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Loeys-Dietz Syndrome is an autosomal dominant connective tissue disease with multi-system involvement.
•
In a systematic review of 3896 reported cases of Loeys-Dietz syndrome the most commonly reported features and complications included: aortic aneurysms and dissections, arterial tortuosity, high arched palate, abnormal uvula and hypertelorism.
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In the peripartum period, the rate of aortic dissections was found to be 4% with a maternal mortality of 1%.
Abstract
Introduction
Loeys-Dietz syndrome (LDS) is a connective tissue disorder that arises from mutations altering the transforming growth factor β signalling pathway. Due to the recent discovery of the underlying genetic mutations leading to LDS, the spectrum of characteristics and complications is not fully understood.
Methods
Our search included five databases (Pubmed, SCOPUS, Web of Science, EMBASE and google scholar) and included variations of “Loeys-Dietz Syndrome” as search terms, using all available data until February 2021. All study types were included. Three reviewers screened 1394 abstracts, of which 418 underwent full-text review and 392 were included in the final analysis.
Results
We identified 3896 reported cases of LDS with the most commonly reported features and complications being: aortic aneurysms and dissections, arterial tortuosity, high arched palate, abnormal uvula and hypertelorism. LDS Types 1 and 2 share many clinical features, LDS Type 2 appears to have a more aggressive aortic disease. LDS Type 3 demonstrated an increased prevalence of mitral valve prolapse and arthritis. LDS Type 4 and 5 demonstrated a lower prevalence of musculoskeletal and cardiovascular involvement. Amongst 222 women who underwent 522 pregnancies, 4% experienced an aortic dissection and the peripartum mortality rate was 1%.
Conclusion
We observed that LDS is a multisystem connective tissue disorder that is associated with a high burden of complications, requiring a multidisciplinary approach. Ongoing attempts to better characterise these features will allow clinicians to appropriately screen and manage these complications.
Loeys-Dietz syndrome (LDS) is an autosomal dominant connective disorder that has been associated with extensive systemic involvement including craniofacial, skeletal, cutaneous and vascular (arterial tortuosity, aneurysm formation and dissection) abnormalities. Since this disease entity has been identified (
). The subtypes of LDS illustrate the spectrum of the disorder, with type 1 being the most severe phenotype and type 5 being the least. LDS type 1 has been associated with mutations in the transforming growth factor β (TGFB) receptor one (TGFBR1) and is characterised by the presence of craniofacial abnormalities whereas LDS type 2 is associated with mutations in transforming growth factor β receptor two (TGFBR2) which is associated with minimal craniofacial abnormalities. Of note, early categorisation of LDS was based on the absence or presence of craniofacial features regardless of genetic mutations (
). However, LDS type 3 was found to be associated with mothers against decapentaplegic homolog (SMAD) 3 mutations, with prominent features of osteoarthritis. LDS type 4 and 5 are associated with mutations in TGFB 2 and 3 ligand respectively. Of note, SMAD2 mutations have been identified to be associated with clinical features of LDS, but have yet to be placed on the spectrum of LDS subtypes (
). Due to a paucity of large observational studies, the full clinical spectrum of LDS is unknown.
While rare, the prevalence of LDS is unknown and there is a paucity of data to characterise these individuals and their complications, limited to small cohorts and case reports. Our objective was to systematically describe the clinical features and complications of patients with genetically confirmed LDS, which may supplement current recommendations for diagnosis and management of this condition (
The search strategy was conducted in accordance to the PRISMA-S extension of the PRISMA statement for reporting literature searches in systematic reviews (
). This review was prospectively registered with PROSPERO, an international prospective register of systematic reviews (CRD42021247713).
2.2 Data sources and searches
The following databases were searched: Pubmed, SCOPUS, Web of Science, EMBASE and google scholar. No study registries or other online resources were searched. Cited references in identified articles were visually screened for additional references. No additional studies were sought by contacting authors. The individual search strategy for each database can be seen in Supplementary Table 1. In brief, using the search terms “loeys-dietz syndrome”, “loeys-dietz”, “loeys dietz syndrome” and “loeys dietz” were utilised with no date, language, study design filters. All original searches were conducted on February 6, 2021. Email alerts from each database were utilised to update the search during the study period. A specialised librarian at the University of Alberta reviewed the search strategy.
All studies were included if they described clinical features or complications of a subject with genetically confirmed LDS. All study types were included. Conference abstracts were excluded if a subsequent full manuscript was identified. Cases of reported genetically-confirmed cases of LDS, without further elaboration on genetic mutation or LDS classification were included to identify the largest possible cohort of patients with LDS, but are labelled as LDS “unknown”.
The final search identified 4049 references, of which 2655 were duplicate references (Supplementary Fig. 1). The remaining 1394 references were loading into the Covidence systematic review manager for title and abstract screening. Each record was reviewed by two investigators for inclusion and exclusion criteria. In the event of discordance, a third investigator was assigned followed by a discussion to reach a consensus. In total, 418 manuscripts were identified for full-text review, which included an additional 17 manuscripts from e-mail alerts/reference lists. During full-text review, a further 26 were excluded due to duplicates (n = 14) and inability to extract any data regarding individuals with LDS due to amalgamated data (n = 12). The resultant 392 manuscripts were included for further analysis.
2.3 Data extraction and quality assessment
Three reviewers independently extracted data from each included manuscript using an internally validated case report form. The case report form was formed based on a comprehensive review of the literature identifying characteristics and complications of interest (Table 1). The case report form was subsequently trialled by four data abstractors on ten of the included articles in this review. Study data were collected and managed using REDCap (Research Electronic Data Capture) electronic data capture tools hosted at the University of Alberta (
). REDCap is a secure, web-based software platform designed to support data capture for research studies. In brief, data on clinical characteristics, genetic testing and complications were extracted. In the event of a manuscript that presents amalgamated data, details of the population cohort were also extracted. Where possible data regarding prevalence in comparison to other connective tissue disorders was also extracted.
Table 1Clinical features and complications of patients with LDS.
Methodological quality of reporting was assessed using components of the Case Report (CARE) guidelines and with reviewers asked to subjectively assess each manuscript to have either a low, intermediate or high risk of reporting bias (
). High-quality studies were defined as those demonstrating a low-risk of reporting bias.
2.4 Data synthesis and analysis
Counts of clinical features and complications were identified in the overall population, stratified by LDS type and by study type (individual data available versus amalgamated data from cohort studies).
2.5 Funding
No funding was received for this work.
3. Results
Of the 392 manuscripts, 266 (68%) were case reports/series with individual-level data and 126 (32%) were reports of cohort studies with amalgamated data on patients with LDS. The majority of included studies demonstrated a high risk of bias (n = 196; 50%), with the remaining demonstrating intermediate (n = 110; 28%) or low (n = 86; 22%) risk of bias. Cohort studies were more frequently reported as having a high-risk of bias (n = 95; 75%) compared to individual-level studies (n = 101; 38%).
In the 266 individual level data manuscripts, 391 individuals with LDS were identified of which 69 (18%) had LDS type 1, 164 (42%) LDS type 2, 39 (10%) LDS type 3, 24 (6%) LDS type 4, 6 (2%) LDS type 5 and 89 (23%) were unknown. In the 126 cohort manuscripts, 3505 individuals with LDS were identified, of which 614 (18%) had LDS type 1, 1057 (30%) LDS type 2, 264 (8%) LDS type 3, 130 (4%) LDS type 4, 79 (2%) LDS type 5 and 1361 (39%) were unknown. The overall prevalence of characteristics and complications of LDS can be seen in Table 1. Due to the high risk of bias due to incomplete reporting, we provide a narrative review of characteristics and complications by LDS type and system involvement. The frequency of observed features and complications stratified by LDS type in individual studies (Table 2) and high-quality cohort studies (Table 3, Supplementary Tables 3–7).
Table 2Frequency of characteristics and complications by LDS type in individual level studies.
LDS Type 1
LDS Type 2
LDS Type 3
LDS Type 4
LDS Type 5
All (n = 69)
High quality (n = 21)
All (n = 164)
High quality (n = 64)
All (n = 39)
High quality (n = 10)
All (n = 24)
High quality (n = 18)
All (n = 6)
High quality (n = 3)
Aortic aneurysm
44 (64%)
18 (86%)
130 (79%)
54 (84%)
21 (54%)
4 (40%)
17 (71%)
11 (61%)
3 (50%)
1 (33%)
Pulmonary artery aneurysm
3 (4%)
1 (5%)
15 (9%)
9 (14%)
0 (0%)
0 (0%)
3 (13%)
1 (6%)
0 (0%)
0 (0%)
Subclavian artery aneurysm
0 (0%)
0 (0%)
9 (5%)
2 (3%)
1 (3%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
Cerebral aneurysm
4 (6%)
0 (0%)
9 (5%)
3 (5%)
3 (8%)
1 (10%)
3 (13%)
3 (17%)
0 (0%)
0 (0%)
Other vessel aneurysm
8 (12%)
2 (10%)
20 (12%)
6 (9%)
8 (21%)
4 (40%)
5 (21%)
5 (28%)
0 (0%)
0 (0%)
Aortic dissection
15 (22%)
5 (24%)
31 (19%)
9 (14%)
13 (33%)
3 (30%)
1 (4%)
1 (6%)
1 (17%)
0 (0%)
Other vessel dissection
5 (7%)
2 (10%)
8 (5%)
4 (6%)
7 (18%)
1 (10%)
1 (4%)
1 (6%)
1 (17%)
0 (0%)
Arterial tortuosity
19 (28%)
9 (43%)
49 (30%)
24 (38%)
4 (10%)
2 (20%)
10 (42%)
739%)
0 (0%)
0 (0%)
Mitral valve prolapse
5 (7%)
1 (5%)
8 (5%)
4 (6%)
5 (13%)
1 (10%)
5 (21%)
4 (22%)
1 (17%)
1 (33%)
Bicuspid aortic valve
2 (3%)
0 (0%)
5 (3%)
1 (2%)
1 (3%)
0 (0%)
2 (8%)
2 (11%)
0 (0%)
0 (0%)
Aortic insufficiency
12 (17%)
3 (14%)
16 (10%)
5 (8%)
4 (10%)
0 (0%)
1 (4%)
0 (0%)
1 (17%)
1 (33%)
Bicuspid pulmonary valve
6 (9%)
2 (10%)
7 (4%)
5 (8%)
2 (5%)
1 (10%)
1 (4%)
1 (6%)
0 (0%)
0 (0%)
Persistent ductus arteriosus
4 (6%)
2 (10%)
29 (18%)
14 (22%)
0 (0%)
0 (0%)
1 (4%)
0 (0%)
0 (0%)
0 (0%)
Atrial septal defect
4 (6%)
1 (5%)
14 (9%)
3 (5%)
3 (8%)
1 (10%)
1 (4%)
0 (0%)
1 (17%)
1 (33%)
Dolichostenomelia
3 (4%)
2 (10%)
11 (7%)
7 (11%)
3 (8%)
1 (10%)
1 (4%)
1 (6%)
0 (0%)
0 (0%)
Arachnodactyly
17 (25%)
8 (38%)
43 (26%)
24 (38%)
3 (8%)
2 (20%)
6 (25%)
4 (22%)
3 (50%)
2 (67%)
Pectus deformity
22 (32%)
13 (62%)
54 (33%)
26 (41%)
6 (15%)
3 (30%)
8 (33%)
8 (44%)
5 (83%)
3 (100%)
Scoliosis
13 (19%)
8 (38%)
51 (31%)
31 (48%)
4 (10%)
2 (20%)
9 (38%)
9 (50%)
4 (67%)
2 (67%)
Camptodactyly
2 (3%)
1 (5%)
37 (23%)
22 (34%)
0 (0%)
0 (0%)
1 (4%)
1 (6%)
1 (17%)
1 (33%)
Joint laxity (Beighton score 5+/9)
22 (32%)
10 (48%)
64 (39%)
34 (53%)
3 (8%)
2 (20%)
15 (63%)
12 (67%)
4 (67%)
3 (100%)
Pes planus
3 (4%)
2 (10%)
6 (4%)
3 (5%)
7 (18%)
1 (10%)
6 (25%)
6 (33%)
2 (33%)
2 (67%)
Meniscal lesions
4 (6%)
0 (0%)
6 (4%)
3 (5%)
2 (5%)
1 (10%)
1 (4%)
1 (6%)
0 (0%)
0 (0%)
Talipes equinovarus
9 (13%)
3 (14%)
42 (26%)
20 (31%)
1 (3%)
1 (10%)
2 (8%)
2 (11%)
0 (0%)
0 (0%)
Cervical-spine instability
2 (3%)
1 (5%)
16 (10%)
11 (17%)
1 (3%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
Postaxial polydactyly
5 (7%)
1 (5%)
7 (4%)
4 (6%)
2 (5%)
1 (10%)
1 (4%)
1 (6%)
0 (0%)
0 (0%)
Hypertelorism
19 (28%)
6 (29%)
70 (43%)
35 (55%)
3 (8%)
1 (10%)
5 (21%)
3 (17%)
3 (50%)
2 (67%)
Abnormal uvula
31 (45%)
11 (52%)
71 (43%)
40 (63%)
5 (13%)
1 (10%)
1 (4%)
1 (6%)
6 (100%)
3 (100%)
Cleft palate
7 (10%)
4 (19%)
33 (20%)
19 (30%)
0 (0%)
0 (0%)
0 (0%)
0 (0%)
3 (50%)
2 (67%)
High arched palate
13 (19%)
4 (19%)
28 (17%)
15 (23%)
3 (8%)
1 (10%)
6 (25%)
5 (28%)
0 (0%)
0 (0%)
Malar hypoplasia
15 (22%)
8 (38%)
16 (10%)
12 (19%)
0 (0%)
0 (0%)
4 (17%)
3 (17%)
0 (0%)
0 (0%)
Retrognathia
14 (20%)
7 (33%)
36 (22%)
19 (30%)
0 (0%)
0 (0%)
6 (25%)
5 (28%)
1 (17%)
1 (33%)
Blue sclerae
8 (12%)
5 (24%)
23 (14%)
17 (27%)
0 (0%)
0 (0%)
3 (13%)
3 (17%)
1 (17%)
1 (33%)
Craniosynostosis
16 (23%)
7 (33%)
23 (14%)
12 (19%)
0 (0%)
0 (0%)
2 (8%)
1 (6%)
0 (0%)
0 (0%)
Exotropia
5 (7%)
2 (10%)
19 (12%)
9 (14%)
0 (0%)
0 (0%)
3 (13%)
3 (17%)
0 (0%)
0 (0%)
Velvety skin
5 (7%)
1 (5%)
12 (7%)
6 (9%)
1 (3%)
1 (10%)
1 (4%)
1 (6%)
0 (0%)
0 (0%)
Easy bruising
0 (0%)
0 (0%)
9 (5%)
5 (8%)
1 (3%)
0 (0%)
5 (21%)
5 (28%)
0 (0%)
0 (0%)
Striae
2 (3%)
2 (10%)
6 (4%)
5 (8%)
7 (18%)
1 (10%)
4 (17%)
4 (22%)
0 (0%)
0 (0%)
Umbilical/inguinal hernia
11 (16%)
6 (29%)
30 (18%)
14 (22%)
4 (10%)
1 (10%)
7 (29%)
7 (39%)
2 (33%)
1 (33%)
Translucent skin
8 (12%)
5 (24%)
17 (10%)
8 (13%)
2 (5%)
1 (10%)
4 (17%)
2 (11%)
1 (17%)
1 (33%)
Dural ectasia
3 (4%)
1 (5%)
7 (4%)
4 (6%)
1 (3%)
0 (0%)
3 (13%)
2 (11%)
0 (0%)
0 (0%)
Developmental delay
7 (10%)
4 (19%)
5 (3%)
2 (3%)
1 (3%)
1 (10%)
1 (4%)
1 (6%)
0 (0%)
0 (0%)
Asthma / chronic sinusitis
4 (6%)
3 (14%)
3 (2%)
1 (2%)
1 (3%)
1 (10%)
3 (13%)
3 (17%)
0 (0%)
0 (0%)
Variables with a frequency of <10 across all LDS types removed including: superior mesenteric artery aneurysm, left ventricular hypertrophy, atrial fibrillation, cardiac arrest, protrusio acetabulae, osteoporosis, osteoarthritis, intervertebral disc degeneration, spondyloses, spondylolisthesis, dental malocclusion, ectopia lentis, atrophic scars, Chiari malformation, hydrocephalus, uterine/bladder/bowel prolapse, varices, food allergies, eczema, eosinophilic esophagitis/gastritis, inflammatory bowel disease.
LDS Type 1 is the results of a mutation in TGFBR1. Amongst individual case reports, the most frequently reported physical characteristics include: aortic aneurysms, abnormal uvula, arterial tortuosity, pectus deformity and arachnodactyly (Table 2). In cohort studies of patients with LDS type 1 (
), ranging from 12 to 176 individuals (Supplementary Table 3), the most frequently reported characteristics include: joint laxity (68%), arachnodactyly (62%), pectus deformity (51%), aneurysms of vessels other than the aorta (50%), arterial tortuosity (50%) and retrognathia (50%; Table 3). The presence of aortic aneurysms varied significantly between studies ranging from 17 to 100% and aortic dissections ranged from 17 to 25%.
3.1.2 LDS type 2
LDS Type 2 is the results of a mutation in TGFBR2. The most frequently reported physical characteristics include: aortic aneurysms, hypertelorism, abnormal uvula, joint laxity, pectus deformity, scoliosis, arterial tortuosity, arachnodactyly (Table 2). In cohort studies of patients with LDS type 2 (
), ranging from 12 to 265 patients (Supplementary Table 4), the most frequently reported features include: velvety skin (82%), malar hypoplasia (75%), easy bruising (67%), aneurysms of vessels other than the aorta (59%), arterial tortuosity (49%), high arched palate (48%) and pectus deformity (47%; Table 3). The prevalence of aortic aneurysm ranged from 23 to 75% as did a history of aortic dissection 16–35%.
3.1.3 LDS type 3
LDS Type 3 (previously known as aneurysms-osteoarthritis syndrome) is the result of mutations in the SMAD3 gene. There were few reported individual cases of LDS Type 3 (n = 39), with only a quarter considered high quality, leading to low quality prevalence estimates from the summation of these studies (Table 2). Amongst high-quality cohort studies (
), that ranged from 9 to 45 individuals (Supplementary Table 5), we observe that this cohort is uniquely characterised by the presence of early onset osteoarthritis (41–96%) and osteochondritis dissecans (56%), which is frequently the symptoms that leads them to present for medical consultation (Table 3). In addition, they demonstrated a high frequency of aortic aneurysms (50–79%), and arterial tortuosity of the cerebral arteries (50%). Aortic dissections were reported to occur in 0–33% of individuals. Patients with LDS type 3 demonstrate the highest prevalence of mitral valve prolapse (41% in cohort studies), compared to other types of LDS. Other common phenotypic anomalies included: varices (58%), striae (20–53%), velvety skin (58–62%), abnormal uvula (11–52%), abnormal palate (53–60%), pes planus (24–91%) and scoliosis (33–61%). In a cohort of 28 patients with SMAD3 mutations with a median follow-up of 10 years, the rate of increase in aortic diameter was 0.4 mm per year with the sino-tubular junction being involved most frequently and during follow-up up, 50% of patients required elective root replacement (
Mutations in TGFB2 lead to the development of LDS Type 4. While there were only 24 identified case reports of LDS type 4, the majority (75%) were of high quality (Table 2). These patients demonstrated a high prevalence of: aortic aneurysms, joint laxity, pectus deformities and scoliosis. Amongst cohort studies (Supplementary Table 6), that included between 3 and 19 individuals (
), other commonly observed features included: arachnodactyly, pes planus, high-arched palate and umbilical/inguinal hernias (Table 3). The prevalence of aortic aneurysms ranged from 22 to 100% and a history of aortic dissection was reported in 9–11% of cases.
3.1.5 LDS type 5
Mutations in TGFB3 lead to the development of LDS Type 5. There were only six reported individual case reports (Table 2) and two cohort studies (Supplementary Table 7) that included between 32 and 43 individuals (
). This cohort demonstrated similar characteristics to other subtypes including: aortic aneurysms, arachnodactyly, pectus deformity, pes planus, hypertelorism, abnormal uvula and joint laxity (Table 3). The prevalence of aortic aneurysms ranged from 14 to 32% and in one cohort a history of aortic dissections was observed in 23% of individuals.
3.2 Cardiovascular involvement
While LDS type 1 and 2 have similar risks of aortic dissection, in LDS type 1 males demonstrated a greater risk of aortic complications compared to females (
Vertebral artery tortuosity index is a novel biomarker of surgery and aortic dissection or rupture in children and young adults: Findings from the national registry of genetically triggered thoracic aortic aneurysms and cardiovascular conditions.
Segmental aortic stiffness in children and young adults with connective tissue disorders: relationships with age, aortic size, rate of dilation, and surgical root replacement.
) with increased aortic risk. Aortic root dilation in children should lead to the suspicion of connective tissues disorders, including LDS. In a cohort of 25 pediatric patients with undiagnosed aortic root dilation, 28% had an underlying undiagnosed connective tissues disease, 5 of which had Marfan syndrome and 1 who had LDS type 3 (
). Of note, non-aortic arterial involvement cannot be predicted by aortic involvement and most frequently effects the carotid, subclavian and intracranial arteries (
). The overall prevalence of arterial tortuosity is also likely under reported. In series that only included participants with neuroimaging, arterial tortuosity was observed in 80–100% of patients depending on the vascular territory examined (
In surgical cohorts, patient with LDS generally demonstrate high rates of aortic reoperation compared to Marfan syndrome and increased risk of post-operative aortic dissections (
), however in a cohort of 107 patients with spontaneous coronary artery dissection who underwent genetic evaluation, only 8% had an underlying connective tissue disease (
Spondylolisthesis and spondylosis is likely underreported, with robust studies demonstrating a combined prevalence of 21% in a cohort of 138 patients, requiring surgery at a median age of 11 years (
). While scoliosis is common in LDS, it lacks specificity for LDS. Of 343 patients with adolescent idiopathic scoliosis, only 2 had undiagnosed LDS type 3 and 1 had Marfan syndrome (
). In a cohort of LDS patients who were reviewed for musculoskeletal involvement, 66% had pectus abnormalities and 17% had talipes equinovarus (club foot). In a cohort of 57 patients with LDS, 33 (58%) patients had reported at least one fracture (
). Overall, patients with LDS have a high burden of musculoskeletal involvement with ~20% requiring surgical intervention, which is frequently complicated and requires additional operations (
In cohorts of LDS patients who underwent detailed oro-dental examination, most patients have an abnormal palate (85–88%), have retrognathia (83%), dental malocclusion (55–97%) and have enamel defects (55%) which were more severe in LDS type 2 (
In ophthalmologic studies, hypertelorism was present in 61%, exotropia in 41% and blue sclera in 47%, with LDS type 1 and 2 demonstrating a higher prevalence of blue sclera (
). In contrast to other reports, in an analysis of 25 patients with LDS who also underwent ophthalmologic examination, there was no difference in pupillary distance (objective assessment of hypertelorism) compared to healthy controls (
). However, they do note that males with LDS type 2, demonstrated a trend towards increased pupillary distance that may explain differences between reports. They also note that patients with LDS demonstrated increase myopia, and reduced central corneal thickness.
3.5 Neurological involvement
In a survey study of 67 patients with LDS and their caregivers, neurodevelopmental concerns are believed to be an underrecognized aspect of LDS, with 30% reporting motor delays, feeding issues (41%), hearing problems (31%), poor vision (77%) and weak muscle tone (62%) (
). In an otologic series, patients with LDS across all subtypes demonstrated hearing loss (42%), with predominant conductive hearing loss in LDS type 1 and 2 and sensorineural hearing loss in LDS type 3 and 4 (
Dural ectasia while rare in the general population, demonstrates an increased prevalence in patients with connective tissue disorders. The prevalence of dural ectasia in neuroimaging studies has been found to be 40–73%, similar in prevalence and severity to patients with Marfan syndrome (
Prevalence of dural ectasia in 63 gene-mutation-positive patients with features of Marfan syndrome type 1 and Loeys-Dietz syndrome and report of 22 novel FBN1 mutations.
Few studies have robustly explored the gastrointestinal manifestations of LDS. In a small survey of 13 patients with LDS, a large proportion describe symptoms of constipation (77%) and diarrhea (46%), which was statistically higher than patients with vascular Ehlers-Danlos syndrome (
). Endoscopy studies of this population is scarce, with a study of four patients in which one was found to have congestive gastropathy and a second was found to have esophageal candidiasis (
). The prevalence of inflammatory bowel disease in LDS (4%) is five times higher than the general population and was frequently refractory to conventional therapies (
). Children with LDS typical have a body mass index significantly below average which can be related to a variety of reasons including repeated surgical interventions, intestinal inflammation and food allergies (
). In a cohort of 182 children with LDS, 6% required a gastrostomy tube which was associated 0.1 increase body mass index z-score per month of tube placement and was not associated with any complications (
), multiple studies have demonstrated the clinical impact of this in patients with LDS. These studies have demonstrated an increased prevalence of asthma (50%), eczema (50%), allergic rhinitis (43%), food allergies (29%) and eosinophilic infiltration of gastrointestinal tract (14%) (
With the wide spectrum of pathologies associated with LDS, patients frequently have a high health burden requiring serial follow-up with multiple healthcare workers. In a survey of 34 patients with LDS, 62% were not working/in-school due to disability and 71% requiring hospital services at least on a yearly basis (
Loeys-Dietz syndrome and pregnancy: two case reports and literature review Síndrome de Loeys-Dietz e gravidez: dois casos clínicos e revisão da literatura.
Clinical features and outcomes of pregnancy-related acute aortic dissection.
JAMA Cardiol.2021; 6 (Epub 2020/10/15) (PubMed PMID: 33052376; PubMed Central PMCID: PMCPMC7557715 Terumo Aortic and personal fees from Cook Aortic outside the submitted work. Dr Ouzounian reported receiving personal fees from Medtronic Inc outside the submitted work. Dr Coselli reported receiving personal fees and other from Medtronic, personal fees and other from W. L. Gore, grants, personal fees, and other from Terumo Aortic, and other from Abbott Laboratories, Edwards, and Cytosorbents outside the submitted work. Dr Eagle reported receiving grants from W. L. Gore, Medtronic, and Terumo outside the submitted work. The International Registry of Acute Aortic Dissection (IRAD) study was supported by unrestricted grants from W. L. Gore, the Ann and Bob Aikens Aortic Fund, The Tom Varbedian Fund for Aortic Research, and grants from numerous participating IRAD aortic centers of excellence. No other disclosures were reported): 58-66
). In total, amongst the 222 women with LDS who underwent 522 pregnancies, 35 (7%) of pregnancies were complicated by at least one complication and included: aortic dissection (4% - of which 10 were Type A, 8 were Type B and 5 were unreported), postpartum hemorrhage (n = 9), uterine rupture (n = 2), uterine prolapse (n = 1), spontaneous coronary artery dissection (n = 1), carotid artery dissection (n = 2), vertebral artery dissection (n = 1) and unexplained sudden death (n = 1). Overall, 4 (1%) deaths were reported during pregnancy or postpartum.
4. Discussion
Although LDS is considered a rare disorder, we have been able to identify 3896 reported cases in the literature. As TGFB-signalling pathways affect multiple organ systems, it is unsurprising that we have observed a wide degree of involvement of the cardiovascular, musculoskeletal, neurological, gastrointestinal systems. Illustrating the prevalence of these phenotypes across the subtypes of LDS demonstrates the wide spectrum of the disease as it pertains to each subtype, allowing clinicians to identifying patients who share multiple attributes of LDS.
Compared to other syndromic inherited aortopathies, LDS demonstrates a similar prevalence of aortic aneurysms (33% in this review), compared to Marfan syndrome (51%), Turner Syndrome (35%) and vascular Ehlers-Danlos (28%) (
). However, they generally demonstrate a much higher risk of dissection (11% in this review) compared to Marfan syndrome (0.8–12%), Turner syndrome (1–5%) and vascular Ehlers-Danlos (1–6%) (
). Additionally, while patients with LDS demonstrate generalised arterial tortuosity and aneurysms beyond the aorta, they are infrequently observed in Marfan syndrome (
). Other key distinguishing features of LDS to other aortopathies include the absence of ectopia lentis (identified in only 4 cases in our review) and a much higher prevalence of hypertelorism, bifid uvula and cleft palate (
Genetic counselling and testing in adults with congenital heart disease: a consensus document of the ESC working group of grown-up congenital heart disease, the ESC working group on aorta and peripheral vascular disease and the European Society of Human Genetics.
). In addition to confirming the diagnosis, genetic testing guides management, provides prognostic information and informs recurrence risk. In addition, the identification of LDS allows for further screening for silent vascular pathology that may require elective intervention to avoid significant, and at times, catastrophic future complications. Current guidelines recommend lower thresholds for elective intervention on the thoracic aorta, due to the aggressive disease course as well as more frequent imaging monitoring for disease progression (
2014 ESC guidelines on the diagnosis and treatment of aortic diseases: document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult the task force for the diagnosis and treatment of aortic diseases of the European Society of Cardiology (ESC).
). Furthermore, a positive genetic test has implications for counselling in regards to future pregnancy and complications surrounding this as well as genetic inheritance given the autosomal dominant nature of the syndrome. In cases where the parent of a patient is known or suspected to have LDS, the recurrence risk is 50%. However, when there is a de novo gene mutation due to germline mosaicism, the recurrence risk in subsequent children is estimated to be less than 1% (
The major limitations of this study are driven by the quality of reporting in the included studies as well as small sample sizes in individual studies, highlight the need for high-quality, collaborative registries.
5. Conclusion
LDS is a heterogenous multi-system disorder, with many case reports that we identified presenting a focused presentation on a single characteristic or complication of LDS, leading to underreporting of many salient features. This is a major limitation of our review, likely leading to underreporting of characteristics and complications. To address this, large-scale international registries have been established and continue to offer important insights into LDS (
Vertebral artery tortuosity index is a novel biomarker of surgery and aortic dissection or rupture in children and young adults: Findings from the national registry of genetically triggered thoracic aortic aneurysms and cardiovascular conditions.
Segmental aortic stiffness in children and young adults with connective tissue disorders: relationships with age, aortic size, rate of dilation, and surgical root replacement.
Prevalence of dural ectasia in 63 gene-mutation-positive patients with features of Marfan syndrome type 1 and Loeys-Dietz syndrome and report of 22 novel FBN1 mutations.
Loeys-Dietz syndrome and pregnancy: two case reports and literature review Síndrome de Loeys-Dietz e gravidez: dois casos clínicos e revisão da literatura.
Clinical features and outcomes of pregnancy-related acute aortic dissection.
JAMA Cardiol.2021; 6 (Epub 2020/10/15) (PubMed PMID: 33052376; PubMed Central PMCID: PMCPMC7557715 Terumo Aortic and personal fees from Cook Aortic outside the submitted work. Dr Ouzounian reported receiving personal fees from Medtronic Inc outside the submitted work. Dr Coselli reported receiving personal fees and other from Medtronic, personal fees and other from W. L. Gore, grants, personal fees, and other from Terumo Aortic, and other from Abbott Laboratories, Edwards, and Cytosorbents outside the submitted work. Dr Eagle reported receiving grants from W. L. Gore, Medtronic, and Terumo outside the submitted work. The International Registry of Acute Aortic Dissection (IRAD) study was supported by unrestricted grants from W. L. Gore, the Ann and Bob Aikens Aortic Fund, The Tom Varbedian Fund for Aortic Research, and grants from numerous participating IRAD aortic centers of excellence. No other disclosures were reported): 58-66
Genetic counselling and testing in adults with congenital heart disease: a consensus document of the ESC working group of grown-up congenital heart disease, the ESC working group on aorta and peripheral vascular disease and the European Society of Human Genetics.
2014 ESC guidelines on the diagnosis and treatment of aortic diseases: document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult the task force for the diagnosis and treatment of aortic diseases of the European Society of Cardiology (ESC).
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