Stickler

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Stickler Syndrome A Physicians Overview
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What do you hear?

• It could just be
• a Zebra and
• not a Horse!

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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

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Stickler SyndromeHistory

• 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 boys family
• Originally published under name Hereditary
  Progressive Arthro-Ophthalmopathy

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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

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Stickler Faces

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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

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Clinical Findings - Auditory

• Sensorineural hearing loss
• Conductive hearing loss
• Otitis media
• Hypermobile tympanic membranes
• Ears tend to be low set

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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)
• Schmorls nodes
• Platyspondylia
• Endplate abnormalities
• Spondylolisthesis
• Femoral head flattening/ failure
• Double jointedness to point of dislocation
• Genu valgum (knock-kneed)
• Pronated feet

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Musculo-skeletal (cont)

• 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

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Jays Knock Knees

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Jay pre/post knee surgery

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Graham pre-hip surgery
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Graham post-hip surgery
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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

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Oro-facial (cont)

• Epicanthic fold or anteverted nares
• Dental
• Enamel hypoplasia
• Orthodontia issues/ malocclusion
• Symptoms become less distinctive with age

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Small Noses!
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Clinical Findings - Other

• Mitral Valve Prolapse in question, now finding
  prevalence may be no higher than general
  population
• Pregnancy Issues
• And more

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Overview

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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

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Genetic Info (cont)

• 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-megaep
  iphyseal dysplasia)
• Type 4- unknown gene mutation - possibly COL5A2
  or others

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Getting More Personal

• Our Family Tree

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Family Symptoms

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

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Family Symptoms (cont)

• 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

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Family Symptoms (cont)

• 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

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Family Symptoms (cont)

• 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

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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

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Stickler Syndrome Diagnostic Criteria
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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
• Wagners syndrome
• Marshalls syndrome
• Weissenbacher Zweymuellers syndrome
• Are there undiagnosed family members?

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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

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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

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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

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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

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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

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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

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Management of Psycho-Social Issues (cont)

• 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

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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_at_sticklers.org
• Support Services
• Annual Conference
• List serve
• Quarterly newsletter
• Educational and support services
• DVD (copy can be ordered at www.sticklervideo.org)
  
• Brochures

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More Resources

• Dave Hawleys Stickler Syndrome Page
• http//members.aol.com/dhawley/stickler.html
• National Organization for Rare Diseases
• www.rarediseases.org
• Free Physicians 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

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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

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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 wasnt near sighted, knock-kneed,
  having joint pain and/ or ear infections

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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
  geneticists opinion and/or treatment
• Multi-disciplinary, TEAM approach with
  specialists, therapists, educators

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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?

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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/detai
  ls.
• Rose, BS, MD, Peter S., Levy, MD, PhD, Howard P.,
  et al., "Thoracolumbar Spinal Abnormalities in
  Stickler Syndrome." Spine. 26 (2001). 403-409.