Stickler Syndrome: A Physician’s Overview

1. Stickler Syndrome: A Physician’s Overview

2. What do you hear? • It could just be a Zebra and not a Horse!

3. Stickler Syndrome: The Basics • Progressive, genetic connective tissue disorder • Autosomal dominant • High degree of penetrance • Wide range of severity/ expression • Affects both sexes/ all ethnicities • Believed to be the most common connective tissue disorder

4. Stickler Syndrome:History • First defined by Dr. Gunnar B. Stickler, a pediatrician at Mayo Clinic, in 1965 • Based on evaluation of 12 year old boy with vision, joint problems; had blind mother; other family members had been seen by Dr. Charles Mayo dating back to 1887 • Multi-disciplinary team studied five generations of boy’s family • Originally published under name Hereditary Progressive Arthro-Ophthalmopathy

5. Stats and Specs • Mutations found in three collagen genes to date • Prevalence between 1 in 7500 and 1 in 3300 • Frequently misdiagnosed or undiagnosed • Average age of children diagnosed - 4.2 years • Average age of adults diagnosed - 32 years • One study found 53% error rate in original diagnosis of patients later determined to have Stickler syndrome • 10% of children born with cleft palate and 12% of children diagnosed at birth with Pierre-Robin sequence were later found to have Stickler syndrome • Problems with vision, hearing, bones/ joints and oro-facial features

6. Stickler Faces

7. Clinical Findings – Ocular Myopia (mild to severe) • Present at birth • Minimal progression Retinal Detachment/Degeneration • Spontaneous • Giant tears/ holes • Bilateral • Patient typically under age 30 Cataracts • Pre-senile • Wedge or comma shaped Vitreous anomalies/degeneration Glaucoma Astigmatism/ Strabismus

8. Clinical Findings - Auditory • Sensorineural hearing loss • Conductive hearing loss • Otitis media • Hypermobile tympanic membranes • Ears tend to be low set

9. Clinical Findings – Musculo-skeletal • Early onset osteoarthritis • Usually most severe in hips and knees • Abnormality to ends of long bones • Spinal abnormalities • Scoliosis • Kyphosis (Scheuermann-like) • Schmorl’s nodes • Platyspondylia • Endplate abnormalities • Spondylolisthesis • Femoral head flattening/ failure • Double jointedness to point of dislocation • Genu valgum (knock-kneed) • Pronated feet

10. Musculo-skeletal (con’t) • Coxa vara( hip joint deformity) • Hypotonia • Posterior slip of capital epiphysis (Leggs-Perthes like disease) • Flattening of epiphyses • Protrusio acetabuli • Slender extremities, long fingers, normal height • Intra-articular loose bodies • Joint pain/ stiffness • Arachnodactyly • and more

11. Jay’s Knock Knees

12. Jay – pre/post knee surgery

13. Graham – pre-hip surgery

14. Graham – post-hip surgery

15. Clinical Findings - Oro-facial • Flat malar/ mid-face area • Small lower jaw/ micrognathia • Posterior-placed tongue • Obstructive airway complications • Cleft palate, submucous cleft or high arched palate • Bifid uvula • Flat nasal bridge • Small, “button” nose

16. Oro-facial (con’t) • Epicanthic fold or anteverted nares • Dental • Enamel hypoplasia • Orthodontia issues/ malocclusion • Symptoms become less distinctive with age

17. Small Noses!

19. Clinical Findings - Other • Mitral Valve Prolapse – in question, now finding prevalence may be no higher than general population • Pregnancy Issues • And more

20. Overview

21. Genetic Info • Natural mutations, not environmental mutation • 10% of cases are 1st generation, spontaneous mutations • 3 specific mutation locations found in collagen; other mutations not yet specified • Mutations are usually a premature stop codon in the region of the gene encoding the triple helical domain of the collagen molecule • Type 1- mutation in COL2A1- 75% of Stickler syndrome pts have this mutation; results in problems with vision, hearing, oro-facial and musculo-skeletal systems

22. Genetic Info (con’t) • Type 2- mutation in COL11A1-same system involvement as Type 1, but Type 1 and Type 2 have visibly different vitreous architecture abnormalities-useful in determining diagnosis • Type 3- mutation in COL11A2- problems with auditory, oro-facial and musculo-skeletal, but not eyes (also called OSMED - oto-spondylo-megaepiphyseal dysplasia) • Type 4- unknown gene mutation - possibly COL5A2 or others

23. Getting More Personal Our Family Tree

24. Family Symptoms • Affected Female- Age 76 • No visual problems • No skeletal problems • Clinical findings • High, arched palate • Treatments/surgeries – none

25. Family Symptoms (con’t) • Affected Female – Age 50 • Vision • Moderate myopia • Retinal detachment – age 16 • Musculo-skeletal • Joint pain/stiffness • Osteoarthritis – from teen years to current • Oro-facial • High, arched palate • Enamel hypoplasia • Treatments/surgeries • Scleral buckle and prophylactic laser on retinas • Cataract surgeries • Bilateral hip replacements • Med management

26. Family Symptoms (con’t) • Affected Male – Age 21 • Vision • High myopia • Retinal detachment – age 14 and age18 • Musculo-skeletal • Genu valgum (Knock-kneed) • Oro-facial • High arched palate • Auditory • Severe otitis media • Treatments/surgeries • Scleral buckle and prophylactic laser on retinas • Scleral buckle on lasered retina • Knee growth plate stapling • Ear tubes

27. Family Symptoms (con’t) • Affected Male – Age 15 • Vision • Mild myopia • Musculo-skeletal • Femoral head failure/ necrosis • Femoral head too large for hip socket • Pronated feet • Oro-facial • Mildly arched palate • Treatments/surgeries • Prophylactic laser on retinas • Femur wedge osteotomy • Triple innonimate hip osteotomies • Ankle growth plate screws • Ankle growth plate removal

28. Diagnostic Criteria • Based on findings of long-term NIH study • Evaluates molecular data, family history, characteristic ocular, auditory and skeletal abnormalities • 12 points possible on 9 criteria • Diagnosis (for Type 1 SS) requires 5 points minimum AND presence of cleft palate, ocular abnormalities or high frequency sensorineural hearing loss

29. Stickler Syndrome Diagnostic Criteria

30. Other Diagnostic Comments • Most common cause of retinal detachment in children • Ocular issues most often addressed retroactively, then patient later diagnosed with Stickler syndrome as other problems develop • Often confused with • Wagner’s syndrome • Marshall’s syndrome • Weissenbacher – Zweymueller’s syndrome • Are there undiagnosed family members?

31. Management of Physical Issues Ocular • Ophthalmologic assessment- as often as every 3-6 months in young children (children will often not complain about sight issues until the 2nd eye is affected) • Normal newborns are hyperopic (+1 diopters or more), so any degree of myopia is suspect • Prophylactic laser photocoagulation or kryo treatment on retinas (UK is also doing prophylactic scleral buckling) • “Evaluation under anesthesia” especially for infants and young children already diagnosed • Meds for glaucoma • Getting infants and children who have vision problems treatment (such as corrective lenses) is important for brain development

32. Management Of Physical Issues • Auditory • Hearing assessment • Check for frequent ear infections/use antibiotic meds • Otolaryngology evaluation- to assess ear and/or palate abnormalities, including submucous cleft and bifid uvula • Evaluate need for hearing aids and speech therapy

33. Management of Physical Issues • Oro-facial abnormalities • Maxillo-facial and feeding assessment, if mid-line clefting • Check for feeding problems • Speech/ swallow evaluations for all individuals with cleft abnormalities • Sleep study for children with breathing issues • Orthodontics

34. Management of Physical Issues • Musculo-skeletal • Skeletal evaluation • Radiographic skeletal survey in childhood • Rheumatology consultation • Splints, braces, aids • Pain management – oral meds, incl. anti-inflammatories, joint lubricants/injections • Rehabilitation, physical, hydro-therapies • Arthroscopy/surgery • Appropriate exercise program to strengthen muscles around lax joints (no contact sports, diving, roller coasters) • Pain Clinic evaluation

35. Management of Physical Issues • Cardiac • Echocardiogram (if reason to suspect mitral valve prolapse) • Prophylactic antibiotics (if MVP or joint replacements) • Genetics • Prenatal testing- if Stickler syndrome in family, consider CVS, amniocentesis or ultrasound; especially important to determine if cleft issues to be dealt with at time of birth

36. Management of Psycho-Social Issues • Normal intelligence, but can be challenged by vision/ hearing/joint issues at school, work, socially • Normal lifespan, but impacts major life decisions such as college, career, marriage, child-bearing • Children and young adults deal with denial issues; want to appear normal • May ignore health issues • Problems may be minimized by parents or teachers

37. Management of Psycho-Social Issues (con’t) • School issues • Manage absences due to doctor appts/surgeries and hospitalizations • Awareness of bullying and teasing • Potentially eliminate PE class or modify involvement • Work with parent on acceptance and communication • Encourage parent to educate themselves on IEP (Individual Education Plan) and 504 plans • Counseling for patients and family members • Address sibling issues

38. Resources/Support - U.S. • Stickler Involved People • 501(c)(3), not-for-profit, all volunteer organization • Mission - educate and give support to all those affected by Stickler syndrome • Contact Information • www.sticklers.org • sip@sticklers.org • Support Services • Annual Conference • List serve • Quarterly newsletter • Educational and support services • DVD (copy can be ordered at www.sticklervideo.org) • Brochures

39. More Resources • Dave Hawley’s Stickler Syndrome Page • http://members.aol.com/dhawley/stickler.html • National Organization for Rare Diseases • www.rarediseases.org • Free Physician’s Guides available (for 9 rare diseases so far) • On-line summaries for over 1100 rare diseases • National Coalition for Health Professional Education in Genetics (NCHPEG) • www.nchpeg.org • National Institute of Child Health and Human Development • www.nichd.nih.gov

40. SIP goal: to educate physicians • Increase awareness, especially of primary care physicians • Why? • NIH and Stickler Group Survey Results • 1997-NIH initiated a long-term study of Stickler syndrome patients • 1998 and 2001 Stickler support groups in US, UK, the Netherlands and Canada surveyed their members • Results (of 330 returned surveys) • Age at Diagnosis • Infants – 9% • Childhood/ Young Adults - 73% • Adults over age 30 – 18% • Diagnosed By – • Genetics- 42% • Ophthalmologists- 38% • Pediatricians- 8% • Other Specialties- 12%

41. Survey Results Diagnosed individuals –childhood symptoms 90%- myopia 41%- frequent ear infections 24%- knock-kneed 41%- joint pain by age 9 So, although not all near-sighted, knock-kneed children with ear infections and/or joint pain will have Stickler syndrome… A Tipping Point to remember is: You would rarely see a child with Stickler syndrome who wasn’t near sighted, knock-kneed, having joint pain and/ or ear infections

42. What do you do? • If you see some combination of myopia, characteristic facial features, hearing loss, skeletal abnormalities, and cleft issues in a 1 year old, you might suspect Stickler syndrome. Then, • Refer to a geneticist • Give the family internet site information for them to review • Likely to help with acceptance, if that is an issue • Allows them to come to the conclusion to seek geneticist’s opinion and/or treatment • Multi-disciplinary, TEAM approach with specialists, therapists, educators

43. Sometimes that zebra and that horse look almost the same! You may well see a Stickler syndrome zebra. Will you recognize it? Not So Different

44. References • Hughes, Wendy - Stickler Syndrome Support Group (UK). Stickler Syndrome - A Child in Your Care. 11/2000. • Hughes, Wendy - Stickler Syndrome Support Group (UK). Stickler Syndrome - A Diagnostic Aid for Professionals. 11/2004. • Francomano, Clair, Wilkin, Douglas J., Liberfarb, Ruth M. "Stickler Syndrome." Management of Genetic Syndromes. : Wiley Liss, Inc. , 2005. • Rose, Peter S., Levy, Howard P., Liberfarb, Ruth M., Davis, Joie, Szymko-Bennett, Y., Rubin, Benjamin I., Tsilou, Ekaterini, Griffith, Andrew J., Francomano, Clair A., "Stickler Syndrome: Clinical Characteristics and Diagnostic Criteria." American Journal of Medical Genetics. 138A (2005). 199-207. • Robin, MD, Nathaniel H., Warmen, MD, Matthew L.. "Stickler Syndrome." geneclinics.org. June 8, 2000. Gene Clinics. 13 July 2001. http://www.geneclinics.org/profiles/stickler/details. • Rose, BS, MD, Peter S., Levy, MD, PhD, Howard P., et al., "Thoracolumbar Spinal Abnormalities in Stickler Syndrome." Spine. 26 (2001). 403-409.