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.

Cardiovascular pathology, inheritance and prognosis in a familial cohort of Loeys-Dietz type III.

INTRODUCTION: Loeys-Dietz syndrome (LDS) is a heritable disease that is the result of dysregulation of the transforming growth factor beta (TGFß) pathway. The pathogenic variants associated with the condition are linked to aortic aneurysms and dissections along with other cardiovascular and non-cardiovascular abnormalities. LDS type III is associated with pathogenic variants in the SMAD3 gene responsible for signally in the TGFß pathway. Most of the current knowledge of LDS stems from studies of LDS I and II patient with limited data on large cohorts of LDS III patients. We sought to identify the prevalence and course of cardiovascular diseases in a large familial cohort of LDS III patients and also to compare these findings with a previously described cohort of similar size with the identical pathogenic variant. METHODS: The cohort was identified by systematic genetic screening of a familial cohort identified through a single proband. Data was collected from retrospective chart review of patients identified to be affected by the syndrome. RESULTS: Screening of 97 patients identified 19 patients (16 through genetic testing and 3 through phenotypic screening of untested direct descendants of genetically positive individuals). The prevalence of cardiovascular abnormalities was 84%. There was significant intrafamilial phenotypic variability within the cohort with the predominant cardiovascular abnormality being mitral valve disease followed by aortic disease. 92% of patients >18 years of age had osteoarthritis which is a further hallmark of LDS III. CONCLUSION: LDS III sets itself apart from the more widely studied LDS types I and II cardiovascular phenotypes by presenting later in life and tending to be more strongly associated with mitral valve disease.

Mitral annular disjunction on cardiac MRI: Prevalence and association with disease severity in Loeys-Dietz syndrome.

BACKGROUND: The purpose of this study was to evaluate mitral annular disjunction (MAD) on cardiac magnetic resonance imaging (MRI) in Loeys-Dietz Syndrome (LDS) and to explore its association with adverse outcomes. METHODS: In this retrospective cohort study, adult patients with LDS who underwent cardiac MRI were evaluated for MAD, aortic dimensions, and ventricular volumetry. Aortic events were defined as aortic surgery and/or dissection and severe arrhythmic events as cardiac arrest or sustained ventricular tachycardia (VT). RESULTS: Among 46 LDS patients (52% female, 37.2 ± 14.3 years), 17 had MAD (37%). MAD and no MAD groups were similar in age, sex, aortic dimensions and left ventricular parameters. After a clinical follow-up of 4.3 years (IQR 1.5-8.4), 3 in MAD and 4 in no MAD groups required aortic valve sparing root replacement (VSRR) and 1 in MAD developed type A dissection. Over a similar imaging follow-up period [4.1 years (IQR 2.7-9.1) vs. 3.2 years (IQR 1.0-9.0), p = 0.65], compared to baseline, increase in native aortic root size was significant only in MAD (39.4 ± 4.6 mm vs. 38.1 ± 5.3 mm, p = 0.02, 19.3 ± 2.4 mm/m2 vs. 18.7 ± 2.4 mm/m2, p = 0.01) compared to those without MAD. Patients with MAD were younger at first aortic event compared to those without (26.7 ± 11.5 years vs. 45.0 ± 14.9 years, p = 0.03). MAD distance correlated with need for VSRR, r = 0.57, p = 0.02. Two patients in the MAD group developed sustained VT. No cardiac arrest or death was observed. CONCLUSION: MAD is highly prevalent in LDS, associated with progressive aortic dilatation, and aortic events at younger age. MAD may be a marker of disease severity necessitating close surveillance.

Intracranial Aneurysms in Loeys-Dietz Syndrome: A Multicenter Propensity-Matched Analysis.

BACKGROUND: Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by a classic triad of hypertelorism, bifid uvula and/or cleft palate, and generalized arterial tortuosity. There are limited data on the prevalence and rupture risk of intracranial aneurysms (IAs) in the setting of LDS, with no established guidelines. OBJECTIVE: To analyze the prevalence and rupture risk of IA in LDS. METHODS: Electronic medical records of patients with a confirmed diagnosis of LDS and available cerebrovascular imaging were reviewed. Patients were divided into 2 groups based on the presence of IA. Unmatched and propensity-matched analyses were used to identify potential risk factors for aneurysm formation. RESULTS: Records of 1111 patients were screened yielding a total of 60 patients with a diagnosis of LDS. Eighteen (30%) patients had IA, 4 (22.2%) of whom had multiple aneurysms for a total of 24 IAs. Twenty-three (95.8%) aneurysms were located in the anterior circulation; none of them were ruptured. On unmatched analysis, age ( P = .015), smoking history ( P = .034), hypertension ( P = .035), and number of extracranial aneurysms ( P < .001) were significantly higher in patients with IA. After matching for age, sex, race, stroke history, family history, and extracranial aneurysms, smoking history ( P = .009) remained significant. CONCLUSION: Patients with LDS have an increased risk of IAs, especially with a history of smoking. The prevalence rate of IAs in our series was 30%. Screening imaging should be considered at diagnosis, and patients should be encouraged to abstain from smoking. Further studies are needed to elucidate the risk of IA rupture and treatment considerations in this unique population.

Pain and fatigue in adults with Loeys-Dietz syndrome and vascular Ehlers-Danlos syndrome, a questionnaire-based study.

The purpose was to study self-reported chronic pain and fatigue symptoms among adults with molecularly verified Loeys-Dietz and vascular Ehlers-Danlos syndrome using a cross-sectional questionnaire design. Seventy adults were invited through a National Resource Centre for Rare Disorders. A study specific questionnaire including Brief Pain Inventory, Standardized Nordic Questionnaire, Fatigue Severity Scale, Hospital Anxiety & Depression Scale, questions on physical activity, and disease burden was used. Fifty-two persons participated, n = 34 with Loeys-Dietz and n = 18 with vascular Ehlers-Danlos syndrome, aged 18-68 years, 58% women. Chronic pain (79%) and fatigue (58%) symptoms were common. Half developed pain during childhood/adolescence. Sleep problems and high multi-organ burden were significantly associated with chronic pain (p = 0.004, p = 0.014) and high fatigue (p < 0.001, p < 0.001). Chronic pain was associated with higher scores of fatigue (p = 0.002). Higher scores of fatigue were associated with lower level of physical activity (p = 0.014), higher cardiovascular burden (p = 0.025), and higher symptoms of anxiety (p = 0.001). In this study, symptoms of chronic pain, fatigue, sleep problems, and disease burden seemed to mutually reinforce each other. Initiatives should consider interventions aimed at postponing the onset and reducing symptoms of pain, fatigue, and sleep problems and thus reduce the total disease burden at an early stage in patients with these complex conditions.

Cardiovascular Outcomes in Aortopathy: GenTAC Registry of Genetically Triggered Aortic Aneurysms and Related Conditions.

BACKGROUND: The GenTAC (Genetically Triggered Thoracic Aortic Aneurysm and Cardiovascular Conditions) Registry enrolled patients with genetic aortopathies between 2007 and 2016. OBJECTIVES: The purpose of this study was to compare age distribution and probability of elective surgery for proximal aortic aneurysm, any dissection surgery, and cardiovascular mortality among aortopathy etiologies. METHODS: The GenTAC study had a retrospective/prospective design. Participants with bicuspid aortic valve (BAV) with aneurysm (n = 879), Marfan syndrome (MFS) (n = 861), nonsyndromic heritable thoracic aortic disease (nsHTAD) (n = 378), Turner syndrome (TS) (n = 298), vascular Ehlers-Danlos syndrome (vEDS) (n = 149), and Loeys-Dietz syndrome (LDS) (n = 121) were analyzed. RESULTS: The 25% probability of elective proximal aortic aneurysm surgery was 30 years for LDS (95% CI: 18-37 years), followed by MFS (34 years; 95% CI: 32-36 years), nsHTAD (52 years; 95% CI: 48-56 years), and BAV (55 years; 95% CI: 53-58 years). Any dissection surgery 25% probability was highest in LDS (38 years; 95% CI: 33-53 years) followed by MFS (51 years; 95% CI: 46-57 years) and nsHTAD (54 years; 95% CI: 51-61 years). BAV experienced the largest relative frequency of elective surgery to any dissection surgery (254/33 = 7.7), compared with MFS (273/112 = 2.4), LDS (35/16 = 2.2), or nsHTAD (82/76 = 1.1). With MFS as the reference population, risk of any dissection surgery or cardiovascular mortality was lowest in BAV patients (HR: 0.13; 95% CI: 0.08-0.18; HR: 0.13; 95%: CI: 0.06-0.27, respectively). The greatest risk of mortality was seen in patients with vEDS. CONCLUSIONS: Marfan and LDS cohorts demonstrate age and event profiles congruent with the current understanding of syndromic aortopathies. BAV events weigh toward elective replacement with relatively few dissection surgeries. Nonsyndromic HTAD patients experience near equal probability of dissection vs prophylactic surgery, possibly because of failure of early diagnosis.

Spontaneous coronary artery dissection is infrequent in individuals with heritable thoracic aortic disease despite partially shared genetic susceptibility.

Spontaneous coronary artery dissection (SCAD) is a potential precipitant of myocardial infarction and sudden death for which the etiology is poorly understood. Mendelian vascular and connective tissue disorders underlying thoracic aortic disease (TAD), have been reported in ~5% of individuals with SCAD. We therefore hypothesized that patients with TAD are at elevated risk for SCAD. We queried registries enrolling patients with TAD to define the incidence of SCAD. Of 7568 individuals enrolled, 11 (0.15%) were found to have SCAD. Of the sequenced cases (9/11), pathogenic variants were identified (N = 9), including COL3A1 (N = 3), FBN1 (N = 2), TGFBR2 (N = 2), TGFBR1 (N = 1), and PRKG1 (N = 1). Individuals with SCAD had an increased frequency of iliac artery dissection (25.0% vs. 5.1%, p = 0.047). The prevalence of SCAD among individuals with TAD is low. The identification of pathogenic variants in genes previously described in individuals with SCAD, particularly those underlying vascular Ehlers-Danlos, Marfan syndrome, and Loeys-Dietz syndrome, is consistent with prior reports from clinical SCAD series. Further research is needed to identify specific genetic influences on SCAD risk.

The differences in surgical long-term outcomes between Marfan syndrome and Loeys-Dietz syndrome.

OBJECTIVE: The aim of this study was to disclose the differences of surgical outcomes between Marfan syndrome with mutations in fibrillin-1 gene and Loeys-Dietz syndrome with mutations in transforming growth factor-beta receptor 1 and 2. METHODS: We reviewed 368 patients aged less than 50 years who underwent surgery for thoracic aortic diseases between 1988 and 2019, and enrolled 99 patients with Marfan syndrome (26.9%; 57 men, 33 ± 7.5 years) and 24 patients with Loeys-Dietz syndrome (6.5%; 13 men, 28 ± 11 years). RESULTS: Freedom from all causes of mortality was similar between the 2 groups (P = .40, log-rank). The cumulative incidence of reintervention was significantly lower in the Marfan syndrome group than in the Loeys-Dietz syndrome group (P = .016, Gray). The cumulative incidence of first aortic arch reoperation for aortic arch aneurysm was significantly lower in the Marfan syndrome group than in the Loeys-Dietz syndrome group (P < .001, Gray). The cumulative incidence of first aortic root reoperation for aortic root aneurysm (P = .57, Gray) and first descending aorta reoperation for descending aortic aneurysm (P = .76, Gray) was similar between the 2 groups. The cumulative incidence of aortic dissection after initial surgery was significantly lower in Marfan syndrome than in Loeys-Dietz syndrome (P = .0059, Gray). CONCLUSIONS: Loeys-Dietz syndrome with mutations in transforming growth factor-beta receptor 1 and 2 revealed higher rates of reoperation, and more specifically the arch reoperation was higher in those with Loeys-Dietz syndrome than those with Marfan syndrome. Aggressive arch surgery in the initial operation on the proximal aorta is recommendable in Loeys-Dietz syndrome to avoid additional aortic events. In Marfan syndrome, this is controversial in patients without dissection because of a low possibility to expand.

Heritable Connective Tissue Disorders in Childhood: Increased Fatigue, Pain, Disability and Decreased General Health.

Heritable Connective Tissue Disorders (HCTD) show an overlap in the physical features that can evolve in childhood. It is unclear to what extent children with HCTD experience burden of disease. This study aims to quantify fatigue, pain, disability and general health with standardized validated questionnaires. METHODS: This observational, multicenter study included 107 children, aged 4-18 years, with Marfan syndrome (MFS), 58%; Loeys-Dietz syndrome (LDS), 7%; Ehlers-Danlos syndromes (EDS), 8%; and hypermobile Ehlers-Danlos syndrome (hEDS), 27%. The assessments included PROMIS Fatigue Parent-Proxy and Pediatric self-report, pain and general health Visual-Analogue-Scales (VAS) and a Childhood Health Assessment Questionnaire (CHAQ). RESULTS: Compared to normative data, the total HCTD-group showed significantly higher parent-rated fatigue T-scores (M = 53 (SD = 12), p = 0.004, d = 0.3), pain VAS scores (M = 2.8 (SD = 3.1), p < 0.001, d = 1.27), general health VAS scores (M = 2.5 (SD = 1.8), p < 0.001, d = 2.04) and CHAQ disability index scores (M = 0.9 (SD = 0.7), p < 0.001, d = 1.23). HCTD-subgroups showed similar results. The most adverse sequels were reported in children with hEDS, whereas the least were reported in those with MFS. Disability showed significant relationships with fatigue (p < 0.001, rs = 0.68), pain (p < 0.001, rs = 0.64) and general health (p < 0.001, rs = 0.59). CONCLUSIONS: Compared to normative data, children and adolescents with HCTD reported increased fatigue, pain, disability and decreased general health, with most differences translating into very large-sized effects. This new knowledge calls for systematic monitoring with standardized validated questionnaires, physical assessments and tailored interventions in clinical care.

Mitral Valve Prolapse and Its Motley Crew-Syndromic Prevalence, Pathophysiology, and Progression of a Common Heart Condition.

Mitral valve prolapse (MVP) is a commonly occurring heart condition defined by enlargement and superior displacement of the mitral valve leaflet(s) during systole. Although commonly seen as a standalone disorder, MVP has also been described in case reports and small studies of patients with various genetic syndromes. In this review, we analyzed the prevalence of MVP within syndromes where an association to MVP has previously been reported. We further discussed the shared biological pathways that cause MVP in these syndromes, as well as how MVP in turn causes a diverse array of cardiac and noncardiac complications. We found 105 studies that identified patients with mitral valve anomalies within 18 different genetic, developmental, and connective tissue diseases. We show that some disorders previously believed to have an increased prevalence of MVP, including osteogenesis imperfecta, fragile X syndrome, Down syndrome, and Pseudoxanthoma elasticum, have few to no studies that use up-to-date diagnostic criteria for the disease and therefore may be overestimating the prevalence of MVP within the syndrome. Additionally, we highlight that in contrast to early studies describing MVP as a benign entity, the clinical course experienced by patients can be heterogeneous and may cause significant cardiovascular morbidity and mortality. Currently only surgical correction of MVP is curative, but it is reserved for severe cases in which irreversible complications of MVP may already be established; therefore, a review of clinical guidelines to allow for earlier surgical intervention may be warranted to lower cardiovascular risk in patients with MVP.

Audit of Gastrointestinal Manifestations in Patients with Loeys-Dietz Syndrome and Vascular Ehlers-Danlos Syndrome.

OBJECTIVES: Loeys-Dietz syndrome (LDS) and vascular Ehlers-Danlos Syndrome (vEDS) are genetically heterogeneous heritable disorders of connective tissue. Both are multi-system disorders with dominant vascular pathology and associated gastrointestinal manifestations. AIM: To summarize the abdominal manifestations found in these two disorders in a cohort of patients seen at Mayo Clinic during a period of 25 years. METHODS: Data were collected via the advanced cohort explorer (ACE) of Mayo Clinic records from 1994 to 2018 in patients with vEDS or LDS confirmed by genetic testing and/or medical genetics consultation. We extracted information concerning gastrointestinal symptoms, abdominal hernias, and vascular manifestations or complications. RESULTS: We identified and reviewed records of 68 vEDS and 13 LDS patients. Patients were similar in age at diagnosis and gender distribution. Gastrointestinal symptoms were frequently reported in both disorders and largely similar, although altered bowel function was more prevalent in LDS patients. Hernias were present in similar proportions of patients with vEDS and LDS; however, ventral hernias were more frequent and more likely to be postoperative in vEDS than LDS. LDS patients had more arterial aneurysms overall (76.9% LDS vs. 58% vEDS, p = 0.02) and a higher proportion required arterial repair (69.2% LDS vs. 32.7% vEDS S, p = 0.03). Co-morbidities of autonomic dysfunction, psychopathology (most commonly anxiety, depression, adjustment disorder), and allergy were more prevalent in LDS than vEDS. CONCLUSION: Patients with vEDS and LDS had a propensity for gastrointestinal symptoms, abdominal hernias, and aneurysm formation, but repair for arterial rupture was more prevalent in LDS than EDS.

Mitral annulus disjunction is associated with adverse outcome in Marfan and Loeys-Dietz syndromes.

AIMS: We aimed to assess the prevalence of mitral annulus disjunction (MAD) and to explore the association with aortic disease and mitral valve surgery in patients with Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). METHODS AND RESULTS: We included consecutive MFS patients fulfilling Revised Ghent Criteria and LDS patients fulfilling Loeys-Dietz Revised Nosology. MAD was identified by echocardiography and was quantified as the longitudinal distance from the ventricular myocardium to the hinge point of the posterior mitral leaflet. Aortic events were defined as aortic dissection or prophylactic aortic surgery. We recorded the need of mitral valve surgery including mitral valve repair or replacement. We included 168 patients (103 with MFS and 65 with LDS). The prevalence of MAD was 41%. MAD was present in all age groups. Aortic events occurred in 112 (67%) patients (27 with dissections and 85 with prophylactic surgical interventions). Patients with MAD were younger at aortic event than those without MAD (log rank = 0.02) Patients with aortic events had greater MAD distance in posterolateral wall [8 (7-10) mm vs. 7 (6-8) mm, P = 0.04]. Mitral events occurred more frequently in patients with MAD (P < 0.001). CONCLUSION: MAD was highly prevalent in patients with MFS and LDS. MAD was a marker of severe disease including aortic events at younger age and need of mitral valve surgery. Screening patients with MFS an LDS for MAD may provide prognostic information and may be relevant in planning surgical intervention. Detection of MAD in patients with MFS and LDS may infer closer clinical follow-up from younger age.

Adults with Loeys-Dietz syndrome and vascular Ehlers-Danlos syndrome: A cross-sectional study of health burden perspectives.

The aim is to study adults with vascular Ehlers-Danlos syndrome (vEDS) and Loeys-Dietz syndrome (LDS) with regard to sociodemographic characteristics, perceived vascular- and multi-organ symptom burdens, and health services utilization. This is a cross-sectional study. In 2018, a postal questionnaire was sent to 71 individuals with genetically verified LDS types 1-4 or vEDS, age ≥ 18 years, recruited through a National Resource Centre for Rare Disorders in Norway. Eighteen patients with vEDS and 34 patients with LDS subtypes 1-4 participated, the response rate was 74%. Median age was 43.5 (range 18-68) years, and 58% were women. Median age at diagnosis was 34 years (range: 6-63). Severe vascular- and multi-organ symptom burdens were found, and chronic pain was reported by 79%. Most respondents (87%) had cardiovascular surveillance visits, 58% yearly or more often, and still 29% had no antihypertensive medications. Three quarters communicated diagnosis-related concerns with their general practitioner. A considerable group (31%) had left work before retirement age. Healthcare professionals should be aware of the spectrum of health burden in adults with vEDS and LDS. A verification of the diagnosis is crucial to counseling, including medical follow-up, education, and work, and advices on precaution and life style decisions.

Management of the aortic arch in patients with Loeys-Dietz syndrome.

OBJECTIVES: We sought to develop strategies for management of the aortic arch in patients with Loeys-Dietz syndrome (LDS) through a review of our clinical experience with these patients and a comparison with our experience in patients with Marfan syndrome (MFS). METHODS: We reviewed hospital and follow-up records of 79 patients with LDS and compared them with 256 patients with MFS who served as reference controls. RESULTS: In the LDS group, 16% of patients presented initially with acute aortic dissection (AAD) (67% type A, 33% type B) or developed AAD during follow-up, compared with 10% of patients with MFS (95% type A, 5% type B). There was no difference between patients with LDS or MFS in need for subsequent arch interventions after aortic root surgery (46% vs 50%, P = 1.0). Among the patients who never had AAD, the need for arch repair at initial root surgery was greater in patients with LDS (5% vs 0.4%, P = .04), as was the need for any subsequent aortic surgery (12% vs 1.3%, P = .0004). Late mortality in patients with LDS after arch repair was greater than in those patients who had no arch intervention (33% vs 6%, P = .007). CONCLUSIONS: In the absence of dissection, patients with LDS have a greater rate of arch intervention after root surgery than patients with MFS. After a dissection, arch reintervention rates are similar in the 2 groups. Arch intervention portends greater late mortality in LDS.

Loeys-Dietz syndrome: Intermediate-term outcomes of medically and surgically managed patients.

OBJECTIVES: Loeys-Dietz syndrome (LDS) is an aggressive connective tissue disorder associated with increased risk of aortic dissection and aneurysm rupture at an early age and smaller aortic diameters. We report our experience with LDS to better understand its natural history and treatment outcomes and help establish treatment guidelines. METHODS: We retrospectively reviewed all patients with LDS who underwent medical or surgical treatment at Cleveland Clinic before April 27, 2017. Primary endpoints were postoperative in-hospital morbidity and mortality. Secondary endpoints were aorta-related reoperations and short- and long-term mortality. RESULTS: We identified 53 patients with LDS. Of these, 33 (62%) underwent aortic surgery. Mean age was 39 ± 14 years, and mean maximum aortic diameter was 4.3 cm. There were 2 (6%) deaths after urgent or emergency surgery. Twenty-two patients (67%) required no aortic reoperation; 20 of these had prophylactic surgery. Multiple aortic operations were performed on 11 (33%) patients, 9 of whom experienced aortic dissections. Six patients (18%) required total aortic replacement. Among 19 patients with modified root reimplantation, no aorta- or valve-related complications occurred. Overall, 33 patients underwent 58 aortic and 81 cardiovascular operations, with 1 late death. Kaplan-Meier survival of the aortic-surgery cohort was 89% at 10 years (median follow-up 5.2 years). There were no late deaths in the non-aortic surgery group (20/53; 38%). CONCLUSIONS: Prophylactic aortic surgical outcomes in LDS are excellent. Surgical reintervention remains high, particularly after aortic dissections. Close surveillance of medically managed and postoperative patients and early prophylactic surgery are crucial to avoid aortic catastrophe and achieve a good long-term prognosis.

Parental-reported neurodevelopmental issues in Loeys-Dietz syndrome.

BACKGROUND: Loeys-Dietz syndrome (LDS) is a congenital multisystem disorder affecting the cardiovascular and musculoskeletal system. Limited data have reported neurodevelopmental (ND) issues in LDS. AIMS: To determine the extent of ND issues in patients with LDS. METHODS: A prospective study was performed of LDS patients or their caregivers. The study included data collected via an online survey of age-specific questions. Standard statistical methods were used for baseline and demographic characteristics, as well as group comparisons. OUTCOMES: Data were obtained from 67 patients with LDS (54% female). Median age was 14.9 years. Gene mutations included TGFBR1 (39%), TGFBR2 (40%), SMAD3 (7%), and unknown (14%). Motor delays (30%, 18/61) and hypotonia (63%, 37/60) occurred frequently. Physical (62%, 39/62), occupational (41%, 23/56), and speech therapies (34%, 20/58) were common. Feeding issues were common (41%, 23/56). TGFBR1 mutations were more frequent among those with motor delays and feeding issues. CONCLUSIONS: Patients with LDS and/or their caregivers report at least one ND problem in most cases, and many require therapies. These data suggest ND disorders should be considered to be part of the phenotype.

Pathophysiology of Eosinophilic Esophagitis.

Eosinophilic esophagitis is an emerging disease that is distinguished from gastroesophageal reflux disease by the expression of a unique esophageal transcriptome and the interplay of early life environmental factors with distinct genetic susceptibility elements at 5q22 (TSLP) and 2p23 (CAPN14). Rare genetic syndromes have uncovered the contribution of barrier disruption, mediated in part by defective desmosomes and dysregulated transforming growth factor beta production and signaling, to eosinophilic esophagitis pathophysiology. Experimental modeling has defined a cooperative role of activated eosinophils, mast cells, and the cytokines IL-5 and IL-13, mediated by allergic sensitization to multiple foods. Understanding these processes is opening the way to better treatment based on disrupting allergic inflammatory and type 2 cytokine-mediated responses, including anti-cytokine therapeutics and dietary therapy.

Loeys-Dietz syndrome and pregnancy: The first ten years.

The physiological and haemodynamic changes that occur in pregnancy and the postpartum period increase the risk of aortic dissection. Loeys-Dietz syndrome results from mutations in the genes encoding components of the TGF-ß signalling pathway; aortic pathology is of particular concern in this condition but other vascular abnormalities can also be present. Significant maternal morbidity and mortality has been described in patients with Loeys-Dietz syndrome, but successful and uncomplicated pregnancies are still possible. Nevertheless, all patients with this condition should, at present, be treated as very high risk in pregnancy and the postpartum period, until reliable risk prediction tools become available. This review summarises the recent advances in the understanding of the pathophysiology of this condition, and the management strategies currently advocated.