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Authors=Sanjanajaiswal Additional contributors=Andrew.G.Lee, Caitlin.hackl, Samir.Cayenne, Elizabeth.Arogundade Category=Cornea/External Disease,Miscellaneous,Oculoplastics/Orbit Date reviewed=August 7, 2024 Meta description=Loeys-Dietz Syndrome (LDS) is a rare genetic connective tissue disorder with significant ophthalmic manifestations including myopia, blue sclerae, and retinal complications. With a prevalence of <1 in 100,000, LDS can lead to serious ocular issues like retinal detachment and tortuosity. Diagnosis involves comprehensive eye exams and genetic testing. Management includes regular ophthalmic monitoring and corrective lenses. Early detection and ongoing eye care are essential for preserving vision and improving quality of life for patients with LDS. This case is rare and unique in its clinical presentation and can assist clinicians in differentiating from other connective tissue disorders that present with significantly different ophthalmological complications.

2 Eyewiki Title: Loeys-Dietz Syndrome

Authors: Samir Cayenne, Caitlin Hackl, Sanjana Jaiswal MD, Elizabeth O. Arogundade MD, Andrew G. Lee MD

1. Disease Entity

1.1 Disease Loeys-Dietz Syndrome (LDS) is a rare multisystem genetic connective tissue disorder characterized by a wide range of manifestations, including significant cardiovascular, skeletal, craniofacial, cutaneous, and ophthalmic abnormalities. The ophthalmic abnormalities observed in LDS can negatively impact a patient's vision, overall ocular health, and quality of life. The estimated prevalence of LDS is <1 in 100,000.[1]

1.2 Risk Factors The primary risk factor for LDS is genetic predisposition due to mutations in genes coding for the transforming growth factor beta (TGF-β) pathway, including: TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2, and TGFB3 genes.[2] These mutations lead to abnormal connective tissue development and function. LDS follows an autosomal dominant inheritance pattern in familial cases, meaning that an affected parent has a 50% chance of passing the condition to their offspring, however non-penetrance may occur. Although familial in many cases, a large proportion of cases of LDS arise due to de novo mutations which typically result in more severe cases than those secondary to inherited mutations.[2] With de novo mutations, the risk of recurrence in children is less than 1%.[3]

1.3 Etiology LDS is caused by mutations in genes that play a critical role in the transforming growth factor-beta (TGF-β) signaling pathway. This pathway is essential for the regulation of cellular growth, proliferation, differentiation, and apoptosis, all of which are vital for the development and maintenance of connective tissues throughout the body. The TGF-β signaling pathway functions through the activation of TGF-β receptors, which transmit signals to intracellular SMAD proteins that regulate gene expression. In LDS, mutations in the TGFBR1 and TGFBR2 genes result in dysfunctional TGF-β receptors. Similarly, mutations in SMAD3, TGFB2, and TGFB3 genes affect the downstream signaling molecules and ligands, respectively. These genetic mutations lead to aberrant signaling, causing either excessive or insufficient activation of the pathway.[4]

The disruption of TGF-β signaling has a profound impact on the connective tissues. Normally, TGF-β signaling is tightly regulated to ensure proper tissue architecture and function. However, in LDS, the abnormal signaling results in compromised structural integrity and function of connective tissues. This manifests as weakened arterial walls, leading to a propensity for aneurysms and dissections, as well as skeletal abnormalities such as scoliosis and joint hypermobility. Craniofacial anomalies and skin abnormalities are also common, reflecting the widespread effects of disrupted TGF-β signaling on tissue development and maintenance.

In the ocular system, the disruption of TGF-β signaling affects the extracellular matrix and structural components of the eye. This can lead to myopia, and blue sclerae, as the integrity of the connective tissues within the eye is compromised. Similarly to the observed systemic vascular complications, vascular wall weakness may result in tortuosity in vasculature such as the retinal artery and components of the circle of willis (image 4).[5,6] Additionally, abnormal signaling may impact the development and maintenance of the retinal structure, increasing the risk for retinal detachment and retinal vasculature abnormalities.[5,7]

Overall, the etiology of LDS highlights the critical role of the TGF-β signaling pathway in maintaining connective tissue integrity. The mutations that cause LDS lead to a cascade of effects, resulting in the various clinical manifestations observed in patients with this syndrome.

1.4 Primary Prevention Primary prevention strategies for LDS include genetic counseling for individuals with a family or personal history of the syndrome to assess the risk of offspring being affected and guide family planning decisions. Regular monitoring and early detection of systemic complications, particularly cardiovascular, are crucial for preventing life-threatening events. Complication prevention measures include lifestyle modifications and medical management to reduce hemodynamic stress on the cardiovascular system.[8] 2. Diagnosis

2.1 History The diagnosis of LDS often begins with a thorough patient history, noting the presence of cardiovascular, skeletal, craniofacial, ocular, and cutaneous abnormalities. A detailed family history may reveal similar symptoms in relatives, which supports the diagnosis of a hereditary condition. A thorough family history tailored to signs and symptoms of LDS is of the utmost importance as familial connective tissue disorders may be undiagnosed, resulting in a diagnostic challenge.

2.2 Symptoms Patients with LDS may present with various symptoms, including those related to ophthalmic issues such as myopia, amblyopia, strabismus, and blue sclerae.[8] Systemic symptoms can include arterial aneurysms, scoliosis, pectus deformities, joint hypermobility, pneumothorax, and distinctive craniofacial features.[8.9] Craniofacial abnormalities including craniosynostosis, micro-retrognathia, cleft palate, narrow or high-arched palate, hypertelorism (image 1), and bifid uvula (image 2) are specific to LDS among the connective tissue disorders and their presence warrants prioritization of LDS over syndromes like Marfan or Ehlers-Danlos.[10]

2.3 Signs Clinical signs of LDS can be observed during a comprehensive examination. Ophthalmic signs may include mild myopia, strabismus, exotropia, amblyopia, decreased corneal thickness, keratoconus, cornea plana, cataracts, and blue sclerae.[5,8,11,12] Recently, retinal artery tortuosity (image 3G-I) has been described and although rare, retinal detachment may occur. Specific LDS mutations causing glaucoma, high myopia, and corneal guttata have been identified.[13] Craniofacial abnormalities such as down slanting palpebral fissures and hypertelorism can distinguish LDS from other connective tissue disorders which lack these features.[7] Systemic signs include arterial tortuosity, aneurysms, kyphoscoliosis, clubfoot, pectus deformities, and translucent skin (image 5).[6]

Image 1. Hypertelorism in a patient with Loeys Dietz Syndrome.[14]

Image 2. Bifid uvula in a patient with Loeys Dietz Syndrome.[15]

Image 3G-I. Retinal Artery Tortuosity in Loeys Dietz Syndrome.[5]

Image 4. Vascular Tortuosity in Circle of Willis of MCA and Internal Carotid Arteries.[5]

Image 5. Systemic findings in mild strabismus (A). Other symptoms include ectopic hair growth on the right mandible (B), high-arched cleft palate with bifid uvula (C), bilateral clubfoot (D), and kyphoscoliosis (E, F).[6]

2.4 Physical Examination A detailed physical examination is essential in diagnosing LDS. The ophthalmic examination should include a slit-lamp examination to exclude lens (sub)luxation, the presecnce of which may suggest an alternate pathology, and corneal abnormalities.[8,13] Fundoscopic examination to assess retinal health is critical as retinal complications may be sight-threatening. Intraocular pressure should be checked due to the disorders propensity to impact corneal thickness, a known risk factor for glaucoma.[13] Lastly, visual acuity should be assessed to allow for correction of refractive errors. Identification of abnormalities on ophthalmic exam may be the first sign of the disease in undiagnosed individuals.[16] A general physical examination should assess cardiovascular health, skeletal deformities, craniofacial abnormalities, and cutaneous findings to provide a comprehensive view of the patient's condition and determine severity.

2.5 Differential Diagnosis Differential diagnosis for LDS includes other connective tissue disorders such as Marfan Syndrome, Ehlers-Danlos Syndrome (particularly Vascular type), and Familial Thoracic Aortic Aneurysm. Careful evaluation of clinical features and genetic testing can help distinguish LDS from these other conditions.

Marfan Syndrome is a genetic disorder affecting connective tissues, caused by mutations in the FBN1 gene that encodes the protein fibrillin-1. Clinically, Marfan Syndrome shares several features with LDS, including a predisposition to aortic aneurysms, scoliosis, pectus deformities, and joint hypermobility. However, Marfan Syndrome typically presents with ectopia lentis (lens dislocation) and specific skeletal manifestations such as arachnodactyly (long, slender fingers). Ectopia lentis has been considered a discriminating feature of the two disease, however, there are rare reports of ectopia lentis in specific LDS genotypes.[17,18] Additionally, the myopia observed in marfan syndrome is more severe than that in LDS in majority of cases.[8] Genetic testing for mutations in FBN1 can help distinguish Marfan Syndrome from LDS.

Ehlers-Danlos Syndrome (EDS) encompasses a group of disorders that also affect connective tissues. The Vascular type of EDS, caused by mutations in the COL3A1 gene, is particularly relevant in the differential diagnosis of LDS. Vascular EDS is characterized by fragile blood vessels, easy bruising, thin translucent skin, and a tendency for arterial, intestinal, and uterine rupture. Unlike LDS, vascular EDS does not typically present with craniofacial abnormalities such as hypertelorism or a bifid uvula. Genetic testing for mutations in the COL3A1 gene can help differentiate vascular EDS from LDS.[18]

Familial Thoracic Aortic Aneurysm and Dissection (FTAAD) is another condition that should be considered. It is characterized by the familial occurrence of thoracic aortic aneurysms and dissections without the additional systemic features seen in LDS. Mutations in several genes, including ACTA2, TGFBR1, TGFBR2, and MYH11, have been associated with FTAAD. While some genetic mutations overlap with those seen in LDS, FTAAD lacks the craniofacial, skeletal, and cutaneous manifestations that are typical of LDS. A thorough family history and genetic testing focused on these specific genes can aid in differentiating FTAAD from LDS.[19]

2.6 Labs/Testing Laboratory and genetic testing are critical for confirming the diagnosis of LDS. Genetic testing can identify mutations in TGFBR1, TGFBR2, SMAD3, TGFB2, or TGFB3. Imaging studies, such as echocardiography, MRI, or CT angiography, are used to detect vascular abnormalities and assess disease severity. Ophthalmic imaging, including optical coherence tomography and fundus photography, provide detailed information about ocular structures.

3. Management

3.1 Medical Therapy Medical management of LDS focuses on cardiovascular health, with beta-blockers or angiotensin receptor blockers commonly used to reduce stress on the aorta and other arteries. Ophthalmic management includes regular eye examinations to monitor for the development of myopia, corneal abnormalities, and, in rare cases, retinal detachment. Corrective lenses or contact lenses can help manage refractive errors. Of particular importance, children require aggressive refraction and visual correction due to the risk of amblyopia.[8] Patching protocols may be used to manage amblyopia in affected individuals.

3.2 Surgery Surgical interventions may be necessary for both cardiovascular and ophthalmic complications of LDS. Cardiovascular surgery is often required to repair aneurysms or arterial dissections to prevent life-threatening events. Ophthalmic surgery may be needed to repair potential retinal detachment and correct strabismus, ensuring the preservation of vision.

3.3 Prognosis The prognosis for patients with LDS depends on the severity of their condition and the effectiveness of their management plan. With early diagnosis and comprehensive management, individuals with LDS can lead relatively normal lives. However, the risk of serious complications, particularly those affecting the cardiovascular system, requires ongoing vigilance. Most cases present in the second decade of life, with a life expectancy is estimated to be around 37 years, however cases vary depending on the severity and management of symptoms.[20] Regular follow-up with a multidisciplinary team, including ophthalmologists, is essential to optimize outcomes and ensure the best possible quality of life for patients with LDS.

References Loughborough WW, Minhas KS, Rodrigues JCL, et al. Cardiovascular Manifestations and Complications of Loeys-Dietz Syndrome: CT and MR Imaging Findings. Radiographics. 2018;38(1):275-286. doi:10.1148/rg.2018170120 Velchev JD, Van Laer L, Luyckx I, Dietz H, Loeys B. Loeys-Dietz Syndrome. Adv Exp Med Biol. 2021;1348:251-264. doi:10.1007/978-3-030-80614-9_11 Gouda P, Kay R, Habib M, Aziz A, Aziza E, Welsh R. Clinical features and complications of Loeys-Dietz syndrome: A systematic review. Int J Cardiol. 2022;362:158-167. doi:10.1016/j.ijcard.2022.05.065 Schepers D, Tortora G, Morisaki H, et al. A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3. Hum Mutat. 2018;39(5):621-634. doi:10.1002/humu.23407 Ghoraba HH, Moshfeghi DM. Retinal Arterial Tortuosity in Marfan and Loeys-Dietz Syndromes. Ophthalmol Retina. 2023;7(6):554-557. doi:10.1016/j.oret.2023.02.014 Uike K, Matsushita Y, Sakai Y, et al. Systemic vascular phenotypes of Loeys-Dietz syndrome in a child carrying a de novo R381P mutation in TGFBR2: a case report. BMC Res Notes. 2013;6:456. doi:10.1186/1756-0500-6-456 Loomba K, Lin D, Lin W, Riley B. Ocular Manifestations of Loeys–Dietz Syndrome. Published online March 28, 2022. Accessed August 7, 2024. https://www.emjreviews.com/rheumatology/article/ocular-manifestations-of-loeys-dietz-syndrome/ Loeys BL, Dietz HC. Loeys-Dietz Syndrome. In: Adam MP, Feldman J, Mirzaa GM, et al., eds. GeneReviews®. University of Washington, Seattle; 1993. Accessed August 7, 2024. http://www.ncbi.nlm.nih.gov/books/NBK1133/ Neuroradiologic Manifestations of Loeys-Dietz Syndrome Type 1 - PMC. Accessed August 7, 2024. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051610/ Baldo F, Morra L, Feresin A, et al. Neonatal presentation of Loeys-Dietz syndrome: two case reports and review of the literature. Ital J Pediatr. 2022;48(1):85. doi:10.1186/s13052-022-01281-y Maghsoudi D, Nixon TRW, Snead MP. Retinal detachment in Loeys-Dietz syndrome. Am J Med Genet A. 2023;191(3):846-849. doi:10.1002/ajmg.a.63077 MacCarrick G, Black JH, Bowdin S, et al. Loeys-Dietz syndrome: a primer for diagnosis and management. Genet Med. 2014;16(8):576-587. doi:10.1038/gim.2014.11 Corneal thinning and cornea guttata in patients with mutations in TGFB2 - PMC. Accessed August 7, 2024. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049842/ Williams JA, Loeys BL, Nwakanma LU, et al. Early surgical experience with Loeys-Dietz: a new syndrome of aggressive thoracic aortic aneurysm disease. Ann Thorac Surg. 2007;83(2):S757-763; discussion S785-790. doi:10.1016/j.athoracsur.2006.10.091 Kim SH, Baek SW, Kwon WK, et al. Anesthetic managements for correction of aortic valve regurgitation in a patient with Loeys-Dietz Syndrome: A case report. Korean J Anesthesiol. 2009;57(3):371-375. doi:10.4097/kjae.2009.57.3.371 Burgess FR, Carroll N, Young SL, Schmoll C, Lampe AK, Chan J. A short-sighted approach to high myopia-not just an eye problem. J AAPOS. 2021;25(4):247-248. doi:10.1016/j.jaapos.2021.03.005 Braverman AC, Blinder KJ, Khanna S, Willing M. Ectopia lentis in Loeys-Dietz syndrome type 4. Am J Med Genet A. 2020;182(8):1957-1959. doi:10.1002/ajmg.a.61633 Meester JAN, Verstraeten A, Schepers D, Alaerts M, Van Laer L, Loeys BL. Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome. Ann Cardiothorac Surg. 2017;6(6):582-594. doi:10.21037/acs.2017.11.03 Guo DC, Regalado ES, Minn C, et al. Familial thoracic aortic aneurysms and dissections: identification of a novel locus for stable aneurysms with a low risk for progression to aortic dissection. Circ Cardiovasc Genet. 2011;4(1):36-42. doi:10.1161/CIRCGENETICS.110.958066 Harky A, Garner M, Roberts N. A late presentation of Loeys–Dietz syndrome associated with an aortic root aneurysm. Ann R Coll Surg Engl. 2017;99(3):e114-e115. doi:10.1308/rcsann.2017.0018