Connective Tissue Disorders Slides - January 17, 2023
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This document discusses several genetic connective tissue disorders including Ehlers Danlos syndromes, Marfan syndrome, Loeys-Dietz syndrome, Stickler syndrome, Shprintzen Goldberg syndrome, Cutis Laxa, and Osteogenesis Imperfecta. It highlights the importance of identifying these disorders to allow for timely detection of serious complications and management by multiple medical specialists. Connective tissues are the most abundant tissues in the body and connect, support, bind or separate other tissues. Identification of a connective tissue disorder through genetic diagnosis guides appropriate care.
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Connective Tissue Disorders Slides - January 17, 2023
- 1. Connective Tissue Disorders Jodi D. Hoffman, MD January 17, 2023 1
- 2. Objectives Increase awareness of the signs of genetic connective tissue disorders Address the most serious aspects of these CT disorders Identify patients with these disorders likely to benefit from genetic evaluation/diagnosis 2
- 3. Outline Ehlers Danlos syndromes • Classical • Hypermobile • Vascular Marfan syndrome Loeys-Dietz syndrome Stickler syndrome Shprintzen Goldberg Cutis Laxa Osteogenesis Imperfecta 3
- 4. Connective Tissues Most abundant tissue in body • Bones • Ligaments • Tendons • Vasculature Role • Connects, supports, binds, or separates other tissues or organs • “Cellular glue" gives tissues shape and strength http://www.mater.ie/media/media,8527,en.jpg 4
- 6. Ehlers-Danlos Syndromes (collagenopathies) • Heterogeneous group of CTDs – Hypermobility, skin hyperextensibility, tissue fragility • Combined prevalence ~1/5,000 6
- 7. Classic EDS: Major Diagnostic Criteria 1. Skin hyperextensibility & atrophic scarring Excessive skin elasticity at ventral aspect of forearm (>1.5cm) – Increases with age; can be present in children Scars are atrophic with "cigarette-paper” look – Wound healing is delayed 7
- 8. Classic EDS: Major Diagnostic Criteria http://www.physiopro.co.za/wp-content/uploads/2012/09/beighton-scale.png • Prepubertal children and adolescents > 6 • Men and women, post- puberty up to age 50 > 5 • Men and women older than 50 > 4 8 2. Joint Hypermobility according to the Beighton Scale
- 9. Beighton Scale Limitations Young children (especially age ≤5 years) tend to be very flexible* and are therefore difficult to assess. Women are, on average, more flexible than men. Older individuals tend to lose “flexibility”, and post-surgical or arthritic joints often have reduced range of motion. *Flexibility may be related to muscle laxity while hypermobility is related to joint laxity 9
- 10. or 3 Minor Criteria 1. Easy bruising 2. Soft, doughy skin 3. Skin fragility (or traumatic splitting) 4. Molluscoid pseudotumors-small fat herniations 5. Subcutaneous spheroids - calcified fat globules 6. Hernia (or history) 7. Epicanthal folds 8. Complications of joint hypermobility -sprains, subluxation, pain, flexible flatfoot 9. Family history of a first degree relative who meets criteria Cardiovascular: (rare) MVP, TVP, aortic root dilatation (6% at dx), and spontaneous rupture of large arteries. researchgate.net/figure /Cutaneous-and- articular-features-in- patients-with-cEDS-a-d- marked- skin_fig1_236183849 10
- 11. 1. Generalized joint hypermobility (GJH); and 2. Two or more of the following features must be present: Feature A—systemic manifestations of a more generalized connective tissue disorder > 5/12 Feature B—>1 first degree relative meeting current criteria for hEDS Feature C—musculoskeletal complications 3. All these prerequisites must be met: -absence of unusual skin fragility -exclusion of other heritable and acquired connective tissue disorders including autoimmune rheumatologic conditions, hypotonia and/or connective tissue laxity disorders -March 2017 11 Hypermobile EDS: Must meet ALL 3 criteria
- 12. 1. Unusually soft or velvety skin 2. Mild skin hyperextensibility 3. Unexplained striae 4. Bilateral piezogenic papules of the heels 5. Recurrent or multiple abdominal hernia(s) 6. Atrophic scarring involving at least two sites and without the formation of truly papyraceous and/or hemosideric scars as seen in classical EDS 7. Pelvic floor, rectal, and/or uterine prolapse 8. Dental crowding and high or narrow palate 9. Bilateral arachnodactyly (i) positive wrist sign (ii) positive thumb sign 10. Arm span-to-height >1.05 11. Mitral valve prolapse 12. Aortic root dilatation with Z-score > 2 *previous ref daviddarling.info This list is not comprehensive, as many systems are involved 12 hEDS: Systemic Manifestations
- 13. • Neuro: headaches, migraines, autonomic dx • Ophtho: many complications • ENT: TMJ dx, tinnitus • Dental: crowding, high/narrow palate, resistance to Novocain • Cardiac: POTS, MVP, Ao dilation, arrhythmia • GI: reflux, slow transit, irritable bowel • Heme: bruising, bleeding • Psychiatric: many with anxiety, depression • Associations still controversial- Mast cell disease, small fiber neuropathy, Chiari malformation hEDS: Non-criteria multi-systemic involvement 13
- 14. vEDS: Major Diagnostic Criteria 14 1. Arterial aneurysms, dissection, or rupture 2. Intestinal rupture 3. Uterine rupture during pregnancy 4. Family history of vEDS Shalhub, Genetic considerations in patients with aortic disease Endovascular Aortic Repair, Oderich ed, 2017
- 15. vEDS: Minor Diagnostic Features – Characteristic facial appearance • Thin lips • Narrow nose • Prominent eyes • Micrognathia • Hollow cheeks – Acrogeria-aged, thin, translucent skin – Easy and severe bruising-spontaneous or with minimal trauma 15
- 16. vEDS: More minor diagnostic criteria • Hypermobility of small joints • Tendon/muscle rupture • Early-onset varicose veins • Pneumothorax/hemopneumothorax • Chronic joint subluxations/dislocations • Congenital dislocation of the hips • Talipes equinovarus (clubfoot) • Carotid-cavernous sinus arteriovenous fistula 16
- 17. Risks of EDS, Vascular Type • Pregnancy – increased risks • 54% of deliveries were complicated (n=39) • third-/fourth-degree lacerations (20%) • preterm delivery (19%). • Life-threatening complications 14.5% of deliveries – arterial dissection/rupture (9.2%) – uterine rupture (2.6%) – surgical complications (2.6%) – 5 maternal deaths in 76 deliveries (6.5%) • Morbidity & Mortality – 25% have significant medical problem by age 20 – 80% have significant medical problem by age 40 – Mean age at death is 48 years – A MedicAlert® bracelet should be worn – Avoid trauma, elective surgery, collision sports 17
- 18. Marfan Syndrome • Prevalence 1/5000 –10,000 • Clinical variability • Autosomal Dominant – 25-30% de novo • FBN1 on chromosome 15 • Truncating mutations milder disorder • Central missense mutations severe • Clinical Manifestations: – Majority in skeleton, eyes, heart • MASS (MVP, stable Ao dilation, Striae, Skeletal) www.Marfan.org nhlbi.nih.gov/news/2017 18
- 19. No Family History • Aortic root dilatation z score ≥ 2 AND ectopia lentis • Aortic root dilatation z score ≥ 2 AND FBN1 mutation • Aortic root dilatation z score ≥ 2 AND systemic score ≥ 7pts • Ectopia lentis AND FBN1 mut with known aortic root dilatation Family History (1st degree relative) • Ectopia lentis AND family history • A systemic score ≥ 7 points AND family history • Aortic root dilatation z score ≥ 2 above 20 yrs. old, (≥ 3 below 20 yrs. old) AND family history 2010 19
- 21. MFS: Management • Yearly evaluations – Cardiology – Ophthalmology – Genetics – Consider Orthopedics • Avoid – contact sports/isometric exercise – cardiovascular stimulants (decongestants, caffeine) – LASIK correction of visual deficits – breathing against a resistance (e.g., playing a brass instrument) or positive pressure ventilation (e.g., SCUBA diving) • Pregnant women – high risk • Medical alert bracelet 21
- 23. • Autosomal Dominant (75% de novo) • Skeletal: features overlap with MFS • Craniofacial: bifid uvula/cleft palate, hypertelorism, craniosynostosis • Tortuous vessels; aortic and arterial aneurysms; dissections • CHD- bicuspid aortic valve, patent ductus arteriosus and atrial septal defect • Pregnancy- death and uterine rupture Loeys-Dietz Syndrome Turkishjournalpediatrics.org ahajournals.org 23
- 24. • AD, sporadic, ~ 50 cases • Craniosynostosis /dysmorphic • Skeletal features • Intellectual disability, DD • Hydrocephalus, Chiari 1 malformation • Cardiovascular anomalies – MVP – MR, AoR – Aortic dilation – Some tortuosity www.nature.com/ejhg/journal Shprintzen-Goldberg Syndrome 24
- 25. Stickler Syndrome • Autosomal dominant, some sporadic – 1/7000-1/9000 – 35% of newborns with Pierre Robin sequence • Ocular: severe myopia, cataracts, retinal detachment • Hearing loss: conductive & sensorineural • Facial: bifid uvula, cleft palate, mid-facial hypoplasia • Skeletal: hypermobility, spondyloepiphyseal dysplasia, early arthritis • Cardiac: mitral valve prolapse 50% 25
- 26. • Group of disorders resulting in loose / lax skin – Heterogeneous; AD, AR, XL – ~400 families world-wide • Joint hypermobility • Diverticula – Intestines and bladder • Emphysema • Cardiovascular – Aortic dilation – Aneurysms, dissections clinmedjournals.org/articles/ijdrt/journal-of- dermatology-research-and-therapy-ijdrt-4-055.pdf 26 curerator.com/?attachment_id=22703 Cutis Laxa
- 27. • Clinical features: – Multiple fractures – Blue sclerae – Bowed femora – Short stature – Deafness – Tooth defects (dentinogenesis imperfecta) imgur.com/gallery/Ue2cE Medicalsubstance.com 27 Osteogenesis Imperfecta
- 28. • Radiological features: – Multiple fractures – Wormian bones in skull – “Crumbled” long bones – “Beaded” ribs • 1/10,000 - 1/50,000 – 25% de novo – Type II ~6% recurrence risk – APA neoreviews.aappublications.org jcnonweb.com 28
- 29. 29
- 30. Summary Multiple disorders should be considered in the differential diagnosis of connective tissue disorders Identification of a CT disorder allows for timely identification of serious complications Patients with connective tissue disorders benefit from genetic diagnosis and multiple specialists coordinating care 30
- 31. Resources and References • F Malfait, C Francomano, P Byers, et al. The 2017 International Classification of the Ehlers–Danlos Syndromes. American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 175C:8–26 (2017). • Maron BJ, Chaitman BR, Ackerman MJ, et al. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation. 2004;109(22):2807. • Meester, A Verstraeten, D Schepers. Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome. Ann Cardiothorac Surg. 2017 Nov; 6(6): 582–594. PMID: 29270370 • Mühlstädt K, De Backer J, von Kodolitsch Y, et al. Case-matched Comparison of Cardiovascular Outcome in Loeys-Dietz Syndrome versus Marfan Syndrome. J Clin Med. 2019;8(12):2079. Published 2019 Nov 29. • Ong KT, Perdu J, De Backer J, Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Lancet. 2010 Oct;376(9751):1476-84. Epub 2010 Sep 7. • Levy HP. Hypermobile Ehlers-Danlos Syndrome. 2004 Oct 22 [Updated 2018 Jun 21]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. 31