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 - 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

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/degenerationGlaucomaAstigmatism/ 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 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

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 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

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

• 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

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

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 symptoms90%- myopia41%- frequent ear infections24%- knock-kneed41%- 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. , 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.