Connective Tissue Disorders Slides - January 17, 2023

1. Connective Tissue Disorders
Jodi D. Hoffman, MD
January 17, 2023
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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
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3. Outline
Ehlers Danlos syndromes
• Classical
• Hypermobile
• Vascular
Marfan syndrome
Loeys-Dietz syndrome
Stickler syndrome
Shprintzen Goldberg
Cutis Laxa
Osteogenesis Imperfecta
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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
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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
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6. Ehlers-Danlos Syndromes (collagenopathies)
• Heterogeneous group of CTDs
– Hypermobility, skin hyperextensibility, tissue fragility
• Combined prevalence ~1/5,000
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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
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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
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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
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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
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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
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14. vEDS: Major Diagnostic Criteria
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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
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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
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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
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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
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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
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20. https://www.marfan.org/dx/score
bmcmusculoskeletdisord.
biomedcentral.com
heart.bmj.com/content/88/1/97
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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

22. Associated Conditions
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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
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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
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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
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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
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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
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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
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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.
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