Loeys-Dietz Research Articles

Burden of Rare Genetic Variants in Spontaneous Coronary Artery Dissection With High-risk Features

The emerging genetic basis of spontaneous coronary artery dissection (SCAD) has been defined as both partially complex and monogenic in some patients, involving variants predominantly in genes known to underlie vascular connective tissue diseases (CTDs). The effect of these genetic influences has not been defined in high-risk SCAD phenotypes, and the identification of a high-risk subgroup of individuals may help to guide clinical genetic evaluations of SCAD. To identify and quantify the burden of rare genetic variation in individuals with SCAD with high-risk clinical features. Whole-exome sequencing (WES) was performed for subsequent case-control association analyses and individual variant annotation among individuals with high-risk SCAD. Genetic variants were annotated for pathogenicity by in-silico analysis of genes previously defined by sequencing for vascular CTDs and/or SCAD, as well as genes prioritized by genome-wide association study (GWAS) and colocalization of arterial expression quantitative trait loci. Unbiased genome-wide association analysis of the WES data was performed by comparing aggregated variants in individuals with SCAD to healthy matched controls or the Genome Aggregation Database (gnomAD). This study was conducted at a tertiary care center. Individuals in the Canadian SCAD Registry genetics study with a high-risk SCAD phenotype were selected and defined as peripartum SCAD, recurrent SCAD, or SCAD in an individual with family history of arteriopathy. Burden of genetic variants defined by DNA sequencing in individuals with high-risk SCAD. This study included a total of 336 participants (mean [SD] age, 53.0 [9.5] years; 301 female participants [90%]). Variants in vascular CTD genes were identified in 17.0% of individuals (16 of 94) with high-risk SCAD and were enriched (OR, 2.6; 95% CI, 1.6-4.2; P = 7.8 × 10-4) as compared with gnomAD, with leading significant signals in COL3A1 (OR, 13.4; 95% CI, 4.9-36.2; P = 2.8 × 10-4) and Loeys-Dietz syndrome genes (OR, 7.9; 95% CI, 2.9-21.2; P = 2.0 × 10-3). Variants in GWAS-prioritized genes, observed in 6.4% of individuals (6 of 94) with high-risk SCAD, were also enriched (OR, 3.6; 95% CI, 1.6-8.2; P = 7.4 × 10-3). Variants annotated as likely pathogenic or pathogenic occurred in 4 individuals, in the COL3A1, TGFBR2, and ADAMTSL4 genes. Genome-wide aggregated variant testing identified novel associations with peripartum SCAD. In this genetic study, approximately 1 in 5 individuals with a high-risk SCAD phenotype harbored a rare genetic variant in genes currently implicated for SCAD. Genetic screening in this subgroup of individuals presenting with SCAD may be considered.

Simultaneous surgical treatment of an aortic root aneurysm and pectus excavatum in a child with Loeys-Dietz syndrome.

Simultaneous surgical treatment of an aortic root aneurysm and pectus excavatum in a child with Loeys-Dietz syndrome.

Long-term risk of arch complications in Loeys Dietz syndrome patients undergoing proximal ascending aortic replacement.

Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder. In LDS patients with normal arch morphology, whether the arch should be prophylactically replaced at the time of proximal aortic replacement remains unknown. We evaluated the risk of long-term arch complications in genetically confirmed LDS patients who underwent proximal ascending aortic replacement. We retrospectively reviewed the records of patients with LDS who have been followed at our institution between 1994 and 2020. Patients were only included if whole exome genetic testing confirmed a mutation in an LDS-causing gene (TGFBR1, TGFBR2, SMAD3, TGFB2, or TGFB3). Mutations were categorized as pathogenic, benign, or of unknown significance. We collected demographic information, aortic dimensions, comorbidities, mortality, and operative course from patients' charts. Descriptive statistics and freedom from reoperation plots were generated. Of the 18 patients with a mutation in an LDS-causing gene, 15 had known pathogenic variants, two had mutations of unknown significance, and one had a benign genetic variant. For the 15 patients with confirmed pathogenic variants of LDS the median follow-up duration was 5 years (interquartile range [IQR]: 4-8). Eleven patients underwent ascending aortic replacements (AAR) ± aortic valve replacement. Two patients required an additional operation; one required arch and staged elephant trunk for a dissection 18 years post-AAR and the other patient required an isolated descending aortic replacement for dissection 5 years post-AAR. Among patients who underwent surgery, the median ascending aortic diameter at intervention was 5.0 cm (IQR: 4.3-5.3). There was no surgical or late follow-up mortality observed for any of the 18 patients in the study. LDS patients who underwent proximal aortic replacement appeared to have low long-term risk of arch complications. While our study is somewhat limited by its sample size and follow-up duration, it suggests that routine prophylactic total arch replacement may not be warranted in LDS patients with nonaneurysmal aortic arches.

Comparative Risks of Initial Aortic Events Associated With Genetic Thoracic Aortic Disease

BackgroundPathogenic variants in 11 genes predispose individuals to heritable thoracic aortic disease (HTAD), but limited data are available to stratify the risk for aortic events associated with these genes. ObjectivesThis study sought to compare the risk of first aortic event, specifically thoracic aortic aneurysm surgery or an aortic dissection, among 7 HTAD genes and variant types within each gene. MethodsA retrospective cohort of probands and relatives with rare variants in 7 genes for HTAD (n = 1,028) was assessed for the risk of first aortic events based on the gene altered, pathogenic variant type, sex, proband status, and location of recruitment. ResultsSignificant differences in aortic event risk were identified among the smooth muscle contraction genes (ACTA2, MYLK, and PRKG1; P = 0.002) and among the genes for Loeys-Dietz syndrome, which encode proteins in the transforming growth factor (TGF)-β pathway (SMAD3, TGFB2, TGFBR1, and TGFBR2;P < 0.0001). Cumulative incidence of type A aortic dissection was higher than elective aneurysm surgery in patients with variants in ACTA2, MYLK, PRKG1, and SMAD3; in contrast, patients with TGFBR2 variants had lower cumulative incidence of type A aortic dissection than elective aneurysm surgery. Cumulative incidence of type B aortic dissection was higher for ACTA2, PRKG1, and TGFBR2 than other genes. After adjusting for proband status, sex, and recruitment location, specific variants in ACTA2 and TGFBR2 were associated with substantially higher risk of aortic event with childhood onset. ConclusionsGene- and variant-specific data on aortic events in individuals with HTAD support personalized aortic surveillance and clinical management.

SMAD3 mutation in LDS3 causes bone fragility by impairing the TGF-β pathway and enhancing osteoclastogenesis

Loss-of-function mutations in SMAD3 cause Loeys-Dietz syndrome type 3 (LDS3), a rare autosomal-dominant connective tissue disorder characterized by vascular pathology and skeletal abnormalities. Dysregulation of TGF-β/SMAD signaling is associated with abnormal skeletal features and bone fragility. To date, histomorphometric and ultrastructural characteristics of bone with SMAD3 mutations have not been reported in humans and the exact mechanism by which SMAD3 mutations cause the LDS3 phenotype is poorly understood. Here, we investigated bone histomorphometry and matrix mineralization in human bone with a SMAD3 mutation and explored the associated cellular defect in the TGF-β/SMAD pathway in vitro. The index patient had recurrent fractures, mild facial dysmorphism, arachnodactyly, pectus excavatum, chest asymmetry and kyphoscoliosis. Bone histomorphometry revealed markedly reduced cortical thickness (−68 %), trabecular thickness (−32 %), bone formation rate (−50 %) and delayed mineralization. Quantitative backscattered electron imaging demonstrated undermineralized bone matrix with increased heterogeneity in mineralization. The patient's SMAD3 mutation (c.200 T > G; p.I67S), when expressed from plasmid vectors in HEK293 cells, showed reduced phosphorylation and transcription factor activity compared to normal control and SMAD3 (p.S264Y), a gain-of-function mutation, somatic mosaicism of which causes melorheostosis. Transfection study of the patients' SMAD3 (p.I67S) mutation displayed lower luciferase reporter activity than normal SMAD3 and reduced expression of TGF-β signaling target genes. Patient fibroblasts also demonstrated impaired SMAD3 protein stability. Osteoclastogenic differentiation significantly increased and osteoclast-associated genes, including ACP5 (encoding TRAP), ATP6V0D2, and DCSTAMP, were up-regulated in CD14 (+) peripheral blood mononuclear cells (PBMCs) with the SMAD3 (p.I67S) mutation. Upregulation of osteoclastogenic genes was associated with decreased expression of TGF-β signaling target genes. We conclude that bone with the SMAD3 (p.I67S) mutation features reduced bone formation, and our functional studies revealed decreased SMAD3 activation and protein stability as well as increased osteoclastogenesis. These findings enhance our understanding of the pathophysiology of LDS3 caused by SMAD3 mutations. Emerging therapies targeting in the TGF-β/SMAD pathway also raise hope for treatment of LDS3.

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

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. To analyze the prevalence and rupture risk of IA in LDS. 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. 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 &lt; .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. 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.

Distinct Contribution of Global and Regional Angiotensin II Type 1a Receptor Inactivation to Amelioration of Aortopathy in Tgfbr1 M318R/+ Mice.

Angiotensin II (Ang II) type 1 receptor (AT1R) signaling controls both physiological and pathogenetic responses in the vasculature. In mouse models of Loeys-Dietz syndrome (LDS), a hereditary disorder characterized by aggressive aortic aneurysms, treatment with angiotensin receptor blockers (ARBs) prevents aortic root dilation and associated histological alterations. In this study we use germline and conditional genetic inactivation of Agtr1a (coding for the AT1a receptor) to assess the effect of systemic and localized AT1R signaling attenuation on aortic disease in a mouse model of LDS (Tgfbr1M318R/+). Aortic diameters and histological features were examined in control and Tgfbr1M318R/+ mice with either germline or Mef2CSHF-Cre mediated genetic inactivation of Agtr1a, the latter resulting in deletion in second heart field (SHF)-derived lineages in the aortic root and proximal aorta. Both systemic and regional AT1R signaling attenuation resulted in reduction of diameters and improvement of tissue morphology in the aortic root of LDS mice; these outcomes were associated with reduced levels of Smad2/3 and ERK phosphorylation, signaling events previously linked to aortic disease in LDS. However, regional AT1a inactivation in SHF-derived lineages resulted in a more modest reduction in aortic diameters relative to the more complete effect of germline Agtr1a deletion, which was also associated with lower blood pressure. Our findings suggest that the therapeutic effects of AT1R antagonisms in preclinical models of aortic disease depend on both regional and systemic factors and suggest that combinatorial approaches targeting both processes may prove beneficial for aneurysm mitigation.

Bioelectrical Impedance Analysis as a Contemporary Biomarker of Obesity in Adults with Marfan- or Loeys-Dietz-Syndrome.

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. 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). 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/ [range: 15.2-41.9 kg/ ]. 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. 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.

Endovascular and Hybrid Repair in Patients with Heritable Thoracic Aortic Disease

In individuals with heritable thoracic aortic disease (HTAD), endovascular repair for treatment of aortic aneurysm and dissection may be lifesaving, but is associated with increased risk of failure of endovascular repair and adverse outcomes. This study reports our experience with early and late outcomes of endovascular aortic and branch vessel repair in patients with HTAD. A retrospective case series was performed by chart review of individuals with HTAD followed at Washington University School of Medicine/Barnes-Jewish Hospital who underwent endovascular aortic and/or branch vessel repair. Clinical features, imaging characteristics, and short- and long-term outcomes were collected. Twenty-nine patients with HTAD (20 male; mean age 45±13years) underwent 37 endovascular procedures between 2006 and 2020 with mean follow up of 54±41months. Seven patients underwent two or more separate endovascular procedures. Each procedure was considered separate for data collection and analysis. Underlying conditions included Marfan syndrome (n=16 procedures), Loeys-Dietz syndrome (n=14 procedures), vascular Ehlers-Danlos syndrome (n=3 procedures), and nonsyndromic HTAD (n=4 procedures). Twenty patients (69%) had prior open surgical aortic repair. Indications for endovascular aortic repair (n=31) included urgent repairs of acute complications of aortic dissection (n=10) or aneurysm rupture (n=3), and elective aortic repair (n=18; 10 chronic dissections and eight chronic aneurysms). Six patients underwent elective endovascular repair of six branch vessel aneurysms or dissections. Six patients underwent hybrid open surgical and endovascular repair. Of the 37 procedures, 25 (68%) proximal landing zones were in the native aorta or branch vessel, 11 (30%) were in a surgical graft or elephant trunk and one was in a previously placed endograft. Thirty-six (97%) procedures were technically successful, and none required emergency surgical conversion. Two patients died: one from sepsis and one from presumed late pseudoaneurysm rupture, for a 5% per-procedure mortality rate. Two procedures were complicated by stroke and one patient developed paraparesis. Of the 31 aortic procedures, seven aortic endografts (23%) developed a stent-induced new entry (SINE) discovered with imaging at 20±15days post-procedure. Seven endografts (23%) developed a Type I endoleak and eight (26%) developed a Type II endoleak. No Type III endoleaks were seen. Within 30days, two endografts (of 37, 5%) required reintervention. After 30days, fifteen additional endografts (of 37, 41%) required reintervention. Two patients (of 6, 33%) who underwent hybrid repair required reintervention. This study is the largest single-center case series examining outcomes of HTAD patients following endovascular repair. Urgent and elective endovascular repairs in patients with HTAD can manage acute and chronic complications of aortic aneurysm and dissection with relatively low risk. However, risk of early and late endoleaks and SINE is high. Close post-procedural surveillance is required, and many individuals will require additional interventions. Hybrid repair shows promise and requires further investigation.

Neonatal presentation of Loeys-Dietz syndrome: two case reports and review of the literature

BackgroundLoeys-Dietz syndrome (LDS) is a rare connective tissue disorder characterized by cardiovascular manifestations, especially aortic dilatations and arterial tortuosity, craniofacial and skeletal features, joint laxity or contractures, skin abnormalities, hypotonia and motor delay. Its diagnosis is established by the identification of a pathogenic variant in TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 or TGFB3 genes. In newborns and toddlers, vascular complications such as aneurism rupture, aortic dissection, and intracerebral incidents, can occur already in the weeks of life. To avoid these events, it is crucial to precociously identify this condition and to start an apunderwent a surgical procedurepropriate treatment which, depending on the severity of the vascular involvement, might be medical or surgical.Case presentationWe report two cases of Loeys-Dietz syndrome precociously diagnosed. The first describes a male, born at 38 + 1 weeks of gestation, with hypotonia, joint hypermobility, arachnodactyly, and fingers joint contractures, as well as senile appearance and facial dysmorphisms. In the suspect of a connective tissue disorder, an echocardiography was performed and revealed an aortic root dilatation of 13 mm (Z score + 3). A trio based Whole Exome Sequencing found a novel de novo variant in the TGFBR2 gene. Despite the onset of a low-dose angiotensin receptor blocker therapy, the aneurysm progressed. The second case describes a female, born at 41 + 3 weeks of gestation. During the neonatal examination a cleft palate was noticed, as well as minor dysmorphisms. Since the family history was suspicious for connective tissue disorders, a genetic panel was performed and identified a pathogenetic variant in TGFB3 gene. In this case, the echocardiography revealed no abnormalities.ConclusionsIn addition to our cases, we identified 14 subjects with neonatal LDS in the medical literature. All of them had aortic involvement. Skeletal and face abnormalities, including eyes and palate malformations, were also highly frequent. Overall, 10 subjects required medical therapy to avoid aneurysm progression, and 8 patients underwent surgical procedures.Benefits of an early diagnosis of LDS are various and imply a potential modification of the natural history of the disease with early interventions on its complications.

Talipes Equinovarus in Loeys-Dietz Syndrome.

Loeys-Dietz syndrome (LDS) commonly presents with foot deformities, such as talipes equinovarus (TEV), also known as "clubfoot." Although much is known about the treatment of idiopathic TEV, very little is known about the treatment of TEV in LDS. Here, we summarize the clinical characteristics of patients with LDS and TEV and compare clinical and patient-reported outcomes of operative versus nonoperative treatment. We identified 47 patients with TEV from a cohort of 252 patients with LDS who presented to our academic tertiary care hospital from 2010 to 2016. A questionnaire, electronic health records, clinical photos and radiographs, and telephone calls were used to collect baseline, treatment, and outcome data. The validated disease-specific instrument was used to determine patient-reported foot/ankle functional limitations after treatment. Patients were categorized into nonoperative and operative groups, with the operative group subcategorized according to whether the posteromedial release was performed. Within our TEV cohort, bilateral TEV was present in 40 patients (85%). Thirty-seven patients underwent surgery (14 involving posteromedial release), and 10 were treated nonoperatively. The operative group had a higher incidence of posttreatment foot/ankle functional limitation (71%) than the nonoperative group (25%) ( P =0.04). The pain was the most common functional limitation (54%). The posteromedial release was associated with a higher incidence of developing hindfoot valgus compared with surgery not involving posteromedial release (43% vs. 8.7%, P =0.04) and compared with nonoperative treatment (43% vs. 0.0%, P =0.02). We found that patients with LDS have a high incidence of bilateral TEV. Operative treatment was associated with posttreatment foot/ankle functional limitations, and posteromedial release was associated with hindfoot valgus overcorrection deformity. These findings could have implications for the planning of surgery for TEV in LDS patients. Level III-retrospective comparative study.

A 45-Year-Old Woman With Loeys-Dietz Syndrome and a 7-cm Intercostal Patch Aneurysm

We have provided a video and illustrations of a 45-year-old woman with Loeys-Dietz syndrome and a rapidly expanding 7-cm intercostal patch aneurysm. Her medical history was significant for prior aortic dissection and multiple open aortic repairs. She was treated with a custom-made stent graft using a total percutaneous transfemoral technique.

Aortic and Arterial Aneurysms and Dissections in Patients With Loeys-Dietz Syndrome Vary by the Causative Variant Gene

Loeys-Dietz syndrome (LDS) is a heterogeneous group of syndromic connective tissue disorders due to pathogenic variants in the genes coding for the transforming growth factor-β (TGFβ) signaling pathway. We aim to describe the aortic and arterial pathology in this population, define the phenotypic clinical examination features, and evaluate the interval to aortic/arterial aneurysms/dissections and extent of repair.

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

BackgroundThe GenTAC (Genetically Triggered Thoracic Aortic Aneurysm and Cardiovascular Conditions) Registry enrolled patients with genetic aortopathies between 2007 and 2016. ObjectivesThe 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. MethodsThe 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. ResultsThe 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. ConclusionsMarfan 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.

Tendon Healing in a Mouse Model of Loeys-Dietz Syndrome: Controlled Study Using a Patellar Tendon Transection Model.

Loeys-Dietz syndrome (LDS) is a rare autosomal-dominant connective tissue disorder caused by genetic mutations in the transforming growth factor-β (TGFβ) signaling pathway. In addition to vascular malformations, patients with LDS commonly present with bone and tendon abnormalities, including joint laxity. While TGFβ signaling dysregulation has been implicated in many of these clinical manifestations, the degree to which it influences the tendinopathy and tendon healing issues in LDS has not been determined. Wound healing after patellar tendon transection was compared between wild-type (WT) and Tgfbr2-mutant (LDS) mice (7 mice per group). In all mice, the right patellar tendon was transected at midsubstance, while the left was untouched to serve as a control. Mice were euthanized 6 weeks after surgery. Tendon specimens were harvested for histopathologic grading according to a previously validated scoring metric, and gene expression levels of Mmp2, Tgfb2, and other TGFβ-signaling genes were assayed. Between-group comparisons were made using 1-way analysis of variance with post hoc Tukey honestly significant difference testing. Expression levels of assayed genes were similar between LDS and WT tendons at baseline; however, at 6 weeks after patellar tendon transection, LDS tendons showed sustained elevations in Mmp2 and Tgfb2 compared with baseline values; these elevations were not seen in normal tendons undergoing the same treatments. Histologically, untreated LDS tendons had significantly greater cellularity and cell rounding compared with untreated WT tendons, and both WT and LDS tendons had significantly worse histologic scores after surgery. We present the first mechanistic insight into the effect of LDS on tendons and tendon healing. The morphologic differences between LDS and WT tendons at baseline may help explain the increased risk of tendon/ligament dysfunction in patients with LDS, and the differential healing response to injury in LDS may account for the delayed healing and weaker repair tissue. Level V.

Syndromic etiology of apparently isolated clubfeet: a child with Loeys-Dietz syndrome 2

Syndromic etiology of apparently isolated clubfeet: a child with Loeys-Dietz syndrome 2

Heritable connective tissue disorders in childhood: Decreased health-related quality of life and mental health.

The psychosocial consequences of growing up with Heritable Connective Tissue Disorders (HCTD) are largely unknown. We aimed to assess Health‐Related Quality of Life (HRQoL) and mental health of children and adolescents with HCTD. This observational multicenter study included 126 children, aged 4–18 years, with Marfan syndrome (MFS, n = 74), Loeys–Dietz syndrome (n = 8), molecular confirmed Ehlers–Danlos syndromes (n = 15), and hypermobile Ehlers–Danlos syndrome (hEDS, n = 29). HRQoL and mental health were assessed through the parent and child‐reported Child Health Questionnaires (CHQ‐PF50 and CHQ‐CF45, respectively) and the parent‐reported Strengths and Difficulties Questionnaire. Compared with a representative general population sample, parent‐reported HRQoL of the HCTD‐group showed significantly decreased Physical sum scores (p < 0.001, d = 0.9) and Psychosocial sum scores (p = 0.024, d = 0.2), indicating decreased HRQoL. Similar findings were obtained for child‐reported HRQoL. The parent‐reported mental health of the HCTD‐group showed significantly increased Total difficulties sum scores (p = 0.01, d = 0.3), indicating decreased mental health. While the male and female MFS‐ and hEDS‐subgroups both reported decreased HRQoL, only the hEDS‐subgroup reported decreased mental health. In conclusion, children and adolescents with HCTD report decreased HRQoL and mental health, with most adverse outcomes reported in children with hEDS and least in those with MFS. These findings call for systematic monitoring and tailored interventions.

Aortic valve reimplantation in patients with connective tissue syndromes: A 15-year follow-up.

The goal of this study was to analyse early- and long-term outcomes of aortic valve reimplantation (David operation) in patients with heritable thoracic aortic disease. This is a retrospective observational analysis using data from a prospectively maintained surgical database from March 2004 to April 2021. Patients with heritable thoracic aortic disease were included in the study. A total of 157 patients with aortic root aneurysm with the diagnosis of heritable thoracic aortic disease received the David procedure. Marfan syndrome was found in 143 (91.1%) patients, Loeys-Dietz in 13 and Ehler-Danlos in 1 patient. The median age was 35.0 (IQR: 17.5) years and the median ascending aorta diameter in the Valsalva sinuses was 48 mm (IQR: 4). A Valsalva graft was used in 8 patients; the David V technique was performed in the rest of the cases. The median follow-up time was 7.3 years [standard deviation: 0.58, 95% confidence interval (CI): 6.12-8.05]. Only 2 patients died during the follow-up period. The overall survival was 99% (95% CI: 95%; 99%); 98% (95% CI: 92%; 99%); and 98% (95% CI: 92%; 99%) at 5, 10 and 15 years. Freedom from significant aortic regurgitation (AR> II), reintervention and postoperative type-B dissection was 90% (95% CI: 77%; 95%), 96% (95% CI: 91%; 99%) and 87% (95% CI: 68%; 95%) at 15 years, respectively. No differences were found in any outcome between Marfan syndrome and Loeys-Dietz syndrome. No statistically significant differences in survival were found when we compared expected gender- and age-specific population survival values. The David operation is an excellent option for the treatment of patients with heritable thoracic aortic disease and dilatated aortic root. Surgical expertise in referral centres is essential to achieve the best long-term results.

Ocular Manifestations of Loeys–Dietz Syndrome

Loeys–Dietz syndrome (LDS) is caused by connective tissue mutations; the resulting defective connective tissue in organs such as the eye may be related to ocular symptoms in patients with LDS. The aim of this study was to review different ocular manifestations in LDS. A literature review of articles published within the past 5 years was performed using Web of Science™ and PubMed to search for ‘Loeys–Dietz’ with the terms ‘ocular’ and ‘ophthalmology.’ Additional search terms were generated from the initial literature assessment, and 32 articles were ultimately reviewed. Reported ocular symptoms in LDS included hypertelorism, ocular misalignment, refractive errors, and more. For LDS, the most reported findings were hypertelorism (n=111), astigmatism (n=25), down slanting palpebral fissures (n=20), myopia (n=9), and strabismus (n=8). However, more research on ocular symptoms in LDS is needed.

Evaluation of cervical spine pathology in children with Loeys-Dietz syndrome.

Background: Loeys-Dietz syndrome (LDS) is a genetic connective tissue disorder associated with multiple musculoskeletal anomalies, including cervical spine instability. We sought to examine the nature of imaging for cervical spine instability in children with LDS due to likely pathogenic or pathogenic variants in TGFBR1, TGFBR2, TGFB2, SMAD3, or TGFB3.Methods: A retrospective chart review was conducted, examining relevant data for all children with LDS screened at our institution from 2004 through 2021. Cervical spine X-rays were used to assess cervical instability, cervical lordosis, and basilar impression.Results: A total of 39 patients were identified; 16 underwent cervical spine screening (56.25% male). Median age at initial screening was 7 years (Q1-Q3: 3.75–14, range: 0.1–19). Six of 16 patients evaluated (37.5%) had radiographical evidence of cervical instability. Mean angles of cervical lordosis were 20° (SD = 14.1°, range = 4°–33°) and 17.3° (SD = 16.4°, range = 2°–41°), respectively. Three patients demonstrated radiographical basilar impression. Radiographic progression of cervical instability was seen in one case. All but two were managed conservatively with observation, one patient underwent surgical fixation and fusion of C1-2, the other underwent complex cervical reconstruction anterior and posterior instrumentation.Conclusion: Cervical spine evaluation is important in this cohort; we identified 37.5% had evidence of cervical spine instability, and many had concurrent spinal pathology. From our experience, we agree with the recent advisement for screening at diagnosis and for those previously diagnosed that have not undergone screening. Future study may outline more specific screening practices.