1. Stickler Syndrome: A Family Story Paula Goldenberg, MD, MSW, MSCE 18 th American Stickler Syndrome Conference Denver, Colorado July 12, 2014

2. Stickler Syndrome Basics What causes Stickler Syndrome? How Stickler Syndrome is passed down in families? How can we modify our genetic risk? What can we do to be in the best health possible?

3. Stickler Syndrome Common (1:7500-1:9000 births) Hereditary arthro-ophthalmopathy Hearing loss is common in people with Stickler syndrome Most common genetic association in patients with Pierre Robin sequence Can affect many individuals in a family

5. Stickler Syndrome Eye Findings High Myopia Retinal tears and detachment Glaucoma Cataracts Snead MP, Eye 2011;1389-1400 http://epharmapedia.com

6. Joints Joint laxity Tall thin stature Degenerative Arthropathy Scoliosis Snead, MP; J Med Genet 36:353-359 http://www.qt.com.au

7. Craniofacial People with Stickler syndrome can resemble each other as well as their families U-shaped cleft palate Bifid uvula Pierre-Robin Sequence http://ginoyton.co m Antunes RB, J Plastic Recon Aesth Surg 2012: 1029

8. Hearing Loss 80% Hypermobility Conductive Sensorineural Mixed Can worsen

9. Heart Mitral valve prolapse

10. Stickler Syndrome Basics What causes Stickler Syndrome? How Stickler Syndrome is passed down in families? How can we modify our genetic risk? What can we do to be in the best health possible?

11. What causes Stickler syndrome? Collagen: the gel, the cushion, and the girders Compressible, Structural (crosslinking)

13. Where is collagen? Joints Bones Cornea and vitreous (eye) Skin Intestines Spinal disks Dentin (teeth) Muscle Usually made by fibroblasts

14. Collagen: Many varieties! Type I-Type XXVIII! Each type has different properties and uses 1,000 identified disease-causing mutations Different types of collagen mutations can cause ▫Brittle Bone Disease (osteogenesis imperfecta) ▫Ehlers-Danlos Syndromes (many types) ▫Alport Syndrome (kidney failure and hearing loss) ▫Stickler Syndrome ▫And many, many others

15. Collagen 9A1

17. What does COL9A1 do? Works with collagen 2 In hyaline cartilage (articular joints)

19. Stickler Syndrome Basics What causes Stickler Syndrome? How Stickler Syndrome is passed down in families? How can we modify our genetic risk? What can we do to be in the best health possible?

20. Stickler Syndrome Family Matters

21. Stickler Syndrome Majority of patients have a parent with Stickler syndrome If a patient is the first person with Stickler syndrome in the family we call this a de novo deletion

22. Chromosomes

26. Stickler Syndrome Inheritance Two types ▫Autosomal Dominant ▫Autosomal Recessive

27. Autosomal Dominant Inheritance Affected Parent to Affected Child

28. Genes in Autosomal Dominant Stickler Syndrome COL2A1: 80-90% Autosomal Dominant ▫Membranous vitreous anomaly with mild hearing loss COL11A1: 10-20% Autosomal Dominant ▫Beaded vitreous anomaly with significant hearing loss COL11A2: Rare Autosomal Dominant ▫“Non-ocular” Stickler Syndrome

29. Autosomal Recessive Parents are carriers and not affected

30. Genes in Autosomal Recessive Stickler Syndrome COL9A1: Very Rare; Autosomal recessive ▫3 families COL9A2: Very Rare; Autosomal recessive ▫Two children in one family

31. Stickler Syndrome Basics What causes Stickler Syndrome? How Stickler Syndrome is passed down in families? How can we modify our genetic risk? What can we do to be in the best health possible?

32. Genetic Counseling: Low Tech Autosomal dominant 50% risk with each pregnancy Autosomal recessive 25% risk with each pregnancy Level II ultrasound 18-20 weeks: micrognathia For parents with all types of Stickler Syndrome ▫Amniocentesis or CVS  If familial mutation(s) known ▫Donor Egg ▫Donor Sperm ▫Adoption

33. Genetic Counseling: High Tech If we know the gene mutation in the family

35. Stickler Syndrome Basics What causes Stickler Syndrome? How Stickler Syndrome is passed down in families? How can we modify our genetic risk? What can we do to be in the best health possible?

36. Unfortunately, this is not the answer

37. Ophthalmology Rheumatology Orthopedics Audiology Craniofacial Cardiology

38. Excellent Care: it takes a village! Ophthalmology Orthopedics Rheumatology Audiology Craniofacial Team (Clefts, Pierre Robin) Oral Maxillofacial Specialists Cardiology Genetics ▫Genetic Testing ▫Can be a quarterback for the team ▫Surveillance

39. The village continued… Physical Therapy Occupational Therapy Physical Medicine and Rehabilitation Vision Therapy Hearing Aid Specialist Social Work Stickler Involved People Stickler Syndrome Support Group (UK) Facebook networks

40. Many Thanks To Our patients and families affected by Stickler syndrome Dr. Ruth Lieberfarb Dr. David Sweetser Dr. Joseph Thakuria

41. http://wendylhughes.blogspot.com/2012_06_01_archive.html