Links to Resources on rare Genetic Heritable Connective Tissue Disorders that present with Scoliosis (spinal deformities) and are at risk for Cardiovascular complications :

Added: March 3. 2026, Revised: March 15, April 2, 2026

It is critically important for Health Care Providers and parents to recognize that children and young adult patients who may first present clinically with scoliosis and/or kyphosis (or extremely rare Kyphoscoliosis ) and often have the feature (pees planus) flat feet and present with additional features/signs (see below) that indicate the following rare genetic/heritable connective tissue disorders, Marfan syndrome (MFS), Loeys-Dietz Syndrome (LDS) (more agressive cardiovascular then MFS ) and some subtypes (esp Kyphoscoliotic EDS (kEDS) & vascular EDS (vEDS)) of Ehlers Danlos Syndrome (EDS) — are at high risk for serious cardiovascular complications especially affecting the aorta, the largest artery in the body attached to the heart and can lead to life-threatening aortic aneurysm (widening/dilitation) and dissection (rupture/tear) causing premature (sudden) death. As well Pregnancy ^{7 9} in MFS, LDS and vEDS carries the high risk of aortic dissection. These life-long genetic connective tissue disorders are characterized by one or more gene mutations that weakens connective tissue which can affect the heart and vascular (blood vessels called arteries) tissues among many other parts of the body and can be profoundly physically challenging. Symptoms can vary from mild to severe with variations of features. Patients require complex medical care from multi-disciplinary health professionals. This group of disorders with their shared cardiovascular risks are referred/classified in medical literature (cardiology) most often as Heritable Thoracic Aortic Diseases (HTAD) and also as Genetic Aortic Disorders (GADs), Syndromic Aortic Diseases (SAD), Heritable Aortic Diseases and Genetic Aortopathy. Early diagnosis is critically important with (referral to a specialist cardiologist or aortic clinic) a cardiac examination/assessment that includes an echo-cardiogram and vascular scans. Referral to a medical geneticist (molecular genetic testing) is important to determine course of treatment and management and more.

Please watch Family of woman who died after undiagnosed Marfan syndrome speaks out   CTV News, Toronto News, Jan 7, 2026 and read/sign the Ontario family's Federal Petition advocating screening for rare diseases.


TRUSTED RESOURCES:

MARFAN SYNDROME (MFS):   

Overview of Marfan Syndrome from the National Institute of Arthritis and Musculoskeletal and Skin Diseases

What are the Signs of Marfan Syndrome? Knowing the signs of Marfan syndrome can save lives.   from

(US) Marfan Foundation

The Marfan Foundation drives research, education and support – and builds community – to improve outcomes, save lives and empower all people to thrive who are living with Marfan, Loeys-Dietz, Vascular Ehlers-Danlos syndromes, and related genetic aortic and vascular conditions.

***The Genetic Aortic Disorders Association of Canada (GADA) ***

"GADA is a registered patient advocacy organization, promoting research-based awareness, education and support to patients with genetic aortic disorders." Formally called the Canadian Marfan Association (CMA) established in 1986, CMA recognized the growing list of genetic aortic disorders being identified in the 2000's, all sharing the increased risk of aortic aneurysm and dissection. Hence, in 2015 they broadened and renamed their organization the Genetic Aortic Disorders Association of Canada (GADA). "GADA will continue with our founder’s mission; we remain dedicated to saving lives and enabling a promising future for individuals living with Marfan syndrome and other genetic aortic disorders through education, awareness, support and research." Promotes and supports key research initiatives. Extensive online resources including educational videos/webinars on their youtube channel and research publications from the Montalcino Aortic Consortium which they are critically intertwined with.

LOEYS-DIETZ SYNDROME (LDS):

Signs and Symptoms of Loeys-Dietz Syndrome  from

*** The Loeys Dietz Foundation Canada ***

"The Loeys-Dietz Syndrome Foundation Canada (LDSFC) founded in 2011 by 3 Canadian families, is a national charitable organization dedicated to the promotion of research, awareness, education, and support for those affected by Loeys-Dietz syndrome (LDS) and related heritable aortic disorders... The Foundation’s impact spans across areas of research, awareness and education, and support for patients and families."

If you are affected by Loeys-Dietz syndrome, you can contact us at 1 888 LDS-FCAN.

Website provides resources for Clinicians and Medical Professionals. "Loeys-Dietz syndrome (LDS) is a genetic connective tissue disorder with multisystem involvement and variability in the type and severity of manifestations. It is best monitored and treated by a multidisciplinary team."

EHLERS DANLOS SYNDROME (EDS):

What is EDS?  from global

*** Ehlers Danlos Society ***
Includes information on What is HSD?   Hypermobility spectrum disorders (HSD) are connective tissue disorders that cause joint hypermobility, instability, injury, and pain. Other problems such as fatigue, headaches, GI problems, and autonomic dysfunction are often seen as part of HSD.

What are the signs of Vascular Ehlers-Danlos syndrome, or VEDS?  from
(US) The VEDS Movement  

What are the " 13 types of EDS, the major and minor diagnostic criteria, genetic markers, prevalence, symptoms, and other useful information to help educate doctors, patients, loved ones, and others."  :from the

Ehlers-Danlos Syndrome Foundation Canada  

"What We Do:   EDS Canada Foundation is a CRA registered charity, operating under The ILC Charitable Foundation, serves the Canadian Ehlers-Danlos Syndromes (EDS) and chronic pain community. We are the national advocate for those affected by this hereditary and complex disease. Established in 2010, we have worked collaboratively with regional and international organizations to bring health care research, education and clinical care together to ensure those affected by EDS have access to the latest advances in care." See What We Support   and   EDS Canada Foundation Publications & Position Statements

WHERE TO FIND HELP IN CANADA:

PLEASE READ/REFER to: Diagnosis and Management of Heritable Aortic Disease HTAD

from the Genetic Aortic Disorders Association (GADA) Canada

and where to find Aortic Clinics across Canada

and also refer below to (more extensive listings that includes genetic clinics):

Find a Clinic from the

The Loeys Dietz Foundation Canada

Links to Publications for Health Care Providers:

The following is a brief curated list of links to peer-reviewed publications: (Refer first and foremost to resources listed above.)

Genetic/Heritable Thoracic Aortic Disease:

1. Melanie Care, MSca,b ∙ Laura Arbour, MDc,d ∙ Liam R. Brunham, MD, PhDc,e,f ∙ Susan Christian, MSc, PhDg ∙ Johannie Gagnon, MSch ∙ Robert A. Hegele, MDi,j ∙ Rebekah Jobling, MDk,l,m ∙ Gavin Y. Oudit, MD, PhDn,o ∙ Thomas M. Roston, MD, PhDp,q ∙ Laura Zahavich, MScb,r,s ∙ Zachary Laksman, MD, MSc, Canadian Cardiovascular Society Clinical Practice Update on Cardiogenetic Testing Canadian Journal of Cardiology, Volume 41, Issue 12 p2312-2333, December 2025 "Abstract This Canadian Cardiovascular Society clinical practice update provides essential guidance on integrating genetic testing into clinical care for inherited cardiovascular conditions, including primary arrhythmias, cardiomyopathies, aortopathies, familial hypercholesterolemia, and congenital heart diseases. Genetic testing for these conditions is crucial for early detection, risk stratification, and management, and significantly influences patient and family outcomes, particularly regarding sudden cardiac death risk. Historically managed within specialized genetics or cardiology clinics, growing demand and limited resources necessitate evolving care pathways for broader integration into general practice. This update outlines foundational steps such as establishing regional cardiogenetic expertise networks, enhancing genetics literacy among providers, and clarifying genetic testing indications and methodologies. It critically examines various clinical care models—traditional medical genetics clinics, multidisciplinary specialty clinics, mainstreaming approaches, and hub-and-spoke models—highlighting their strengths and barriers within the Canadian health care context. Key implementation challenges, including variant interpretation, secondary findings, informed consent complexities, and cascade testing barriers are addressed with practical recommendations for clinicians, genetic counsellors, and health care systems. Furthermore, this document emphasizes strategic planning to effectively manage increasing cardiogenetic testing demands, advocates for increased professional training, equitable resource allocation, national standardization, and policy frameworks...."
2. Elendu, Chukwuka BSc, MDa,*; Nzeako, Tochukwu R. MDb; Nwachukwu, Nwachukwu O. MBBSc; Akpa, Kenneth N. MBBSd; Omiko, Raymond A. MBBSe; Ayobami-Ojo, Petra S. MBBSf; Orji, Uguru W. MBBSg; Nwankwo, Vivian C. MBBSh; Amaefule, Kingsley C. BSc, MBBS, MPHi; Chima, Chiamaka S. MBBSj; Chika, Nwafor W. MBBSj; Olukorode, John O. MBBSj; Oloyede, Praise O. MBBSj; Falade, David M. MBBSj; Fayemi, Temiloluwa E. MBBSc; Ezeamaku-Humphrey, Chisom P. MSck; Vansh, Roshni R. MBBSl; Enaholo, Tobechukwu M.O. MBBSm; Anukam, Lordsfavour I. BSc, MScn; Chukwuneke, Osita M. MBBS, MPHo. Genetic factors and management strategies in aortic health: a literature review of inherited aortopathy. Annals of Medicine & Surgery 87(2):p 598-615, February 2025. | DOI: 10.1097/MS9.0000000000002969 "Abstract Inherited aortopathies, including Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome, are genetic disorders characterized by structural abnormalities of the aorta that predispose individuals to life-threatening complications like aneurysms and dissections. These conditions result from mutations in genes essential for maintaining aortic wall integrity, such as FBN1, TGFBR1, and COL3A1, affecting extracellular matrix components and the transforming growth factor-beta (TGF-β) pathway. Marfan syndrome has a prevalence of approximately 1 in 5000, while Loeys-Dietz syndrome and vascular Ehlers-Danlos syndrome are rarer, with estimated prevalences of 1 in 100 000 and 1 in 20 000, respectively. Familial thoracic aortic aneurysms and dissections (FTAAD), linked to mutations in genes like ACTA2 and MYH11, highlight the genetic heterogeneity of aortopathies. Management strategies focus on early diagnosis, risk stratification, regular imaging, lifestyle modifications, and timely surgical intervention. Advances in genetic testing and targeted therapies offer promise for personalized care...."
3. Asta L, D'Angelo GA, Marinelli D, Benedetto U. Genetic Basis, New Diagnostic Approaches, and Updated Therapeutic Strategies of the Syndromic Aortic Diseases: Marfan, Loeys-Dietz, and Vascular Ehlers-Danlos Syndrome. Int J Environ Res Public Health. 2023 Aug 20;20(16):6615. doi: 10.3390/ijerph20166615. PMID: 37623198; PMCID: PMC10454608."Abstract: Syndromic aortic diseases (SADs) encompass various pathological manifestations affecting the aorta caused by known genetic factors, such as aneurysms, dissections, and ruptures. However, the genetic mutation underlying aortic pathology also gives rise to clinical manifestations affecting other vessels and systems. As a consequence, the main syndromes currently identified as Marfan, Loeys–Dietz, and vascular Ehlers–Danlos are characterized by a complex clinical picture. In this contribution, we provide an overview of the genetic mutations currently identified in order to have a better understanding of the pathogenic mechanisms. Moreover, an update is presented on the basis of the most recent diagnostic criteria, which enable an early diagnosis. Finally, therapeutic strategies are proposed with the goal of improving the rates of patient survival and the quality of life of those affected by these SADs...."
4. Caruana M, Baars MJ, Bashiardes E, Benke K, Björck E, Codreanu A, de Moya Rubio E, Dumfarth J, Evangelista A, Groenink M, Kallenbach K, Kempers M, Keravnou A, Loeys B, Muiño-Mosquera L, Nagy E, Milleron O, Nistri S, Pepe G, Roos-Hesselink J, Szabolcs Z, Teixidó-Tura G, Timmermans J, Van de Laar I, van Kimmenade R, Verstraeten A, Von Kodolitsch Y, De Backer J, Jondeau G. HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN. Eur J Med Genet. 2023 Jan;66(1):104673. doi: 10.1016/j.ejmg.2022.104673. Epub 2022 Nov 29. PMID: 36460281. "Abstract Heritable thoracic aortic diseases (HTAD) are rare pathologies associated with thoracic aortic aneurysms and dissection, which can be syndromic or non-syndromic. They may result from genetic defects. Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism. Timely diagnosis allows for prompt aortic surveillance and prophylactic surgery, hence improving life expectancy and reducing maternal complications as well as providing reassurance to family members when a diagnosis is ruled out. This document is an expert opinion reflecting strategies put forward by medical experts and patient representatives involved in the HTAD Rare Disease Working Group of VASCERN. It aims to provide a patient pathway that improves patient care by diminishing time to diagnosis, facilitating the establishment of a correct diagnosis using molecular genetics when possible, excluding the diagnosis in unaffected persons through appropriate family screening and avoiding overuse of resources. It is being recommended that patients are referred to an expert centre for further evaluation if they meet at least one of the following criteria: (1) thoracic aortic dissection (<70 years if hypertensive; all ages if non-hypertensive), (2) thoracic aortic aneurysm (all adults with Z score >3.5 or 2.5–3.5 if non-hypertensive or hypertensive and <60 years; all children with Z score >3), (3) family history of HTAD with/without a pathogenic variant in a gene linked to HTAD, (4) ectopia lentis without other obvious explanation and (5) a systemic score of >5 in adults and >3 in children. Aortic imaging primarily relies on transthoracic echocardiography with magnetic resonance imaging or computed tomography as needed. Genetic testing should be considered in those with a high suspicion of underlying genetic aortopathy. Though panels vary among centers, for patients with thoracic aortic aneurysm or dissection or systemic features these should include genes with a definitive or strong association to HTAD. Genetic cascade screening and serial aortic imaging should be considered for family screening and follow-up. In conclusion, the implementation of these strategies should help standardise the diagnostic work-up and follow-up of patients with suspected HTAD and the screening of their relatives..."
5. Regalado ES, Morris SA, Braverman AC, Hostetler EM, De Backer J, Li R, Pyeritz RE, Yetman AT, Cervi E, Shalhub S, Jeremy R, LeMaire S, Ouzounian M, Evangelista A, Boileau C, Jondeau G, Milewicz DM. Comparative Risks of Initial Aortic Events Associated With Genetic Thoracic Aortic Disease. J Am Coll Cardiol. 2022 Aug 30;80(9):857-869. doi: 10.1016/j.jacc.2022.05.054. PMID: 36007983."...This 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....As thoracic aortic aneurysms progressively enlarge, the risk for life-threatening type A aortic dissections increases. These dissections are preventable if at-risk individuals are identified early and aneurysms surgically repaired in a timely manner.1,2 Less deadly type B aortic dissections are also part of the thoracic aortic disease spectrum, but typically occur with little or no prior enlargement.3 Pathogenic variants in both FBN1 and the genes encoding proteins involved in the canonical transforming growth factor (TGF)-β signaling pathway predispose to highly penetrant thoracic aortic disease in patients with Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS), respectively.4-8 Importantly, up to 20% of patients with thoracic aortic disease, but without syndromic features, have a family history of the disease.9...TGFBR1 and TGFBR2 groups have the highest burden of childhood-onset aortic events...."
6. Fusco A, Mauriello A, Lioncino M, Palmiero G, Fratta F, Granato C, Cirillo A, Caiazza M, Monda E, Credendino A, Signore G, Natale F, Chiosi F, Scarano G, Della Corte A, Nistri S, Russo MG, Limongelli G, Pepe G. The Heart Muscle and Valve Involvement in Marfan Syndrome, Loeys-Dietz Syndromes, and Collagenopathies. Heart Fail Clin. 2022 Jan;18(1):165-175. doi: 10.1016/j.hfc.2021.07.007. Epub 2021 Oct 25. PMID: 34776077.
   "Key Points:
   • Thoracic aortic syndromes are hereditary diseases that directly or indirectly affect the genesis of various organs mostly after a mutation of the TGF-β pathway.
   • Cardiac involvement is typical of several inherited connective tissue disorders including Marfan syndrome, vascular Ehlers-Danlos syndrome, and Loeys-Dietz syndromes.
   • The main cardiovascular anomalies involve the mitral and aortic valves as well as the aorta.
   Clinics care points:
   • The characterizing manifestations of MFS involve cardiovascular, ocular, and systemic features (SF).
   • Almost 50% of LDS patients present thoracic aneurysm previously undetectable by echocardiography and abdominal arterial aneurysms and/or dissections tortuosity affecting cerebral and sovra-aortic vessels.
   • LDS type1/TGFBR1 and LDS type2/TGFBR2 can usually be distinguished from MFS by the unique presence of hypertelorism (widely spaced eyes), bifid uvula, and/or cleft palate."
   
   
7. 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 Nov;6(6):582-594. doi: 10.21037/acs.2017.11.03. PMID: 29270370; PMCID: PMC5721110."Abstract:...MFS is typically characterized by cardiovascular, ocular, and skeletal manifestations and is caused by heterozygous mutations in FBN1, 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 TGBR1/2, SMAD2/3, or TGFB2/3, 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...A higher incidence of pregnancy-related complications, particularly aortic dissection, has been described in patients with MFS (20). However, in LDS the incidence is even higher. The increased risk is related to a combination of hemodynamic changes, hormonal influences, and the change of elastic fiber organization during pregnancy (19)...."
8. Takeda N, Komuro I. Genetic basis of hereditary thoracic aortic aneurysms and dissections. J Cardiol. 2019 Aug;74(2):136-143. doi: 10.1016/j.jjcc.2019.03.014. Epub 2019 Apr 15. PMID: 31000321. "Introduction: Improved technology and decreased costs for DNA sequencing have identified the predisposition genes in hereditary thoracic aortic aneurysm and dissection (HTAAD), including those associated with Marfan syndrome (MFS), Loeys–Dietz syndrome (LDS), vascular Ehlers–Danlos syndrome (vEDS), and familial non-syndromic TAAD, and such genetic tests to guide precision medicine have been covered by health insurance in Japan since 2016...."
9. Wanga S, Silversides C, Dore A, de Waard V, Mulder B. Pregnancy and Thoracic Aortic Disease: Managing the Risks. Can J Cardiol. 2016 Jan;32(1):78-85. doi: 10.1016/j.cjca.2015.09.003. Epub 2015 Sep 18. PMID: 26604124."Abstract The most common aortopathies in women of childbearing age are bicuspid aortic valve, coarctation of the aorta, Marfan syndrome, Ehlers-Danlos syndrome, Loeys-Dietz syndrome, SMAD3 aortopathy, Turner syndrome, and familial thoracic aneurysm and dissection. The hemodynamic and hormonal changes of pregnancy increase the risk of progressive dilatation or dissection of the aorta in these women. The presence of hypertension increases the risk further. Therefore, appropriate preconception counselling is advised. For women who become pregnant, serial follow-up by a specialized multidisciplinary team throughout pregnancy and postpartum period is required. In this review we discuss risk assessment and management strategies for women with aortopathies...."
10. Warnink-Kavelaars J, de Koning LE, Rombaut L, Alsem MW, Menke LA, Oosterlaan J, Buizer AI, Engelbert RHH, On Behalf Of The Pediatric Heritable Connective Tissue Disorders Study Group. Heritable Connective Tissue Disorders in Childhood: Increased Fatigue, Pain, Disability and Decreased General Health. Genes (Basel). 2021 May 28;12(6):831. doi: 10.3390/genes12060831. PMID: 34071423; PMCID: PMC8229209.
    
    
    MARFAN SYNDROME:
    
    
11. Accord RE, Koster C, Dulfer E, du Marchie Sarvaas GJ, Maass SWMC, Berger RMF, van den Berg MP. Diagnostic yield and therapeutic implications of 25 years of specialized pediatric Marfan clinic. Eur J Pediatr. 2024 Nov 18;184(1):25. doi: 10.1007/s00431-024-05857-0. PMID: 39557716. "Abstract The purpose of this study is to evaluate the diagnostic and therapeutic yield of a specialized clinic for children with suspicion of a hereditary thoracic aortic disease (HTAD), including Marfan Syndrome (MFS), and to investigate the diagnostic value of presenting symptoms and findings during evaluation. This retrospective observational study included all patients younger than 18 years old at initial referral between 1998 and 2018....Younger age at referral, ectopia lentis, aortic dilatation, and facial features were among the strongest predictors of MFS and other HTAD, while pectus excavatum and arm span-height ratio had no predictive value at childhood age. Of patients with MFS, 65% received antihypertensive medication, and 8% of patients with HTAD underwent prophylactic aortic surgery, in some cases even during childhood. Conclusion: Evaluation of children for HTAD in our specialized Marfan clinic resulted in a high diagnostic yield and subsequent therapeutic implications. Indeed, early recognition of symptoms and signs and referral to such a specialized clinic may lead to early diagnosis, surveillance, and timely treatment, thereby possibly limiting acute aortic events and even mortality..."
12. Dietz H. FBN1-Related Marfan Syndrome. 2001 Apr 18 [updated 2022 Feb 17]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 20301510."Summary Clinical characteristics. FBN1-related Marfan syndrome (Marfan syndrome), a systemic disorder of connective tissue with a high degree of clinical variability, comprises a broad phenotypic continuum ranging from mild (features of Marfan syndrome in one or a few systems) to severe and rapidly progressive neonatal multiorgan disease. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. Ocular findings include myopia (>50% of affected individuals); ectopia lentis (seen in approximately 60% of affected individuals); and an increased risk for retinal detachment, glaucoma, and early cataracts. Skeletal system manifestations include bone overgrowth and joint laxity; disproportionately long extremities for the size of the trunk (dolichostenomelia); overgrowth of the ribs that can push the sternum in (pectus excavatum) or out (pectus carinatum); and scoliosis that ranges from mild to severe and progressive. The major morbidity and early mortality in Marfan syndrome relate to the cardiovascular system and include dilatation of the aorta at the level of the sinuses of Valsalva (predisposing to aortic tear and rupture), mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery. Severe and prolonged regurgitation of the mitral and/or aortic valve can predispose to left ventricular dysfunction and occasionally heart failure. With proper management, the life expectancy of someone with Marfan syndrome approximates that of the general population...."
13. Al-Thani H, Mekkodathil A, El-Menyar A. Management and Outcomes of Aortic Dissection in Pregnancy with Marfan Syndrome: A Systematic Review. Curr Vasc Pharmacol. 2020;18(3):282-293. doi: 10.2174/1570161117666190408164612. PMID: 30963974. "...Conclusion: Women with MFS are at high risk of aortic dissection during pregnancy and women with aortic root 41-45 mm should consider avoiding pregnancy. Guideline-specific management of aortic aneurysms in pregnancy will reduce the risk of dissection. Diagnosis and Management of MFS need a multidisciplinary approach and team that should start working early in pregnancy. Further studies are needed to optimize medical and surgical approaches in addition to preconception counselling in highrisk subjects."
14. Cha, Myung-Jin BSA; ElNemer, William BS; Sponseller, Paul D. MD, MBA. Surgically Relevant Anatomy of Marfan Vertebrae. Journal of Pediatric Orthopaedics 45(7):p 445-450, August 2025. | DOI: 10.1097/BPO.0000000000002968 "... In this study, we explored Marfan vertebrae morphology and compared it to that of idiopathic scoliotic vertebrae. We investigated whether the pedicles and laminae of patients with Marfan syndrome (1) would differ from those with idiopathic scoliosis (IS) and (2) would be affected by the position in the curve and by dural ectasia....Results: Marfan pedicle channels were significantly thinner than those with idiopathic scoliosis (P<0.001). This difference increased significantly from cranial to caudal...Pedicles became progressively thinner than IS pedicles at descending levels of the spine...The average thickness of the Marfan lamina was significantly thinner (by a mean of 1 mm) than that of the IS lamina (P<0.001). Marfan patients with dural ectasia had significantly thinner laminae in the lumbar spine than those without (P=0.023).
    Conclusions: Marfan spines were associated with thinning of fixation sites, most pronounced at the curve apex. Laminar thinning was more common on the concavity and with dural ectasia. Radiographs often overestimate the width. Therefore, preoperative MRI or CT is helpful when operating on Marfan spine with pedicle screws and laminar."
15. Andersen NH, Hauge EM, Baad-Hansen T, Groth KA, Berglund A, Gravholt CH, Stochholm K. Musculoskeletal diseases in Marfan syndrome: a nationwide registry study. Orphanet J Rare Dis. 2022 Mar 5;17(1):118. doi: 10.1186/s13023-022 02272-2. PMID: 35248143; PMCID: PMC8898450.
16. Taniguchi Y, Takeda N, Inuzuka R, Matsubayashi Y, Kato S, Doi T, Yagi H, Yamauchi H, Ando M, Oshima Y, Tanaka S. Impact of pathogenic FBN1 variant types on the development of severe scoliosis in patients with Marfan syndrome. J Med Genet. 2023 Jan;60(1):74-80. doi: 10.1136/jmedgenet-2021-108186. Epub 2021 Dec 16. PMID: 34916231; PMCID: PMC9811093. "...Conclusions: We elucidated the genetic risk factors for the development of severe scoliosis in patients with Marfan syndrome. Patients harbouring pathogenic FBN1 variants with these genetic risk factors should be monitored carefully for scoliosis progression."
17. Rava A, Dema E, Palmisani M, Palmisani R, Cervellati S, Girardo M. Sublaminar fixation versus hooks and pedicle screws in scoliosis surgery for Marfan syndrome. J Craniovertebr Junction Spine. 2020 Jan-Mar;11(1):26-30. doi: 10.4103/jcvjs.JCVJS_12_20. Epub 2020 Apr 4. PMID: 32549709; PMCID: PMC7274359.
18. Palmisani M, Dema E, Rava A, Palmisani R, Girardo M, Cervellati S. Surgical treatment of spinal deformities in Marfan syndrome: Long-term follow-up results using different instrumentations. J Craniovertebr Junction Spine. 2019 Jul-Sep;10(3):172-178. doi: 10.4103/jcvjs.JCVJS_68_19. PMID: 31772430; PMCID: PMC6868540.
19. Sponseller PD, Bhimani M, Solacoff D, Dormans JP. Results of brace treatment of scoliosis in Marfan syndrome. Spine (Phila Pa 1976). 2000 Sep 15;25(18):2350-4. doi: 10.1097/00007632-200009150-00013. PMID: 10984787. "...Conclusions: The success rate for brace treatment of Marfan scoliosis is 17%, which is lower than that reported for idiopathic scoliosis. Possible reasons include increased progressive forces, altered transmission of corrective pressure to the spine, and younger age at inception of bracing. Because there was no control group, it is unknown whether bracing slowed curve progression. Physicians should understand that most patients with Marfan syndrome who have a curve of more than 25 degrees and a Risser sign of 2 or less will reach the surgical range, even with brace treatment...."
    
    
    LOEYS-DIETZ SYNDROME:
    
    
20. Loeys BL, Dietz HC. Loeys-Dietz Syndrome. 2008 Feb 28 [Updated 2024 Sep 12]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1133/ " ...Clinical characteristics. Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, and cervical spine malformation and/or instability), craniofacial features (hypertelorism, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant....Management...Important considerations when managing cardiovascular features of LDS include the following: aortic dissection can occur at smaller aortic diameters and at younger ages than observed in Marfan syndrome; vascular disease is not limited to the aortic root; angiotensin receptor blockers, beta-adrenergic receptor blockers, or other medications are used to reduce hemodynamic stress; and aneurysms are amenable to early and aggressive surgical intervention. Consider subacute bacterial endocarditis prophylaxis in those undergoing dental work or other procedures expected to contaminate the bloodstream with bacteria..."
21. MacCarrick G, Black JH 3rd, Bowdin S, El-Hamamsy I, Frischmeyer-Guerrerio PA, Guerrerio AL, Sponseller PD, Loeys B, Dietz HC 3rd. Loeys-Dietz syndrome: a primer for diagnosis and management. Genet Med. 2014 Aug;16(8):576-87. doi: 10.1038/gim.2014.11. Epub 2014 Feb 27. PMID: 24577266; PMCID: PMC4131122. "Abstract: Loeys–Dietz syndrome is a connective tissue disorder predisposing individuals to aortic and arterial aneurysms. Presenting with a wide spectrum of multisystem involvement, medical management for some individuals is complex...This narrative review will describe the classification of LDS, genetic etiologies, cardinal clinical manifestations, and best-evidence management recommendations for the panoply of serious sequelae associated with this syndrome."
22. Callewaert B, De Paepe A, Coucke P. Arterial Tortuosity Syndrome. 2014 Nov 13 [updated 2023 Feb 23]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 25392904.
23. Kirby DJ, Dietz HC, Sponseller PD. Spondylolisthesis is Common, Early, and Severe in Loeys-Dietz Syndrome. J Pediatr Orthop. 2018 Sep;38(8):e455-e461. doi: 10.1097/BPO.0000000000001203. PMID: 29889773. "...Conclusions: High-grade spondylolisthesis is common in LDS and usually associated with spondylolysis. Patients requiring surgery for spondylolisthesis present during childhood and do well after instrumented PSF. Interbody fusion and stabilization of S1 and S2 can prevent physeal deformation. LDS should be considered in patients with high-grade spondylolisthesis. Patients with LDS should be monitored for spondylolisthesis and spondylolysis starting when they are young."
24. LoPresti MA, Athukuri P, Khan AB, Prablek M, Patel R, Mayer R, Bauer DF, Gerow FT, Morris SA, Lam S, Ravindra V. Thoracolumbar Scoliosis in Pediatric Patients With Loeys-Dietz Syndrome: A Case Series. Cureus. 2023 Mar 19;15(3):e36372. doi: 10.7759/cureus.36372. PMID: 37090272; PMCID: PMC10113178. "...Conclusions Principles of adolescent idiopathic scoliosis management such as bracing for CA of 20-50° and surgery for CA of >50° can be applied to LDS patients with good outcomes. This augments our understanding of the treatment algorithm for pediatric patients with LDS."
25. Prablek MA, LoPresti M, Bertot B, Morris SA, Bauer D, Lam S, Ravindra V. Evaluation of cervical spine pathology in children with Loeys-Dietz syndrome. Surg Neurol Int. 2022 Mar 18;13:96. doi: 10.25259/SNI_48_2022. PMID: 35399906; PMCID: PMC8986760. "...CONCLUSION Patients with LDS are at risk for a myriad of spinal pathology, including cervical instability and basilar impression. We explored our experience with cervical spine instability evaluation in a pediatric cohort with LDS to identify the pathology diagnosed with screening to help inform and improve the role of screening in management in this group. We found that while screening was not universal, there was a 37.5% prevalence of cervical spine instability, presence of reduced cervical spine lordosis, and basilar impression in conjunction with other spinal abnormalities. We believe our results underscore the benefits of screening in these children, congruent with recommendations in the literature. Future studies may target more specific screening guideline improvements, including set intervals, and inform future treatment protocols."
26. Bressner JA, MacCarrick GL, Dietz HC, Sponseller PD. Management of Scoliosis in Patients With Loeys-Dietz Syndrome. J Pediatr Orthop. 2017 Dec;37(8):e492-e499. doi: 10.1097/BPO.0000000000000833. PMID: 27379784. "Abstract  Background: Loeys-Dietz syndrome (LDS) is a genetic connective tissue disorder. We sought to determine the incidence of scoliosis in patients with LDS, characterize the spectrum of spinal deformity, determine the results of bracing and surgery, and define surgical complications. Results: Eighty-eight of 141 (62%) patients with LDS had scoliosis, with main thoracic and thoracolumbar curves being most common. Fifteen patients were braced (mean age, 9±3 y) for a mean of 2.3 years. They had a mean postbracing curve progression of 12±21 degrees (5±9 deg./y). There were no significant differences in age, sex, curve type, or prebracing curve magnitude between successfully braced (n=4) and unsuccessfully braced (n=11) patients (P>0.05). Nine patients, (mean age, 12±3 y), underwent 24 surgical procedures (16 growing rod procedures, 8 fusions). Mean curve corrections were 61% for growing rods and 73% for fusions. Associated blood loss for these procedures was 400 mL and 1293 mL, respectively, and normalized blood loss for fusion was 2.34 mL/kg/level. Fifteen of 24 surgical procedures involved complications (63%), including cerebrospinal fluid leaks (n=7) and blood loss >20% of estimated total blood volume (n=11).
    Conclusions: Scoliosis was present in 62% of our sample of LDS patients. Bracing did not halt curves in 11 of 15 patients, whose curves progressed >5 degrees or to >50 degrees by completion of bracing. At latest follow-up, 47% of the braced patients had undergone surgery after prior bracing attempts. The high blood loss associated with these operations is believed to be related to vascular fragility in patients with LDS.... " Methods: Patients were selected from our institution’s database of 183 patients with LDS.
27. Farshad M, Winkler E, Betz M. Anterior Surgical Treatment of Scoliosis in a Patient With Loeys-Dietz Syndrome. J Am Acad Orthop Surg Glob Res Rev. 2017 Oct 17;1(7):e039. doi: 10.5435/JAAOSGlobal-D-17-00039. PMID: 30211363; PMCID: PMC6132299.
28. Fuhrhop SK, McElroy MJ, Dietz HC 3rd, MacCarrick GL, Sponseller PD. High prevalence of cervical deformity and instability requires surveillance in Loeys-Dietz syndrome. J Bone Joint Surg Am. 2015 Mar 4;97(5):411-9. doi: 10.2106/JBJS.N.00680. PMID: 25740032; PMCID: PMC4344594."Abstract:...Loeys-Dietz syndrome is a connective tissue disorder characterized by vascular, craniofacial, and musculoskeletal malformation. Our goal was to report the manifestations, surgical treatment, and complications in the cervical spine in patients with Loeys-Dietz syndrome.
    Methods: We reviewed the clinical and cervical spine imaging data of eighty patients with Loeys-Dietz syndrome who were seen at our institution from January 2005 through January 2014. Their mean age at presentation was 17.3 years (range, three months to seventy-five years)...Results: Vertebral anomalies and cervical instability were common; we found no significant association of TGF-βR-type with cervical abnormalities or age at presentation. Twenty-eight patients had atlas defects (anterior and/or posterior arch defects or hypoplasia), fifty-three had axis malformations (elongation, apex-anterior dens angulation, or spondylolysis), and twelve had focal kyphosis. Ten patients had hypoplastic subaxial vertebrae, leading to focal kyphosis (eight) and subaxial instability (nine). Eight patients had atlantoaxial instability. Of the thirteen patients with cervical instability, nine were treated surgically: fusion (eight patients) and halo application (one) (mean age, four years; range, three months to twelve years). Postoperative complications (seven patients) were pseudarthrosis, failure of fixation, junctional kyphosis or instability, and development of occipital-cervical instability.
    Conclusions: Cervical midline defects (most often C1-C3) are common in Loeys-Dietz syndrome. Patients have a high prevalence of cervical instability, particularly a pattern of instability at C2-C3 associated with C3 vertebral body hypoplasia and C2-C3 focal kyphosis. Patients requiring surgery typically present in early childhood. "
    
    
    EHLERS-DANLOS SYNDROME:
    
    
29. "The genetic cause(s) of hEDS have not yet been identified, so there is currently no genetic test available to diagnose hEDS. The diagnosis of hEDS is given to those who meet the Clinical Diagnostic criteria for hEDS ". from the Ehlers Danlos Society.
30. Doolan BJ, Lavallee ME, Hausser I, Schubart JR, Michael Pope F, Seneviratne SL, Winship IM, Burrows NP. Extracutaneous features and complications of the Ehlers-Danlos syndromes: A systematic review. Front Med (Lausanne). 2023 Jan 23;10:1053466. doi: 10.3389/fmed.2023.1053466. PMID: 36756177; PMCID: PMC9899794."Abstract: Introduction   The Ehlers-Danlos syndromes (EDS) comprise a group of inherited connective tissue disorders presenting with variable fragility to skin, soft tissue, and certain internal organs, which can cause significant complications, particularly arterial rupture, bowel perforation and joint difficulties. Currently, there are 14 proposed subtypes of EDS, with all except one subtype (hypermobile EDS) having an identified genetic etiology. An understanding of the extracutaneous features and complications within each subtype is key to maximizing clinical care and reducing the risk of further complications....Methods A systematic review of EDS-related extracutaneous features and complications was undertaken. Results We identified 839 EDS cases that met the inclusion criteria. We noted a high prevalence of joint hypermobility amongst kyphoscoliotic (39/39, 100%), spondylodysplastic (24/25, 96.0%), and hypermobile (153/160, 95.6%) EDS subtypes. The most common musculoskeletal complications were decreased bone density (39/43, 90.7%), joint pain (217/270, 80.4%), and hypotonia/weakness (79/140, 56.4%). Vascular EDS presented with cerebrovascular events (25/153, 16.3%), aneurysm (77/245, 31.4%), arterial dissection/rupture (89/250, 35.5%), and pneumothorax/hemothorax. Chronic pain was the most common miscellaneous complication, disproportionately affecting hypermobile EDS patients (139/157, 88.5%). Hypermobile EDS cases also presented with chronic fatigue (61/63, 96.8%) and gastrointestinal complications (57/63, 90.5%). Neuropsychiatric complications were noted in almost all subtypes...."
31. Rashed ER, Ruiz Maya T, Black J, Fettig V, Kadian-Dodov D, Olin JW, Mehta L, Gelb BD, Kontorovich AR. Cardiovascular manifestations of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders. Vasc Med. 2022 Jun;27(3):283-289. doi: 10.1177/1358863X211067566. Epub 2022 Jan 10. PMID: 35000503; PMCID: PMC9677229."...We performed a retrospective review of 258 patients (> 94% adults) referred to a multidisciplinary clinic for evaluation of joint hypermobility between January 2017 and December 2020 and diagnosed with hEDS or a hypermobility spectrum disorder (HSD) to determine the incidence and spectrum of cardiovascular involvement. Results: Mitral valve prolapse was present in 7.5% and thoracic aortic dilatation in 15.2%. Aortic dilatation was more frequent in individuals with hEDS (20.7%) than with HSD (7.7%) and similarly prevalent between males and females, although was mild in > 90% of females and moderate-to-severe in 50% of males. Five individuals (1.9%) with hEDS/HSD had extra-aortic arterial involvement, including cervical artery dissection (CeAD, n = 2), spontaneous coronary artery dissection (SCAD, n = 2), and SCAD plus celiac artery pseudoaneurysm (n = 1). This is the first series to report the prevalence of CeAD and SCAD in hEDS/HSD. Conclusion Cardiovascular manifestations are present in up to 15% of subjects with hEDS and HSD and mainly include mild aortic dilatation and mild MVP. We report, for the first time, that SCAD and CeAD occur, respectively, in 1.8% and 0.7% of patients with hEDS/HSD. Until the natural history of aortic dilatation is fully elucidated, a baseline echocardiographic study in adults under evaluation for hEDS is reasonable and those for whom dilatation is noted should have ongoing surveillance. Patients with extra-thoracic arteriopathy and joint hypermobility should be screened for hEDS/HSD, as these underlying diagnoses are likely under-recognized. "
32. Malek S, Köster DV. The Role of Cell Adhesion and Cytoskeleton Dynamics in the Pathogenesis of the Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders. Front Cell Dev Biol. 2021 Apr 21;9:649082. doi: 10.3389/fcell.2021.649082. PMID: 33968931; PMCID: PMC8097055."Abstract:...This review departs from the traditional view of EDS/HSD, where pathogenesis is mediated by the structurally defective ECM. Instead, we propose EDS/HSD may be a disorder of membrane-bound collagen, and consider how aberrations in cell adhesion and cytoskeleton dynamics could drive the abnormal properties of the connective tissue, and be responsible for the pathogenesis of EDS/HSD...."
33. Gensemer C, Burks R, Kautz S, Judge DP, Lavallee M, Norris RA. Hypermobile Ehlers-Danlos syndromes: Complex phenotypes, challenging diagnoses, and poorly understood causes. Dev Dyn. 2021 Mar;250(3):318-344. doi: 10.1002/dvdy.220. Epub 2020 Aug 17. PMID: 32629534; PMCID: PMC7785693.
34. Ritelli M, Colombi M. Molecular Genetics and Pathogenesis of Ehlers-Danlos Syndrome and Related Connective Tissue Disorders. Genes (Basel). 2020 May 13;11(5):547. doi: 10.3390/genes11050547. PMID: 32414079; PMCID: PMC7288446.
35. Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP, Castori M, Cohen H, Colombi M, Demirdas S, De Backer J, De Paepe A, Fournel-Gigleux S, Frank M, Ghali N, Giunta C, Grahame R, Hakim A, Jeunemaitre X, Johnson D, Juul-Kristensen B, Kapferer-Seebacher I, Kazkaz H, Kosho T, Lavallee ME, Levy H, Mendoza-Londono R, Pepin M, Pope FM, Reinstein E, Robert L, Rohrbach M, Sanders L, Sobey GJ, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Wheeldon N, Zschocke J, Tinkle B. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017 Mar;175(1):8-26. doi: 10.1002/ajmg.c.31552. PMID: 28306229.
36. Shalhub S, Byers PH, Hicks KL, Coleman DM, Davis FM, De Caridi G, Weaver KN, Miller EM, Schermerhorn ML, Shean K, Oderich G, Ribeiro M, Nishikawa C, Charlton-Ouw K, Behrendt CA, Debus ES, von Kodolitsch Y, Zarkowsky D, Powell RJ, Pepin M, Milewicz DM, Regalado ES, Lawrence PF, Woo K. A multi-institutional experience in vascular Ehlers-Danlos syndrome diagnosis. J Vasc Surg. 2020 Jan;71(1):149-157. doi: 10.1016/j.jvs.2019.04.487. Epub 2019 Jul 26. PMID: 31353273; PMCID: PMC7245161."OBJECTIVE. Vascular Ehlers-Danlos syndrome (vEDS) is a rare disorder and one of 13 types of Ehlers-Danlos syndrome (EDS). The syndrome results in aortic and arterial aneurysms and dissections at a young age. Diagnosis is confirmed with molecular testing via skin biopsy or genetic testing for COL3A1 pathogenic variants. We describe a multi-institutional experience in the diagnosis of vEDS from 2000 to 2015...."
37. Brady AF, Demirdas S, Fournel-Gigleux S, Ghali N, Giunta C, Kapferer-Seebacher I, Kosho T, Mendoza-Londono R, Pope MF, Rohrbach M, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Zschocke J, Malfait F. The Ehlers-Danlos syndromes, rare types. Am J Med Genet C Semin Med Genet. 2017 Mar;175(1):70-115. doi: 10.1002/ajmg.c.31550. PMID: 28306225.
38. D'hondt S, Van Damme T, Malfait F. Vascular phenotypes in nonvascular subtypes of the Ehlers-Danlos syndrome: a systematic review. Genet Med. 2018 Jun;20(6):562-573. doi: 10.1038/gim.2017.138. Epub 2017 Oct 5. PMID: 28981071; PMCID: PMC5993673.
39. Wheeler SM, Russo M, Wilson-Murphy M, Shen W. Gynecologic and surgical complications in type IV Ehlers-Danlos syndrome. Obstet Gynecol. 2014 Feb;123(2 Pt 2 Suppl 2):431-433. doi: 10.1097/AOG.0000000000000001. PMID: 24413228; PMCID: PMC6596992.
40. Hakim A. Hypermobile Ehlers-Danlos Syndrome. 2004 Oct 22 [updated 2024 Feb 22]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 20301456.
41. Tofts LJ, Simmonds J, Schwartz SB, Richheimer RM, O'Connor C, Elias E, Engelbert R, Cleary K, Tinkle BT, Kline AD, Hakim AJ, van Rossum MAJ, Pacey V. Pediatric joint hypermobility: a diagnostic framework and narrative review. Orphanet J Rare Dis. 2023 May 4;18(1):104. doi: 10.1186/s13023-023-02717-2. PMID: 37143135; PMCID: PMC10157984. "...We propose that children should not be assessed with the 2017 criteria or diagnosed with hEDS until they have reached biological maturity, so a pediatric specific framework was developed. The diagnoses are fluid, allowing children with GJH to be reclassified over time as: typical if GJH resolves, asymptomatic GJH as symptoms improve, or pediatric generalized HSD (pgHSD) upon presentation of new signs and symptoms. An accurate pgHSD diagnosis provides the foundation for appropriate current treatment and support, but not a lifelong diagnosis which may result in over medicalization and potential harms. The framework supports identifying those with hypermobility as a physical trait, which is relatively common, those with musculoskeletal issues related to their hypermobility, and those who may develop the rarer hypermobile Ehlers–Danlos syndrome as they mature..."
42. Shere C, Clark EM. Systematic review of the association between isolated musculoskeletal hypermobility and adolescent idiopathic scoliosis. Arch Orthop Trauma Surg. 2023 Jun;143(6):3055-3076. doi: 10.1007/s00402-022-04508-z. Epub 2022 Jul 16. PMID: 35841409; PMCID: PMC10192177.
43. Giunta C, Rohrbach M, Fauth C, Baumann M. FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome. 2019 May 23. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 31132235.
44. Tinkle B, Castori M, Berglund B, Cohen H, Grahame R, Kazkaz H, Levy H. Hypermobile Ehlers-Danlos syndrome (a.k.a. Ehlers-Danlos syndrome Type III and Ehlers-Danlos syndrome hypermobility type): Clinical description and natural history. Am J Med Genet C Semin Med Genet. 2017 Mar;175(1):48-69. doi: 10.1002/ajmg.c.31538. Epub 2017 Feb 1. PMID: 28145611.
45. Stern CM, Pepin MJ, Stoler JM, Kramer DE, Spencer SA, Stein CJ. Musculoskeletal Conditions in a Pediatric Population with Ehlers-Danlos Syndrome. J Pediatr. 2017 Feb;181:261-266. doi: 10.1016/j.jpeds.2016.10.078. Epub 2016 Nov 28. PMID: 27908650. "...Conclusions: Many pediatric and adolescent patients with EDS experience joint pain, instability, and scoliosis, along with other musculoskeletal issues. Despite extensive workup, the etiology of pain may not be identified. Large numbers of office visits, imaging studies, treatment prescriptions, and specialist referrals indicate considerable use of medical resources and highlight a great need for injury prevention and additional study."
46. Engelbert RH, Juul-Kristensen B, Pacey V, de Wandele I, Smeenk S, Woinarosky N, Sabo S, Scheper MC, Russek L, Simmonds JV. The evidence-based rationale for physical therapy treatment of children, adolescents, and adults diagnosed with joint hypermobility syndrome/hypermobile Ehlers Danlos syndrome. Am J Med Genet C Semin Med Genet. 2017 Mar;175(1):158-167. doi: 10.1002/ajmg.c.31545. PMID: 28306230.