Stickler Syndrome: A Physician’s Overview

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

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

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

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 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

Stickler Faces

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

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

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

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

Jay’s Knock Knees

Jay – pre/post knee surgery

Graham – pre-hip surgery

Graham – post-hip surgery

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

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

Small Noses!

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

Overview

Genetic Info Natural mutations, not environmental mutation 10% of cases are 1 st 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

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

Getting More Personal Our Family Tree

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

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

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

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

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

Stickler Syndrome Diagnostic Criteria

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?

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 2 nd 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

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

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

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

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

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

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

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 –Support Services Annual Conference List serve Quarterly newsletter Educational and support services DVD (copy can be ordered at Brochures

More Resources Dave Hawley’s Stickler Syndrome Page National Organization for Rare Diseases – –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) – National Institute of Child Health and Human Development –

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%

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

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

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

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., 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) Robin, MD, Nathaniel H., Warmen, MD, Matthew L.. "Stickler Syndrome." geneclinics.org. June 8, Gene Clinics. 13 July Rose, BS, MD, Peter S., Levy, MD, PhD, Howard P., et al., "Thoracolumbar Spinal Abnormalities in Stickler Syndrome." Spine. 26 (2001)