Connective Tissue Disorders Slides - January 17, 2023

Connective Tissue Disorders Slides - January 17, 2023

1. Connective Tissue Disorders Jodi D. Hoffman, MD January 17, 2023 1

2. Objectives 2

3. Outline 3

4. 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

5. The Ehlers Danlos Syndromes 2017 * ehlers-danlos.com/pdf/2017-FINAL-AJMG-PDFs/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf 2 5

6. Heterogeneous group of CTDs Hypermobility, skin hyperextensibility, tissue fragility Combined prevalence ~1/5,000 6

7. 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. 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. *Flexibility may be related to muscle laxity while hypermobility is related to joint laxity 9

10. 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. Generalized joint hypermobility (GJH); and 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. 14 Arterial aneurysms, dissection, or rupture Intestinal rupture Uterine rupture during pregnancy Family history of vEDS Shalhub , Genetic considerations in patients with aortic disease Endovascular Aortic Repair, Oderich ed, 2017

15. 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. 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. 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. 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. 2010 19

20. https://www.marfan.org/dx/score bmcmusculoskeletdisord.biomedcentral.com heart.bmj.com/content/88/1/97 20

21. 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

22. 22

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 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 24

25. Autosomal dominant, some sporadic 1/7000-1/9000 35% of newborns with Pierre Robin sequence Ocular: s evere 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 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