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International Journal of Cardiology Sep 2022Loeys-Dietz syndrome (LDS) is a connective tissue disorder that arises from mutations altering the transforming growth factor β signalling pathway. Due to the recent... (Review)
Review
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.
Topics: Aortic Dissection; Arteries; Connective Tissue Diseases; Female; Humans; Loeys-Dietz Syndrome; Mutation; Pregnancy
PubMed: 35662564
DOI: 10.1016/j.ijcard.2022.05.065 -
Annals of Cardiothoracic Surgery Nov 2017Many different heritable connective tissue disorders (HCTD) have been described over the past decades. These syndromes often affect the connective tissue of various... (Review)
Review
Many different heritable connective tissue disorders (HCTD) have been described over the past decades. These syndromes often affect the connective tissue of various organ systems, including heart, blood vessels, skin, joints, bone, eyes, and lungs. The discovery of these HCTD was followed by the identification of mutations in a wide range of genes encoding structural proteins, modifying enzymes, or components of the TGFβ-signaling pathway. Three typical examples of HCTD are Marfan syndrome (MFS), Ehlers-Danlos syndrome (EDS), and Loeys-Dietz syndrome (LDS). These syndromes show some degree of phenotypical overlap of cardiovascular, skeletal, and cutaneous features. MFS is typically characterized by cardiovascular, ocular, and skeletal manifestations and is caused by heterozygous mutations in , coding for the extracellular matrix (ECM) protein fibrillin-1. The most common cardiovascular phenotype involves aortic aneurysm and dissection at the sinuses of Valsalva. LDS is caused by mutations in , , or , all coding for components of the TGFβ-signaling pathway. LDS can be distinguished from MFS by the unique presence of hypertelorism, bifid uvula or cleft palate, and widespread aortic and arterial aneurysm and tortuosity. Compared to MFS, LDS cardiovascular manifestations tend to be more severe. In contrast, no association is reported between LDS and the presence of ectopia lentis, a key distinguishing feature of MFS. Overlapping features between MFS and LDS include scoliosis, pes planus, anterior chest deformity, spontaneous pneumothorax, and dural ectasia. EDS refers to a group of clinically and genetically heterogeneous connective tissue disorders and all subtypes are characterized by variable abnormalities of skin, ligaments and joints, blood vessels, and internal organs. Typical presenting features include joint hypermobility, skin hyperextensibility, and tissue fragility. Up to one quarter of the EDS patients show aortic aneurysmal disease. The latest EDS nosology distinguishes 13 subtypes. Many phenotypic features show overlap between the different subtypes, which makes the clinical diagnosis rather difficult and highlights the importance of molecular diagnostic confirmation.
PubMed: 29270370
DOI: 10.21037/acs.2017.11.03 -
Human Mutation May 2018The Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with...
The Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-β (TGF-β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF-β signaling. More recently, TGF-β ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF-β pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF-β signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database.
Topics: Animals; Disease Models, Animal; Genetic Association Studies; Humans; Loeys-Dietz Syndrome; Mice; Mutation; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta2; Transforming Growth Factor beta3
PubMed: 29392890
DOI: 10.1002/humu.23407 -
Indian Journal of Plastic Surgery :... 2014The term orbital hypertelorism (ORH) implies "widely apart orbits." This may also be associated with the abnormal vertical orientation of the orbits (dystopia). This...
The term orbital hypertelorism (ORH) implies "widely apart orbits." This may also be associated with the abnormal vertical orientation of the orbits (dystopia). This deformity may be unilateral or bilateral, symmetric or asymmetric and may be present in a variety of craniofacial conditions. The treatment is primarily carried out for aesthetic reasons. The timing of treatment is dictated by the underlying condition and the type of procedure envisaged. The mainstay of treatment consists of moving the orbits medially to near normal position. This is accomplished by either an orbital translocation or facial bipartition technique. The choice of procedure is governed by the shape of the maxillary arch and associated occlusal conditions. We must differentiate between the telecanthus (also called pseudo-hypertelorism) and a true ORH as the management differs in these two conditions. The ORH involves extensive intracranial and extracranial operation whereas the telecanthus correction is relatively simpler surgery. The article will discuss the aetiology, classification, presentation, treatment options, timing of surgery and the choice of surgical procedures. Illustrative case reports with long-term results will be used to explain the management of these patients.
PubMed: 25593412
DOI: 10.4103/0970-0358.146572 -
BMC Medical Genetics Mar 2020Noonan syndrome (NS), an autosomal dominant developmental genetic disorder, is caused by germline mutations in genes associated with the RAS / mitogen-activated protein...
BACKGROUND
Noonan syndrome (NS), an autosomal dominant developmental genetic disorder, is caused by germline mutations in genes associated with the RAS / mitogen-activated protein kinase (MAPK) pathway. In several studies PTPN11 is one of the genes with a significant number of pathogenic variants in NS-affected patients. Therefore, clinically diagnosed NS individuals are initially tested for pathogenic variants in PTPN11 gene to confirm the relationship before studying genotype-phenotype correlation.
METHODS
Individuals (363) with clinically diagnosed NS from four hospitals in South India were recruited and the exons of PTPN11 gene were sequenced.
RESULTS
Thirty-two previously described pathogenic variants in eight different exons in PTPN11 gene were detected in 107 patients, of whom 10 were familial cases. Exons 3, 8 and 13 had the highest number of pathogenic variants. The most commonly identified pathogenic variants in this series were in exon 8 (c.922A > G, c.923A > G), observed in 22 of the affected. Congenital cardiac anomalies were present in 84% of the mutation-positive cohort, the majority being defects in the right side of the heart. The most common facial features were downward-slanting palpebral fissures, hypertelorism and low-set posteriorly rotated ears. Other clinical features included short stature (40%), pectus excavatum (54%) and, in males, unilateral or bilateral cryptorchidism (44%).
CONCLUSION
The clinical features and mutational spectrum observed in our cohort are similar to those reported in other large studies done worldwide. This is the largest case series of NS-affected individuals with PTPN11 mutations described till date from India.
Topics: Adolescent; Adult; Child; Child, Preschool; Cohort Studies; DNA Mutational Analysis; Family; Female; Genetic Association Studies; Genetic Predisposition to Disease; Germ-Line Mutation; Heart Defects, Congenital; Humans; India; Infant; Infant, Newborn; Male; Noonan Syndrome; Phenotype; Polymorphism, Single Nucleotide; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Young Adult
PubMed: 32164556
DOI: 10.1186/s12881-020-0986-5