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«STICKLER SYNDROME: A GUIDE TO THE DISORDER FOR MEDICAL AND HEALTHCARE PROFESSIONALS BY WENDY HUGHES INFO 12 11/2006 Text © Wendy Hughes and the ...»

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STICKLER SYNDROME

SUPPORT GROUP

(SSSG)

Registered Charity: 1060421

STICKLER SYNDROME:

A GUIDE TO THE DISORDER

FOR

MEDICAL AND HEALTHCARE

PROFESSIONALS

BY

WENDY HUGHES

INFO 12 11/2006

Text © Wendy Hughes and the Stickler Syndrome Support Group. All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission.

This publication was printed thanks to the generosity of the 2005/2006 4th year Fashion Marketing students, School of Design, University of Northumbria, who raised funds at a charity auction.

Illustrations: Figs 1-8 and 11 by kind permission of the Department of Ophthalmology, Addenbrooke’s Hospital, Cambridge.

Figs 9 and 10 by kind permission of Dorset Centre for Cleft Lip and Palate, Poole.

Various sections of the booklet verified by Mr Martin Snead, Dr Philip Bearcroft, Dr David Baguley and Mr Anthony Markus

TABLE OF CONTENTS

1. WHAT IS STICKLER SYNDROME? 1

2. THE HISTORY OF THE CONDITION 3

3. THE FUTURE 5

4. WHO IS AFFECTED? 5

5. DIAGNOSING STICKLER SYNDROME 6

5.1. OCULAR 6

5.2. ORO-FACIAL 7

5.3. AUDIOLOGICAL 7

5.4. MUSCULOSKELETAL 7

6. DIAGNOSTIC GUIDELINES FOR PROFESSIONALS 8

7. EYE INVOLVEMENT 10

7.1. THE VITREOUS AMOMALY 10

7.2. RETINAL DETACHMENT 11

7.3. MYOPIA 13

7.4. LATTICE DEGENERATION AND GIANT TEARS AND HOLES 13

7.5. PRE-SENESCENT CATARACT 16

7.6. GLAUCOMA 17

8. JOINT INVOLVEMENT IN STICKLER SYNDROME 17

8.1. THREE MAIN CAUSES OF JOINT PROBLEMS IN STICKLER SYNDROME 20

8.2. DRUG THERAPY 21

8.3. NSAID’S 21

8.4. OTHER TREATMENTS 21

8.5. SURGICAL INTERVENTION 22

9. UNDERSTANDING GENETICS 23

9.1. WHAT WENT WRONG 23

9.2. GENETIC TESTING FOR STICKLER SYNDROME 26

9.3. IDENTIFYING DNA CHANGES 27

10. ORO FACIAL ABNORMALITIES WITHIN STICKLER SYNDROME 28

10.1. CLEFT PALATE 30

–  –  –

1. WHAT IS STICKLER SYNDROME?

Stickler Syndrome (hereditary Arthro-ophthalmopathy, OMIM (Mendelian Inheritance in Man) 108300 and

184840) is an autosomal dominant disorder of collagen (connective tissue), resulting in characteristic abnormalities of the vitreous gel with a variable degree of oro-facial abnormalities, deafness and arthritis. It is usually associated with high myopia, which is congenital and nonprogressive. There is a substantial risk of retinal detachment, and is the most common inherited cause of rhematogenous retinal detachment (detachment due to holes or tears in the retina) in childhood. Although the systemic features are widespread, the sight threatening complications are perhaps the most conspicuous and serious manifestation, particularly the risk of giant retinal tears (GRT) which are often bilateral and, if left untreated, lead to blindness.

The non-ocular features show a great variation in expression. Children who present with Stickler Syndrome typically have a flat mid-face with a depressed nasal bridge, short nose, and micrognathia (one or both jaws are abnormally small). These features become less pronounced with age. If present, midline clefting ranges in severity from the extreme of Pierre-Robin Sequence (PRS), through to clefting of the hard and/or soft palate, to the mildest manifestation of bifid uvula.

There is joint hypermobility which declines with age or is lost completely and degenerative arthropathy of variable severity may develop by the 3rd and 4th decade of life.

Joint pain, of varying degrees, is a problem for many affected by this disorder throughout life. By midlife some patients require joint replacement surgery for the hips or knees, and mild spondylo-epiphyseal dysplasia is often apparent radiologically. Sensorineural deafness with high tone loss is usually asymptomatic or mild. Stickler 1 INFO 12 11/2006 Text © Wendy Hughes & SSSG Stickler Syndrome - A Guide To The Disorder For Medical And Healthcare Professionals Syndrome is caused by an embryological problem occurring in utero, and life expectancy is normal.

At least 4 genes that control and direct collagen synthesis are known to cause Stickler Syndrome.

• COL2A1 is responsible for Stickler Syndrome in 75% of those affected by the condition who show the characteristic Type 1 vitreous phenotype which has been classified as Type 1 Stickler Syndrome. This causes 'full' Stickler Syndrome including joint, hearing, eye and cleft abnormalities.

Two other genes are known to cause some of the features of Stickler Syndrome.

• COL11A1 manifests as a characteristic Type 2 vitreous phenotype and again causes ‘full’ Stickler Syndrome including joint, hearing, eye and cleft abnormalities and has been classified as Type 2 Stickler Syndrome. The main difference between Type 1 and Type 2 Stickler Syndrome is in the abnormal formation of the vitreous gel, which is described in more detail in the Eye Involvement section of this booklet under vitreous anomaly.





• COL11A2 causes a 'Stickler-like' non-ocular syndrome, which affects only the joints and hearing.

This condition has now been given the name of otospondylo-megaepiphyseal dysplasia or (OSMED) for short.

In a fourth group of individuals the genetic cause is yet to be determined. Research into Stickler Syndrome is still ongoing to try and identify other genes involved and explain why the different clinical features vary both within and between families.

–  –  –

Recently a report has described a recessive form of Stickler Syndrome that is caused by mutations in the gene for yet another collagen gene COL9A1 that makes up part of the type IX collagen molecule. This protein connects the type II/XI collagen fibrils to other components of the extracellular matrix present in cartilage and vitreous. (A New Autosomal Recessive form of Stickler Syndrome is caused by a mutation in the COL9A1 Gene) Van Camp G.

et al: Am J Hum Genet.: Sept 2006 79: 449-457.)

2. THE HISTORY OF THE CONDITION

Stickler Syndrome is named after Dr Gunnar B Stickler, who, in 1960, examined a twelve-year-old boy at the Mayo Foundation in Minnesota, USA. The boy had bony enlargements of several joints and was extremely short sighted. His mother was totally blind. Dr Stickler discovered that there were other members of the family with similar symptoms, the first family members having been seen by Dr Charles Mayo in 1887. With colleagues he worked to define the condition, the results being published in June 1965 in the Mayo Clinical Proceedings.

Dr Stickler tentatively named the condition Hereditary Progressive Arthro-ophthalmopathy. The authors of that report renamed the condition Stickler Syndrome, and it is now known world-wide as Stickler Syndrome.

In 1965 when Dr Stickler defined the condition, it was not possible to accurately diagnose and classify the disorder.

There was some controversy when Dr Stickler first published his paper as to whether it was a completely new disorder or just a different manifestation of a previously reported disorder such as Wagner or Marshall Syndrome.

Subsequently most of these patients were shown to have Stickler Syndrome. A recent paper concluded that the distinction between Wagner Syndrome and

–  –  –

predominantly ocular Stickler Syndrome is now apparent, the two conditions are both clinically and genetically distinct. (Clinical Characterisation and Molecular analysis of Wagner Syndrome: Meredith SP, et al: Br. J. Ophthalmol. Oct 2006).

The situation today is that the condition can be diagnosed by a combination of clinical examination and molecular genetic testing with a high degree of confidence, and can be confirmed in the majority of cases with genetic testing.

As mentioned it can also be sub-classified into at least four genetic groups—Type 1, Type 2, OSMED and ‘other’.

However, a survey carried out by the Stickler Syndrome Support Group (SSSG) and others in 1999 showed that the average age of diagnosis for adults was thirty-two years, whilst the average age of diagnosis in a child was 4.2 years, confirming the need to raise awareness, especially amongst GP’s and the medical profession in general.

With the amount of knowledge that has been gained by studying patients with Stickler Syndrome over a number of recent years, it is now possible to assess the risk regarding retinal detachments and hearing loss. Advances in micro-surgical techniques now make it possible to repair retinal detachments with a high degree of success. Using keyhole surgery the back of the eye is filled with either a gas bubble or silicone oil to reposition the retina back in place and hold it there with oil or gas, which acts as a splint keeping the retina stable and the break(s) sealed whilst healing matures to full strength. The level of vision restored after such an operation is variable and will not generally be as good as before the detachment occurred.

Patients are now offered prophylactic cryotherapy treatment whereby a broad ribbon of treatment is applied

–  –  –

to the edge of the retina without any gaps. Whether the patient will encounter a retinal detachment or whether this is a successful treatment is a very difficult question to answer. It can only be properly answered over a life-time study not 10-20 years as the risk is life-long. So far there is reasonable evidence to suggest that it does substantially reduce the risk of a retinal detachment to less than 10% for patients who receive prophylactic cryotherapy. Even if patients present with a retinal detachment after having cryotherapy, it will often have limited the progression so that it is easier to deal with and less extensive, and therefore the visual outlook is better. It must be noted that the view of prophylactic cryotherapy is not universally accepted by all vitreoretinal surgeons and one always needs to balance the risks with the possible benefits for the individual patient.

3. THE FUTURE

In the near future it will be possible to offer patients a ‘test’ for Stickler Syndrome. The work being carried out at Addenbrooke’s Hospital in Cambridge is currently funded on a ‘Research’ basis, but the hospital is hoping to convert the genetic testing that is possible into a service that can be delivered to patients and their families sometime in

2006. More work is now necessary to identify the other genes responsible for variations between individuals and families.

4. WHO IS AFFECTED?

One in 10,000 persons may be affected by Stickler Syndrome. Some medical professionals believe that as many as 3 in 10,000 persons are affected, and according to the Institute of health website it is estimated that Stickler Syndrome now affects 1 in 7,500 to 9,000 new-borns. It is now believed to be the most common connective tissue 5 INFO 12 11/2006 Text © Wendy Hughes & SSSG Stickler Syndrome - A Guide To The Disorder For Medical And Healthcare Professionals disorder in Europe and the Americas. However, further research is needed to confirm this. As an inherited condition, Stickler Syndrome is normally passed from parent to child. There is a 50% chance of children being affected in this way although there are some recorded cases where it has occurred for the first time, a sporadic mutation. Mildly affected relatives may only become apparent on careful clinical evaluation with a slit lamp examination of the vitreous to determine any abnormalities.

All members of the family should be checked so that those family members not affected can be eliminated, and those affected can be assessed, offered prophylactic treatment against retinal detachment if appropriate and offered genetic advice. It is also important that the nonocular group is identified. However, the vast variation in expressivity and severity complicates counselling because of the uncertainty in severity in affected offspring.

5. DIAGNOSING STICKLER SYNDROME

As mentioned, the expressivity and severity of Stickler Syndrome is variable, even within a family, therefore patients can present with a variety of symptoms. This can make diagnosis extremely difficult. Patients may or may not have a family history of cleft palate, myopia, retinal detachments and degenerative joint disease, and there are some recorded cases of sporadic occurrence. All the symptoms mentioned below have been clinically or radiologically identified in patients with Stickler Syndrome, and will help to aid diagnosis.

–  –  –

5.4. MUSCULOSKELETAL Clinically

• Hypermobility of joints with a Beighton score of 4 or more.

• Premature osteoarthritis

• Arachnodactyly

• Creaking of joints Radiologically

• Protrusio acetabuli

• Posterior slip of capital epiphysis

• Flattening of femoral heads

• Broadening of the heads of metacarpal and metatarsal - short 4th and 5th metatarsals

• Metaphyseal widening at knees and ankles

• Flattening of epiphyses

–  –  –

6. DIAGNOSTIC GUIDELINES FOR

PROFESSIONALS

Until recently there has never been a published diagnostic criteria, although Mr Snead and his team at Cambridge in the UK use the following criteria to diagnose Stickler Syndrome. Anyone attending Mr Snead’s clinic is diagnosed with Stickler Syndrome when the following clinical

manifestations are present:

–  –  –

In 2005 Rose et. al. published a paper outlining the diagnostic criteria with a confirmed COL2A1 mutation, Type 1 Stickler Syndrome.

(Rose et al: ‘Stickler Syndrome:



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