EVAR) in patients with Marfan (MFS) or Loeys-Dietz (LDS) syndrome. METHODS: We analysed data from 2 European centres of patients with MFS and LDS undergoing EVAR. Patients were analysed based on (i) timing of the procedure (planned versus emergency procedure) and (ii) the nature of the landing zone (safe versus non-safe). The primary end-point was freedom from reintervention. Secondary end-points were freedom from stroke, bleeding and death. RESULTS: A population of 419 patients with MFS (n = 352) or LDS (n = 67) was analysed for the purpose of this study. Thirty-nine patients (9%) underwent EVAR. Indications for thoracic endovascular aortic repair or EVAR were aortic dissection in 13 (33%) patients, aortic aneurysm in 22 (57%) patients and others (intercostal patch aneurysm, penetrating atherosclerotic ulcer, pseudoaneurysm, kinking of frozen elephant trunk (FET)) in 4 (10%) patients. Thoracic endovascular repair was performed in 34 patients, and abdominal endovascular aortic repair was performed in 5 patients. Mean age at 1st thoracic endovascular aortic repair/EVAR was 48.5 ± 15.4 years. Mean follow-up after 1st thoracic endovascular aortic repair/EVAR was 5.9 ± 4.4 years. There was no statistically significant difference in the rate of reinterventions between patients with non-safe landing zone and the patients with safe proximal landing zone (P = 0.609). Furthermore, there was no increased probability for reintervention after planned endovascular intervention compared to emergency procedures (P = 0.916). Mean time to reintervention, either open surgical or endovascular, after planned endovascular intervention was in median 3.9 years (95% confidence interval 2.0-5.9 years) and 2.0 years (95% confidence interval -1.1 to 5.1 years) (P = 0.23) after emergency procedures. CONCLUSIONS: EVAR in patients with MFS and LDS and a safe landing zone is feasible and safe. Endovascular treatment is a viable option when employed by a multi-disciplinary aortic team even if the landing zone is in native tissue.

Physical fitness in children with Marfan and Loeys-Dietz syndrome: associations between cardiovascular parameters, systemic manifestations, fatigue, and pain.

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.

Functional analysis of cell lines derived from SMAD3-related Loeys-Dietz syndrome patients provides insights into genotype-phenotype relation.

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.